Podcasts about social media editor

A new survey has found that less than one third of end-of-life patients in Irish emergency departments have their own room. This is only one of the shortcomings found in end-of-life care, explored in two papers to start this episode. Following on from that is a comparison of video and direct laryngosocopy for intubation outcomes. There's also a "Best Evidence" review of the use of nasal clips for stopping nosebleeds, an approach which appears likely to offer advantages over the hands or inventive tongue-depressor contraptions. The finish up this month's episode, there's a return to a topic previously visited one year ago - the RCEM guidelines on cannabinoid hyperemesis syndrome. A study from Wales follows up on the adherence to this guidance. Read the highlights: May 2025 Primary Survey Dying matters in the emergency department Emergency clinician perceptions of end-of-life care in Irish emergency departments: a cross-sectional survey Video laryngoscopy may improve the intubation outcomes in critically ill patients: a systematic review and meta-analysis of randomised controlled trials Use of nasal clips as first aid for anterior epistaxis Awareness and management of cannabinoid hyperemesis syndrome among staff in emergency departments in Wales The EMJ podcast is hosted by: Dr. Richard Body, EMJ Deputy Editor, University of Manchester, UK (@richardbody) Dr. Sarah Edwards, EMJ Semior Associate Editor and Social Media Editor, Royal Derby Hospital, UK (@drsarahedwards) You can subscribe to the EMJ podcast on all podcast platforms to get the latest podcast every month. If you enjoy our podcast, please consider leaving us a review or a comment on the EMJ Podcast Apple (https://apple.co/4bfcMU0) or Spotify (https://spoti.fi/3ufutSL) page.

Send us a textWe are joined by Dr. Sharief Hendricks from the University of Cape Town — a leading figure in sports science and medicine. Dr. Hendricks is the Senior Associate Editor for the Journal of Science and Medicine in Sportand has served on the editorial boards of the British Journal of Sports & Exercise Medicine and the European Journal of Sport Science as Social Media Editor since 2014.He is also the Past President of the South African Sports Medicine Association, and currently chairs the Sport Science, Technology, and Research Commission at the South African Sports Confederation and Olympic Committee. With over 135 publications focused on injury prevention and athlete welfare, and consultancy roles with organizations like World Rugby and the South African Cricketers' Association, Dr. Hendricks brings unmatched expertise to the conversation. -       Dr Hendricks introduction to Sports Science (02:11)-       Tackling Heights in Rugby Union and Contact Sports (03:50)-       Action Vs Outcome and Preventative (07:30)-       Lead author of paper Consensus on “A video analysis framework of descriptors and definitions by the Rugby Union Video Analysis Consensus group” (08:30)-       Key Definitions and Outcomes of “What is A Tackle” (10:46)-       Broad Over View of Video Analysis in Concussion (15:32)-       Understanding Injury Prevention (17:12)-       Study Design (21:10)-       Smart Mouth Guards and Video Analysis (22:05)-       Over Arching Goal of Video Analysis (26:10)-       HIA numbers and Implications of Rule Changes (28:35)-       Your future/ current research, how can we help and find your work?   https://scholar.google.co.za/citations?user=Ot2SLnwAAAAJ&hl=en Consensus on a video analysis framework of descriptors and definitions by the Rugby Union Video Analysis Consensus group: https://bjsm.bmj.com/content/54/10/566.abstract Twitter/X: @Sharief_H Instagram: Sharief_H

Trauma and paediatrics are the themes for this month's collection of papers. Starting off is a review of the effectiveness of prehospital ultrasound in detecting lung injury, with some surprising statistics. Next is a letter on the topic of self-presentation by paediatric patients with major trauma, which is thankfully a rare occurrence. The third paper looks at prehospital testing of trauma patients for  low fibrinogen levels, a condition which can lead to worse bleeding, increased transfusions, and higher mortality. The final paper discusses the worrying topic of delayed presentation with testicular pain, a phenomenon which leads to significantly lower salvage rates. This can arise from lack of information or embarrassment, particularly in younger males.   Read the highlights: April 2025 Primary Survey   Diagnostic accuracy of prehospital ultrasound in detecting lung injury in patients with trauma: a systematic review and meta-analysis Identifying the walk-in wounded: paediatric major trauma patients self-presenting to a paediatric major trauma centre Comparison between point-of-care international normalised ratio, COAST, TICCS and truncated FibAT scores to rule in clinically significant hypofibrinogenaemia in the prehospital setting Experiences and perceptions of acute testicular pain, with a focus on reasons for delayed presentation to hospital: a qualitative evidence synthesis   The EMJ podcast is hosted by: Dr. Richard Body, EMJ Deputy Editor, University of Manchester, UK (@richardbody) Dr. Sarah Edwards, EMJ Semior Associate Editor and Social Media Editor, Royal Derby Hospital, UK (@drsarahedwards) You can subscribe to the EMJ podcast on all podcast platforms to get the latest podcast every month. If you enjoy our podcast, please consider leaving us a review or a comment on the EMJ Podcast iTunes (https://apple.co/4bfcMU0) or Spotify (https://spoti.fi/3ufutSL) page.

#BeAGoodFriend and check out episode #130  of #FeeneyTalksWithFriends featuring Allie Belluci. It was great to talk with my #friend, Allie! Allie is the owner of Bellu Jean Creative LLC. We talked about:West Hartford (minute 1)Bellu Jean Creative (minute 3)Allie created the Friends of Feeney website (minute 3)Allie's inspiration and story (minute 5)Teaching during Covid-19 (minute 8)Cameras, photos and storage (minute 12)Social Media Editor (minute 14)Garlic knots (minute 15)What makes Alex a good #friend? (minute 17)Dave at GolfTec (minute 18)Allie's dad, Harry (minute 20)Videos from Golf Tournament and Holiday Stroll (minute 22)Erika Smith Rappaport from Home to Home CT (minute 24  &27)Brewster, Cape Cod (minute 29)Allie's favorite teacher, Joannie Greenfield (minute 33)Chamber photos with Victor (minute 36)Google Reviews (minute 38)Allie's favorite restaurant(s) with 4 dinner guests (minute 42)Podcast sponsors (minute 47)The Fix IV Therapy (minute 48)Our youngest podcast guest ever, Baby Matthew! (minute 50)3 Keys (sponsored by West Hartford Lock) to being a Content Creator (minute 55)3 Keys (sponsored by West Hartford Lock) to being a Big Sister (minute 57)Upcoming podcast guests (minute 59)Allie's favorite superhero and superpower (minute 1.01)Being a “Dog Mom” (minute 1.02)Book and podcast recommendations (minute 1.04)Podcast Sponsors: The Fix IV - www.thefixivtherapy.comWest Hartford Lock - www.westhartfordlock.comKeating Agency Insurance - www.keatingagency.comGoff Law Group - www.gofflawgroup.netParkville Management - www.parkvillemanagement.comLuna Pizza - www.lunapizzawh.com/lunas-menuPeoplesBank - www.bankatpeoples.comFloat 41 - www.float41.comMaximum Beverage - www.maximumbev.com

In this episode, Dr Elle Wadsworth talks to three generations of tobacco/nicotine researchers: Dr Sarah Jackson and Emeritus Professors Martin Jarvis and Robert West, all from the Department of Behavioural Science and Health at University College London. They discuss a recent editorial, ‘The price of a cigarette: 20 minutes of life?' – why the message resonated, what was and is difficult to convey in tobacco research, and how the media coverage has changed for tobacco research over the years. · What the editorial is about [00:56]· Why the editorial resonated with the public and the media [01:40]· What messages were difficult to convey to the public [03:05]· Why the number of ‘20 minutes of life' has increased since the last estimate and why it is longer for women [07:43]· Choosing persuasive pieces and soundbites to communicate to the public [12:13]· The misinterpretation of research in the media and the difficulty in delivering nuance [14:08]· How the media coverage on tobacco and smoking has changed over the years [16:23]Dr Sarah Jackson is a Principal Research Fellow within UCL's Tobacco and Alcohol Research Group. She has authored >100 peer-reviewed articles on nicotine and tobacco. Her research activity focuses primarily on modelling population trends in smoking, evaluating smoking cessation interventions and policies, and advancing the evidence base on vaping. She is President of SRNT Europe, Senior Editor for Addiction, and Social Media Editor for Nicotine & Tobacco Research. Martin Jarvis is Professor Emeritus of Health Psychology at the Department of Behavioural Science and Health, UCL, having for many years worked with Michael Russell's smoking research group at the Institute of Psychiatry and then Cancer Research UK's Health Behaviour Unit. He has researched and published widely on tobacco smoking, with special interests in the role of nicotine, social and family influences on smoking, smoking cessation methods and passive smoking. He was awarded an OBE in 2002.Robert West is Professor Emeritus of Health Psychology at UCL. He specialises in behaviour change and addiction. He is former Editor-in-Chief of Addiction, and has acted as an advisor to the English Department of Health on tobacco control and currently advises the Public Health Wales Behavioural Science Unit. He helped write the blueprint for the UK's national network of stop-smoking clinics and is co-founder of the Capability-Opportunity-Motivation, Behaviour (COM-B) model of behaviour, the Behaviour Change Wheel framework for intervention development, and the PRIME Theory of motivation. Original article: The price of a cigarette: 20 minutes of life? https://doi.org/10.1111/add.16757 Authors praised the seminal work of the late Professor Michael Anthony Hamilton Russell (1932–2009). For further reading on the legacy of his landmark research, see here: https://doi.org/10.1111/add.14043The opinions expressed in this podcast reflect the views of the host and interviewees and do not necessarily represent the opinions or official positions of the SSA or Addiction journal. The SSA does not endorse or guarantee the accuracy of the information in external sources or links and accepts no responsibility or liability for any consequences arising from the use of such information. Hosted on Acast. See acast.com/privacy for more information.

Advance clinical practitioners (ACPs) can have a big role to play in the emergency department, but their career paths are not always well understood. This episode features three papers from the journal which begin to address that - a census survey of over 1000 ACPs, a qualitative study on their experiences in emergency care, and a commentary on how to improve ACP training. There is also a paper from Canada discussing considerations to be made for patients living with dementia, as well as their care partners who may be accompanying them to the hospital. A bit of a curveball to close out, with a review on hidradenitis suppurativa, a challenging skin condition which can take years for a diagnosis.   Read the highlights: March 2025 Primary Survey   Care for older adults living with dementia in the emergency department: a systematic review and meta-synthesis of care partner roles and perspectives Emergency medicine advanced clinical practitioners: an English workforce census A qualitative study exploring the experiences of advanced clinical practitioner training in emergency care in the South West of England, United Kingdom How can we improve on advanced clinical practitioner training? Diagnosis and management of hidradenitis suppurativa: a review for the emergency clinician   The EMJ podcast is hosted by: Dr. Richard Body, EMJ Deputy Editor, University of Manchester, UK (@richardbody) Dr. Sarah Edwards, EMJ Semior Associate Editor and Social Media Editor, Royal Derby Hospital, UK (@drsarahedwards) You can subscribe to the EMJ podcast on all podcast platforms to get the latest podcast every month. If you enjoy our podcast, please consider leaving us a review or a comment on the EMJ Podcast iTunes (https://apple.co/4bfcMU0) or Spotify (https://spoti.fi/3ufutSL) page.

Why is peer review important? Is AI changing peer review? How can you become a better peer reviewer? Find out in this special episode, with our newest host and Social Media Editor, Dr. Emily Schehlein, and Dr. Matilda F. Chan. Dr. Chan, in collaboration with editors of several ophthalmic and optometric journals and the National Eye Institute, administers the new Council of Vision Editors Fellow Program designed to train early career vision scientists on the peer-review process. The Academy's family of journals is a proud participant in the mentoring program. For more, read Dr. Chan's editorial in Investigative Ophthalmology & Visual Science, “Peer Review in Ophthalmology: A Collaborative Approach to Training the Next Generation of Reviewers.”

Natalie Salmon is an accomplished journalist, currently serving as the Editor of Hello! Fashion Magazine, and formerly holding positions as Digital Editor at Vogue Scandinavia and Social Media Editor at Harper's Bazaar. In 2019, Salmon founded The Modems, a go-to destination for all things fashion, beauty and lifestyle tech.In this week's episode of CEO YOURSELF, we explore Natalie's CEO superpower, Patience. Together, we explore the power of being patient in your career and the often overlooked truth about the time and work it takes to reach your dream role. Natalie debunks the myth of an overnight success, highlighting that true, lasting career growth comes from seeking support and having the courage to put yourself out there. This episode is for anyone wanting inspiration from someone who rose through the ranks purely through grit and determination - no shortcuts, no handouts. You can find Natalie on Instagram @nataliesalmon (https://www.instagram.com/nataliesalmon/)The Modems is on Instagram @themodems (https://www.instagram.com/themodems/) and online via https://themodems.comHello! Fashion is on Instagram @hellofashion_uk (https://www.instagram.com/hellofashion_uk/) and online via https://www.hellomagazine.com/hfm/CEO YOURSELF is a community designed to inspire and motivate you on your journey. We deliver weekly podcasts on a Monday, interviewing diverse women and deep diving their CEO superpowers, so you can adopt their learnings to become the CEO of your life. You can find us on instagram @whynotceoyourself with further resources online at www.ceoyourself.com Our host Hermione Olivia is on instagram & TikTok @hermioneolivia Hosted on Acast. See acast.com/privacy for more information.

Roommates: can't live with them, can't (afford to) live without them. They're the people who use your dishes and don't wash them. They're the people who apparently have a huge influence on your career choice and drinking habits. This hour, we're getting to know them better! GUESTS:  Ken Jennings: Colin's college roommate Kelli María Korducki: Journalist who writes about work and the family Bruce Sacerdote: Professor of Economics at Dartmouth College Francesca Fontánez: Social Media Editor at CT Public and a former college RA Join the conversation on Facebook and Twitter. The Colin McEnroe Show is available as a podcast on Apple Podcasts, Spotify, Google Podcasts, Stitcher, or wherever you get your podcasts. Subscribe and never miss an episode! Subscribe to The Noseletter, an email compendium of merriment, secrets, and ancient wisdom brought to you by The Colin McEnroe Show. Colin McEnroe, Cat Pastor, Lily Tyson, and Dylan Reyes contributed to this show, which originally aired on May 23, 2024. Support the show: http://www.wnpr.org/donateSee omnystudio.com/listener for privacy information.

Happy Halloween! Is Connecticut the spookiest place in the country? We're not sure, but our guests today are pretty haunted! All this hour, we'll be talking about all things Spooky Connecticut, and not just our favorite haunted spots. There will be candy debates, talks of our favorite horror flicks filmed right here in Connecticut, and more. Watch the Connecticut Public documentary "Trail of Terror" here. GUESTS: Colin McEnroe: Host of the Colin McEnroe Show Chion Wolf: Host of Audacious with Chion Wolf Francesca Fontanez: host of Spooky CT and Social Media Editor at Connecticut Public Support the show: http://wnpr.org/donateSee omnystudio.com/listener for privacy information.

Sub-reddits, karma, AMAs and more all jargon-busted and explained how they can help your newsroom get closer to highly engaged audiences

The first-ever commercial spacewalk has taken place.It was broadcast live to millions around the world through cameras on the SpaceX's Crew Dragon spacecraft, as well as ones fitted to the helmets of the actual astronauts.Billionaire Jarred Isaacman, who funded the Polaris Dawn mission, was the first private astronaut to carry out the spacewalk, followed by crew member Sarah Gillis shortly after. Also in this episode:Dress to Impress: Why Roblox's viral game is taking the world by storm with our Social Media Editor, Sophie Butcher. We find out about London Natural History Museum's new mixed-reality exhibition which allows visitors to tour our planet 100 years from now Data centres in the UK are to be classified as critical national infrastructureFancy going to Antarctica? How you can send your name on a journey to the frozen wildernessFollow us on X or on Threads. Hosted on Acast. See acast.com/privacy for more information.

This week I, Kelly-Anne Taylor, am joined by the best-selling author, Emma Gannon. She began her career working in magazines – she's written columns for The Telegraph and The Sunday Times and was the Social Media Editor at Glamour. She created the hit podcast, Ctrl, Alt, Delete which racked up over 13 million downloads and saw her sit down with the likes of Elizabeth Gilbert, Lena Dunham and Gillian Anderson to talk about their work, wellbeing and creativity. She is also the writer behind The Hyphen on Substack, a six-figure business – which is described as ‘a cosy, online space for curious readers'. On top of that – she has written six best-selling books to date including The Success Myth, and, her debut novel Olive. Now, she is releasing A Year of Nothingness – a memoir, focusing on her time spent doing nothing following a period of burn-out. In this episode, we talk about the joys of slowing down, the beauty of cold water swimming, the power of slow news – and learning to say ‘no'. Learn more about your ad choices. Visit podcastchoices.com/adchoices

Dr. Shannon Westin and her guest, Dr. Chao Cao, discuss the paper "Prevalence and Cancer-Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022" recently published in the JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth with authors and manuscripts that have been published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, gynecologic oncologist by trade and Social Media Editor for the JCO. And it is my pleasure to welcome Dr. Cao, a research fellow in medicine, Department of Medical Oncology, Dana Farber, Cancer Institute, Boston, Massachusetts. Welcome. Dr. Cao: Thanks for having me. Dr. Shannon Westin: Of course. And we're going to be discussing your very important work, “The Prevalence and Cancer Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022,” which was published in the Journal of Clinical Oncology on April 4, 2024. And Dr. Cao has no conflicts of interest in regards to this podcast.  So let's get right into it. I'd love to level set. Can you speak a little bit about the definition of cancer survivorship and the number of cancer survivors currently in the United States?  Dr. Cao: I think this is an important question because everyone somewhat has confusion about the definition of cancer survivorship. So based on the definition by the National Cancer Institute, cancer survivorship refers to the phase of life following the diagnosed cancer. And nowadays, it's estimated about 80 million American individuals are living after being diagnosed with cancer. And this number is projected to rise to 26 million by 2040. Dr. Shannon Westin: Wow. So obviously, any research that we can do in this population is going to be so important as that number absolutely continues to grow.  And before we get into the specifics of your work, I'd love for you to speak a little bit about the importance of functional disability, which is what we studied in this work and why it might be observed in cancer survivors.  Dr. Cao: Yeah, sure. So, maintaining physical function is fundamental to perform life tasks and engage in fruitful jobs. In terms of cancer survivors, many cancer survivors experience side effects from cancer and its treatment. These side effects, include the pain, fatigue, and musculoskeletal dysfunction, which can induce physical limitation and eventually physical disability. And specifically, this is such a burden for the US, social, societal and economic burden. Here I have the specific number: so in 2019, an estimate of over 100,000 people living with and beyond cancer were unable to work and they received a Social Security Administration disability benefit with the resulting cost of US$1.8 billion in disability claims. Dr. Shannon Westin: Wow. We always think about the impact on the survivor, on their family, but I think it's also really important to look at those other objective data about the impact on society as a whole. Thank you, that was great detail.   Do we know anything about who might be proportionately more affected by cancer induced physical impairments and disabilities? Dr. Cao: Actually, this is our key question for our manuscript, but before we developed our hypothesis, we also looked at the data from the general population. So we observed that visual minorities and underserved populations, such as people with lower socioeconomic status and living in the rural area, and also those with unhealthy types of behavior, for example, smoking, obesity, and physical inactivity, are more likely to have physical limitations and disabilities. And also the comorbidity in cancer survival, such as diabetes, cardiovascular disease, also increase the likelihood of physical disability. We also have cancer survivors, particularly for cancer patients who are currently receiving cancer treatment, for example, chemotherapy and radiation therapy, they also are more likely to report side effects from the treatment, also have the reduced physical function. So we also think the cancer patients during the treatment also have a higher likely chance to have physical disability. Dr. Shannon Westin: Absolutely. That makes sense, and that really dovetails nicely into the objective of your study. We'd love for you to briefly summarize your objective and the methods you employed to achieve that goal.  Dr. Cao: Yeah, sure. We used the six-year data, 2017 to 2022 from the Behavioral Risk Factor Surveillance System to investigate problems and factors of functional disability in over 47,000 cancer survivors and 2.4 million adults without cancer diagnosis aged 80 years and older. And we specifically focused on two types of functional disability. The first one is mobility disability, which is defined as self reported severe difficulty walking or climbing stairs. And also another one is self care disability, which is defined as self reported difficulty dressing or bathing. And also we examined the factors, for example, social demographic characteristics, lapse of behavior, and health related factors, and some cancer related factors, how these factors related to the functional disability. Dr. Shannon Westin: Okay, great. So before we get into your findings, I'd love to hear just a little bit more about the BRFSS, the Behavioral Risk Factor Surveillance System. Why did you choose data from this survey for your study?  Dr. Cao: This is a very key question, because nowadays there are no specific cohort studies for cancer survivors. And also actually, in the population based study, there is no field data specifically for the cancer survivor. But fortunately, in the United States, the CDC conducted several nationally representative surveys to examine the health status of the people living in the United States. So we used the data from the Behavioral Risk Factor Survival System, we also called BRFSS. So BRFSS is a nationwide telephone based survey conducted by the CDC and it collects information on health related risk factors and chronic micro conditions among the US adults aged 80 years or older. And specifically for our papers, because recently, the BRFSS also added a section on the cancer survivorship, which included a lot of the variables on cancer, diagnosed cancer type, and also cancer related factor symptoms, for example, the cancer or cancer treatment related pain. So we used this data to realize our idea.  Dr. Shannon Westin: Okay, great. So let's start with what you found in regards to the first aspect with mobility disability.  Dr. Cao: First, we observed the problems of mobility stability are much higher in cancer survivors than non-cancer adults. And also among cancer survivors, more than 25% of cancer survivors reported mobility disability. We also observe the prevalence of mobility disability is much higher in racial minority groups and underserved populations and those with unhealthy behavior and medical conditions. Dr. Shannon Westin: In addition to the underrepresented minorities, were there any other kind of socioeconomic, demographic factors associated with high prevalence of mobility disability? Dr. Cao: Yes, the factors like lower level of education, income, being unmarried, and living in non metropolitan areas were associated with higher prevalence of mobility disability. And also, I forgot to mention another factor is cancer related factors. We're also including several cancer related factors such as cancer and cancer related pain. So we also observed a higher prevalence of the mobility disability in people, in cancer survivors with cancer and cancer related pain. We also see the prevalence of the mobility disability is much higher in the patients who are currently receiving the cancer treatment than those who already completed the cancer treatment. Dr. Shannon Westin: Yeah, that makes a lot of sense. And to that end, with regards to treatment, were there any cancer specific patterns of mobility disability? Dr. Cao: Yeah, and also, I think this is another strength of our study, because the BRFSS high sample size, which clearly evaluates the mobility disability in over 47,000 cancer survivors,  which allowed us to do the cancer specific part of mobility disability. We observed that the survivors of lung cancer and brain cancer and bone cancer have the highest prevalence of mobility disability. And interestingly, we also observed that the women with cancers also had, for example, ovary, cervical cancer survivors also have higher problems of mobility disability. Probably you know, better than me, and I just tell the data. Dr. Shannon Westin: Well, it's interesting, I was thinking, it seems like we have a lot, but I have no, obviously, frame of reference with other cancer types. So it's intriguing to me that that's definitely what we see in our clinic. So I'm intrigued to understand more about this.  But before we get into the next steps and that type of thing, I do want to make sure we touch on that other aspect that you looked at, the self care disability and give the listeners a little bit of an idea of what you found there?  Dr. Cao: The self care disability is kind of the more severe of the functional disability, which means, we say candidates, lower prevalence compared to the mobility disability, but still the patterns or factors associated with self care disability are much similar with mobility disability. An interesting finding is that in terms of the mobility disability, we find that older survivors are more likely to report mobility disability than younger survivors. In contrast, in terms of the self care disability, younger survivors are more likely to report than the older cancer survivors.  Dr. Shannon Westin: You've touched a little bit on some of the socioeconomic and demographic factors that were different with self care disability. Was there anything else that really caught your eye? Cancer specific factors or anything else like that? Dr. Cao: Yeah, besides this, I think also we observe that women are more likely to report self care disability. I think also this is driven by the cancer specific, particularly the woman cancers have a higher prevalence of the self care disability. Dr. Shannon Westin: Well, it's definitely something for me to take back to my clinic. Now that you've covered all these results, how are your data compared to existing literature in this area?  Dr. Cao: Yeah, we have tended to do comprehensive literature reviews. When we discuss our results and compare it with existing literature, our result is quite aligned with previous literature and particularly we clearly see the racial ethnic minority have a higher prevalence of physical limitation and physical function decline. But our paper focused on the physical disability which is much more severe than the physical function. And also we also looked at another study conducted in Australia, we quite find very similar results even for cancer specific patterns of the functional disability.  Dr. Shannon Westin: I guess the next question I have is was there anything that surprised you about your results?  Dr. Cao: I just mentioned that what surprised me the most is that the older people are more likely to report the mobility disability, but the younger people are more likely to report self care disability. Our data don't support or explore why this happened and what's the etiology behind this. But our hypothesis is that the younger cancer survivor, younger cancer patients are more likely to receive the aggressive treatment that can play a significant role in the functional outcome.  Dr. Shannon Westin: Yeah, it sounds like that's definitely an area of unmet need for more research. But I like your hypothesis. I do wonder if that's somewhat related.   And I guess that leads us to our final question. What are your next steps and how can I potentially use this in practice? How can our listeners employ these findings in their practice? What do you recommend? Dr. Cao: I think our findings highlight the importance of screening for functional limitations at the baseline and throughout the cancer treatment and even the cancer survivorship. Oncology providers also should encourage patients to be physically active. And also American Society of Clinical Oncology and also American College of Sports Medicine recommend that regular exercise during the treatment can help cancer patients preserve their fitness and reduce the incidence and the severity of the cancer related disability. And also providers can provide referral to rehabilitation services and support groups for additional care.  For the next step, our finding highlights the importance of developing ways to limit the long term side effects of cancer treatment both during and after treatment to preserve fixed function and prevent disability. Particularly, target intervention should in particular address special needs in vulnerable populations, including the racial ethnic minorities and those living in the rural areas to improve their quality of life during a long term survivorship. And also due to the advance in the technologies, now we want to see whether wearable sensors, wearable devices can be a novel tool to monitor their physical functions during the treatment because better monitors can lead into their better treatment and their prevention. Dr. Shannon Westin: That's great. Yeah, what a great way to end. I think that exercise clearly is key not only for preventing these issues, but also we know that it potentially can even improve response to therapy and recurrence free survival. So I think lots of reasons to be focusing on physical activity in our clinics and ensuring our patients and our cancer survivors are really participating in those types of activities.  Well, Dr. Cao, it was such a pleasure. I cannot believe you are only a research fellow. I can't wait to see where your career takes you. Congratulations on this great work. Dr. Cao: Thank you. Thank you for this great opportunity to share my work and I look forward for my future work in the field. Dr. Shannon Westin: Oh, yeah. So you guys, if you're looking for somebody to come and push the boundaries of functional disability and activity, you know where to look.  And again, thank you all our listeners for tuning in to another episode of JCO After Hours. Again, we were discussing, “The Prevalence and Cancer Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022.” Original research published in the JCO, April 4th, 2024. So if you're looking for more podcast offerings, check out other JCO After Hours offerings wherever you get your podcasts. Have an awesome day.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

We partnered with @HealthyWomen with support from Pfizer to answer some of the most popular questions about the difference between headaches and migraines.Our expert guest, Dr. Rashmi Halker Singh, shares real-time solutions to know the following:The difference between a headache and migraineHow to understand symptoms and why they are not the same for every womanWhy women of color are often misdiagnosed due to pain biasWhy clinical trials play a role in validating pain managementWhat you need to know when speaking with your doctorWhy you need a great girlfriend at your next appointment!Listen now and share your iTunes review with us!Follow now

Welcome to the Dojo, the podcast where we turn marketing news into marketing tasks. This week we're joined by Danielle Nicholls, Content Creator and Social Media Editor at Alton Towers Resort, and we talk about: AI Corner: Update on Google's AI Overviews Boosting Brand Awareness with Social Communities Decathlon's No Tent Left Behind Campaign Timestamps 00:00 – Intro 03:49 – Story 1 –  AI Corner: Update on Google's AI Overviews 14:59  – Story 2 – Boosting Brand Awareness with Social Communities  32:27 – Story 3 –  Decathlon's No Tent Left Behind Campaign  40:32 – The Tasks   Get a FREE review of your website https://exposureninja.com/rpod/review/ Get the show notes https://exposureninja.com/podcast/dojo-23/ Watch the podcast recording on YouTube: https://exposure.ninja/dojo-23 You May Also Enjoy… How We 10x'd Leads for a Finance Company https://exposureninja.com/podcast/dojo-22/ Email Marketing Just Got a Whole Lot More Competitive https://exposureninja.com/podcast/dojo-21/ Google's AI Overviews Fiasco | ft. Joe Glendinning https://exposureninja.com/podcast/dojo-20/ HUGE Google Leak Confirms SEO Theories | ft. Lucy King  https://exposureninja.com/podcast/dojo-19/ The Future of SEO Changed AGAIN | ft. Annabelle Baugh https://exposureninja.com/podcast/dojo-18/ What Went Wrong with Apple's Controversial Ad? | Ft. Gustavo Uy https://exposureninja.com/podcast/dojo-17/ Marketing Lessons from Aldi's Brilliance | ft. Danielle McMullen    

JCO PO author Dr. Samuel J. Klempner shares insights into his JCO PO article, “PD-L1 Immunohistochemistry in Gastric Cancer: Comparison of Combined Positive Score and Tumor Area Positivity across 28-8, 22C3, and SP263 assays”. Host Dr. Rafeh Naqash and Dr. Klempner discuss assessing the analytical comparability of three commercially available PD-L1 assays and two scoring algorithms used to assess PD-L1 status in gastric cancer samples. TRANSCRIPT  Dr. Abdul Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I am your host, Dr. Abdul Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center. Today we are excited to be joined by Dr. Samuel J. Klempner, Director of Gastro Esophageal Medical Oncology and Assistant Professor at Harvard Medical School Mass Gen Cancer Center and author of the JCO Precision Oncology article, “PD-L1 Immunohistochemistry in Gastric Cancer: Comparison of Combined Positive Score and Tumor Area Positivity Across 28-8, 22C3, and SP263 Assays.” At the time of this recording, our guest disclosures will be linked in the transcript. Dr. Klempner, welcome to our podcast and thanks for joining us today.  Dr. Samuel J. Klempner: Happy to be here. Thanks for having me. Dr. Abdul Rafeh Naqash: For the sake of this podcast, we'll be using our first names. So, Sam, it was great to see you at ASCO recently, where I believe you presented these data as an abstract as well. Dr. Samuel J. Klempner: Yes, we had a poster presentation for this paper, which was published in parallel with the meeting. Dr. Abdul Rafeh Naqash: Congratulations, and I'm very happy that you chose JCO PO as the destination for these data. So we're going to be talking about a lot of different things today in the context of gastric cancer, which I know you treat very often in your clinic. So could you tell us what the treatment landscape for advanced gastric cancer currently is? Because that goes into the context of why I believe you and your colleagues went ahead with this project.  Dr. Samuel J. Klempner: Yeah, happy to. As you know, unfortunately, half or more of our patients, by the time they come to medical attention for a gastric or GE junction or esophageal adenocarcinomas, unfortunately have advanced disease, often metastatic at presentation. So we have this large population of patients with advanced disease, and over the last couple years, we've actually made some substantial advances in the management and survival of this population. This has been mainly driven by biomarker selection, whether it be adding immunotherapy on top of HER2 therapy, whether it be testing for claudin and seeing the results with claudin directed therapies. And perhaps the vast majority of patients are potentially eligible for immune checkpoint inhibitors. We've seen several phase three trials, perhaps highlighted by CheckMate 649, KEYNOTE 859, rationale studies confirming that there are populations of patients who derive significant survival advantages from the addition of anti PD-1 on top of chemotherapy. So the landscape has really evolved into a biomarker directed world, which is exactly what we hope, because ultimately, the goal is, of course, to match patients with the best drugs at the right time. And that's really the background of where this analytical effort came from.  Dr. Abdul Rafeh Naqash: Thank you for giving us that overview. Going to the second part, which, as you mentioned in your initial overview about the role of immunotherapy, and as we all know, immunotherapy has changed the treatment landscape for a lot of different tumor types. And as clinicians, we often see or ask, what is the PD-L1 positivity for, let's say, lung cancer, which is what I treat, and gastric cancer, which is what you treat. Some of the nuances that we don't necessarily go into when we're looking at those reports is the combined positivity score, the tumor proportion score, or the tumor area positivity. Could you give us an understanding, for the sake of our audience or for the sake of our trainees who might be listening to this podcast, what the CPS, or what the TAP  mean and where they are used in the treatment landscape for biomarker selection in the context of gastric cancer? And how do you approach the different cutoffs for CPS when you're treating an individual in the standard of care setting for gastric cancer? Dr. Samuel J. Klempner: For sure, happy to. So I think eventually it all comes back to patients. When we're sitting in a clinic room with the patient, we want to be able to have features about the tumor that's going to tell us if a therapy is more or less likely to work, maybe if there's a prognostic implication so we have predictive and prognostic biomarkers. And PD-L1 expression does not appear to be particularly prognostic, but it does appear to be predictive of benefit from immune checkpoint inhibitors. Therefore, all of the phase 3 trials that we've seen in some way have linked the biomarker expression to outcomes, whether it's the primary endpoint, whether it's post hoc retrospective analyses, etc. What we've seen is that all of these phase 3 trials have largely used different antibodies to define PD-L1 strata within the trial. So whether that's 22C3,  whether it's 28-8, whether it's 263, those are the predominant antibody clones used to examine PD-L1 expression in tumor samples. And it's been pretty clear across these large phase 3 trials that there is a trend with increasing PD-L1 expression and increasing magnitude of benefit. We see this in the improved hazard ratios in the CPS greater than five or greater than ten versus less than one, etcetera.  However, the scoring systems have varied. There is TPS tumor positivity, which only accounts for tumor cells. There is combined positive score, which accounts for tumor cells and mononuclear infiltrates and involves counting cells. And then perhaps the most recent one is the tumor area positivity, which is essentially a non counting method to look broadly at the area of the sample that is expressing PD-L1. It was on this background that we said, is there analytical concordance among the main antibodies? Our work does not address whether there is difference in clinical outcomes between testing 28-8 and 22C3 and SP263. It is simply a pure analytical comparison of the three antibodies. Is a CPS 5, when you call it by 28-8, somewhat agreeable to a TPS or a TAP greater than five with the same antibody and with a different antibody. So we felt that this was kind of a question that hadn't really been fully addressed in the field and may help contextualize results for clinicians and ultimately cross trial comparisons.  Dr. Abdul Rafeh Naqash: Thank you for that explanation. And you bring forth a very important question. And I remember this example of a patient with lung cancer who had tissue NGS done, and they had a limited gene panel with PD-L1 testing sent that showed a PD-L1 of close to 15 or 20%, and then another NGS panel with a different antibody, suggesting that they had a PD-L1 of close to 60-70%, which significantly changes the overall approach for treatment in the context of blood cancer. Is that something that you experience in gastric cancer also, in terms of variability for CPS, determining what treatment combinations you might be able to put an individual patient on? Dr. Samuel J. Klempner: It's rare that we have samples at any institution tested in multiple methods, but these types of papers and others had looked at some stuff similar and prior to our publication, but we know that there is both spatial heterogeneity. So if you test a tumor versus metastasis, you may have different PD-L1 scoring even in regions of large samples, like surgical resections, there will be some intra tumor heterogeneity in regions of expression. And then we also know that sometimes after therapy, for example, post radiation, there's some data that at the time of surgery, the PD-L1 expression may be higher than what the presurgical sample was. So there's a lot of variables that are factored in. But one thing that wasn't really well known is, across the standard antibodies, how well is the inter assay comparison? There had been some work from a group in Singapore, a very nice paper suggesting that at the higher cut points, the agreement was pretty good across the assays, CPS greater than 5 and greater than 10, and maybe slightly less so at the lower. They had used a different method, which was not really what is standard, and they had used multiplex immunofluorescence or IHC. This is not a validated method for PD-L1 scoring. So that was an open question, sort of. Although they laid a very important piece of data down, we wanted to use the most standard assays and essentially do a very similar analysis, but using the standard scoring criteria. Dr. Abdul Rafeh Naqash: Very interesting. So, could you walk us through the approach of how you looked at this question, what kind of samples you used and what kind of testing algorithms you implemented to look at the cross validation of these three different antibodies? Dr. Samuel J. Klempner: The antibodies were chosen primarily because those are the standard ones that either have companion diagnostics or have been used most commonly in phase 3 trials. So 22C3 has most commonly been linked to pembrolizumab, 28-8 to nivolumab, and 263 used with Roche and Genentech trials primarily. And so we selected the antibodies based on the common use. We selected the scoring systems of CPS and TAP, again based on the most commonly used and validated scoring algorithms in gastric cancer. And then, although most patients in clinic and metastatic disease present with biopsy samples from the primary tumor, there may be some limitations in biopsy samples in terms of small amount of material and ability to reliably count 100 cells, etc., for CPS. So we actually use surgically resected samples from a commercial biobank, 100 samples, and essentially 28-8 was really the reference. And we picked samples that, using 28-8 CPS PD-L1 expression represented the entire spectrum, meaning we had CPS less than 1, we had greater than 1 and less than 5, greater than 5 and less than 10, and greater than 10, so that we could compare across these different strata, because those are the most common strata that have been used in clinical trials and linked to magnitude of benefit. Dr. Abdul Rafeh Naqash: And something that, interestingly, I see here when we go to some of the results, and I'm pretty sure you'll talk about the concordance, is the correlation coefficient seems to increase as the percentage positivity increases for a certain antibody. Could you try to help us understand why that might be the case? Is it because it's easier for the pathologist to look at the slide when there is a certain level of positivity that crosses a certain threshold? Or could there be some other factors that are not well understood. Dr. Samuel J. Klempner: Yeah, it's a totally good question, and I think it's something that's seen in other IHC biomarkers as well. If you look at HER2, you'll see some similar trends. The agreement at IHC 3+ is pretty good and greater than it is at lower cut points. And having talked to multiple pathologists, and I'm not a pathologist, we had three pathologists scoring all of these samples, and essentially, it's what you might expect. It is just easier when there's a lot of the marker. It is easier to judge the high extremes of the strata. So the agreement at greater than 10 is quite good, and this has already been shown by others. It's just an easier thing to score for anyone. The agreement is better across all of the assays at higher cut points, whether it's TAP greater than 10% or CPS greater than 10%. And you can see that pretty clearly in our data, and it's also been shown in other data sets looking at roughly similar questions in other tumor types.  Dr. Abdul Rafeh Naqash: Going to the interesting results that you have in this paper, could you highlight for us some of the important findings that you had and put them into context of what their clinical implications may be? Dr. Samuel J. Klempner: Yeah, I think I'll start with the clinical implications so that what clinicians, and we're both clinicians, what we want to know is, if I have a report that says the CPS is greater than 1 and it's done with a 22C3 test, is that also likely to be greater than one if it had been done with a 28-8 test or scored with a different algorithm - CPS versus TAP? So, essentially, some degree of confidence on the interchangeability between the assays themselves, that is really the clinical implication. And so, to accomplish this, we set out to basically do the comparisons you'd have to do to convince yourself that that is true. So you take samples against a reference range, in this case, across the PD-L1 strata, you pick a reference test, in this case, 28-8, you have one pathologist be the start, and then you compare other pathologists against each other and that person, and you look. And in the pathology literature, they have strata of agreement which tend to go from poor, moderate, good to excellent. And these are sort of accepted standards in the pathology world about inter reader agreement. So between one pathologist and another, and things that are moderate or good are considered essentially acceptable at interchangeable levels.  And so, as you suggested, at the higher cut points, the agreement is very good. The clinical interpretation of that is that if you get a TAP greater than 10% scored on a 22C3 antibody on a Dako staining system, you can feel relatively confident that that would also be called a TAP or a CPS greater than 10 by a 28-8 antibody, suggesting there is good agreement between the two antibodies at that cut point. As you move down, there is a little bit less agreement, and that is consistent with what's been shown before. But in our data set, the agreement was still pretty good across all three of the antibody clones, even at the lower cut point, so greater than 1% for TAP or CPS greater than 1. And that provides, I think, some reassurance to clinicians that whatever test their own pathology lab is using, if it's one of these three assays, they can provide some degree of confidence that what they're seeing would be similar to what they were seeing if it had been done with another test. Dr. Abdul Rafeh Naqash: I think that that is very important, because even though we do want broad testing in general for metastatic tumors, as you probably will agree with, but there's a lot of practices still that institutions tend to do their own testing with limited gene panels or even IHCs. So I think to put that in the context of your study, as you said, if you have a certain antibody that is positive, as you've shown, then that also likely means that with another antibody that your institution may not test for, it's likely the tumor sample is likely going to be positive at a similar level.  So I think you also used digital pathology as part of this project, even though that may not be the most important aspect. As we move slowly and steadily towards artificial intelligence and machine learning, could you tell us how you incorporated the digital assessments and how you utilize them to correlate with the pathologist assessment and the futuristic perspective of how we could eventually try to incorporate digital pathology assessments for this kind of staining approach, which might limit interobserver operability differences as well as time constraints? Dr. Samuel J. Klempner: I hope I can do this part justice, because, again, I'm not a pathologist. But the digital imaging analysis was really essentially used as a quality check and verification tool in our own paper. Our intent was not to establish DIA directly as a superior methodology to TAP or CPS, but simply to provide ourselves some degree of confidence in the staining pattern and distribution across the three assays, and whether or not this would generate significant differences in what the PD-L1 score would have been called. And so, the bottom line is, the digital imaging analysis suggested there were very minor differences across the three assays in terms of, like, percent cell positivity, which is one of the main readouts, and the mean difference was actually quite small. So we felt that the digital imaging analysis, which was really considered somewhat exploratory in our own work, supported what we saw with the pathology comparators read in traditional methods. I think it sets somewhat of an initial pilot data benchmark to say that maybe we can think about moving tools like digital imaging analyses forward in terms of PD-L1 scoring approaches in the future. But it does not provide adequate data to say that we can do this now or we have enough samples and enough comparisons to say that, “Hey, for sure, digital imaging is equivalent to pathology reading.” I think that we're getting there and our data supports that that may ultimately be the conclusion, but for us it was really essentially an orthogonal support and sanity check for our traditional approach, which is, of course, a pathologist based scoring. So supportive and suggestive, but not definitively conclusive. Dr. Abdul Rafeh Naqash: Definitely early days for visual pathology assessments, but I think that it's a very rapidly evolving field, and hopefully we'll see more of this in the next few years, as well as incorporating some assessments into clinical trials.  Now, shifting away from your honorary pathologist role as part of this project to your actual role as a clinician investigator/clinician scientist, could you tell us your career trajectory, how you started, how you've self paced yourself, and how you've tried to mentor certain different individuals in your current role? Dr. Samuel J. Klempner: Yeah, I remember my grandfather and other people telling me, just try to leave it a little bit better than you found it. And so that's, I think, a guiding principle. I hope that at the end of my own career, I can leave oncology a little bit better than when I started. I think the best way to do that is to mentor and train the next generation who are going to drive these practices. I started, like many others, personally touched by cancer in my family, which started me on a journey towards oncology, was somewhat frustrated by the lack of options available to my mom, and then became deeply interested in the science and how come we knew so little about cancer, so spent a fair amount of time in labs, and had a really formative experience with Lew Cantley looking at PI3 kinase resistance and signal transduction, and wanted to learn to speak the language and interact with people driving the lab based work. And that's been something I've tried to keep as central to my career as someone who has a very strong translational interest.  And so I try to think of ways that I think we can learn from every single patient and every subgroup. I mean, for example, in our own work here, it's very unclear if there's a biology linked to the different PD-L1 strata. So for example, does a PD-L1 CPS greater than 10 tumor have a very high interferon gene signature? Or are there features of the T cells that are different between a CPS 10 or higher versus a less than 1? So PD-L1 is a biomarker, but is it really telling us about biology? And so these are the types of questions that I try to stimulate in all the residents and fellows and hopefully it will drive translational projects. But I think just having the conversations and asking the questions and talking to people. I mean, I love the ASCO Career Lounge and always try to do that when possible. I know you do the same. I think staying curious is really the thing that I try to remain in life and also in my career and have fun and enjoy with your colleagues. And I think that will make us all better researchers and ultimately translate to better outcomes for our patients, which is, of course, why we all do this. Dr. Abdul Rafeh Naqash: Wonderfully said Sam, thank you so much. Thanks again for choosing JCO PO as the final destination for your work. Hopefully we see more of the similar work that you do in your field in JCO PO. And thank you for talking to us about your journey as well.  Dr. Samuel J. Klempner: Yes, thanks for having me. I'll talk to you sometime soon.  Dr. Abdul Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.     Disclosures Dr. Klempner Stock and Ownership Interests TP Therapeutics Nuvalent, Inc Honoraria Merck Serono Consulting or Advisory Role Atellas Pharma Bristol-Myers Squibb Merck Daiichi Sankyo/UCB Japan Sanofi/Aventis Mersana Exact Sciences Novartis SERVIER AstraZeneca Amgen I-Mab iho Oncology    

Dr. Shannon Westin and her guest, Dr. Bryan Schneider discuss the article “ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer” recently published in the JCO and presented at the 2024 ASCO Annual Meeting. TRANSCRIPT  The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncology Extraordinaire and also the Social Media Editor of the Journal of Clinical Oncology. And it is my great pleasure to present some really incredible work today that is going to be a dual publication in the Journal Clinical Oncology and a presentation at the American Society of Clinical Oncology Annual Meeting on Monday, June 3. And this is the “ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer.” And I am joined today by the senior author on the presentation and the primary author on the manuscript, Dr. Bryan Schneider. He is the Vera Bradley Professor of Oncology, the Professor of Medicine and Medical Molecular Genetics at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center in Indianapolis. Welcome, Dr. Schneider. Dr. Bryan Schneider: Dr. Westin, thank you for having me on today. Shannon Westin: We're so excited and we're really excited to really summarize this incredible work that's being presented today. So, first, let's just levelset. Can you speak a little bit about peripheral neuropathy and the most common causes in patients with cancer? Dr. Bryan Schneider: Yeah, I mean, I think for those of us who treat patients using the taxanes, we recognize probably one of the most important and common side effects that we deal with is peripheral neuropathy, and one that can, I think, impact both quality of life, but also impacts the ability to maintain dose intensity. When we think about risk factors for neuropathy, historically, I think obesity has been reported as a potential risk factor, as has diabetes and other conditions which put people at risk for neuropathy. Shannon Westin: And prior to your work that you'll discuss with us today, what do we know about the incidence of peripheral neuropathy in patients that identify as black? Dr. Bryan Schneider: Yeah. So, interestingly, I think we've recognized that patients who self identify as black have disparate outcomes in terms of inferior survival and more aggressive subtypes of breast cancer, like triple negative breast cancer. But I think the idea of toxicity being a disparate factor as well is probably a more recent one. Interestingly, as we set out to identify biomarkers to predict outcomes in the large adjuvant trial E5103, we weren't really setting out to look at this by race. We were using at that time, genome-wide approaches to identify biomarkers for toxicity and also efficacy. But what was interesting as we did that one of the most important predictors, as we looked across a number of important toxicities, was ancestry. And really the science spoke to us, it was very clear that patients of African ancestry had higher rates of bev-induced hypertension, anthracycline-induced cardiomyopathies and also peripheral neuropathy. Shannon Westin: That's so interesting. We have so much overlap in gynecologic oncology and breast cancer. And I don't know that I've ever seen work like this. And now it's making me very intrigued and making me want to move forward to that. Can you talk a little bit more about this ECOG-ACRIN E5103, like briefly about the study and what it demonstrated specifically? Dr. Bryan Schneider: Yeah. So E5103 was an adjuvant breast cancer trial that really set out to look at the impact of bevacizumab in the curative setting. This was a 5000 patient trial that randomized patients the standard backbone of chemotherapy. So everyone received four cycles of doxorubicin and cyclophosphamide, followed by weekly paclitaxel, and then with or without the addition of bevacizumab. So the parent clinical trial showed, as we know now, bevacizumab didn't add benefit, but certainly this was a fertile ground for us to use genomic markers to try to identify a number of other important factors and predictors. Shannon Westin: And what did you find genomically in that study that led to kind of where we are now? Dr. Bryan Schneider: Initially, what we found is that ancestry was a major predictor of neuropathy. And in that trial we saw essentially a doubling of the risk of grade 2 and above and a doubling of the risk of grade 3 and above neuropathy. When we then looked comprehensively across the genome for common variants that might put patients at risk for neuropathy, we had enough patients in the black population to identify some markers that seemed to differentially predict the risk of neuropathy in the patients of African ancestry. So there we found a variant in the gene FCAMR, which appeared to be protected from neuropathy, and FCAMR is known to have an immune modulatory effect. But importantly, we also found that rare variants, so we did this using an exome wide approach in a gene called SPF2, predicted an increased risk of neuropathy. Now, interestingly, that gene SPF2 is also thought to contribute to a hereditary form of neuropathy, Charcot-Marie-Tooth. Here, what we found, obviously, is that if you inherit two of these variants, you probably have a hereditary neuropathy, but if you inherit one, you may not have neuropathy at baseline, but if exposed to a neurotoxin, much more predisposed to that event. Shannon Westin: That is so intriguing and makes so much physiologic sense. So, can you talk a little bit about how that led to the development of the current study, the objectives design, that type of thing? Dr. Bryan Schneider: Yeah. I think, overarching question and concern is, and we see this with all clinical trials in the United States, is that we're seeing disparate outcomes in a population that are largely underrepresented in our clinical trials. And so one of the first things we wanted to do was really focus on the population that was being disparately affected. So EAZ171 was set out to accrue patients, and in fact, only accrue patients who were self described as a Bck race or African American. So the goal of this trial then was to see if, number one, we could further predict which patients were going to get neuropathy based on our germline genotyping, and then also to better personalize the type of taxane based, again on genomics, but also on the risk of dose reductions, risk of neuropathy, impact on financial toxicity, quality of life, and a number of other, what we felt to be, important clinical variables. Shannon Westin: So let's get into the details. What did you find regarding the incidence of neuropathy in the study, and how was it impacted by the type of chemotherapy the patient received? Dr. Bryan Schneider: Yeah. So the starting point, the primary objective of that study, was to try to validate a high and low risk composite score for neuropathy. And the trial was negative, meaning our genotypes did not predict significantly differences based on the germline genotyping. Now, interestingly, the genotyping did numerically separate, meaning those in the high risk category had about a 12% higher risk of neuropathy, but this did not meet statistical significance. Another major or key secondary endpoint, though, was to look at the type of taxane and its impact in this population. And indeed, what we found is that patients who received paclitaxel had a markedly and statistically significantly higher risk of both grade 2 and above and grade 3 and above peripheral neuropathy. And in addition, we saw more dose reductions, both because of TIPN and all causes in the paclitaxel arm. Shannon Westin: So why do you think you were unable to validate the genomic predictors in the current study? Dr. Bryan Schneider: This is an incredibly important question. So, number one, I mean, we were happy to see the directionality of our preliminary data be correct. But I do think that neuropathy is a very complicated toxicity, and it's probably a multigenic effect, and it probably is also impacted a lot by a variety of clinical factors. So some of the future work we'll be doing is looking at polygenic risk scores and other known genes that may be impactful, and also melding that with a number of really important clinical variables, because I still think we have the potential to predict this ahead of time. Shannon Westin: I know that this was such a patient driven topic, really focused on the patient experience and how to improve not only survival outcomes, but also toxicities and quality of life. Can you speak a little bit about the role of patients in the design of this trial, and maybe with helping it be as successful as it was with accrual? Dr. Bryan Schneider: Yeah. This has truly been one of the most exciting projects I've ever embarked on, and largely because of the incredible team atmosphere and contributions by so many people. Real thanks to the late Worta McCaskill-Stevens and also the late Edith Mitchell, who were two really fundamental disparities experts who really helped motor this trial to where it was. And also our patient advocates and the community at large really were part of the design and part of this from the very beginning, all the way through the publication, I think, have made it a clinically relevant study, and one that I think we're all very proud of. Shannon Westin: Is paclitaxel typically, what is the go-to? Or are more people using, let's say, docetaxel? Dr. Bryan Schneider: I think it depends a little bit on the disease setting and type. And again, is a function of historical clinical trials. One of the pivotal trials, E1199, actually compared a number of these. So it compared weekly paclitaxel to every three week paclitaxel to weekly docetaxel to every three week docetaxel in a two by two design. And essentially the conclusion there is that weekly paclitaxel and every three week docetaxel both outperformed what at the time was a standard of care, every three week paclitaxel. Now, weekly paclitaxel, at least through ECOG-ACRIN, has been adopted as kind of the standard reference therapy and schedule of choice, but largely because of the side effect profile. And again, this is based predominantly on white patients, where the tolerability is much better. Shannon Westin: Well, I mean, I think that this leads to really great information around how we're designing these trials and how we're potentially making those differences. What are your next steps here? Dr. Bryan Schneider: So I think one of the things this clinical trial did was first validate that we do see high rates of peripheral neuropathy in Black patients with breast cancer. This was a prospective study using both physician and patient adjudicated variables. So I think this is a really nice validation that this is a problem in this population. I think it also shows us that docetaxel is probably a more tolerable drug for black patients with breast cancer. The goal, though, I think in our future work, is really going to try to bring equity in terms of outcome and side effects. So we're working with ECOG-ACRIN now on our second trial, where really the primary endpoint is going to be to nullify the disparities and try to bring equity in terms of toxicity. One of the other pieces of work we're really excited about is we're doing some ex vivo work. So from patients in EAZ171, we have a blood stick where we're taking white blood cells and differentiating those into peripheral neurons. And here we're hoping to look at really important changes in both gene expression and epigenetics that might lead us to a little bit deeper understanding of the mechanism of the disparities in neuropathy, maybe what's causing some of the neuropathy. And we hope ultimately, these may lead to nice drug targets to help prevent or treat neuropathy down the road. Shannon Westin: Those are some really great ideas. The other thing that really caught my eye around your findings was what you all found regarding the physician reported and patient reported toxicity. I'd love for you to summarize that, because I think that's always a concern as well. Dr. Bryan Schneider: Historically, I think we recognize that physicians probably underreport side effects. And so we felt, and our team felt, that having patient reported outcomes would be a really critical piece to this study. What was fairly astonishing to me, if you look at the CTCAE, both patient and physician reported outcomes, they were actually pretty similar. And I think what this is a testament to is if physicians are actually thinking about the side effect, they do a pretty good job of predicting it. Now, one thing we're looking very forward to is that we have a long term follow up out to three years. So it'll be interesting to see if physicians continue to pay close attention to neuropathy, because I know the patients will be. So we'll be looking at the discordance at these longer term follow up time points as well. Shannon Westin: Well, great. This is such incredible work, and I'm like literally taking notes to get in touch with people I know that do this type of work and gynecological malignancies because I think that this is going to have far reaching consequences. So just thank you so much for taking the time to review this and congratulations on the JCO publication and ASCO presentation. It's very well deserved. Dr. Bryan Schneider: Thank you Dr. Westin. Shannon Westin: And thank you to all of our listeners. Again, we have been discussing the “ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer.” We're so grateful you joined us, and please do check out our other offerings wherever you get your podcasts. Have an awesome day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Disclosures Research Funding Company name: Genentech/Roche Company name: Pfizer Company name: Foundation Medicine      

Roommates: can't live with them, can't (afford to) live without them. They're the people who use your dishes and don't wash them. They're the people who apparently have a huge influence on your career choice and drinking habits. This hour, we're getting to know them better!   GUESTS:  Ken Jennings: Colin's college roommate Kelli María Korducki: Journalist who writes about work and the family Bruce Sacerdote: Professor of Economics at Dartmouth College Francesca Fontánez: Social Media Editor at CT Public and a former college RA Join the conversation on Facebook and Twitter.   The Colin McEnroe Show is available as a podcast on Apple Podcasts, Spotify, Google Podcasts, Stitcher, or wherever you get your podcasts. Subscribe and never miss an episode!   Subscribe to The Noseletter, an email compendium of merriment, secrets, and ancient wisdom brought to you by The Colin McEnroe Show.   Colin McEnroe, Cat Pastor, and Dylan Reyes contributed to this show.Support the show: http://www.wnpr.org/donateSee omnystudio.com/listener for privacy information.

Dr. Shannon Westin and her guest, Dr. Patrick Stone, discuss the article, Methylphenidate Versus Placebo for Treating Fatigue in People with Advanced Cancer, a Randomized, Double-Blind, Multicenter Placebo-Controlled Trial, recently published in JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts and research published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for JCO and a Gynecologic Oncologist by trade. I am thrilled today to present Methylphenidate Versus Placebo for Treating Fatigue in People with Advanced Cancer, a Randomized, Double-Blind, Multicenter Placebo-Controlled Trial. This manuscript is a dual publication in the Journal of Clinical Oncology and presentation at the European Association of Palliative Care Congress here on May 17, 2024.   And to review this incredible research with us will be Professor Patrick Stone, the Head of Department of Marie Curie Palliative Care Research Department, Division of Psychiatry at University College London. Welcome, Dr. Stone. Dr. Patrick Stone: Thank you very much. Thank you. Shannon Westin: Let's get right to it, we'll level set. Can you speak a bit about the definition of cancer-related fatigue and how common it is in people with advanced cancer? Dr. Patrick Stone: Sure. I think fatigue is a difficult thing to nail down really and define it clearly, and there are lots of definitions out there. In many ways, the simplest definition is the EAPC, the European Association of Palliative Care's definition of just a subjective sensation of weakness, feeling tired, and exhaustion. The reality is that that symptom is very common in the general population. And so if you really want to get a handle on it, I think a good way to do it is to think about taking an operational definition and say, “Look, if fatigue is normally distributed approximately in the general population, then we should consider severe fatigue or pathological fatigue could be defined as fatigue that is worse than 95% of the general population. And if you think that definition, then prevalence of fatigue in patients with newly diagnosed breast or prostate cancer, for instance, is around 15%, so three times as common as the most severe fatigue in the general population. If you come to patients with newly diagnosed non-small cell lung cancer, it's up to about 50%. And if you come to my area, which is palliative care and you go to a hospice and you ask people to complete a fatigue questionnaire, 78-80% of people complain of fatigue that is more severe than 95% of the general population. So that I think gives us a good handle on sort of the severity of this problem in cancer patients and how it progresses as disease progresses. Shannon Westin: I love this because I think we always struggle with exactly how to nail down the definition and exactly how to treat it. So I think that it's a really nice transition to existing treatment options for this issue and exactly how they might work. Dr. Patrick Stone: The first thing to say is in medicine if you can find a cause then you give a treatment directed at the cause and obviously that applies to fatigue as well. So the first thing is to do a thorough assessment of your patient, and if you can find an easily remediable cause such as anemia, hypocalcemia, or hypomagnesemia, or maybe other things like depression, which might manifest as fatigue, then you should try and give a treatment directed at that cause. But, for many patients, there won't be a single clearly identifiable cause you can target. And then people use more broad spectrum approaches if you like. The most well-studied I think is exercise. And exercise, there have been lots of randomized controlled trials in different types of exercise and it's a well attested treatment, which I think has good evidence of effectiveness, certainly in patients who are on treatment and in disease-free survivors. There is less evidence in advanced cancer because the trials are fewer. I would still say that there's moderate quality evidence that exercise is effective in advanced cancer.  The other group of treatments, broadly speaking, would be psychological therapies, cognitive behavioral therapy and psychoeducational approaches, mindfulness based stress reduction, that sort of thing. And again, in earlier stage disease and in patients on treatment and in survivors, there's more quality evidence that that sort of approach can help, if not alleviate fatigue, allow people to cope better with fatigue. But the evidence in advanced cancer is weaker than for exercise. So I think the evidence for the effectiveness of those psychological therapies is not so strong.  And then you come on to pharmacological therapies and there have been lots of trials of different agents. I won't list them all because most of them are negative and don't show any benefit. A few things which perhaps still show promise from previous trials, there have been, for instance, a few trials looking at ginseng as a herbal therapy. One very good quality trial showed benefit. Although another trial in advanced cancer didn't replicate that finding, so that ginseng is out there. Steroids, widely used in advanced cancer for general relief of many symptoms like fatigue, lack of energy, low moods, appetite. But although widely used, surprisingly little hard evidence or effectiveness, specifically for fatigue, but one relatively recent, well conducted randomized control trial, provides us with some firm evidence, also, that dexamethasone can help in the short term in advanced cancer patients. It obviously wouldn't be a recommended treatment longer term because of its side effects.   And then we really come on to the crux of this study which is probably the most widely studied single agent beyond that, is methylphenidate, which is a psychostimulant agent, raises central dopamine catecholamine levels in the brain. And there's probably a thousand or so randomized control trials sort of being conducted looking at that prior to prize of this study that we're talking about. Shannon Westin: I would love to hear a summary of the data that were pre-existing in this study. So how well does methylphenidate seem to work, or what were the conflicting results that were seen prior? Dr. Patrick Stone: I think the rationale for this study was that it was the perfect background to justify another randomized controlled trial, which there have been– Well, I can't remember exactly how many there were in existence before my trial started, but when I last looked, there were 10 studies, 10 randomized controlled trials in cancer patients. Most of those trials have been neutral. They've shown no benefit over placebo, so most of the individual trials are negative. But meta-analyses always tend to show a positive result. So when you count the trials together, it gets you over the finishing line and you can see a positive benefit. But individually, the trials were quite heterogeneous, they're quite different. There were only four trials prior to the publication of this one that were done specifically in advanced cancer patients. One of them was published only a couple of years ago while my study was going on. And of those four trials, three of those have also been neutral, not showing a benefit over placebo. One study involving 28 patients and using a PRN as required dosing schedule showed some benefit. But the other studies with a total of about 330 odd patients have been neutral.   Shannon Westin: I think that brings us to a great transition, just to talk a little bit about the design and objectives of your current study. Dr. Patrick Stone: Well, what we wanted to do was take the best bits, if you like, of the previous studies, and try to give ourselves the best chance of finding a clinically meaningful improvement in fatigue in patients with advanced cancer. And I was focusing on advanced cancer, principally because I'm a specialist in palliative medicine. That's the group of patients I'm most working with, whereas a lot of the studies have involved mixed groups of cancer patients or patient's disease-free or on treatment. But we looked at patients who were under the care of palliative care services, with incurable cancer, with a prognosis estimated to be less than a year or around a year.  We wanted to try to get the dose of the medication up to a good level because some of the other studies which have shown benefit have got up to quite high levels of methylphenidate, approximating to about 40 to 60 milligrams of methylphenidate a day or equivalent. And we wanted to give the drug in an individually titrated dose because that would reflect the way it is used in clinical practice. You would adjust the dose like you might with morphine for pain relief. You would expect to adjust the dose of this medication up to get a therapeutic benefit. So we had this titration period where we adjusted the dose of the drug every week. We reviewed whether patients were feeling better, worse, or the same. We asked about side effects. And on the basis of the response to those questions, we either went up with the drug or kept the dose the same, or, if necessary, would come down. The primary endpoint was designed to be fatigue after six weeks of dose titration, plus or minus a window of two weeks, accepting the fact that we might miss a few patients at the six-week mark, for whatever reason. So we had a little window around that. That's what we were looking to do.  Shannon Westin: And why did you choose the six-week time point? Dr. Patrick Stone: Well, there was no obvious time point to choose. One of the biggest positive studies previously was by Lower and colleagues back in 2009, and they had found their maximum benefit at around four weeks, or it took rather four weeks to reach the maximum benefit. So we wanted to give the patients in our trial every chance of demonstrating the benefit, and they'd also escalated the doses in their study up to above 40 milligrams or equivalent. And so we wanted to go up as high as we could, and we didn't feel that if we were adjusting the dose every week, that we could get up to a sufficiently high dose in any shorter time span. So six weeks sort of fitted, allowing us to titrate the dose up to a maximum of 60 milligrams a day, which is where we wanted to get up to. Shannon Westin: And what about a little bit more detail on the population you included, and maybe give us a sense of how well you think that represents your general population affected by fatigue in the setting of advanced cancer? Dr. Patrick Stone: We recruited patients from hospices, so that's inpatient palliative care units in the UK, but also from hospital palliative care services, from oncology outpatient services as well, oncology patients who are under the care of palliative care services, and we also recruited from some community palliative care services. So we had quite a good spread of settings, and all of our patients had advanced incurable cancer under the care of palliative care services. But I would say, I think by the nature of doing this randomized controlled trial, inevitably we ended up with quite a selected population, just because of the inclusion and the exclusion criteria that we had to apply. And the regulators were quite clear about who we shouldn't be putting on the drugs. And I think by the time you've excluded all the potential adverse consequences of using methylphenidate, we probably have ended up with a group of patients who were relatively fit compared to the general run-of-the-mill palliative care population, I would say. So I think that that is a limitation with regards to the generalizability of our result. Shannon Westin: How did you measure fatigue in this study? What was the mechanism for that objective? Dr. Patrick Stone: It's a subjective rating scale. We use a very well-established and well-validated measurement instrument. It's the Functional Assessment of Chronic Illness Therapy FACIT-F which is the fatigue subscale of their anemia subscale, which is a 13-item questionnaire, very well validated and widely used in lots of previous studies. Higher scores represent better quality of life and, therefore, lower levels of fatigue. So that's the scale that we used. Shannon Westin: Got it. So let's get to it. How well did methylphenidate work to impact fatigue compared to placebo? And were there any groups that seemed to have a bigger impact? Dr. Patrick Stone: Well, the bottom line, of course, is that at six weeks, plus or minus two weeks, there was no statistically significant benefit for methylphenidate over placebo. There was a two-point improvement in fatigue scores, but it wasn't statistically significant. And two points on the FACIT-F did not reach our predetermined five-point difference that we regarded as representing a minimally clinically important difference. We looked at lots of secondary fatigue endpoints. We measured fatigue every week over the whole course of the study. And actually, at weeks 2, 3, 4, 5, and 6, there was indeed a statistically, nominally statistically significant difference in fatigue scores. But I really would not want anybody to read anything over much into that finding because it was not a pre-stated hypothesis of our study. It wasn't a pre-stated endpoint, it was a secondary outcome. And moreover, even if this was regarded as a statistically significant finding, and as I say, it was only nominally statistically significant finding, the magnitude of the change was still not sufficiently large that I think it would want to influence your clinical decision making. With other groups just to say, we did look specifically at whether patients with the most severe fatigue would experience benefit over and above other patients, because in a previous study, that looked at modafinil, an agent that promotes vigilance, although the overall finding was neutral in a subgroup of patients with the most severe fatigue, modafinil seemed to work. So we thought we better check in this study whether patients with the most severe fatigue had a differential benefit. But we found no such effect. We found no difference in patients who were on or off treatment or indeed among the patients who scored highest with the depression subscale on the hospital anxiety and depression scale. None of these subgroups showed any benefit over placebo. Shannon Westin: How did patients tolerate methylphenidate? Was it tolerable? Dr. Patrick Stone: That was the thing I think that I was most relieved about. I am a cautious and anxious investigator, and the last thing I wanted to do was to put palliative care patients at risk by giving them a drug which might cause some harm. So I was very relieved when we analyzed the results to confirm that methylphenidate was very well tolerated. There was no real pattern of evidence for any increase in adverse effects over placebo. In fact, when we looked at just people who self-reported severe adverse effects, we found a higher rate in the placebo group than in the methylphenidate group in fact. And in terms of serious adverse events, there were 25 serious adverse events in both groups, so there was, again, no pattern that suggested methylphenidate was causing harm. So, yes, it was well tolerated, but did not result in a clinically important improvement in fatigue. Shannon Westin: Were you surprised by the results?  Dr. Patrick Stone: I honestly went into this with an open mind. I didn't come in with a real fixed agenda that I want to prove that this thing works. In fact, although methylphenidate was being used by some of my colleagues around the country and I know it's used by some colleagues internationally, personally I was not using it because I didn't feel the evidence was strong enough to justify using it. So I was waiting for the results of my own trial before making my decision. And I don't plan now to be using it on the basis of the results of the study. Shannon Westin: Sounds pretty definitive. It's always frustrating, and I know our patients, when we tell them to exercise when they're exhausted, they're like, “Are you kidding me?” Right? So it would be wonderful if there is like the perfect pill that we can give them. It's certainly disappointing. What do you think we should be exploring next for the resolution of fatigue in this patient population?  Dr. Patrick Stone: Well, I think one thing. Going back to your very first question to me about defining fatigue, I think one problem is we don't really have a mechanistic understanding of what we're talking about here necessarily with cancer related fatigue. And it's a bit of an umbrella term, I suspect, for a lot of different things, and may have a common endpoint in terms of the symptom. But maybe if we could better define, if you like, for want of a better word, the phenotype of fatigue, it may be that we could actually target a treatment in certain subgroups of patients that may be of more benefit. So maybe some greater basic science pinpointing what is causing fatigue, so that we can design the treatments, rather than just try repurposing existing drugs on the off chance that they work. And the other thing is okay, maybe we can't pinpoint a particular cause, we think it's multi factorial. If we think it's multifactorial, then perhaps we ought to be using a multimodal treatment approach and maybe it's actually exercise, psychological therapies, and diet, plus or minus a drug, and that's the approach if we can't pinpoint a specific cause. Shannon Westin: I love the idea of incorporating the  translational work to really try to understand the etiology better and then use something more targeted. It's that version of precision medicine but for palliative care as well. I really like that.   Well, this has been awesome. Thank you so much, Dr. Stone. I think that your insight is so much appreciated, and thank you for putting together this definitive work to help us treat our patients better every day. I really appreciate the time you took.  Dr. Patrick Stone: Thank you very much. Shannon Westin: You're so welcome.  And thank you to our listeners. This has been methylphenidate versus placebo for treating fatigue in people with advanced cancer, randomized, double-blind, multicenter, placebo-controlled clinical trial. And again, this is a dual publication in the JCO as well as a presentation at the European Association of Palliative Care Congress on 5/17/24. And we are so thrilled that you could join JCO After Hours and we hope you will check out our other offerings wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

JCO PO author Dr. Jun Gong shares insights into his JCO PO articles, “Phase II Study of Erdafitinib in Patients with Tumors with FGFR Amplifications: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K1" and “Phase II Study of Erdafitinib in Patients with Tumors with FGFR Mutations or Fusions: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K2”. Host Dr. Rafeh Naqash and Dr. Gong discuss the limited activity of FGFR inhibition in solid tumors with FGFR amplifications and mutations or fusions in this NCI-MATCH phase II trial. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the Stevenson Cancer Center at the University of Oklahoma.  Today, we are excited to be joined by Dr. Jun Gong, Associate Professor in the Division of Medical Oncology at Cedars-Sinai Medical Center and lead author of the JCO Precision Oncology article entitled "Phase II Study of Erdafitinib in Patients with Tumors Harboring FGFR Amplifications: Results from the NCI-MATCH ECOG-ACRIN Trial EAY131 Subprotocol K1" and "Phase II Study of Erdafitinib in Patients with Tumors with FGFR Mutations or Fusions: Results from the NCI-MATCH ECOG-ACRIN Trial EAY131 Subprotocol K2."   Our guest's disclosures will be linked in the transcript.   Dr. Gong, welcome to our podcast and thank you for joining us.  Dr. Jun Gong: Thank you, Dr. Naqash and JCO Precision Oncology for having me. Dr. Rafeh Naqash: We are excited to be discussing some interesting aspects that you have led and published on from the NCI-MATCH trial. We were trying to understand from a background perspective, since this master protocol has been going on for quite some time, could you give us a little bit of background for the sake of our listeners on what the NCI-MATCH is and what were the specific objectives for these two subprotocols?  Dr. Jun Gong: Yes, of course, Dr. Naqash. So, as you may all know, the importance of targeted therapies in the current era of precision oncology. And on that backdrop, the NCI-MATCH was a national multicenter study designed essentially to look for signals of efficacy across various solid tumor and hematologic malignancy types, with a focus on specific mutations. The master protocol is unique in that there are several arms to the trial, each targeting a specific potential targetable alteration using available agents in cancer today. Dr. Rafeh Naqash: Excellent. Thank you for that background. I know this master protocol has been going on for quite some time with different subprotocols. I believe some of them are immunotherapy-based. Also, you've led two important subprotocols, which are the FGFR amplification and the FGFR mutation or fusion. There are some differences, from what I gather, in responses for the fusions versus the amplifications or mutations versus the amplifications. Could you first delve into the first paper of the fusions, and describe what were the tumor types? As you mentioned in the paper, some tumors were excluded. What was the reason for the exclusion of some of those tumor types? Why did you want to study the fusions and mutations versus the amplifications separately? What was the background for that? Could you highlight some of those points for us? Dr. Jun Gong: Firstly, as a kind of a more background, FGFR has been a recognizable target for a couple of tumor types. And if you look at the broad landscape of FGFR alterations, they occur in about 5%-10% of cancers, with the majority being FGFR amplifications actually, and mutations and rearrangements following second and third respectively in most commonly identified alterations. With that being said, FGFR mutations and rearrangements have already been established in a couple of tumor types. Actually, the first FDA approval for an oral FGFR inhibitor was erdafitinib, which was the agent used in both of these back-to-back trials. However, erdafitinib was first approved in urothelial carcinoma, and since then, there has been an explosion in oral FGFR inhibitors targeting fusions and mutations in other cancer types, such as cholangiocarcinoma.   More recently, there was even an FDA approval in a myeloid malignancy as well. So, we used erdafitinib, being that it was the first FDA-approved, orally available agent to target this alteration. We conducted the two back-to-back studies in recognition that although rearrangements and mutations have already been established in certain tumor types, we were more interested in looking at the more common FGFR alteration, that being amplifications. However, the efficacy in that was a little unknown, and so these two separate subprotocols were developed: K2, which was to look at FGFR mutations and fusions in tumor types, excluding urothelial carcinoma, to look if there was a signal of efficacy beyond currently FDA-approved indications, and amplification as a separate cohort. Dr. Rafeh Naqash: That's a very good explanation of why you concentrated on the tumor types in these protocols.  Now, going back to subprotocol K1, could you tell us what were some of the tumor types that you did include, and what was the sample size, and what was the hypothesis for the sample size as a meaningful level of activity that you wanted to see and would have potentially led to a bigger, broader trial? Dr. Jun Gong: So, subprotocol K1 was the arm investigating erdafitinib in those with FGFR amplifications, and these were predefined on the NCI-MATCH protocol, looking at FGFR 1, 2, 3, and 4 amplifications essentially. These were allowed to have local testing through a local CLIA-certified assay, but then they needed to be confirmed on a central assay, which is the NCI-MATCH Oncomine assay. These statistics are uniform for the NCI-MATCH trials, and the goal was at least 31 patients, with the hypothesis that if the response rate was 16% or more, this was considered a signal of activity. However, there was an additional protocol specific requirement in that if the sample size was fewer than 31 patients, then the primary efficacy population would be assessed against a null hypothesis overall response rate of 5%. Meaning that if there were less than 31 subjects, an overall response rate of greater than 5% would be defined as positive. Again, the NCI-MATCH was uniform. Secondary objectives included progression-free survival, overall survival, and safety and toxicity. With that being said, K1 originally began accrual. The NCI-MATCH actually launched in 2015, but in the subprotocol K1, 35 patients were initially enrolled in the study. If you go down the eligibility criteria, however, a lot of these patients dropped out due to a lack of central tumor confirmation and various reasons. Ultimately, 18 patients were included in the pre-specified primary efficacy cohort. Dr. Rafeh Naqash: Thank you. I did see for subprotocol K1, you mostly had stable disease in a couple of patients, no responses, and I think one individual with breast cancer had a prolonged stable disease.   Now, from an FGFR amplification standpoint, did you or were you able to correlate - again, this is not objective responses, it's not a partial response or a complete response - was there any correlation from the level of amplification to the duration of stable disease?  Dr. Jun Gong: That's actually the core of our discussion about why K1, despite a variety basket of solid tumor types, somewhere, preclinical data had suggested FGFR amplifications could be targeted, that K1 was ultimately a negative trial with a 0% response rate. We dive in that although we included as an eligibility criteria a copy number variation of seven as the threshold for amplification, we realized that if you look at some of the literature out there, that even in the FGFR 1 and 2 amplification cohorts, where these are the more common cohorts of amplified tumor types that have been targeted, you really needed a high level of amplification, more than 99% of tumor cells being amplified in the previous studies, to actually generate a response.  The thought was that we assumed that FGFR amplification would lead to protein expression and dependence on FGFR signaling, providing sensitivity to FGFR inhibition. However, we realized that there is a certain degree where a high level of amplification needs to happen, and it may not be for all FGFR amplifications. We looked into the literature that FGFR 1 and 2 were the more commonly studied FGFR amplifications. FGFR 1, if you actually look at the amplicon structure, it tends to amplify a lot of other genes because it's such a huge amplicon structure. But FGFR 2 is shorter and centered on just FGFR 2 with a few other genes co-amplified. So, actually in the literature, they've already been seeing that maybe FGFR 2 amplification tumors are more readily targetable based on the robustness of evidence, rather than FGFR 1. But across all of these, the higher the level of amplification, seems the more targetable. Dr. Rafeh Naqash: Those are interesting discussions around protein expression on the tumor that could imply therapeutic vulnerability. So I've always thought about it, whether trials like NCI-MATCH trials or ASCO TAPUR, for example, would be perhaps more informative if, on a secondary analysis standpoint, proteomics is something that could be done on the tumor tissue, because similar to NCI-MATCH, ASCO TAPUR has other sub protocols where some of these mutations or amplifications don't necessarily result in antitumor responses. But I think from a biology standpoint, as you mentioned, a certain amplification might correspond to RNA expression and that might correspond to protein expression, which is downstream. So looking at that would be something interesting. Have you planned for something like that on these tumor specimens? If you have biobanked any of those specimens. Dr. Jun Gong: I think that's a great future direction. And I know you, Dr. Naqash, being involved in so many cooperative trials, I think it is possible, but it really depends on good trial planning from the onset. When designing such massive trials like this, I think the more important thing is if your trials are negative, but they are informative for the field to go back and have these postdoc available biobanks that you said. And I think having it integrated firstly, is way more efficient than to have kind of an amendment kind of going through halfway or when the trial is started. That could be a little bit more logistically difficult.  Dr. Rafeh Naqash: I completely agree. And you mentioned corporate groups, I think we've been discussing, and I'm pretty sure you have also, there's a lot to be learned from clinical trials that are negative. We often, in the academic or non-academic setting, end up not publishing some of those negative results, pharma or corporate group based studies. And I think the resources, the specimens, and the negative results could correlate to some other novel findings if some of those exploratory analyses are done in the appropriate manner.   Now, going to the drug itself or the erdafitinib here, it's a pan-FGFR inhibitor. Is that something that you think is a limitation in the drug development space? I do early phase trials, and I'm pretty sure you do a lot of these basket early phase trials. Is that something that you feel is a limitation when you have a drug that targets different mutations or different protein changes of the same gene or different amplifications? Could that be a reason why something like this doesn't necessarily work because it doesn't have as much specificity against the isoform as one might need to inhibit the downstream kinase activation?  Dr. Jun Gong: That is also a great point. The NCI-MATCH sub protocol K1 and K2 used erdafitinib, which was the first FDA-approved FGFR inhibitor. But as many of the listeners and yourself may know, there have been newer iterations in next-generation development of the FGFR inhibitors. And it's very fascinating, the tyrosine kinase inhibitors, with each iteration, you seem to have a little more potency and the ability to bypass some of the resistance mutations, almost paralleling the lung cancer space, where we kind of follow that, and they've been kind of the pioneers in that space. And to your point, yes, we consider– the NCI-MATCH was developed nearly a decade ago, and the available agents at that time, would it have changed the findings if we used a kind of a newer generation or more potent FGFR inhibitor? It's possible, I think, especially in the K1 cohort with the amplifications. We even suggested in the discussion of the paper future directions, is that one way to kind of bypass the amplification issue is to use more potent and specific FGFR inhibitors. And so I think it's very possible that you highlight this point.  Dr. Rafeh Naqash: And for the sake of our listeners, Jun, especially trainees, could you highlight what are currently some of the FDA-approved FGFR inhibitors, and what tumor types are they currently approved in?  Dr. Jun Gong: The first one, as we have hinted, was in treatment of refractory, essentially urothelial carcinoma with FGFR mutations and rearrangements, mainly 2 and 3. And this is where oral erdafitinib was approved. And it's interesting, I kind of teach my fellows and our health staff that erdafitinib is interesting in that its FDA label insert requires a starting dose of about 8 milligrams daily, and it's a 28-day cycle. But during the first 14 days, we're really looking at the serum phosphate levels. If they are within a certain level, if they are within 5.5 to 7, for example, you continue the current dose. But if they are less than 5.5, the FDA label actually mandates that you increase it to 9 milligrams oral daily, continuously. This is biologically logical to me. FGFR is located to the renal tubules, and so this is a major phosphate kind of metabolism pathway here. And so you're using that as a surrogate, essentially, if the right dosing is achieved. And so that's unique.  And then the subsequent kind of FGFR inhibitors that came about, you had a couple in cholangiocarcinoma, where, unlike urothelial carcinoma, where it's about 30% of the time, you'll find the FGFR alterations of target. It's about half of that 15% in cholangiocarcinoma, and it's mainly intrahepatic cholangiocarcinoma in that sense. And here you have pemigatinib, which is one of the FGFR inhibitors approved for cholangiocarcinoma. And then you also had infragatinib, which is approved. But however, infigratinib eventually had their FDA label culled. It was withdrawn by the company, I think it was in 2022. And then more recently, you had even a more potent FGFR inhibitor in cholangio approved and futibatinib. It's interesting that with these more later generations of FGFR inhibitors, they do show a correlation with phosphate levels, but they don't have that specific kind of dosing early on in the first cycle, like erdafitinib. And so it's interesting to see that with the later generations, you're seeing more potency as well. Dr. Rafeh Naqash: Thank you for that overview, which I'm sure most of the trainees appreciate since this is an up and coming field in the space of precision medicine, especially FGFR. From a side-effect profile standpoint, you mentioned phosphate issues. Do you think that is a drug class effect here, or is that an FGFR receptor subtype effect, depending on which FGFR receptor, 1 or 2 or 3, that is being targeted?  Dr. Jun Gong: I do think this is a class effect that you'll see across a lot of the trials where phosphorus elevations or decreases are going to be probably your most common treatment-related adverse event. And I actually emphasize this is probably one of the most trickier side effects of this class, where we're almost having to have to monitor the phosphorus levels pretty routinely, pretty closely. And you also have other class effects on the nails. There's some rare retinal ocular toxicities that's unique to the FGFR class as well. And so it's a very exciting class of compounds, but it does require some close monitoring of some unique class effects as you've hinted. Dr. Rafeh Naqash: Based on the results from your K1 sub protocol, are FGFR inhibitors still the approach within, let's say, within cholangio or urothelial with FGFR amplifications? Is that still something that has been established and seen from a clinical response standpoint? Dr. Jun Gong: The FDA approvals are really for mutations and fusions. So this K1 sub protocol, essentially, I think provides one answer that we've been all wondering about for the longest time, “Hey, could amplifications be targeted as well?” Unfortunately, we didn't include urothelial carcinomas in this study because of the FDA approval. But from a kind of a basket solid tumor perspective, I think this really dampens the enthusiasm. As of right now, it really is fusions and mutations that are targetable. Amplifications need further investigation before becoming established in solid tumors. Dr. Rafeh Naqash: Going to the discussion with the second K2 protocol, which is mutations and fusions, can you highlight again which tumor types there where you saw some clinical outcomes that you saw and any unique insights on certain mutations or protein changes that were a little more relevant than some others?  Dr. Jun Gong: Sure. So this is the parallel study to K1, in that now we are looking at fusions and mutations of FGFR1, 2, 3, and 4. And essentially, we, again, excluded those with urothelial carcinoma, given the FDA approval for erdafitinib in this trial. The trial actually opened then the FDA approvals for the FGFR inhibitors for cholangiocarcinoma happened. So this trial didn't really exclude those with FGFR mutated or rearranged cholangiocarcinoma as well. If you look at the breakdown of the cohort in K2, you saw a good mix of breast cancers or a couple of gynecologic malignancies. There were a couple of head and neck cancers. There were several brain tumors as well. There was one lung cancer. There were four noted intrahepatic cholangiocarcinomas. Again, we could not exclude those due to the fact that the trial had opened and was accruing when the FGFR inhibitors approved for cholangiocarcinoma happened. Similar design, with a phase II, single-arm, open-label of erdafitinib, and again, the same statistical design was implemented in that if it's higher than 31 patients, 16% overall response rate was a primary endpoint goal. If it was less than that, it was against the 5% overall response rate.   And here in K2, 35 patients were enrolled and 25 patients were ultimately included in the primary efficacy analysis. So because it was fewer than 31 in the primary efficacy cohort, it followed the NCI-MATCH to be specified with a primary endpoint goal of 5% or higher. And here, in a heavily pre-treated cohort of more than 50% of subjects who have received prior than 3 or higher lines of therapy, overall response rate essentially confirmed was 16% with the p value of 0.034, which met the positivity cutoff of 5%. However, an additional seven patients experienced stable disease as best confirmed response. And it's important to note that four of these were grade IV glioblastomas with prolonged progression-free survival. So ultimately, this trial was positive in reading the endpoint that outside of urothelial carcinoma, could FGFR inhibition be pursued in other tumor types that had FGFR rearrangements or fusions? Dr. Rafeh Naqash: You mentioned glioblastoma, which is an area of huge unmet need. Do you think a trial like this as an upfront approach in glioblastoma, perhaps maybe after Temodar, could be a more meaningful way using the strongest, more precise therapy earlier on when there are certain mechanisms that inhibition of which would result in anti-tumor responses? Do you think doing this earlier on rather than second, third, fourth line would be more intriguing in some ways?  Dr. Jun Gong: I think you've hit upon several key points there. Firstly, just a high unmet need in glioblastomas, in general. And then to us, although it was a stable disease it was quite noticeable that four of these occurred in IDH1 and 2 wild-type brain tumors. We kind of discussed that in the discussion as well. And of these, we actually realized that in the pre-clinical and other published literatures space that for some reason, IDH1 and wild-type tended to have more FGFR alterations, while 0% were found in IDH1 and 2 mutant high grade gliomas. So I think there is something hypothesis generating coming out of this study as well even though there were stable disease. And that you may be selecting for– We may be able to have future studies to select for a specific niche of glioblastomas. And as to your point, Dr. Naqash, I think  if we can have a design trial looking for these specific molecular subsets, I think it's wide open for trials of this nature in the first line, second line, or refractory space. Even piggybacking into cholangiocarcinoma, you see, they're now looking at these in the neoadjuvant and adjuvant space as well. So I think we can identify the subset - it's wide open out there. Dr. Rafeh Naqash: I completely agree. I remember my program director a few years back when immunotherapy was in the metastatic setting, it was very exciting. He gave a talk in which he said "Early, earlier, earliest," and the more early, the better it seems. So I'm guessing that it's probably something similar for precision medicine-based approaches like targeting FGFR perhaps earlier.   So what is next for some of these two studies, or these ideas that have come out of these two studies? Are you trying to develop something subsequently, or is NCI-MATCH looking at it from a certain perspective? Or what would you want to do as a next step, ideally if you had the funding and the pharma support? Dr. Jun Gong: That's the million dollar question. So just from the broad strokes, I think what these two back to back papers and studies comment is that amplifications may not be the more targetable of FGFR subset, but there is avenue for improvement there and further investigation. FGFR fusions and mutations however seem to go along with what we know in some of the FDA approved types now. Now the next step is in the area of precision oncology is could we expand the label indications now to other subtypes with FGFR fusions and mutations. And this is I think following precedent. You and the audience may know that there are a lot of different tumor agnostic approvals now for both immunotherapy and other targeted therapy types. So I think the goal of this study was to provide momentum for, perhaps, advancements into a tumor agnostic indication for FGFR inhibitors.  And we do cite in the K2 manuscript the results of a phase II study that was also published around the time we were writing the study up. It was the phase II RAGNAR study. And that enrolled patients, again, with FGFR fusions and mutations. And that trial was positive, too. That one was a larger study of 217 subjects. We highlight some differences in study populations as to why maybe the difference in responders were detected. Both were positive studies. It was reassuring that the overall survival impulse studies were about the same. And again, I think they don't compete. I rather think they complement each other in providing this body of evidence that  may meet- at one point, the FDA should be approached with this evidence for a tumor agnostic mutation so that more patients with this subset could be benefitting.  Dr. Rafeh Naqash: Excellent. Thank you so much, Jun.  Now, could you tell us briefly what your background is, where you've trained, and your interests, and how you balance clinical research with some of your personal interests?  Dr. Jun Gong: Sure. Thank you for that interest. I did my training in medical school in New York. I went to New York Medical College. And then I did my residency at Cedars-Sinai for medicine. And I went to City of Hope for fellowship where I was trained in GU by Dr. Monty Powell who maybe you folks are familiar with. And my GI training was with Dr. Fakih at City of Hope. And since then I returned back to Cedars-Sinai where I serve as a dual GI/GU focused medical oncologist. I do clinical trials in both and translational science, really focused on targeting tumor metabolism in both as well. My advice to the listeners and trainees and I tell my own fellows this, I think it's very rare now unless you're in phase I to do a dual focus. So I actually emphasized to my trainees that the more focused you can be, the better. Unless you are going into phase I, for example. With that, you can hone in, develop your craft. But then again, I have known several mentors who do multiple tumor types. But I think the more traditional mechanism is to focus as much as you can is my advice for the listeners.  Dr. Rafeh Naqash: Thank you again, Jun, for all those interesting scientific and personal insights. We appreciate you and working with JCO Precision Oncology for both of your manuscripts. This is the first time we have ever invited a lead author for two manuscripts at the same time. It's always good to be the first in something, and I learned a lot and hopefully, our audience would have learned a lot. Dr. Jun Gong: Thank you, Dr. Naqash, for having me. It was a pleasure speaking with you and the crew. Dr. Rafeh Naqash: Thank you.   Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

JCO PO author Dr. Christian Rolfo shares insights into his JCO PO article, “Liquid Biopsy of Lung Cancer Before Pathological Diagnosis Is Associated With Shorter Time to Treatment.” Host Dr. Rafeh Naqash and Dr. Rolfo discuss how early liquid biopsy in aNSCLC in parallel with path dx is associated with shorter time to treatment. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the Stephenson Cancer Center, University of Oklahoma.   Today we are thrilled to be joined by Dr. Christian Rolfo, Associate Director of Clinical Research at the Center of Thoracic Oncology at the Tisch Cancer Institute at Mount Sinai Health System. He is also the lead author of the JCO Precision Oncology article entitled "Liquid Biopsy of Lung Cancer Before Pathological Diagnosis is Associated with Shorter Time to Treatment."  Our guest's disclosures will be linked in the transcript.  Christian, it's great to have you here. Welcome to our podcast and we are excited to learn about some of the interesting results from your study.  Dr. Christian Rolfo: Thank you very much, Rafeh. It's a pleasure to be here and discuss about liquid biopsy. Dr. Rafeh Naqash: You have a very important role in different liquid biopsy consortiums. This is an initiative that you have been leading and spearheading for quite a while, and it's nice to see that it is becoming something of a phenomenon now on a global scale where liquid biopsies are being implemented more and more in earlier stages, especially. For the sake of our audience, which revolves around academic oncologists, community oncologists, trainees, and patient advocates or patients themselves, could you tell us a little bit about the background of what liquid biopsies are? And currently, how do we utilize them in the management of lung cancer or cancers in general? Dr. Christian Rolfo: Liquid biopsy has been gaining importance over the years. We started to talk about liquid biopsy in 2009 when we started to see some correlations with EGFR mutations. In practicality, what we are doing is the most common or most applicable indication is to go for liquid biopsies from the blood, peripheral blood. So we are doing a blood draw and from there, what we are capturing is the DNA or fragments of DNA that are still in circulation. But the liquid biopsy definition is a little bit more broad and we can apply the concept of a minimally invasive approach to different fluids of the body, including pleural effusion, urine, and including CSF that is another indication, there, we are going to be a little bit more invasive than peripheral blood, but it is also an emerging tool that we will have to find specific indicators. In cancer, we started the history of liquid biopsy in advanced disease with the identification of biomarkers, and then from there, we are moving to other scenarios, including, nowadays, monitoring minimal residual disease and early detection. And that is applicable also for other tumors. Dr. Rafeh Naqash: Thank you, Christian, for that summary. Now, as you've rightly pointed out, we have come to implement liquid biopsies more and more, both in the academic setting and the community setting. And this has definitely led to faster turnaround time in some ways compared to tissue. In this study that you have authored with the help of many other collaborators and Foundation Medicine Flatiron Health data, the goal here, from what I understand, was to look at liquid biopsies that were done before, resulted before the pathological diagnosis. Could you tell us a little bit more about the premise of this study, why you thought about this question and how did you try to implement that idea to get to some of the interesting results that you see here? Dr. Christian Rolfo: Yeah, so what we are seeing generally in lung cancer and also in people with other tumors is that patients are having a journey and that they start seeing different doctors until they get a diagnosis. Generally, after the pathological diagnosis, if you don't have an in-house technology that is doing reflex testing, generally, oncologists need to request for testing and that is taking time. So if we are looking for comprehensive days until a patients are able to get a molecular profiling before we start the treatment is sometimes very long. We are talking, in some cases, about months. So, how we can speed the process, that was the main question. We tried to include liquid biopsy in the staging procedures that we generally were doing when we have a clinical diagnosis of lung cancer. It's either images that we are used to do, PET scans, MRIs, and other assessments, we want to include liquid biopsy there before the biopsy. And that's what we did. We were searching for this specific aim using the Flatiron Health Foundation Medicine electronic health records from 280 centers across the United States. We included a big number of patients in this analysis, more than 1000 patients for the first analysis. Dr. Rafeh Naqash: That's phenomenal that you had real-world data from 200+ centers across the US. Of course, when you have patients on a clinical trial versus patients in the real-world, we all know that there are differences in terms of approaching, overseeing, and managing these individuals. So this data set is an extension of what we could see in the real-world setting.  Could you tell us a little bit about the number of patients that you eventually identified that had liquid biopsies done before pathological diagnosis? I think you have different cohorts here, a group that was before and a group that was after, and you compared several important metrics treatment-wise from what I see. Could you highlight those for our listeners? Dr. Christian Rolfo: Yeah. So we were looking for patients who had a liquid biopsy CGP, comprehensive genomic profiling, ordered within 30 days pre diagnosis and post diagnosis. We focused on 5.2% of patients, which corresponded to 56 patients who ordered a liquid biopsy before diagnosis. The median time was eight days between the order and diagnosis and the range was between 1 to 28 days. And that was compared with 1020 patients who ordered a liquid biopsy after diagnosis. It is important to be clear that both cohorts had a similar stage and ctDNA tumor fraction. We can explain later what tumor fraction is, because it was done in addition with a paper that we just published last week. Liquid biopsy patients were consulted to have this CGP median one day after diagnosis, versus 25 days after for patients who had their diagnosis and their liquid biopsy later on. So, from these patients, the majority of the patients, 43% of LBx-Dx were positive for an National Comprehensive Cancer Network driver, and 32% had ctDNA TF >1% but were driver negative, so that is what we call presumed true negative. From here, maybe I can explain what is tumor fraction and, in general, how we use it.  Dr. Rafeh Naqash: I think that would be great for our listeners. We see this often in more and more liquid biopsy results nowadays, and I've tried to explain it to some of my fellows also. So, it would be nice if you explain for the sake of our listeners what tumor fraction is, what does it mean clinically, can you use it in a certain way, what biological relevance does it have. Dr. Christian Rolfo: So we are analyzing another paper that came out this week in cancer research on the concept of tumor fraction and it's a new definition. So what we are doing with tumor fraction is an algorithmic calculation or mathematical calculation on the amount of DNA of the cells also taking into consideration the math, the quantity of DNA present in the sample. So we are going very low in the sensitivity of this analysis and capturing there the real informative results of the ctDNA of the liquid biopsy. So in practicality, when you see a report that says the threshold that was established in this study was more than 1% or less than 1%, so patients who have a tumor fraction of more than 1%, we can really consider this liquid biopsy informative. And also in this next publication, we compared with tissue. In patients with a tumor fraction of more than 1%, were completely 100% correspondent with what we found in the reflected tumor tissue, the NGS. But what happened in patients with a tumor fraction of less than 1%, we can say that these patients are not informative. So we need to wait for the tissue biopsy result to come in because we were able to recuperate several patients that the liquid biopsy was negative with the tissue biopsy positive. This is an important concept because we are distinguishing not only the informativeness of liquid biopsy, but also we can distinguish between patients who are considered not shedder based on what is considered a shedder. And that was a problem until this kind of introduction was a problem before with the technology because the technology wasn't very fast to distinguish the sensitivity or high sensitivity. Now, the sensitivity is no longer a problem. Maybe, there is really value of information in what we have in liquid biopsy, and using this mathematical help, we can get these patients distinguished and help more people. So that would be really interesting. Dr. Rafeh Naqash: You touched on a few important concepts here, and one question I have, and I think there's no better person to answer this question. You're the right person to answer this question for our audience. Do you think when you have a liquid biopsy tumor fraction of less than 1%, and you have a tissue that is pending with an NGS, where tissue NGS has not resulted yet, but liquid biopsy results come in and tumor fraction is less than 1%. But let's say you have a non-smoker with a typical driver mutation and clinical characteristic positive individual in the clinic, and the tumor fraction is less than 1%. How much can you trust that liquid biopsy when the tumor fraction is less than 1%. Because do you think some of these driver mutations, like you mentioned, could be low shedders and you could miss a potentially actionable mutation on a liquid biopsy if the tumor fraction is less than 1%? Is that something that you've looked at or correlated or understood what would be the clinical meaning of that? Dr. Christian Rolfo: Absolutely. So there are two concepts here. A liquid biopsy could be non-informative, and that is what we saw in this paper. So you have patients that have a liquid biopsy negative, and that we see in the clinic, a liquid biopsy negative tissue biopsy positive. That could be because the liquid biopsy is not informative, but it could be also that the patient, for some biological reason, and we don't have an answer about that, they are not shedding the ctDNA in the bloodstream, ctDNA that we can capture. What we saw in different studies, including one of the papers that we presented also in ASCO last year with a MET amplification and  METex14, for example. In the study that was the VISION study using tepotinib, you see that patients who have a liquid biopsy negative are doing a better outcome compared to a patient who have a liquid biopsy positive. So I believe that we still have patients who are not shedders for some biological reason, that could be put in together with patients who have more bone metastasis than organ metastasis, or patients who have more in location, for example in the brain. These patients are difficult to capture in ctDNA due to some biological reasons. But also you have patients who are non-shedders. For the technicality of the parts of this tumor fraction analysis, it is really important to distinguish that and we will hear more and more. So, as you say, we have already some reports in some companies like Foundation are doing, but some others like to incorporate this tumor fraction. And several in-house technologies allow also to have this kind of mathematical calculation. So that is what we are facing now, to really understand better the power of liquid biopsy. Dr. Rafeh Naqash: Now, some of the other things that your project or paper that you published with JCO PO does not necessarily cover is the payer aspect of this. Now, we've had more and more discussions, obviously, and more and more information has been highlighted with the payers that this is an important test and needs to be reimbursed, even though if you do tissue NGS, liquid biopsies are complementary to tissue. So taking both together is probably a better view of the overall tumor or the mutational status of the tumor. But one of the biggest holes in this whole process, and this is my personal experience, I want to know what you think, is that we can't order these tests when the patient is admitted to the hospital, and 50% or more patients end up getting diagnosed in the hospital during an inpatient stay. The average hospitalization for someone with lung cancer is five to seven days on average, and then another one to two weeks to get into the clinic to see an oncologist. So what would your thoughts be there? How can we improve things there in terms of, can we try to do something different so that the payers agree that, yes, you can send a liquid biopsy when the patient is admitted, because there's that 14-day Medicare rule? Has your team, or have you in particular, tried to navigate some of those issues, and what are your thoughts on how we can try to improve some of those conversations?  Dr. Christian Rolfo: Yeah, that's a really good question, because here we are talking about inequities in access to the technology and the results and it's crucial. Several of our patients, specifically in lung cancer, they are coming to our consultations or to the emergency with a very bad situation so they need to be admitted immediately. And as you say, they can be there for one month waiting for results or for recovery or for stabilization of their general condition before we can start. Several of these patients will have some biomarkers that we can target with treatment. So in other words, I will say that this is a stupid rule because we cannot have in 2024 these kinds of limitations to access to treatment when we have on one side, the FDA is doing a terrific job to get drugs approved in a very short time, and on the other side we have payers who are not understanding the concept of molecular or precision oncology.  So what we are trying to do in these cases, to be honest, is to navigate with the vendors and try to get this done. I generally send the samples because I consider that personally that it is a very crucial information. And in several cases, we have started targeted therapies while the patient is still admitted. So I think it's something that we need to put in a better effort, because already we are not doing enough for our patients, if you look at the data of the MYLUNG Consortium that was presented in ASCO some years ago on the testing performance in the community practice, 50% of the patients with lung cancer were tested there were only some in minority groups, African Americans, 39%. So I think we need to do better in education, but also from the payer side, it's really crucial that they understand this concept.  Advocacy groups have a lot of say here. They are also doing an important job on that. We are now launching with ISLC, ISLB, Lung Cancer Europe, and Longevity in a survey that is to make also the patients aware what is the importance of molecular profiling, tissue or liquid biopsy, it's very important that you get something to treat the patient and select the right treatment. And even to say, there'll be a whole other work in your case so that is really important.  Dr. Rafeh Naqash: Absolutely, I completely agree. We have made a lot of strides, but there is still a lot of room for improvement in terms of equity, access, and reimbursement.   Now, one of the things that I noticed in your paper, and you could tell me a little bit more about this, when you looked at the pre-diagnosed liquid biopsies, meaning before tissue diagnosis, 56 individuals there suspected to have lung cancer, community-based testing was identified in 53 individuals versus academic being three. This is very encouraging when you see something like this happening in the community. Did you look at that? Did you try to understand why or how that was the case? Because in a general community setting, I would think that community practices have a more complicated system of reimbursement because they are dependent on direct reimbursement, whereas in bigger academic centers, there's some leeway here and there. So did you try to understand how they were able to order this before tissue, could you give us some insights there? Dr. Christian Rolfo: Yes, I think it was not big in this specific question, but it's a very interesting topic. Because we, generally, in academia, will believe that we are doing the things in advance and we are more, compared with the practical and the general practitioners or the general colleagues in the community practice, we have more resources. But sometimes, and it's true, obviously, we have more resources in terms of research and more opportunities in terms of clinical trials in some cases. But I think we understood with this minimal example that there is an important interest among general oncologists in the community practice to get this done. And this is something we need to emphasize, because sometimes we are putting the blame on our colleagues that are outside the academic centers on this lack of testing, and it's not really true sometimes. So this is a good point to start to work together and try to get more things done for our patients and try to get also the reality.   I think one of the problems we will have in the future that we can face right now is the lack of new figures in this molecular profiling. I am referring, for example, molecular nurses or personnel that is working and helping to get this done. We need to have more people that are working in this education for the patients in the access to treatment and access to the technology, but also to navigate better these problems with payers that sometimes in some patients that seem to be overwhelming. Because when you talk about the $100 that could be extra, it's hard for some patients. So we need to be very conscious about that. So having a new figure in the hospitals and the community practices could help to test more patients.  Dr. Rafeh Naqash: And I think at the end of the day, the payers or the reimbursement mechanisms need to understand that genomics is part of the diagnosis these days. It's not ancillary, it's not an addition, but it is part of the diagnosis. I'm pretty sure you have had similar instances where you get a confusing pathology result but then a genomic result points in a certain direction. You treat the patient in that direction, and then you see the patient benefiting in the tumor shrinking, which suggests that genomics is complementary to the path diagnosis. It's not necessarily a surrogate.You can't replace pathological diagnosis, but you can use genomics as a complementary diagnosis as part of the whole paradigm of treating the entire patient. So I think we definitely need more and more conversations like the ones that you're having or your liquid biopsy consortium is having and then more education from the FDA. Of course, more legislation, more advocacy.   Going back to the paper, I did notice another interesting thing, which is, again, very encouraging is patients with lung cancer with a performance status of 2 or about had a decent proportion of testing done. Which, again, points out to the important concept of avoiding these preconceived biases that, “Hey. If somebody is not a great performance status, testing and finding something in that individual could potentially change a lot for the individual.” Do you have any personal examples from patients you have treated or seen in the clinic for our listeners where you identified something and maybe they were not doing as great initially, and then you identified something in liquid biopsy, treated them and it changed the entire course of their illness and whole trajectory for them? Dr. Christian Rolfo: Being working in lung cancer for years, everyone has this kind of patient that we see that their performance state was very bad. Obviously, as a clinician, we need to identify why the performance is bad and is deteriorating. So we see some patients in lung cancer, some of them, they can have a very important comorbidity packet that is associated with lung cancer. So in patients who have a deterioration for lung cancer, and we find a driver help in some patients that were doing a kind of a weakness, and that is something that we see in several patients, specifically in patients living with leptomeningeal disease. In some cases, when we start to do drivers that have a big impact in the crossing the blood-brain barrier, I have a good response.  I have patients that had an important recovery. So this is something we need to distinguish and sometimes when the patients seem very bad they say, “Okay, we go directly to targeted care or supportive care.” We try to test these patients as well because these patients have an important impact on the quality of life that we are treating. We will not be able to cure patients in this setting with targeted therapies, but we can certainly make an impact in the quality of life and also in our form of survival.  Dr. Rafeh Naqash: One of the other questions that comes up often when you're in a multi display team, since most cancers these days are on the multi display decision making opportunities to treat the patient the best possible way is: Who orders the liquid biopsy? I remember from my fellowship several years back, our program director Paul Walker, who is, again, an amazing lung cancer thoracic oncologist, he had advocated that our endoscopic suite folks, the bronchoscopist, whether it was pulmonary, interventional pulmonology or CT surgeons, whoever did the bronchoscopy for the first time in the patient that they would send it whenever they see the patient from the bronchs. This was around six, seven years back. And I think Paul was a little ahead of his time and I didn't necessarily understand the implications that this would have.  And now, as I progress in my own little career, I can see the vision that he had, which I think a lot of other sectors have tried to do, and I'm pretty sure you have a certain process, too. Is that something we should try to talk more and more about? Because, of course, when you do the bronch, then you get a diagnosis and the patient sees the oncologist. This whole process takes anywhere from two to three weeks, maybe even more for smaller centers. So, is that something that you're doing or you see that you're having more conversations that, “Hey. Whoever sees the patient first should be able to order the liquid biopsy.” It's not necessarily the medical oncologists, it doesn't mean I love to order sequencing results or  sequential tests, but it could cause a delay in the patient care. So, could you tell us a little bit more of that?  Dr. Christian Rolfo: So it's really important, this part, because we need to create in our institution flows that will have this very well organized. And ideally, in the ideal world will be that we have reflex tests coming from the pathologist, but it's not happened in several places, because we don't have our NGS at home, or we are sending to vendors, and sometimes we are not sending to them. So that is one of the aspects.  The second aspect, and that I think is still a problem in some treatment, is that we still have 24:30 cytologists coming out in place of covariances. And in our institution, we were working very hard with our interventional pulmonologists and interventional radiologists to get this quality of tissue appropriate, and we have a very good rate of success and issues in a very minimal quantity of patients. Obviously, some patients are very difficult to get samples, and we need to refer still with cytology. But in some cases, where our surgeons or our pulmonologists have sent in samples for NGS, and I think this is we are coordinating. “I will see this patient next week. Can you please start to order?” And here, our nurse practitioner, our nurses in the team are also playing an important role for the reason I insist in the idea to have new figures that could be these molecular navigators we can call, or molecular nurses that helping coordinate this, not only the coordination, but also in the discussion of molecular tumor boards. We did an experience like that some years ago at Maryland University, and actually it was a very important opportunity to decrease the number of quantities of issues and get the results done very quickly. So I think it's important to come to have conversations with our colleagues, pulmonologists, radiation radiologists, interventional radiologists, pulmonologists and pathologists to get this done very quickly.  Dr. Rafeh Naqash: I love the idea of molecular navigators. And of course, everybody in the current day and age, we're having staffing issues, so getting a molecular navigator would be awesome, but I'm not necessarily sure how everybody would be able to implement it. But I think in the bigger picture, whether it's molecular navigators or multi disciplinary nurse navigators in general, liaisons in general, I think we all can do a better job in trying to coordinate some of these testings. And we have tried to do that through our thoracic oncology group and of course, there's a lot of progress that needs to be made, one step at a time. Dr. Christian Rolfo: If somebody is interested in this topic on the International Society of Liquid Biopsy, we started with a project that is called a Certificate for Advanced Studies in Precision Oncology. So we are educating the healthcare team for all this process and trying to get practical insights to have this career later. Because I think it will be something that's interesting for nurses or pharmacists to get this kind of career later or get another approach in their career.  Dr. Rafeh Naqash: Thank you so much, Christian.  Now, going to not the scientific part, which I think is the most interesting part of this conversation is to talk about you and your personal journey. Could you tell us a little bit about where you started, what your career has been like, how did you progress? Because you have a lot of junior faculty that listen to this and it's always good to take inspiration from people like yourself.  Dr. Christian Rolfo: Thank you. As you can hear my accent, it's not from here. So I was born in Argentina, I did my medical degree there. And then I had the opportunity to get a scholarship in Italy. I went to Italy and I stayed there for seven years. I did my fellowship there again, and I started to know there precision oncologists. My journey started in sarcoma. And actually I was working in the group of Dr. Casali's group, a very well known sarcoma expert. And at that time we were running phase I trials for imatinib, I remember, known as GIST. I saw this kind of response and awakening of patients that were really in very bad condition, with only through this imatinib. Very little to treat that disease at that moment, a median overall survival of two months. So I started to be interested in that. Then I moved from there to Spain and met Dr. Rafael Rossell, who was my mentor. In Italy, I have also a mentor in breast cancer, Dr. Luca Gianni, one of the pioneers in breast cancer treatment. So knowing all these people and having the support of them, was really crucial.  So I think this is the first advice for junior faculty: try to choose your mentor, even if your mentor is not in your center. Like the case, for example, Rafael Rossell was not in my hospital, but he was my mentor. So having this kind of discussion, I did my PhD in EGFR mutation, at that time was the fashion, not immunotherapy, of the moment. And then from there, after eight years in Spain, I moved to Belgium. I have a short period of completing my training at MD Anderson and I went to Belgium to Antwerp University and that was the opportunity to become the Director of the phase I program in the Early Clinical Trials Unit. It was really exciting to see growing a unit, and now they continue  at the center in Belgium. My colleagues that stayed there, they are doing a terrific job of continuing this idea. And from there I went to Baltimore, three years working at Maryland University being the Director of Thoracic Oncology and early clinical trials as well. Three years after, I moved to New York, and here doing this journey in clinical research, also being the Director of Clinical Research at the Center for Thoracic Oncology.  Life has put me in different places, different cultures, different opportunities. For me it was a really good journey to be in different countries, knowing different ways to see oncology as well, and immediately to work, because it was a shock coming from Belgium to the area of Baltimore where I had the reality to discuss peer to peer conversations and things that are not usually discussed in Europe. So it was really a very nice journey to learn, to have the capacity to adapt.  That is the other thing, my second advice, if I can give advice, but if you have the opportunity to go to some place, adaptation is the most important. So try to enjoy what you're doing and try to enjoy and learn from the patients, hopefully, and contribute your knowledge as well. Dr. Rafeh Naqash: Thank you so much, Christian. Two last questions. For all the places that you visited, what is your favorite place? And what is your favorite food? Dr. Christian Rolfo: My favorite place to live, I have Italy in my heart. Obviously, Argentina is my place, family. But Italy is in my heart. And then Spain, Spain gave me my wife and my son. So I have very good memories there and it's a very nice place. Obviously, I'm Argentinian, so for me it means meat in some places, Asado, that is a typical Argentinean one. But also, I am very eager to enjoy the pasta and paella, so we have several things. Anyway, here in New York, the pizza of New York is great. It is not Italian. This new way to make pizza from New York is fantastic.  Dr. Rafeh Naqash: I can try to see you're trying to keep everybody happy in a politically correct way. Dr. Christian Rolfo: I didn't mention Belgium, but we have chocolates there.  Dr. Rafeh Naqash: That is true. Every place is special and unique in different ways.  Christian, thank you so much. This was very entertaining and very informative for me and hopefully for the audience. Thank you so much for being a part of this conversation. And thank you so much for submitting your work to JCO PO. We hope you consider JCO PO for future research in this exciting area as well.  Dr. Christian Rolfo: Thank you. Thank you very much, Rafeh, for the opportunity. And JCO Precision Oncology is a really great forum to discuss precision medicine. Congratulations for all your work. The last, if you allow me to give an advertisement here. We have our Liquid Biopsy Congress, the ISLB, the annual conference will be in Denver from 20 to 25 November, so just before Thanksgiving day. So if you are able to go there, we will have a lot of discussion on liquid biopsy like we did today. Thank you very much.  Dr. Rafeh Naqash: Thank you so much for highlighting that, and hopefully, our listeners will try to register and be part of that meeting.  Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review. And be sure to subscribe so you never miss an episode. You can find all our shows at asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Editor’s Choice Paper:Identifying safe diagnostic algorithms for sentinel lymph node mapping in high-risk endometrial cancer: The SENTIREC-endo study Editorial:Sentinel lymph node biopsy in high-risk endometrial cancer: The dénouement Hosted by:Gregg Nelson, MD, Social Media Editor of Gynecologic OncologyFeaturing:Sarah M. Bjørnholt, MD, Aarhus University Hospital, DenmarkSean Dowdy, MD, Mayo Clinic, USA

Dr. Shannon Westin and her guests, Dr. Emily S. Tonorezos and Dr. Michael Halpern, discuss their article, "Myths and Presumptions About Cancer Survivorship" recently published in the JCO. TRANSCRIPT The guests on this podcast episode have no disclosures to declare.   Shannon Westin:Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Social Media Editor of the JCO, Shannon Westin, and also a GYN Oncologist by trade. I'm thrilled to bring a topic that is very close to my heart. We're going to be talking about a Comments and Controversies article published in the JCO on November 16, 2023, entitled "Myths and Presumptions about Cancer Survivorship." I know you all will find this topic as enthralling as I have, and the authors do not have any conflicts of interest.  I'm joined by two of the authors on this important work. The first is Dr. Michael Halpern, he's the Medical Officer in the Health Assessment Research Branch of the Health Care Delivery Research Program. Welcome, Dr. Halpern. Dr. Michael Halpern: Thank you for having us on. Shannon Westin: We're also accompanied by Dr. Emily Tonorezos, the Director of the Office of Cancer Survivorship, and both of them work in the Division of Cancer Control and Population Sciences at the National Cancer Institute, National Institutes of Health. Welcome.  Dr. Emily Tonorezos: Thank you for having us. Shannon Westin: So, let's get right into it. I want to level set first. I would love for one or both of you to speak a little bit about the state of cancer survivorship currently. What's the prevalence of cancer survivors here in the US? Globally? What do we expect as time passes? Dr. Emily Tonorezos: Thank you for starting with this question. In the Office of Cancer Survivorship, we use a definition of cancer survivor that we got from the advocacy community many years ago. We use a definition that says “a person is a cancer survivor from the time of diagnosis through the balance of life.” That means in the United States, we estimate that we have a little over 18 million cancer survivors, and globally, it's a little more difficult to estimate those numbers. Not every country has a cancer registry to count the number of cases, but we think there are upwards of 53 million cancer survivors diagnosed within the last five years in the world. Shannon Westin: Wow. And so this is why it's so important, such a large number, and that's just an estimate. And we know this is only going to be growing. I personally learned so much from your manuscript, which is critically based on the understanding that our beliefs as practitioners truly impact the way we care for our cancer survivors. I admit, I definitely held or hold some of these beliefs, and I'm certainly grateful that you're providing that objective evidence to support or refute these claims.  So, with that being said, let's tackle the first one that you all approached: Shared care results in the best outcomes for cancer survivors. I think first I'd love to hear about what your definition of shared care is. What does that really mean in the context of cancer survivorship? Dr. Michael Halpern: Shared care is a deliberate process to coordinate and integrate components of survivorship care between specialty, in this case, oncology providers, and primary care providers. And part of the issues with this belief about shared care being the best have to do with the broad practice experience of survivorship care. While the ideal definition is this integrated and coordinated care, shared care can range from one extreme to being essentially oncologist-led care - where the oncologist also sends information to the primary care providers; and to the other extreme - care led by primary care providers and an oncologist is available to answer questions as needed. So part of the issue with the available literature is that there is a tremendous range in terms of the definition of shared care that's being used in studies. Shannon Westin: So, understanding those limitations, obviously, based on what you just said, what have we seen in some of the studies that have been exploring shared care and what it might mean for cancer survivors? Dr. Michael Halpern: So there have been some wonderful studies and some very well-done research in shared care. The majority of it indicates essentially no benefits, not any worse, but definitely not any better than other survivorship care models among multiple domains, quality of life, patient preference, clinical outcomes, in some cases, costs. So there isn't at this point a rationale for believing that shared care leads to better outcomes than does other types of models of care. And that's not to say that we don't think that shared care is a valuable model, that it's potentially very useful and beneficial for certain groups of cancer survivors. It's just that at this point, we don't have evidence to say who it is going to have optimal outcomes for compared to other kinds of survivorship care models.  Shannon Westin: And that makes sense. I mean, I think we're seeing this over and over again in all aspects of cancer care that one broad stroke or one broad plan isn't right for everybody, whether that's therapeutic or surgical or prevention, so it makes sense to me that that's what we're seeing here in survivorship as well. So I see this manuscript as a call to action about what are we missing, what data do we need to generate to really be able to move this care forward. So that makes total sense to me. And I guess in line with that, another belief, and I've heard this all the time from my patients, too, is this idea that primary care providers feel unable to provide survivorship care. They're not comfortable. “Oh, you have a diagnosis of cancer. You have to be seen there at the cancer center.” What does our evidence demonstrate here? Dr. Emily Tonorezos: This is another belief that was found to be a presumption. So that means that this is a belief that we think was true, but which convincing evidence does not confirm or disprove. So what the available evidence tells us is that primary care providers do have challenges in taking care of cancer survivors, particularly with regards to certain cancer-related care needs. But at the same time, we found lots of evidence that primary care providers are more than willing and able to take care of cancer survivors. They express confidence in their skills. They think that they are capable of taking care of cancer survivors. And especially for survivors of more common cancers, primary care providers, in general, express a lot of confidence in their ability to take care of those patients. What they might lack could be things along the lines of survivorship-specific knowledge. So that is a gap that we identified. But this idea that primary care feels unable to take care of survivors really was not supported by the evidence. Shannon Westin: I mean, and that makes sense, right? If we're seeing more and more cancer survivors, primary care is going to adapt to that. We adapt to the things we see commonly in our clinics, and that goes across all specialties. So that certainly makes sense. I guess you've already kind of said this, and I'll just highlight it for the listeners. You know, clear guidelines seem to be a clear, nice option to potentially improve this situation.  So let's discuss this next myth that you all identified, that oncology providers are hesitant to transition survivors to primary care. Now, I understand this one because I definitely, we get this a lot, and I'm a center medical director in GYN, and we've definitely tried to put patients that are free of disease out back in the community to be able to free up space for other patients. And we definitely get pushback because seeing patients that are in this state of being free of disease and they're living their life, it's inspiring. We remember why it is we're doing the things we do. What did the data show us about this myth? And are we creating barriers to this transition to survivorship care outside of the oncology centers? Dr. Emily Tonorezos: Exactly. So this belief is a myth. We found evidence that this belief is not true, and it seems to be one of those things that feels true, that oncologists want to take care of cancer survivors, that it contributes to the joy of medicine. But that evidence really does not suggest that that's the case. In fact, the opposite is true in the evidence. We found when we looked at the available research Oncologists want to take care of people who are diagnosed with cancer and need treatment. That is really what they think their role is. That's what they feel they're contributing. And so, even though there is a pleasure in seeing a person who has finished treatment, most oncologists say that the amount of time that they spend taking care of people who are done with treatment is appropriate - meaning they're not looking to expand their panel of post-treatment patients. They really want to take care of people who need treatment currently and then perhaps have a little bit mixed in of people who are done with treatment or who are in that survivorship phase. We found a lot of evidence, also hard evidence, that oncologists are, in fact, transitioning survivors to primary care. There is a lot of evidence that people who have been diagnosed with cancer are being seen in primary care and that that proportion increases over time. So if oncologists were really creating these insurmountable barriers to transition to primary care, we would not be seeing so many survivors in the primary care setting. But the fact is they're there, and they are being moved there by their providers. Shannon Westin: I love hard evidence. I do have a few patients that have said, "Can I just come see you every once in a while?" And I love seeing them, but I agree, we can't fill our panels with that. So that makes good sense.  So the next topic centers around finances, and this is the idea that survivorship clinics lose money. What truth did you all discover here regarding reimbursement for this type of care?  Dr. Michael Halpern: We discovered that this is a presumption. It's a belief that there isn't compelling evidence one way or the other. Part of the issue with this is probably some confusion about what constitutes survivorship care. There are certainly difficulties in obtaining reimbursement for certain survivorship services, such as sexual health and fertility counseling, and wellness and exercise services. It's understandable that there may be problems getting reimbursement or appropriate reimbursement for those. But when looking at overall survivorship care, there are actually very few studies that have done a financial analysis of the cost of providing that care versus the reimbursement. And those that have done more detailed analyses generally show that the reimbursement for survivorship care is greater than the cost. Survivorship care clinics actually do break even or make money.  Now, it's also true that providing survivorship care likely doesn't provide the same level of reimbursement as providing oncology treatments, which involves administering systemic agents and different kinds of imaging or diagnostic procedures. And so there are other streams of reimbursement possible for that. But overall, there really isn't compelling evidence to indicate that survivorship clinics lose money. There is a concern that having this widespread belief that they do may be a disincentive for hospitals or healthcare systems to start different kinds of survivorship clinics. Shannon Westin: I think this is an area where it would really behoove us to do more work so that we can encourage institutions to do this. And, I know in our center, the things that you're mentioning, it's exactly like the problems that these people are having around sexual health and fertility and exercise, wellness in general, I mean, those are the soft things that I feel like it's harder to kind of gain momentum to really develop established programs that really make an impact. And so I was so glad to see that you mentioned that in this paper, and I hope it will encourage people to really move that forward.  So finally, I was interested in this presumption around the shared electronic health records and how that might help with survivorship care coordination. Is this our solution for smooth communication and care of these people? Dr. Emily Tonorezos: This one was actually almost something that's sort of funny to think about, how naive we were about electronic health records. We found a number of examples from five or ten years ago where leaders in survivorship research and clinical care were saying, "Well, once we have electronic health records, we will not have these same problems of care coordination or communication." And that has just not been true, unfortunately. So this one was also a presumption, meaning the evidence of a benefit for electronic health records just was not out there. So we know that consolidation and transfer of diagnostic and treatment information can increase knowledge. So you can show that you can increase knowledge about diagnosis and treatment with a shared electronic health record. So the primary care provider is able to look, for example, at the pathology from the original diagnosis. But whether that actually results in anything in terms of improved care is an open question. Shannon Westin:I think that's what we've learned a lot about electronic health records in general. I remember when we were transitioning to our new system, and everyone thought, "Oh, this is going to be the end all, be all." And it has been good in a lot of ways, but it certainly hasn't been the cure for everything that ails us.  Well, I'm just so thrilled. Thank you all so much. This has been really educational and so important, given what we've already talked about, about the increasing population of cancer survivors that we're seeing in the clinic and globally. I think just to kind of tie a bow on it, I would just love to hear each of your bottom lines regarding kind of where we are right now with the care of our cancer survivors and what we need to be addressing maybe in the short term to move things forward. Dr. Emily Tonorezos: So I'll go first. I just want to say it's really important, I think, when we are around other investigators and in our meetings and talking about clinical care, that we think critically about the things that we hear people saying. This idea, especially the one that oncology providers don't want to transition their survivors to primary care, but the others as well. I think the way that we need to address this or carry this forward is to just be aware when we're in those settings and we hear people say things, to ask the question, "Is that really supported by the evidence?" And you may find that there are even more of these commonly held beliefs that really aren't supported by the evidence or that deserve a little bit of a deeper dive. Dr. Michael Halpern: I very much agree with that. And it's critical that we be willing to question some of these beliefs, be willing to discuss them, and not accept them as facts in order to be able to develop new research programs, hypotheses, to explore really what can help produce the best outcomes for survivors, because that's really what we're all about.   The other bottom-line issue, I think, one, Dr. Westing that you brought up, is that survivorship isn't a one-size-fits-all. The best survivorship care is the care that is tailored towards the survivor - the individual needs and wants. What kind of supports will be most effective in terms of enhancing their health? So, we really need to pay attention to the individual and, most importantly, what outcomes for survivorship care matter most to the survivor? What do they want to see happen? What do they want their subsequent future to look like? And how do we measure those outcomes to ensure that they get the best care on the terms that they want?  Shannon Westin: Well, great. I think that's a perfect place to end. I just want to, again, thank my guests. This went by so fast, and I learned a ton, and I hope all of you did as well. Again, we were discussing the Comments and Controversies manuscript "Myths and Presumptions about Cancer Survivorship" published in the JCO on November 16, 2023.  Thank you again to our listeners for joining JCO After Hours. And please do check out our other offerings wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

JCO PO authors Lauren C. Leiman and Dr. Emma Alme share insights into their JCO PO article, “Recommendations for the Equitable and Widespread Implementation of Liquid Biopsy for Cancer Care”. Host Dr. Rafeh Naqash and guests discusses increasing access to liquid biopsy for cancer, reviewing the barriers and examining the proposed solutions. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor of Medicine at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, we are excited to be joined by Lauren Leiman, Executive Director of BloodPAC, and Dr. Emma Alme, Public Policy Director at Guardant Health. They are both authors of the JCO Precision Oncology article titled "Recommendations for the Equitable and Widespread Implementation of Liquid Biopsy for Cancer Care."  Our guest disclosures will be linked in the transcript.  For the sake of this conversation, we will refer to each other using our first names. So, Lauren and Emma, welcome to the podcast and thank you for joining us today. Lauren Leiman: Thank you for having us. Dr. Emma Alme: Thank you so much.  Dr. Rafeh Naqash: So, this article is an opinion piece that addresses something that is emerging and current and tries to connect it to something that is futuristic also and hopefully, will address a lot of different needs relevant to patients with cancer. For starters, since our audience is pretty diverse, could you tell us what the BloodPAC is? Since the article is somewhat a combined piece from different stakeholders, could you explain what this BloodPAC Consortium is as an entity and what is its role for this BloodPAC? Lauren Leiman: Sure, this is Lauren Leiman. The BloodPAC was formed almost seven years ago as an initial commitment to the White House Cancer Moonshot back in 2016. I was the head of external partnerships and had this idea with a colleague of mine, Dr. Jerry Lee: Could you accelerate the development and approval of liquid biopsy assays for cancer patient benefit if you were able to create some standards and frameworks for the field broadly, and also if you could aggregate data to support those standards and frameworks? So, we brought together about 20 different organizations across pharmaceutical companies, diagnostic partners, foundations funding in the space, government agencies, all to think through can we create these frameworks, are we willing to submit data. We were extremely successful in that first round, and by the end of 2016, we were able to have our first data deposit into- we built a BloodPAC Data Commons, which is housed in Chicago and was created by Dr. Bob Grossman up there. In 2017, when it became clear that the last administration was not going to continue the White House Cancer Moonshot, we became an independent non-profit 501(c)(3). And we have grown substantially since that time from those original 20 different organizations to about 66 different organizations today, across all those areas again, including today, payers, which is very exciting. And we have added on to our mission statement one word that we will discuss today, which is very exciting, which is “accessibility”. After our five-year anniversary and even slightly before then, we decided that we really feel that we have been able to contribute, as a community, to accelerating the development and approval of these tests. But, in actuality if we don't get them into patients' hands, what is the point of all of our hard work? So, we added the word "accessibility." Today, we have these 66 different organizations that collaborate, essentially, to compete. They're pulling together projects and deliverables in about ten different working group areas to contribute products to the liquid biopsy community to help accelerate those three things. Dr. Rafeh Naqash: Thank you for explaining that. That seems like a very important initiative.  Now, when you say that you're contributing data, does it mean that different companies and entities are contributing patient-level data so that you can pool that and assess what is the utilization, what is the utility, what is the payer-related aspects, coverage aspects. Is that all part of the initiative?  Lauren Leiman: It is. We started with the idea, which is kind of scary, I think, for a lot of different companies: Are you willing to submit your protocols essentially, pre-analytical data? I think, much to the FDA's surprise, I was kind of, “Of course, everyone should be willing to do this, they should absolutely do this, it'll be really exciting. Why wouldn't they?” And I think others were a little skeptical that these companies who are highly competitive including Emma's company, Guardant, would be willing to contribute data. And in fact, Guardant is probably one of the first ones, first two at the table to actually submit their data which was just extremely exciting. And the data was around mostly protocols and pre-analytical variables, what tube types are you using? As we moved on, our pharmaceutical partners did submit full clinical trials with deidentified patient data, which was extremely exciting.   Today, our Data Commons sits in two different areas or visibilities for our members. One is membership-only data that only our members can see, so have been been contributed by them potentially sometimes for certain projects we're working on. And then we also have an open segment of our Data Commons that's open to the public, that includes published data and studies that anyone can take a look at and see. Our goal is to continue to open up all of our data over time, so that anyone can take a look at it. We are, I think, the leading liquid biopsy repository.  As we move into the future though, I think because we are mostly an organization that has pharmaceutical companies and diagnostic partners, we are company driven, aggregating large sums of research data is not necessarily their goal. And so to try to identify an area of mutually beneficial interests for everyone, I do think that over the next year or two, you'll see a potential shift or pivot in the use of Data Commons to where the industry is today which is probably, hopefully a little bit more coverage focused. How do we pivot from being a source of aggregated research to a source of identifying and approving the value of liquid biopsy to the full community? And again, that's for the full spectrum all the way through payers and the coverage of these tests, which I do think would add a tremendous amount of value to everyone on the life cycle of this industry but would also add a tremendous amount of value for access in getting these tests into patients' hands.  Dr. Rafeh Naqash: Of course, you importantly covered a bunch of different concepts. One is data democratization, which is extremely important in the current day and age for different people in the public domain if they have access to data, they can do a lot of interesting and important things and add to the overall understanding of what we know or don't know in this space of liquid biopsy utilization. And then, of course, the aspect of disparities and coverage assessments.  Now, going to Emma, for the sake of our listeners, some of them are trainees, and many of them are oncologists, perhaps many are patients. What is the current landscape for liquid biopsies? Where do we use them, and what are the general approaches and principles of where things stand?  Dr. Emma Alme: That's a great question, and it really spans the cancer care continuum. And I think the space where it's most established is in the advanced cancer stage for therapy selection. So that's where we actually have some even FDA approved assays for liquid biopsy, with Guardant 360 test being one of them. It's comprehensive genomic profiling to identify actionable biomarkers to get patients on targeted therapy. So that's where it's really been integral to precision medicine. And we're seeing an increase in utilization of liquid biopsy as the technology becomes more established. It's not just in cases where tissue is insufficient now. Most recently, we've seen NCCN guidelines and non-small cell lung cancer change for concurrent testing for liquid biopsies. So that's been an exciting trend in adoption.   And then as you move across the cancer care continuum, there's residual disease monitoring and response, where we can actually use ctDNA to look at a patient's response to therapy, even after surgery - is there still ctDNA there? Instead of just having imaging as an option, we can actually look sooner to see how the patient is responding and if there is still cancer present. So that's a really exciting place where we're seeing growth in liquid biopsy. And then moving even earlier, before a patient even has cancer, there's a tremendous opportunity for liquid biopsy in early cancer detection. I think that's something that has been previously discussed on this podcast and we see it a lot in popular media. But it's not just for multi-cancer, we have the opportunity for single cancer as well liquid biopsy tests in cancer screening.  That's a really exciting space, really thinking about the accessibility of these tests. Because a lot of cancer screening modalities today are hard for a lot of patients to access. And it requires going to a medical facility. So if the first step is a blood test, that really opens that up to communities that traditionally have been left out of screening. So I think there's a huge opportunity there, not just when we're thinking about screening for cancers that don't have screening modalities currently, but also screening for those that do, where maybe a first non-invasive step can really open the door to patients who don't have access.  So it's a long answer to say that, really, it's across the entire cancer care continuum. We see a lot of opportunity here for liquid biopsy to be a way to advance the field but also increase access for patients who have been left out of precision medicine. Dr. Rafeh Naqash: I think access is definitely the focus here. And I can give you my example. So I do early phase drug development and I do a lot of research in liquid biopsies and ctDNA monitoring. In the center of care, I treat people with lung cancer also and there have been instances, probably about a year or a year and a half back, where a patient could not come to the clinic. The clinic wasn't done and on my to-do list for that individual patient, I put in ctDNA testing just to remind me when I see the patient, to get it done. But the patient didn't make it to the clinic. Surprisingly enough, mobile phlebotomy was available. And later I came to know that this is something that can be done and provided to the patient at their home and you can still get the same results, which was very surprising in a good way. And it did help in making some treatment decisions for some patients who, sometimes in a state like Oklahoma, which is where I am based, we have a significant rural population and people drive six hours for some of our trials, especially the early phase trials. And then if you tell them, “Well, if you don't make this appointment, XYZ cannot get done,” it doesn't necessarily change things for them. So something of this sort definitely helps. Now, going to Lauren, I noticed this interesting sentence in the article, "fork in the road," where you describe, based on the current practices and policies, in the direction that we're going in, we can either increase or deepen the divide and disparities or decrease it. Could you tell us a little bit more about what currently exists on the disparity side and how do you see us narrowing that gap in the near future and implementing something that is equitable? Lauren Leiman: What's exciting about this paper is I think as we are talking about trying to condense this discussion down to something that's really digestible for everyone in the community, there are six barriers that we've identified. And I also should start by saying the working group that we have within BloodPAC that wrote this paper is intended to look at two different areas. One is that broadly, liquid biopsy still isn't available for the majority of the population domestically here in the US so that's a problem. In addition, it's clearly not available in underserved areas, and that's an even deeper divide. So we're kind of at this fork in the road because it's not broadly accessible to the majority of patients today. And so we have this moment in time where we're able to make a decision to bring everyone along with us, which is very exciting but also will take a lot of work. And these six barriers that the paper identifies, I think are very clearly articulated. They are: lack of uncertainty around test performance, the lack of familiarity with this technology, inconsistent payer coverage is an issue, mistrust of the medical establishment - especially in underserved areas, fear of discrimination in seeking this kind of technology, and the difficulty with terminology.  I think that the whole liquid biopsy community has a role to play in addressing these six areas. I think that BloodPAC, in particular, as a consortium and a collaborative process for 66 different organizations that work in the field, we have a role to play, most certainly in helping to address specifically some of these areas. We have working groups that specifically address reimbursement and policy, so that would obviously fall into payer coverage of these tests. We have working groups creating lexicons both in the molecular residual disease area, as well as our multi-cancer early detection areas. So creating terminology and lexicons that are consistent across the entire community and also digestible for patients, which is really important. And so mitigating these barriers is going to be a collaborative process across all stakeholders in the liquid biopsy field. And I think BloodPAC is uniquely positioned to address many of these  because of our diverse stakeholders and membership, which is exciting. But I do think that this is the perfect moment in time now to start addressing these challenges, and we shouldn't wait much longer, as we think through how we can bring everyone along with us and make sure we're not leaving anyone behind. Dr. Rafeh Naqash: As this entity or consortium, as you call it BloodPAC, has moved forward, this is a question for both of you, Emma and Lauren. Emma, I guess you can start. How were things five years back? What are some of the things that you have been able to achieve, and where do you potentially see the next five years? Dr. Emma Alme: I think we have made a lot of strides on the coverage side when it comes to advanced cancer testing for liquid biopsy. By no means are we there by any stretch of imagination, but we're starting to see some coverage adoption, which does make a huge difference because at the end of the day, that's so important to ensure equitable access. Especially when we're talking about a technology that has the potential to close some of the barriers in precision medicine because of the fact that you don't need access to some of the medical facilities, as you pointed out earlier, rural patients don't have access to. Because transportation is not necessarily a barrier here the way it is for some for some of these other treatment aspects. But if you don't have consistent pay or coverage, that's a place where you're really going to see drop off in terms of patients not getting equitable care and not getting standard of care as liquid biopsy enters into that realm.  The increase we've seen in private payers adopting coverage, the way we see Medicare coverage for advanced cancer liquid biopsy, is encouraging. We've seen states adopt legislation to require coverage of biomarker testing, that's passed in 15 states now, thanks to the work of the American Cancer Society and a broad coalition of stakeholders. I think that's beginning to make a difference, but we have a long road to go. We still, on the MRD side, that's just emerging. And so one space where we have some recommendations on this is continued evidence generation - continue to gather that clinical utility data that will support payer adoption increasing on the advanced cancer side, but then moving across that cancer care continuum to those other types of liquid biopsy tests. I think that's hugely important and there's a role for BloodPAC to play in that as well, especially in making sure that we bring everyone to the table to have these conversations on what is the evidence that, we need to generate, what should that look like, what are the standards to ensure that everyone feels confident in these tests. That's one area that we're really excited to see.  And I also think another space is on the diversity in clinical trials. It's so important to make sure that when we are bringing these tests to market, the data that we gather to support that is representative of all patients who can benefit. It is so important to make sure that the tests work, but also to build confidence in all of the people who are going to get these tests and feel like, “Okay. I know that this test works for patients that look like me, too.” And so that is something that at Guardant we are working really hard on. We read out our clinical trial, ECLIPSE, for our blood based test screening for colorectal cancer a little over a year ago, and we were really happy to be able to say that our trial was representative of the US population, particularly for Black Americans, where colorectal cancer incidence is increasing, 30% to 40% higher rates of mortality, in Black patients than White patients for CRC. So it's especially important to make sure that the population is representative in the clinical trial of the patients who will benefit.   And I think we are seeing companies increasingly realize their responsibility in that space and it's something that we can all really prioritize moving forward with things like making sure transportation is accessible to patients, making sure that clinical trial materials are accessible, culturally sensitive in a broad set of languages. There are a lot of different activities. You have mentioned mobile phlebotomy earlier, that can be incorporated into trials working with community centers and not just academic medical centers to ensure that the trials are taking place close to where patients live and work. This is a tractable problem and I think we've made a lot of headway in the five years. But looking to the future, there's still a lot more we can do together to ensure that work continues. Dr. Rafeh Naqash: All excellent points. And I completely agree with you. Bringing the trial to the patient is more important and likely to lead to better outcomes than the patient driving six hours to a facility to come on for trial.  So, the question for Lauren that I have from a physician or scientist standpoint, is what gets covered or does not get covered is not necessarily that I know about in my daily clinic of 15-20 patients. What is the difference between different states having different coverage policies for something like this? If it's the same payer in state A and the same payer in state B, why is the coverage policy in state B different from that in state A? And what are some of the things we can do locally and at a national level to help bridge some of these disparities and gaps? Lauren Leiman: I'm going to hand that question over to Emma. This is her bread and butter.  Dr. Emma Alme: That is such a great question, and I wish I had a more satisfactory answer for you. The reality is that when it comes to diagnostics, coverage is really a patchwork, compared to when we think about drugs whether it's FDA approved, we expect to be covered. With diagnostics, it's really up to the insurer. And I keep going back to the advanced cancer space because that's where we see the broadest coverage because it has been around the longest. But we see broad coverage from Medicare for these types of tests. But, for private payers, it's really a patchwork. We see a lot of payers only just starting to cover these tests, maybe where there's a CDX indication with an FDA-approved drug we see it, but not more broadly for tumor profiling. Especially not for the larger, more expensive comprehensive genomic profiling panels that are more expensive. I think you can extrapolate the obvious reasons why that might be. But, as this is being moving into NCCN guidelines, we see very slow adoption by some private payers.  And you touched on the legislation in different states. This coalition on American Cancer Society has been spearheading is trying to pass state-level legislation that will align coverage with a strong, robust set of evidence, and that's an FDA-approved companion diagnostic indication, medicare coverage, whether it's an NCD National Coverage Determination, a Local Coverage Determination, or National Clinical Practice Guidelines like NCCN, so really a robust set of evidence. And so this is resonating with state legislators across the country where we are seeing that take off in 15 states. But the political climate is different in different states so there are differences in terms of which state will adopt this, some of the differences are in language that they put into this. But even now that these are passing, we're seeing differential implementation, some plans are not necessarily reading this legislation and saying, “Okay, I have to cover all the tests that Medicare covers.” They are thinking that maybe they have some agency to put on other medical necessity criteria. So I think there's a lot that will play out on the individual state level to see how this nets out. But it's really kind of how different insurance companies and plans are interpreting these mandates, are interpreting guidelines, etc.  But you touched on the differences between the states and one of the things that has actually been shown in data from the precision medicine coalition is that even when you change insurance coverage for one individual plan, it doesn't necessarily translate into adoption in the direct correlation that you would expect. And part of that is because it's such a patchwork and it's so chaotic. Providers don't necessarily know for their patients which plan will cover, which one won't. They're very hesitant to subject their patients to out of pocket costs and so you get providers being reticent to order liquid biopsy just because of this coverage landscape. And so there really is that need not just to go step by step but get broader coverage for these patients across the board.  And so I think the long term vision is can we get to a change at the federal level. That's hard compared to the state level. It's a long road ahead. That's why I started this with I don't have a satisfactory answer. There is still a lot of chaos ahead even though we made some progress along the way. Dr. Rafeh Naqash: I completely agree. Lots of things to do together. But, in my daily role as a physician or a scientist, I come across situations where a patient's situation was denied for liquid biopsy, then the company went and appealed or insurance doesn't want to pay for it, and then they ask for peer-to-peer review, which is a lot of time and energy on the provider's side, the physician's side, even for as simple as a CAT scan for cancer, let alone a liquid biopsy. I started thinking at that time, is there a scenario where if I were ordering a Guardant or a foundation or any liquid biopsy for that matter, can they not provide additional support where I don't have to do a peer to peer and I can spend time and energy concentrating on the more important patient issues that are right in front of me, rather than having to wait for an insurance company to call me at a certain time of the day where I may or may not be available and then having to reschedule the call and spend another 30 minutes to them explaining. So I don't know if you guys on the other side of the aisle also think about some of these issues, but could that be a scenario that could potentially be implemented in the near future?  Dr. Emma Alme: Yes, absolutely. This is something that we at Guardant think about a lot. One of the challenges is that, as a laboratory offering liquid biopsy, you are an ancillary provider, and so I think you touched on it, a lot of this role falls to you as the physician to secure prior authorization and to be the patient's advocate. And not all plans – this is often true for Medicare Advantage – allow the laboratory to be the one to, for example, initiate prior authorization and provide the medical necessity information to make sure that that test is approved by the insurance company, and then to be the advocate for that patient in appeal process as you mentioned. And I think there is a lot of education that needs to happen among policymakers to make some tweaks to this process to ensure that the patient can have access, that the laboratory can be involved in the process where it makes sense, to smooth out this process.   And exactly right, I think you touched on a place where it is a huge burden for providers. There are places where the laboratory is best equipped to move the patient through that process and there's a lot of red tape that we can help overcome. And that's not specific to liquid biopsy. I think that's true across the diagnostics industry. But you're exactly right that it is another hurdle to access is if this is a process that has a lot of red tape. So I'm pleased to hear you think about this the same way.  Dr. Rafeh Naqash: I'm glad you guys are having those conversations, having conversations is the first important step to make a change in the near future.  If there's a patient listening out there and that patient has gotten a recent bill of $5,000 for liquid biopsy, what are some of the steps that you would like to highlight for them from a patient standpoint so that they can advocate for themselves? And should they talk to the physician in the company? Should they directly approach the company to not have that additional financial toxicity in situations where it may not be covered?   Lauren Leiman: I would 100% encourage those patients to please reach out to the company. I can only speak for Guardant but we have a patient access program. Our team calls any patient that's going to have more than $100 out of pocket because our goal at Guardant is to make sure that patients have access to the testing they need to inform their treatment and get the best possible care. I think we're all aligned across these companies across both- like we want to make sure that we are lowering the burden for cancer patients. There's already so much stress on these patients initiating treatment. They don't need to have the added stress of battling insurance. So we're here to help and no patient should be on their own in that space. So please tell your patients to reach out to the company in those instances, but I would hope that they would already have gotten outreach from the company in the first place. Dr. Rafeh Naqash: I often discuss with some of my colleagues about the financial burden of cancer care, unfortunately, that people tend to have. And I remember this scenario a couple of months back where a patient of mine, when I sat down in the clinic room, they had this big, thick folder with them. And after I finished the discussion about what was going on with the cancer, they said, "Could you help figure this out?" And they opened this folder. It had so many bills, and one of the bills was obviously a liquid biopsy bill. And that was my understanding, too, that there is a lot of resources available to these people. And eventually things worked out. The company took the cost of whatever was not being covered by the insurance. But again, you touched upon an aspect in the article about educating the physicians, the providers. I think definitely a lot of work needs to be done there so that the patients can advocate for themselves and the healthcare providers can advocate for the patients, too, like having those checks and balances and those resources present and in the institutions where these people get cared for or knowing what's the right way to channelize these issues and to whom within the companies, so that all of this gets taken care within a timely period, so that the patient doesn't come back with the same issue six months later, “I still have this bill,” that even if it's being sent to the patient or their family by mistake, it does add a lot of psychological pressure.   So I think a lot of things potentially need to be done in that space, and hopefully you guys are still doing that and continue to do that, make progress in that space to help mitigate and alleviate some of that patient level burden, which is extremely crucial in their care. Lauren Leiman: I think what's interesting about what we're looking at now is BloodPAC is thinking through these financial challenges, the coverage challenges for someone who's probably made it to an academic center to access these tests to begin with. And so to go back a little bit in the conversation, I think there still are challenges, which I'd love to hear more about from the experience of a clinician. But we have talked about, does mobile phlebotomy access everyone? Is it capable of providing access for everyone? I don't know. There's new technologies that we are looking at, like home blood collection. Most of the companies that we work with right now, they're not getting enough quantity. The quantity isn't there. But is that something that we should be pursuing? Because as you've already said, people drive six hours, and sometimes you can't make that drive. And sometimes a mobile phlebotomy lab is not able to get those six hours away. There's a limit on how far they can go. That's a huge challenge.  I'm also fascinated by the idea that if you were to eliminate coverage as an issue, so if we were to say we're offering tests for free, is there still the educational barrier, the understanding barrier that we are not putting enough emphasis on? I don't know the answer to that question. I think there is a large element to that, though. And I think that when you say education, I have asked colleagues, "Okay, guys, who are we educating? Are we educating the clinician on specific tests? Are we educating the community health worker somewhere else outside of an academic center? Are we educating the patients themselves? Do they need to really understand exactly what this kind of futuristic technology is and what it can do for them?" Those are a lot of permutations of what if, what if, what if, what is the barrier? And so to take a step back, the reality is for that big bucket of individuals that I talked about at first, yes, coverage is going to be the primary barrier for them. But if you were to remove that barrier for some individuals, I think you still have a lot of challenges left ahead of you, which is essentially what the paper is saying. But I think that that is the really big question that I still have in my mind. If we can eliminate coverage, what's left and how do we address it? Dr. Rafeh Naqash: To that point, I would like to add also- you pointed out educational barriers and there's definitely educational barriers on the provider side also, physicians, whether it's academic or community, that's a different discussion altogether. And this is not just one example, but this is an example that I'm giving because there's several other examples similar I've seen where somebody gets a liquid biopsy done in the community setting, or maybe even in an academic setting somewhere else. And somebody like me who deals with some of these results, I do a lot of precision medicine, I do a lot of genomics, but that's not everybody's interest or forte. That's not something that everybody's necessarily interested in or I try to read each and every detail in a report and understand implications, and not everybody necessarily thinks that that's the best utilization of their time. And I have identified a lot of patients that have been in the system within our state or outside our state where liquid biopsy two years back showed a certain potential germline mutation with a very high variant allele frequency and never got any germline testing. And then I see the patient and I start connecting the dots and the patient gets germline testing done - patients is positive, children are positive, children get XYZ procedures done as part of surveillance or mitigation strategies to prevent future cancers, which again, prevention is cure. At the end of the day, you catch something earlier, as we all know, higher chances for cure.  So I think that part of education, we still need to do a lot more on educating the providers, the physicians, or making it somewhat easy, like is there a way that, well, if you have a potential finding of a germline mutation, let's say on a report, instead of just mentioning the potential of germline mutations, maybe we can go to the next level and offer free germline testing and free genetic counseling and make sure that you communicate with that provider versus the responsibility being on the provider or the physician that, “Hey, did you read this carefully? Did you miss something? Did you not miss something?” This is something I have come across and we're actually doing a project right now looking at some of that and analyzing the data and the percentage is pretty significant, and hopefully, if and when the results of that project are published, you will understand how much of a difference it actually can make in the lives of patients and their families to catch something early.  Dr. Emma Alme: I think you raise a really good point and your example of germline testing along with tumor profiling is a good example of the kinds of questions that we'll encounter as liquid biopsy moves across that cancer care continuum. So I think we do have to be thinking about what kind of education will we be giving to providers for how they integrate, for example, MRD liquid biopsy testing with standard of care imaging, what does that patient management process look like? On the early cancer screening side, what happens when you get a positive test for a patient? What does that diagnostic workup look like? Especially when there isn't necessarily a standard of care screening pathway- isn't a diagnostic pathway. Whose responsibility is that? There are so many outstanding questions through how we think about provider education across this board that really will take all stakeholders together to really formulate what this looks like.  I think you raise a really good point. Right now, I think we all have more questions than answers, but I think it's an important place for us all to be working really hard on right now, to ensure that this doesn't roll out in a way where there is confusion, especially where the providers offering liquid biopsy, maybe primary care physicians who aren't necessarily, as you said, going to be well versed in the literature on liquid biopsy, thinking about these tests report the way that you are right now. There's a lot of work to be done there. Dr. Rafeh Naqash: Absolutely. It was a pleasure talking to both of you about the science, logistics, and payer aspects. A couple of quick minutes on both of you as individuals. I like to start with you, Lauren, can you tell me briefly, what's your background? How did that background connect to what you're doing today? And what else have you learned in this process? Lauren Leiman: Sure. I am Lauren Leiman. I'm the Executive Director of BlooPAC. My backgrounds are primarily in communications and business and developing collaborations that are mutually beneficial for all participants. I have worked in finance. I've worked in Africa for many years for an economist and really decided during that time that health care and health initiatives were really what interests me and ended up working in a melanoma foundation for many, many years, developing interesting collaborations between academic institutions and funding formats, and took that to the White House for the first White House Cancer Moonshot as the Head of External Partnerships, and work towards identifying collaborations between different government agencies and different companies, as well as straight corporate commitments to the Cancer Moonshot, which was “a decade of progress in half the time”, the mission statement.  And having worked in melanoma for a while and working at the Moonshot, I'd heard about this liquid biopsy technology. It's out there and I thought it was pretty cool. I have melanoma in my family, and was like, wouldn't it be really interesting if you could get your blood drawn and just tell me if I have melanoma as opposed to kind of scanning my body every six months? And my colleague Jerry Lee, at the time kind of dropped a ream of paper on my desk and said, “Read this.” So I'm neither MD nor PhD, I'm a lowly MBA, who went home and read through everything and came back and said, “You don't have a science problem. You have the collaboration problem, you need to work together, you need to share your data and share your information, which was kind of the birthplace I guess for BloodPAC - could we again, aggregate our data, bringing together these experts in the field to help accelerate the development and approval and accessibility of these technologies. That is my background. Again, an interest in things, going back to Africa and the time I spent there, I'm heavily interested in underserved populations, not just domestically but globally. My hope is that eventually BloodPAC starts really engaging in how do we increase access for all to these really exciting new tests? I do receive, BloodPAC and I as the executive director, receive calls probably once a month from different startups around the world saying, “Good luck with all your $500 test. I want a $5 test, how are we going to get there?” Which you know, I think is the absolute goal for everyone. But slowly but surely, I think we are going to work towards increasing access for all not just domestically here and not just underserved populations here in the US, but hopefully locally as well. Dr. Rafeh Naqash: Thank you, Lauren. Same question to you, Emma. Could you tell us about your background and how it led to your current work and some of the things you learned? Dr. Emma Alme: Absolutely, my background began on the science side. I did a PhD in biochemistry at UCSF University of California, San Francisco. About halfway through my PhD, which I think is a realization many have, I discovered that I loved talking about science and thinking about science and reading about science, but it would be okay if I didn't have to pick up a pipette again. At the time, I was so invigorated by all of the research going on around me but realized that, similar to what Lauren said, it wasn't the science that was the barrier in a lot of cases of this research really reaching patients and changing their care. There were so many policy barriers that were standing in the way of that that I felt like I really wanted to help tackle and so I was fortunate in the fact that there are a lot of fellowships out there for PhDs in science to move into policy roles and serve as science advisors, so I did a smattering of those all around DC. I worked at the National Academy of Science. I worked at NIH and then I went to Congress, where I was a Health Policy Fellow for Anna Eshoo and got to interact with so many different companies in the biotech space and learn about all of their amazing technology, including liquid biopsy that folks were working on where there again, were so many barriers to adoption, where there were policy solutions, and I got really excited to work on that. It was the perfect nexus of my background and biochemistry and genetics and health policy.  And so the opportunity came up to work on policy for Guardant who was really thinking about those issues. And so I jumped at the chance to spend all of my time thinking about how do we increase access for patients? How do we make sure that this innovation actually gets into their hands through changes in coverage and reimbursement? And also thinking about most of the things that we've been talking about today - diversity in clinical trials, how we brought in education for patients and providers. So it's been a really exciting space to work in. It's been super fun to get to help the Guardant work with BloodPAC and I think it's an amazing group of collaborators that brings me a little bit back to my academic roots in terms of enjoying the kind of conversations that all these folks have together as we think about standards. That's been a really exciting place for me to sit in the health policy world combining all of that experience together. Dr. Rafeh Naqash: Thank you so much. It looks like all of you within the BloodPAC and perhaps outside the BloodPAC are people driven by a common vision and mission and hopefully will succeed in all of those things that you're trying to achieve. Thank you for giving us the opportunity to talk to you guys and thank you for publishing in JCO Precision Oncology. Hopefully we'll see more of your work with regards to implementation and some of the next steps that you're taking and perhaps even the data for some of these studies that you're combining together, within JCO Precision Oncology in the near future. Dr. Emma Alme: Thank you so much for having us.  Lauren Leiman: Thank you.  Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe, so you never miss an episode.  You can find all ASCO shows at asco.org/podcast. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Leiman COIs: Stock and Other Ownership Interests:Company: Illumina Company: Eli lillyAlme COIs:Employment: Company: Guardant Health  Stock and Other Ownership Interests: Company: Guardant Health  

Dr. Shannon Westin and her guests, Dr. Herbert Duvivier and Dr. Richard Schilsky, discuss the paper “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study” published in the JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth into articles published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. As always, it is my pleasure to serve and bring this information to you.  Today, we will be discussing, “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study.” And this was published in the JCO on August 10th, 2023.  None of the authors have any conflicts of interest to disclose.  Joining me today are two of the authors, Dr. Herbert Duvivier, the principal investigator of this arm of the TAPUR trial. Welcome. Dr. Herbert Duvivier: Thank you.  Shannon Westin: And then, of course, many of you know Dr. Richard Schilsky, who is the former CMO and Executive Vice President of ASCO and a principal investigator on the TAPUR study.   Dr. Richard Schilsky: Thank you, Shannon.  Shannon Westin: So, let's get going. I think the first thing would be great is to level set and make sure everyone knows exactly what this TAPUR basket trial is, the Targeted Agent and Profiling Utilization Registry study. Can you guys give the audience a brief description of the objective of TAPUR and maybe how it came to fruition?  Dr. Richard Schilsky: Sure. This is Richard Schilsky. Maybe I can start with that. The TAPUR study is a prospective, phase II, multi-basket, multi-center genomic-matching trial. Its primary objective is to identify signals of drug activity for targeted agents that are already marketed. But in the TAPUR study they are being used outside of their FDA-approved indication. The study, as you may know, was conceived in 2014, launched in 2016, and is still enrolling patients across the country. Really, the genesis of the study came from the fact that it began at the time where genomic profiling of patients with advanced cancer was becoming more commonplace. Genomic alterations that could be targeted by already marketed drugs were being identified. However, patients and doctors were having difficulty accessing these drugs because they were not used on label and were unlikely to be covered by insurance. And moreover, even if they could access the drugs, there was no organized mechanism to collect outcome data and report on the results of the patient experience receiving that treatment.  So those factors led to the development of TAPUR, which attempts to solve both the drug access problem by having collaborating pharmaceutical companies donate their drugs to the trial so they're available to patients at no cost, but also implements a structured data collection mechanism so all of the relevant clinical outcomes with the patients can be collected and ultimately reported. And that's how TAPUR came about. Shannon Westin: Well, it was so necessary, and I think we do so much of our oncology treatments off-label, but as we get more and more expensive drugs when we move away from chemotherapies and more targeted immunotherapies, it's very hard to get those drugs off label. So this was such a relevant and necessary trial that had to happen, and it's a great example of leadership that you had the vision to put this together through ASCO.  I think the natural next question for me is having not put patients on the TAPUR study, how does a patient join this study? How do they get started? Walk us through that. Dr. Herbert Duvivier: At our institution, normally, all the physicians are aware of the TAPUR trial through internal conversations. When they have patients who have been treated with multiple lines of standard therapy, usually the next step for them is to get NGS testing. We have a research team that reviews all NGS testing for these patients and knows the open arms of the TAPUR trial. And if there happens to be a particular patient who may match with one, they will inform the physician. It is then up to the physician to speak to the patient about that option.  Shannon Westin: Do you have people come looking for the TAPUR trial or are these generally more established patients? Dr. Herbert Duvivier: From my perspective, I think it is usually established patients. Shannon Westin: I think what I love about this trial, and I have spoken about this trial in lectures around baskets, it's such a pragmatic design making it as straightforward as possible to really implement across different centers, whether academic or community, or wherever they are. I guess one of the questions always around these targeted therapies is the molecular selection. How do you make sure that people are being appropriately molecularly selected and how do you decide which testing to utilize?  Dr. Richard Schilsky: As you pointed out, Dr. Westin, the goal of the study from the beginning was to have a very pragmatic design, in a sense to have this study attempt to replicate the way oncologists were deploying precision medicine in their practice. The study has broad eligibility criteria, it has minimum necessary data collection, it uses conventional clinical evaluations, there are no additional clinical evaluations required that are not part of routine clinical care. And it just makes it easy to embed the study into the clinical workflow. The study is based largely at community sites, about 85% of the 268 participating sites are located in smaller communities. The study has a set of genomic matching rules that are listed in the protocol and baked into the IT platform for the study as a rules engine. For every treatment available in TAPUR, there is a set of genomic inclusion and exclusion criteria.  So in essence the way it works, the physician determines that NGS testing is appropriate for their patient and can use any NGS test they want, as long as the test is performed in a CLIA certified, CAP, or New York State-accredited laboratory. They select the test, they select the biospecimen to be tested, they get the results, they look at the results, and they determine if there is a genomic alteration in the patient's tumor that is targeted by one of the study treatments in the TAPUR study. They can enter that into the rules engine, the rules engine will confirm or not that the appropriate alteration of treatment has been selected. If it is confirmed, then the patient can immediately be enrolled in the study if they meet the clinical inclusion and exclusion criteria.  If the rules engine does not confirm the treatment match is appropriate, or in some cases there are multiple possible treatment matches, if there are multiple alterations that can be targeted, or another case is the doctor is simply uncertain about which alteration is best to target, then the clinical site can send that patient case to the TAPUR molecular tumor board. A group of experts convenes weekly that reviews the clinical history, the pathology report, genomic test report, the prior therapy the patient has received, and they make a determination as to whether or not there is an appropriate therapy that's available on TAPUR for the patient. And if not, then are there other potential therapies  that are available that could be considered. That information is sent back to the treating physician who determines whether or not here she feels that treatment option is appropriate for their patient, and if so, the patient can then be enrolled and receive the therapy. Shannon Westin: So awesome. I love the idea. If we don't have an arm for you on our trial, we can help assist you potentially determine an option for your patient outside of that. That's so clever.  Okay. So let's get into this particular arm. Obviously, our audience is quite savvy and are aware of the role of immune checkpoint inhibition across a number of solid tumors. Could you describe what you sought to determine in this particular arm of the TAPUR study?  Dr. Herbert Duvivier: I think one of the most important things to remember about this study is that this study was opened and accruing prior to pembrolizumab becoming FDA approved in, I think, June of 2020. So prior to June of 2020, there was no indication for pembrolizumab in high TMB tumor types and the goal of the study was to determine if pembrolizumab had any overall response rate, duration of responses, progression-free survival, or overall survival advantage over what would be considered standard chemotherapy at that time in patients with high TMB. Dr. Richard Schilsky: Yeah, that's exactly right. And in this paper that we're discussing, we're reporting on two different groups of patients. So there's a group of 28 patients, all with colorectal cancer, all of whom had high tumor mutation burden, as defined by the protocol. And that's one group. Then there's a second, larger group of patients, which is a very heterogeneous group of solid tumor patients. And the reason that that group is reported is there were patients who were being enrolled with multiple different tumor types with high tumor mutation burden. Each tumor type determined a specific, tumor-specific cohort in the study, and they were enrolling at different rates depending upon how common the particular tumor type was. But once the FDA approval for pembrolizumab, for any tumor with a high tumor mutation burden, was granted, then all of those cohorts essentially had to close to new enrollments because there was no longer an off-label use for pembrolizumab in that setting - everything was now on the label.  The result was that we then basically collapsed all of the open cohorts that were not then going to be able to complete into this one large, heterogeneous cohort that's being reported in this paper. And going back to the colorectal results, in the paper, we describe a disease control rate of 31%, an objective response rate of 11%. There were three patients who had partial responses lasting 12, 27, and 97 weeks each. And I think it's important to point out that in this particular cohort, essentially all of the colon cancer patients were microsatellite stable. So that's an interesting nuance here because we know that pembrolizumab is active and has an FDA approval in microsatellite high tumors. But this particular group of patients was essentially all microsatellite stable, suggesting that even in that population, if the tumor also has a high tumor mutation burden, the patient has the potential to respond and benefit from the treatment. Shannon Westin: I found that very intriguing. And, of course, as a gynecologic oncologist that treats endometrial cancer, I'm always thinking about MSI and microsatellite stability. So I was very intrigued by this. We are not seeing a ton of TMB high in our population, but there are some patients that do have that.  So let's talk a little bit about the results for the collapsed all solid tumor group. What did you find there? Dr. Herbert Duvivier: In the histology pool cohort, there were 47 patients representing 21 different tumor types, with a median tumor mutational burden of approximately 13 mutations per megabase with a range of 9 to 228. 40 of 47 patients had MSS disease, microsatellite stable disease. 6 of the 47, MSS was not reported, and 1 case was ambiguous. The disease control rate was about 45%, and the objective response rate was 26%. There were 3 complete responses: 1 in bladder, 1 in parotid, and 1 in squamous cell carcinoma. 9 partial responses and 9 stable disease 16 plus weeks. Of interest in the patients that were responding, 10 out of the 21 patients had POLE or POLD1 mutations, and 9 of the 21 patients had BRCA1 or BRCA2 mutations, although most of those mutations were classified as variants of uncertain significance. Shannon Westin: That's really interesting. We've seen pretty good data for POLE and benefit from immunotherapy, although at least in the GYN tumors and especially in endometrial cancer, those patients usually do well no matter what you do with them. And so they don't often make it to get immunotherapy because they have a complete response up front to their surgeries. So very intriguing to see that driving benefit. I'm just interested to see because it seems like there's a range that you were quoting of what was considered to be TMB high. So did you see a correlation for response to therapy based on how high the tumor mutational burden was in a given tumor or tumor type? Dr. Herbert Duvivier: Yes, actually we did see a moderately negative correlation between maximum percent change from baseline in a tumor and increasing TMB, which indicated an association between a higher TMB and greater shrinkage of tumor lesions. Dr. Richard Schilsky: I should point out, by the way, that when we introduced this arm into the TAPUR study, this high tumor mutation burden arm, as Dr. Duvivier has already pointed out, it was prior to, of course, the FDA approval, and the FDA approval is for tumors that have at least 10 mutations per megabase. It was also prior to the adoption of that threshold of 10, based on work by Friends of Cancer Research and others as sort of the convention for what defined a high tumor mutation burden. So when we put this into TAPUR, we essentially consulted with some of the testing laboratories. We consulted with Merck, the sponsor for pembrolizumab and actually in the TAPUR study, we defined a threshold of 9 mutations per megabase as defining high tumor mutation burden.  Now, as Dr. Duvivier said, there's a broad range of tumor mutation burden represented in this population, and there does seem, if you look at, if the readers want to look at figure 4 in our paper, there does seem to be a general correlation between best response and number of mutations per megabase, which also holds true in a modest way for both progression-free and overall survival. So, TMB is somewhat predictive of favorable outcomes. It's not a perfect biomarker by any means, but generally speaking, if you have enough patients, you can define this sort of trend to support the notion that the more mutations, the greater the likelihood of benefit. Shannon Westin: That makes a lot of sense. One other thing that I just wanted to comment on before we kind of bring the podcast to a close is I was really struck by the high proportion of underrepresented minorities in this arm of TAPUR, and I just would love to hear your thoughts on how the design improves recruiting in this population of patients. Dr. Richard Schilsky: This was a goal of the study, very intentional. When you look at the overall study demographics, there are about 2800 patients now that have been enrolled on TAPUR overall. Almost 12% are black, about 6% are Hispanic, about 4% Asian. The median age is about 64. So it's a slightly older population. The goal always was to enroll a population of patients in TAPUR that was broadly representative of the patients that oncologists treat in practice. In the way we accomplished what we've accomplished, we still have work we can do to improve it. But the clinical sites were carefully selected and vetted. We focused on sites that served a significant fraction of minority patients. We made the eligibility criteria simple and broad, so many of the eligibility criteria that might typically exclude minority populations or older patients from clinical trials are not exclusion criteria in TAPUR. We made the operations of the trial simple, so patients really aren't asked to do much more than what they would normally be asked to do in the course of their routine cancer care. So I think all of those things together have made it possible to attract and enroll a more representative patient population in the study. And we're very gratified by that because when you look at many of the registration trials for many cancer drugs, minorities and older people are terribly underrepresented. So we feel that TAPUR is adding value there and adding useful information. Shannon Westin: I think it's so generalizable and really the way people are practicing, and so to see similar results or concordant results, despite not as much of the rigorous testing and potentially exclusion of certain patient populations is really reassuring and certainly very exciting.  The last question is what's coming next? What other arms are coming soon? And can sites still join? Is this something where it's ongoing enrollment and participation? Dr. Richard Schilsky: So sites can still join. There's a place on the ASCO website where sites can find more information about TAPUR, and there's essentially a form available where sites can indicate their interest in joining the study. And then those sites are then evaluated by the TAPUR study team to determine if they meet the minimum necessary requirements to qualify to join the study. There's a lot more data coming out, many more papers that are in press and being written. There are two abstracts that will be presented in April at the AACR meeting. There are three abstracts that have been submitted for the ASCO annual meeting. So a lot more data to come.  This is a study that, at least hypothetically, could continue in perpetuity as long as we're able to continue to attract new drugs and new treatment combinations onto the TAPUR study platform. So the TAPUR team is always on the lookout for drugs that are about to get an FDA approval and that could be appropriate for the TAPUR study and continue to talk to many pharmaceutical companies about their interest in potentially putting their drugs on the platform. Shannon Westin: Well, great. Thank you both for taking the time. I know you're both incredibly busy.  Again, this has been “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study.” I'm your host, Shannon Westin, and I'm so grateful that you joined us on JCO After Hours. Please check out our other offerings on the website or wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Duvivier's COIs: Speakers' Bureau Company name: Guardant Health Company name: AstraZeneca Company name: Regeneron  Schilsky's COIs: Leadership Company name: Clarified Precision Medicine Company name: Leap Therapeutics Stock and Other Ownership Interests Company name: EQRx Company name: Leap Therapeutics Consulting or Advisory Role Company name: Cellworks Company name: Scandion Oncology Company name: Bryologyx Company name: Illumina Company name: EQRx Company name: Syapse Company name: Zephyr AI Company name: AADi Research Funding Company name: AstraZeneca Company name: Bayer Company name: Bristol-Myers Squibb Company name: Genentech/Roche Company name: Lilly Company name: Merck  

Dr. Shannon Westin and her guest, Dr. Reshma Jagsi, discuss the paper "Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA" recently published in the JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth with manuscripts that were published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the JCO. It is my pleasure to speak with Dr. Reshma Jagsi. Hello, Dr. Jagsi. Dr. Reshma Jagsi: Hello. Thanks for having me. Shannon Westin: I am so excited that you're here. Dr. Jagsi is the Lawrence W. Davis Professor and Chair of the Department of Radiation Oncology at Emory University School of Medicine, Winship Cancer Institute. She is going to be talking about her incredible work, "The Omission of Radiotherapy After Breast Conserving Surgery for Women with Breast Cancer with Low Clinical and Genomic Risk: Five-year Outcomes of IDEA," which was published in JCO in February 2024.  All right, let's get right to it. First, I want to levelset. Can you run us through some brief facts and figures about breast cancer just to make sure that all the listeners are on the same page?  Dr. Reshma Jagsi: Breast cancer is the most common cancer in the world. It's 12.5% of all new annual cancer cases worldwide and is the most commonly diagnosed cancer among US women. About a third of all newly diagnosed cancers in women are breast cancer, and about 13% of US women develop invasive breast cancer over their lifetime. In 2023, there were nearly 300,000 new cases of invasive breast cancer. The median age of breast cancer diagnosis is 62, meaning an awful lot of people are getting diagnosed with breast cancer in the population that we specifically chose to study.  Shannon Westin: Wow, you're really good at this. That's like the perfect transition to move to the next piece. So, first, I think I'd love to hear about the standard of care for the population that you were studying and how we got to this point.  Dr. Reshma Jagsi: We offer women who are diagnosed with early-stage invasive breast cancer the option of breast conservation, and we encourage breast conservation because, of course, it is a better-tolerated surgery than mastectomy. Many women are eligible for breast-conserving therapy. And years ago, we as radiation oncologists encouraged our surgical colleagues to refer to breast-conserving therapy as lumpectomy plus radiation, just as one set. Because the studies that have been done in the 1970s and 1980s to establish that breast conversation was equally safe and effective in treating breast cancer relied on radiation therapy to minimize in-breast tumor recurrence rate, which one of those trials independently showed that there was no difference in survival. But the ones that compared lumpectomy surgery alone to lumpectomy followed by radiation therapy did show a pretty substantial improvement in local control with the addition of radiation treatment. And so radiation treatment became a part of a parcel of breast conservation in the early 1990s when consensus statements came out favoring breast conservation as a treatment approach.  And so the net analysis has combined all of these studies together and showed that overall, without radiation treatment, a patient treatment with a lumpectomy had a 30% risk of in-breast tumor occurrence in those historical studies. And it was reduced by about two thirds to about 10% when that lumpectomy was followed by radiation in those historical randomized trials. But of course, we've made many advances in our understanding since that time, and so that's what this study is seeking to build on. Shannon Westin: It makes sense. We all know that radiotherapy can lead to other issues, acute and chronic morbidities, as well as cost and having to do the treatment itself. So we're all interested in de-escalation of therapy. Tell me, prior to your study, what data were out there potentially supporting the de-escalation and avoiding radiotherapy in that specific population? Dr. Reshma Jagsi: In the ‘90s, after those landmark foundational historical trials have been completed, there was a lot of interest in seeing if we could identify a population of patients in whom the risk of local recurrence was sufficiently low that they might safely choose to omit radiation therapy. All of these randomized trials have shown very consistently that there is a relative risk reduction. Whatever your risk is without radiation, radiation reduces that risk. The overall disease recurrence risk is cut in half with the addition of radiation treatment. But, if I told you that your overall risk was 1%, and I could cut that in half with radiation, you might say, “I might be willing to tolerate the 1%.” At least some women might be willing to tolerate that. So can we find a population in whom the risk is low enough that at least some of those women say, "Look, I want to go without radiation." And of course, the balance of where that number should be changes as we get better and better at delivering radiation. So you mentioned, radiation comes with toxicity, comes with burden and yet, there have been some tremendous advances, and particularly in recent years, to shorten the course of radiation. We have evidence that we can treat partial breast radiation safely in five treatment fractions. We have five-year data that we can treat the whole breast in five-treatment fraction. We certainly have long term evidence that we can the whole breast with 15 fractions from many patients diagnosed with breast cancer. So the burden has decreased. We've also found that with hypo fractionated shorter courses of radiation, the toxicities are much lower, patients tend to tolerate radiation treatment both in terms of acute side effects and long term side effects extremely well.  So that balance of what is low enough is changing with time.  But the trials that were started in the 1990s included the CALGB 9343 trial, a landmark trial published in the New England Journal of Medicine, with its five-year results showing only a 4% risk of recurrence at five years in patients who were 70 or older with clinical stage one disease that was hormone receptor-positive if they received a lumpectomy and tamoxifen alone, not receiving radiation - that risk, if we added radiation in this randomized trial, was only 1%. So there was still a substantial relative risk reduction with radiation treatment. This was published in 2004 in the New England Journal of Medicine.  At the same time, there was a Canadian trial that was published, and in that trial that included women who were 50 years of age and older, there were more concerning results with, even in a very favorable prespecified subgroup of patients who had node-negative breast cancer and T1 hormone receptor-positive tumors, the risk of ipsilateral breast tumor recurrence was 15% at eight years. So that started to feel excessive for women 50 and older.  Meanwhile, we went on to get the update of the CALGB trial, and the 10 -year results showed that the risk was, in the women 70 and older, was only about 10% without radiation. It was 2% with radiation. So again, there was a benefit from radiation, and it's up to each individual woman to decide whether they'd prefer to proceed and minimize their risk, or would be willing to tolerate something like a 10% risk. More recently, just this past year in the New England Journal, the PRIME 2 study from the United Kingdom, looking at women 65 and older, again, early-stage node-negative hormone receptor-positive tumors, and very similar results - 10% versus 1% local control at 10 years.   So you get an improvement with radiation. But there are some women who are 65 or 70 and older who say, I'm willing to tolerate the 10% risk. And so the question was, could we identify some patients who are younger than 65 to 70, but still postmenopausal, like in that Canadian trial, who might actually have similar outcomes - low risks at five and ten years - such that they might want to entertain the option of omitting radiation therapy, which right now is not standard or in any guidelines? So we have some promising information from some retrospective analysis of that Canadian trial that suggested that looking at biology might help. And in fact, the LUMINA trial, published just this year from Canada, did a prospective cohort study selecting patients based on immunohistochemistry, and suggested very low risks, five years in patients who were somewhat younger, although it ended up that the median age of the patients in that study was 67. So we still sort of had this question of what about the younger postmenopausal patients? And that's what took us to IDEA.  Shannon Westin: And just for my education and for the education of the listeners, when you have an in-breast recurrence, how likely are you to be able to cure that? Is that tough to cure, or can you usually get control again? Dr. Reshma Jagsi: It's an excellent question. And so often these recurrences are caught early and are still completely curable with additional intervention. Now, there can be an impact, of course. You can talk to any survivor about the devastating impact of being diagnosed with breast cancer recurrence, and no one wants to go through that. And so there are reasons that people will want to reduce that, and there are implications for breast conservation because it may be that the remaining breast tissue is insufficient to allow a second breast conserving surgical procedure. It may also be that when one experiences recurrence, one decides, "I'm done with this. I'm having a mastectomy at this point." So, in-breast recurrences are very meaningful to patients and something that we should not take lightly. Shannon Westin: It seems, though, the majority of the studies that you were talking about, aside from the LUMINA study, were predominantly based on those clinical features like stage and things like that. So, can you talk a little bit about the role of molecular features, genomic testing, things like that, to select patients?  Dr. Reshma Jagsi: Yeah. So, we have seen a tremendous change in the way we think about breast cancer in recent years, with a real focus on tumor biology, rather than classic clinical pathologic features alone to help us make decisions about systemic therapy. And so, there is a body of work that suggests that genomic assays, including the 21-gene recurrence score, that's commonly used for treatment decision making already ordered in many of these patients and available to us, that it may be useful in understanding patients' risk of local recurrence, both when they are treated with radiation and when they are treated without radiation. So, Terry Mamounas did some wonderful work looking at NSABP data where you know that the mastectomy patients at the time of the studies that were included were not receiving radiation treatment. And it did appear that the 21-gene recurrence score was helping to discriminate for local regional recurrence risk, suggesting it might be useful to use that to select patients who might be at lower risk.   Shannon Westin: All right, perfect. So, that leads us to your study. So, let's talk a little bit about the design and the population and kind of how you put it together.  Dr. Reshma Jagsi: This was really a true collaboration, a partnership across multiple 13 collaborating sites, where my colleagues, the lead investigators at each site, were extremely committed to this question. And we sought to do a preliminary cohort trial, really involving 200 patients. And over the course of three years, we enrolled those 200 patients who were aged 50 to 69 years old and had unicentric invasive breast cancer and lumpectomy surgery that led to negative margins of 2 mm or greater. And their disease needed to be PR positive, HER2 negative, it needed to be node negative, pathologically node negative, and the Oncotype DX 21-gene recurrence score needed to be less than or equal to 18. And then these patients were offered the opportunity to consent and register on a trial to receive five years of endocrine therapy as standard of care alone, and 10 years of surveillance on study, or to proceed with the standard of care treatment off trial, which would have been a recommendation to receive radiation treatment. And so, we ended up with patients with a mean age of 62 years, which, as I said, that's really more mapping the overall population of patients in the country. And we were able to report our results at the San Antonio Breast Cancer Symposium and with simultaneous publication in JCO, with a median follow up of 5.2 years. Shannon Westin: Okay, and let's talk about a little bit about your major findings. Tell us what your good work demonstrated. Dr. Reshma Jagsi: So, the overall and breast cancer-specific survival rates at five years were both 100%, and the five-year freedom from any recurrence was 99%, with a 95% confidence interval that went from 96% to 100%. But I want to emphasize that these are five-year data in a younger postmenopausal population, where five-year data are not typically sufficient to guide decision making. So, I really want to emphasize that these are very early results. But really, what happened here was we only had a couple of patients who had recurrences before five years, two patients, and that was one isolated ipsilateral axillary recurrence, and one ipsilateral breast event. But we also did see six additional patients who recurred later than five years after breast conserving surgery. And because we don't have much long-term follow-up, it makes it incredibly important for us to continue to follow this cohort over time before people make any Monday morning practice implications of offering this cohort of patients, or patients like this cohort of patients, omission off trial.  The good news is that there are ongoing trials that are building on this work, including NRG-BR007, the DEBRA ,that includes a population of patients really similar to those enrolled on IDEA and randomizes them to radiation or no radiation, which is actually incredibly important. Because what we want to understand is also the quality of life effects of omitting radiation therapy because what we don't want is to inadvertently cause an increase in worry about recurrence. Or, you could imagine that patients who omit radiation treatment then feel really stuck with their endocrine therapy. Now, endocrine therapy is the standard of care, but if they're experiencing terrible endocrine therapy side effects and they didn't get radiation treatment, are they more likely to persist with that endocrine therapy and to be miserable because they omitted a treatment that, as I mentioned earlier, can be administered now in five days or less?  And one of the questions that keeps coming up from older patients that I treat, where we already offer the option of omitting radiation, those CALGB and PRIME II patients, those patients will often say to me, "I've got to say, Doc, that whole experience of radiation that you described for five days, and the toxicity, and that doesn't sound so bad to me. What sounds bad to me is multiple years of endocrine therapy." And so, there are also ongoing trials in Europe, and I hope one day in the United States, also looking at older women and offering them a de-escalation of a different sort. Now that we have made so many advances in radiation treatment, maybe the optimal monotherapy for an older adult is actually, for many patients, given their values and preferences, going to involve omission of endocrine therapy. And we need to find out if that's safe. And again, Europa in Europe is investigating that question, and I hope that the American cooperative groups take up something similar. Shannon Westin: That's awesome! And what else is going on in this space? Any other trials? That was like, such a great review of ongoing trials, and I'm sure our listeners would love to have your expertise. Anything else that you're looking forward to that might impact the treatment landscape here? Dr. Reshma Jagsi: Absolutely, and if there are listeners in other parts of the world, there are trials going on also looking at this. There is PRIMETIME, which is a cohort study designed, but with a much larger cohort that's going on in the United Kingdom. There's the EXPERT trial that is randomizing patients to radiation treatment or not in Australia and New Zealand. So, there are many trials that are ongoing, again, looking at de-escalation of radiation therapy. And I want us all, regardless of our specialty, to think about ways that we can de-escalate and optimize the options that are offered to our patients. And I think there's a tendency for patients to be very scared of radiation, sometimes, for our colleagues to be very scared of radiation. I mean, we are the only specialty that has a special “danger radiation sign” that comes to mind when you hear the word radiation therapy. So, it can be this very frightening thing that we often leap to efforts to avoid.  And what I don't want to be the conclusion of this is, “Isn't it great? Radiation oncologists themselves recognize that radiation is terrible and that you should avoid it.” That's not the case. What I hope people will say is, “Isn't it great that radiation therapists are trying to offer as many options to patients as possible?” Because it means a lot to a patient who's had the sense of power and control and autonomy ripped away from them by a breast cancer diagnosis, to be given many options to articulate their values and their preferences and to decide what treatment makes most sense for them. I think, for a lot of patients, that involves radiation treatment. And I think what we need to do as physicians is think about what other things are our patients really concerned about.   Our medical oncology colleagues have done tremendous work to de-escalate systemic therapy in the form of chemotherapy. Our colleagues in surgery have, again, de-escalated mastectomies, axillary dissection. So, there are these ongoing efforts, and I do honestly believe that the next frontier is endocrine therapy and optimization of endocrine therapy. It is so powerful. It is why we have such wonderful outcomes. We know that we should have a healthy respect for ER-positive cancer, which can recur in the long term. We don't want to throw out the baby with the bathwater, but baby steps towards understanding what happens if we peel back our treatments is our obligation.  Shannon Westin: I think this is a perfect place to end/ I agree - less is more is really becoming a resonant statement across all of our different subtypes. We're certainly seeing it in GYN oncology, and just like you said, systemically or even surgically. So I agree. I think we have a call to action to really assess what we've always done and make sure that we're not over-treating patients for whom it's inappropriate.  So I think this is great. And I just want to commend you again on your work. These types of multicenter trials are really hard to do, and getting it done in such a short period of time and really getting the data out to patients is so important. And I appreciate what you're saying about needing more follow-up, but it is certainly very reassuring and very in line with what we've seen. So congratulations on your work. Dr. Reshma Jagsi: Thank you. And I just again want to thank all the patients who enrolled, the Coleman Foundation for their support, the University of Michigan for doing the multi-site coordination and the biostatistic support, and all of the collaborating investigators. I mean, this was a labor of love for everyone involved. Shannon Westin: Yeah, these types of trials definitely take a village. Well, great work. Thank you for taking the time. I know how busy you are. So again, we are so honored and so excited to talk about "The Omission of Radiotherapy After Breast Conserving Surgery for Women with Breast Cancer with Low Clinical and Genomic Risk: Five-year Outcomes of IDEA,” just published in print, February 2024 in the JCO. Definitely check it out. And please check out our other episodes of JCO After Hours. We'd love to have your feedback. Take care. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Dr. Jagsi: Stock and Other Ownership Interests Company name: Equity Quotient Research Funding Company name: Genentech"

JCO PO author Dr. Eric Klein shares insights into his JCO PO article, “Performance of a Cell-Free DNA-Based Multi-Cancer Detection Test in Individuals Presenting with Symptoms Suspicious for Cancers” Host Dr. Rafeh Naqash and Dr. Klein discuss how a multi-cancer detection test may facilitate workup and stratification of cancer risk in symptomatic individuals. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.   Today, we are excited to be joined by Dr. Eric Klein, Emirates Professor and Chair at the Glickman Urological and Kidney Institute at the Cleveland Clinic Lerner College of Medicine. Dr. Klein is also a distinguished scientist at Grail and author of the JCO Precision Oncology article titled "Performance of a Cell-free DNA-based Multi-cancer Detection Test in Individuals Presenting with Symptoms Suspicious for Cancer."   Our guest's disclosures will be linked in the transcript.  For the sake of our conversation today, we'll refer to each other using our first names. It's great to have you here today, Eric, and welcome to our podcast.  Dr. Eric Klein: Thanks, Rafeh. I'm happy to be here. Dr. Rafeh Naqash: So today, we're going to try to delve into this very interesting paper. We've had a couple of very interesting podcasts on liquid biopsies, or plan to have a few more. And this is a different aspect of liquid biopsy assessment, and the context here is early cancer detection. Now, the story as it starts, is based on the methylation profile of cancer. Can you tell us, for the sake of our listeners, as we have a very broad audience ranging from trainees to community academic oncologists, what do you understand by methylation profile on a cancer? Dr. Eric Klein: Sure. Happy to start with that. There are lots of cancer signals in the blood. Cancer cells secrete or otherwise supply the bloodstream with DNA that has methylation signals that are specific to cancer. That's a hallmark of cancer-specific mutations. You can look at chromosome fragments, you can look at proteins and mRNA and exosomes and that sort of thing. In Grail's development study, we focused on using methylation because that, as I mentioned, is a fundamental process. A fundamental property of cancer cells is altered methylation. And in our original development studies, that was the strongest signal, the one that allowed us to have the lowest limit of detection when cancer was present, and the one that allowed us to have the best predictive accuracy for the cancer signal origin. Some people think about that as predicting the tumor origin or the tumor type. And that's the basis of Grail's assay, a pan-cancer methylation profile. Dr. Rafeh Naqash: Excellent. And now to understand some of the methodology that you used here, before we go into the details because there's a lot of sensitivity and specificity obviously associated with any cancer detection test, and you want a high sensitivity and specificity. And the idea here is that this would help in triaging patients appropriately using this non-invasive tool. Could you tell us the patient population that you were trying to enroll in this study? And I think there is, again, background to other studies that you have done using the Grail test. Could you put that into context of this specific study?  Dr. Eric Klein: Sure. The population in this particular publication was from substudy 3 of a much bigger study called the Circulating Cell-free Genome Atlas, or CCGA. That was a discovery, refinement, and validation study of this methylation-based signal. And in total, all three substudies together was about 15,000 people, and it was a case-control study. About 10,000 of the individuals enrolled had cancer and about 5000 were not known to have cancer and served as controls. In the first part of the study, substudy 1 of CCGA, we simply asked the question: In individuals with known cancer, could we detect a methylation-based signal? And the answer was ‘yes'. The second question was: In patients not known to have cancer, did we not see a signal? And by and large, the answer was ‘yes'. The second substudy was a refinement and validation of the original methylation-based test. And then this study, what we refer to colloquially as CCGA3, or substudy 3 of CCGA, was the final validation that underlies the methylation assay that is currently on the market.   So, in CCGA3, we determined what the performance characteristics of this test were in a case-control fashion, and what we found, importantly, was that the specificity was very high, at 99.5%, which means the false-positive rate is only half a percent. We found that the overall sensitivity for detecting cancer varied by stage, but when you included all stages 1 to 4, the overall sensitivity for detecting known cancers was about 51%. We found that the ability of this methylation-based test to predict the correct cancer signal origin was right around 90%. And finally, the final performance characteristic was really important, which is the positive predictive value. So in individuals who had a positive signal detected, the positive predictive value was 43%, which compares very favorably to existing screening tests, all of which are below 10%.  That was the background, and the development there was focused on eventually developing a test that will screen the general population, the asymptomatic population, at risk for developing cancer. This is a subset of CCGA3, or the substudy 3 of CCGA, where we looked at the performance characteristics of this test in individuals who had symptoms that could possibly be due to cancer and individuals who had underlying medical conditions that could result in a false positive, and individuals in particular over age 65, because the risk of cancer goes up over age 65. Dr. Rafeh Naqash: Thank you for explaining that. So, again, going to some of the finer details in this study, you mentioned some very important numbers here, 99%, 63%, or something in that range for sensitivity and specificity. Could you explain a little more on that based on the cancer types? As you mentioned, stage 4, when I read the paper, has more true positives likely based on or related to how much cell-free DNA is released in the tumor. The tumor burden may be playing a role there. Could you explain that a little more for our listeners? Dr. Eric Klein: A cancer that sheds cell-free DNA into the bloodstream is more likely to be aggressive, and that's been shown in multiple different studies using multiple different platforms. And the reason for that is that the ability to shed cell-free DNA into the bloodstream goes along with biologic processes that we know are related to tumor aggressiveness. So that's a higher mitotic rate, it's neovascularization or the angiogenic switch, it's the ability to be an invasive cancer. And so the fact that you can detect cell-free DNA in the bloodstream implies some degree of biologic aggressiveness, which is not to say that tumors that shed cell-free DNA into the bloodstream are not curable. They are, in fact, curable at the same rate as cancers in people who are not tested for cell-free DNA. We know that for sure. It's just a signal that is there for us to exploit for the detection of cancers in asymptomatic individuals. And the hope is when we screen the general population, the general asymptomatic population for cancer, as we do with mammography and colonoscopy and PSA and so forth, that we can detect cancers at earlier stages, when they are far easier to cure. So I mentioned in CCGA3 that the overall sensitivity across all stages for detecting the presence of known cancers was 51%. That varied from about 16% for stage 1 cancers to 40% for stage 2 cancers to over 80 and 90% for stage 3 and 4 cancers. Dr. Rafeh Naqash: Right. And again, to provide more background to this, what we've come to understand gradually, as you mentioned, is that shedding is an important event in cancer trajectory. Do you think detection of cancers that are likely positive, driver mutation positive, have a lesser tendency to shed and maybe resulting in lesser tendency to earlier detection also, or is that not something that's true?  Dr. Eric Klein: No, I don't think it has anything to do with the presence of driver mutations. The methylation signal that we see is a reflection of the perturbation of methylation in normal cells. So normal cells turn genes on and off using methylation. That's well known. Cancer cells exploit that biologic process of methylation by - in a gross oversimplification, but in a way that makes it understandable - they use methylation to turn off all the genes that prevent cell growth and turn on all the genes that allow cells to proliferate and get all these other biologic properties that make them invasive and so forth. So it's really important to understand that the test that was used in this study and that was developed in CCGA3 measures a shared cancer signal across multiple different cancer types. In CCGA3, we were able to detect more than 50 different individual kinds of cancers. It's a shared cancer signal that is fundamental to the biology of cancers, not just a specific cancer, but cancers.  Dr. Rafeh Naqash: I see. I think what I was trying to say, basically was, when we do liquid biopsies in the regular standard of care clinic, and you're trying to assess VAFs or variant allele frequencies for a certain mutation, you tend to see some of these BRAFs or EGFRs that are very low VAF, and the data that I've seen is that you treat irrespective of the low VAF, if it's a driving mutation process. If your VAF is 0.1%, you still treat it with a targeted inhibitor. The context that I was trying to put into this is it all depends on shedding. So this liquid biopsy that we currently use, whether other platforms that are out there, if you're not shedding as much cell-free DNA or circulating tumor DNA, you're probably not going to catch that subclone or clone that is a driver. So, does that play a role in your test also? If you have, let's say, a lung cancer that is an EGFR stage 4, if the shedding is low, following a general conceptual context that these driver mutation-positive tumors do have less shedding in general than the non-driver mutation-positive, would you think that would somehow impact the detection using your test or your approach? Dr. Eric Klein: So, generically speaking, any test that looks for a cancer signal in blood is going to have a lower limit of detection. So there are analytic variables that make it such that, if you have extremely low levels of cell-free DNA or your other target shed into the blood, it's not going to be detected by the test. That's an analytical issue. Having said that, it's important to distinguish the fact that this test that we're developing isn't really a liquid biopsy. A liquid biopsy, really, if you think about it, is on patients who have known cancer, and you're doing a biopsy of the blood to determine if you can see a signal in the blood. This test has been developed to screen asymptomatic individuals who are at elevated risk of cancer, who actually may not have cancer. So we don't really view it as a liquid biopsy. But conceptually, you are correct that every test is going to have an analytical lower limit of detection so that not every tumor that sheds minuscule amounts of cell-free DNA will be detected. But that's not really relevant to this particular paper, I would say. It's not really relevant to the performance characteristics that we saw in this population. Dr. Rafeh Naqash: Understood. Thank you for differentiating the usual liquid biopsy approach that we use currently in the clinic, and this approach, which is meant more for detection in asymptomatic individuals.  Going to some of the results, could you highlight some of the interesting findings that you had in this paper as far as performance is concerned? Dr. Eric Klein: Sure. Let me put it in a clinical context because we were just discussing asymptomatic individuals. That's what the test is ultimately meant for - screening asymptomatic individuals. But a common problem in oncology is this: patients present to primary care physicians with vague or nonspecific symptoms. Someone with COPD, for example, who presents with a cough, the cough could be due to the COPD, but if they have an underlying lung cancer, the cough could also be due to the lung cancer. Or someone presents with GI symptoms, could be related to cancer, or it could be related to a whole host of other things. And so there is a challenge for primary care physicians to sort out who might have cancer and who does not, particularly if they present with vague symptoms. In fact, most cancer diagnoses in the United States and Great Britain are actually found by primary care providers.   In this paper, we looked retrospectively, after the fact, in CCGA3, the case-control study that we did, to see how this methylation-based test performed in individuals who had symptoms that could be associated with cancer, or could be due to cancer, or might not be, might be due to other things. What we found was that the performance characteristics were as good or better in this symptomatic population, where the physician is facing a diagnostic dilemma, as they were in the asymptomatic population. This is really important, specificity false negative rate across all the patients in the study was the same as it was in CCGA3. It was 99.5%. Again, the false positive rate was only 0.5%. We found, however, that overall sensitivity was better in the symptomatic population, and it was 64% instead of, or as compared to 43% in the asymptomatic population. That is not surprising because some patients who present with symptoms are more likely to have cancer.   We also looked at a subset of patients who had GI cancers because that's a very, very common presenting symptom in primary care practice, and this test performs exceptionally well for detecting GI cancers. We found that the overall sensitivity was 84%. Finally, and importantly, in terms of the clinical utility of a blood-based test to detect cancer and direct a diagnostic workup, what we call the clinical signal origin accuracy - the likelihood or prediction that a positive signal was related to a particular tumor type - overall accuracy in this population was 90%. So if you had a cancer signal detected and you had a clinical signal of origin assigned to it, let's say, the test came back with cancer signal detected, the CSO prediction was GI cancer, the overall accuracy in actually finding a GI cancer was 90%. Actually, it was a little higher for GI cancers, but overall, for all cancers, it was 90%. Dr. Rafeh Naqash: You mentioned that GI cancers had a very high sensitivity, around 84% or so. Is that, again, related to the tumor shedding compared to some other tumor types?  Dr. Eric Klein: Yes, there is a broad range of shedding across tumor types. So if you look at our data from CCGA, cancers like thyroid, prostate, and kidney do not shed a lot of cell-free DNA into the bloodstream, whereas GI cancers, hematologic malignancies, ovarian and pancreatic cancers shed much more cell-free DNA, and therefore their sensitivity for detection of those cancers is better.  Dr. Rafeh Naqash: What would be the alternate approach? Your sensitivity here is 64%, which is pretty good, but it's not perfect. So the patients who potentially would be missed using this test, what would be the alternate approach capturing those patients also and hopefully avoiding a missed cancer diagnosis?  Dr. Eric Klein: Well, it would be whatever the standard workup is that a primary care physician orders for someone who has vague symptoms. So, he idea here was to develop this, what we call a diagnostic aid for cancer detection in the symptomatic population. The idea here is to make the workups more efficient and to lend a greater degree of certainty as to what the diagnostic pathway ought to be. So, if you have a patient with vague symptoms and you're not sure if they are due to cancer or not, you might order a pretty broad diagnostic evaluation that might not end up finding cancer. In fact, if you take all the patients in a primary care setting, only about 7% of those individuals have cancer. Whereas, if you have a blood test that has a sensitivity of 64% and a positive predictive value of 75%, and you did that blood test early in the diagnostic workup and it was positive, you can do a much more tailored and perhaps a more efficient evaluation in speeding the diagnostic resolution.  Dr. Rafeh Naqash: As you mentioned, perhaps avoid unnecessary testing, which adds to the overall cost burden in the healthcare field.   Dr. Eric Klein: Correct. This was tested in another study called SYMPLIFY, which was done in a similar population of patients as this study - symptomatic patients presenting with vague symptoms or GI symptoms or weight loss, fatigue, those sorts of things, to primary care practice in the UK. And that was a prospective study. And the performance characteristics were very similar to what we saw in this study, although the overall positive predictive value in that study was 75% if you look at all cancers. And that would be very useful to a primary care physician and a patient to know what the likelihood of their having cancer is at the time they present or within a few days of presenting. Dr. Rafeh Naqash: Absolutely. And perhaps, to complement this approach with some of the other diagnostic approaches, maybe the possibility of detecting cancer earlier increases. So this is likely complementary and not necessarily the one-stop-shop. Dr. Eric Klein: It's important to understand that even in the symptomatic population, this is a screening test. And so, like all screening tests, if you have a positive mammogram that shows a nodule, you need to have a diagnostic workup to prove whether or not you have cancer. This blood test does not make the diagnosis of cancer; it simply helps direct a diagnostic evaluation that's necessary to confirm whether or not cancer is present or absent. That's true for both the asymptomatic and symptomatic populations. Dr. Rafeh Naqash: Could you tell us a little bit more about the CSO prediction in the general context of oncology and NGS, or the whole transcriptome sequencing that we do these days? We often see on a report that says,“What is the likely tumor of origin?” if you have an unclear primary. Can you explain that in the context of the approach that you guys use for CSO prediction? How does it differ from methylation versus mRNA prediction of tumor of origin or cell of origin?  Dr. Eric Klein: Methylation has a rich signal in it, and it can distinguish cancer cells from a non-cancer signal, and using a second algorithm, specific methylation patterns that are specific to given lineages can identify lung cancer versus colon cancer versus liver cancer.  Dr. Rafeh Naqash: Understood. Do you see this as becoming an approach that could be used, using, for example, urine or other sources that we can easily acquire versus blood? Dr. Eric Klein: Possibly. There is a lot of work in the field looking at urine-based markers for cancers, particularly, obviously, urologic cancers. And so there are already some products on the market made by other companies using methylation and other specific mutation patterns, for example, in urine to detect bladder cancer and to determine bladder cancer aggressiveness. It is an area of active investigation.  Dr. Rafeh Naqash: This is definitely an exciting field, and the way the entire field of liquid biopsies in general is moving as it's detecting cancers or identifying mutations, and then implementing appropriate approaches, whether it is more screening or more treatment and all the drugs, etc.  Are there any other interesting future approaches that you guys are planning as part of this paradigm shift that I envision will hopefully happen in the next few years?  Dr. Eric Klein: Yes, as a company, Grail is focused on using this methylation-based technology across the entire cancer spectrum. So that's screening asymptomatic individuals, it's helping to direct diagnostic workups in individuals who present with symptoms to primary care practice, and also in the post-diagnostic space and all the possible uses there. So the detection of minimal residual disease and the decision on whether or not additional treatment is necessary, predicting response to particular therapeutic agents, or even choosing the correct therapeutic agents. All of that is under development. Dr. Rafeh Naqash: Definitely exciting. Now, the last portion of this podcast is specifically meant to highlight your career and know a little bit more about you. Could you tell us about your career trajectory and how you shifted focus towards a biomarker-driven approach?  Dr. Eric Klein: Sure. Biomarkers have been a part of my career for a long time. I am trained as a urologic oncologist and did my residency in urology at the Cleveland Clinic and a fellowship at Sloan Kettering. At the dawn of the molecular biology era, the lab I worked in bought one of the very first PerkinElmer RT PCR machines for $5,000. It took up a whole desktop. I got very interested in genomic science at that time. So I spent well over 30 years practicing urologic oncology at the Cleveland Clinic, primarily focusing on prostate cancer. In the course of my career, I had the opportunity to work on a number of blood-based, urine, and tissue-based biomarkers. I have always been interested in understanding how our ability to measure molecules in blood and urine can help improve patient outcomes either through a streamlined diagnostic process or understanding of the biology of the disease better, picking the appropriate therapy, and so forth.  In the course of that, I worked with someone at a company called Genomic Health in developing  a biopsy-based RT PCR gene expression assay that helped select men for active surveillance. That individual subsequently joined Grail and he came knocking on my door in 2016 when Grail was just getting started to tell me about this exciting new technology. He said, “This isn't about urologic cancers in particular, but would you be interested in helping us accrue patients for this big clinical trial we're doing, CCGA, and determine if this technology would be useful in some way in helping patients.” And being the curious individual that I am, I said, “Sure.” And so I helped accrue lots of patients to CCGA. The results were shared, and I was quite excited by them and continued to work with the company on other studies, including PATHFINDER and some others, and eventually became a consultant for them.  When I reached what I thought was the end of my clinical career by choice, I decided to step away from clinical practice, I had the opportunity to join Grail as a scientist, and that's where it's been. And what I would say, in the big picture, is this: as a surgeon, I was able to help a lot of patients on an individual basis. So I did about 10,000 major cancer operations in my career. So I helped those 10,000 people. As an academician, I was able to make certain observations and publish them in a way that taught people about different kinds of surgical techniques and how they may work better, and so I was able to expand my impact beyond the patients that I actually touched.  When I heard about and understood what Grail was trying to do, I thought, “Wow, if we could develop a screening test that detects lots of cancers that we don't screen for - about 70% of all cancer deaths in the US are from cancers that we have no screening tests for - and if the screening population in the United States, individuals between ages 50 and 79, that's how CMS defined screening populations, well over 100 million a year, if this works, think about the impact that that could have.” That is really why I got excited about it. It fit my scientific interest, and I could see the big picture.  Dr. Rafeh Naqash: Thank you for giving us some insights about your personal career. It is definitely a very interesting topic. I learned a lot, and hopefully, our listeners will find it equally interesting. Thank you again for being here today.  Dr. Eric Klein: My pleasure. Thank you for having me. Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to rate and review this podcast, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast. The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   The guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not reflect the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.        

In this JCO Precision Oncology Article Insights episode, Miki Horiguchi provides a summary on “Clinical Trial Diversity: A Bend in the Arc Towards Justice”, by Tannenbaum, et al published on September 19, 2023 in JCO Precision Oncology. The editorial discusses the need for inclusion of under-represented groups in clinical trials. See the accompanying Original Report, “Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP),” by Vaidya, et al as well as an interview with co-author, Dr Mary Redman. TRANSCRIPT Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Miki Horiguchi, an ASCO Journals Editorial Fellow. Today, I will be providing a summary of the article titled “Clinical Trial Diversity: A Bend in the Arc Toward Justice” by Drs. Susan Tannenbaum and Jennifer Miller. This editorial accompanies the article “Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP)” by Dr. Vaidya and colleagues.  In the previous episode of this series, our Social Media Editor, Dr. Rafeh Naqash, interviewed Dr. Mary Redman, a Senior Author of the Lung-MAP article. Dr. Redman shared the background behind the Lung-MAP development, some highlights from her paper, and her career trajectory as a biostatistician. I strongly recommend listening to the interview if you haven't done so. To begin I'll provide a brief summary of the Lung-MAP information before discussing the editorial.  The Lung Cancer Master Protocol or Lung-MAP is a biomarker-driven master protocol that evaluates multiple molecularly targeted therapies for patients with advanced non-small cell lung cancers under a single trial infrastructure. Since Lung-MAP began enrolling patients in 2014, it has addressed the challenges of implementing precision medicine at oncology clinics and assuring equitable patient access to molecularly targeted therapies. In addition to meeting an unmet need in terms of treatment, Lung-MAP meets an unmet need in terms of accessibility to precision oncology clinical trials for all types of patients who get lung cancer in the United States. Specifically, Lung-MAP utilizes a public-private partnership that includes the National Cancer Institute's National Clinical Trials Network, the SWOG Cancer Research Network, Friends of Cancer Research, the Foundation for the National Institutes of Health, Foundation Medicine, pharmaceutical companies, and lung cancer advocacy organizations. There are thousands of sites around the country that can offer Lung-MAP. In the Lung-MAP article, the authors sought to examine whether Lung-MAP improves access to precision oncology clinical trials compared to conventional standalone trials. To this end, the authors compared accrual patterns by sociodemographic characteristics between Lung-MAP and a set of ten clinical trials for advanced non-small cell lung cancer conducted by the SWOG Cancer Research Network. The authors found that patients enrolled in Lung-MAP were more likely to be older, from rural or socioeconomically deprived areas, and with Medicaid or no insurance compared with conventional clinical trials. However, female patients and patients of Asian race or Hispanic ethnicity were underrepresented. The authors emphasized in their conclusion that further research examining participation barriers for underrepresented groups in precision oncology clinical trials is warranted. In the associated editorial with the Lung-MAP article, Drs. Tannenbaum and Miller discuss some efforts to include diverse populations in clinical trials such as those of Lung-MAP and the continuing challenges we are facing.  The editorial begins with a striking example of an industry-funded trial, where pharmaceutical companies submitted a new drug for US Food and Drug Administration approval to treat patients with non-small cell lung cancer in the United States. However, the pivotal trial was conducted wholly in China, enrolling significantly younger patients than those with that type of cancer in the United States. There were no Black nor Hispanic-identifying patients and far more men than women in the trial. The product was not approved by the US FDA. Although the US FDA has approved many other products where the trials were unrepresentative , this example suggests that in order to capture elements in future patient populations in the United States, study samples need to include patients from under-represented groups as well. The authors also introduced a recent study result that showed racially and ethnically under-represented patients, and their clinicians, are more likely to trust and use new medical products when the trials have enrolled a diverse population. This fact suggests that clinical trials that include a higher proportion of women and older adults, as well as patients from racially and ethnically under-represented groups, help to gain acceptance for the drug even after its approval. The authors then introduced some efforts toward enhancing clinical trial diversity, including the National Institutes of Health Revitalization Act of 1993, the Institute of Medicine's 2003 report, the US FDA's 2020 guidance, and the innovative public-private collaboration of Lung-Map. While several studies suggested that clinical trials funded by the National Institute of Health have improved enrollment of patients from under-represented groups, industry-funded trials have still fallen short of these goals. Since industry-funded trials play a crucial role in developing novel drugs, industry must be held accountable for clinical trial diversity and make greater efforts to improve the situation. The authors introduced additional guidance toward this end. They include the US FDA's 2022 new draft guidance to industry, recommending that sponsors of clinical trials submit a Race and Ethnicity Diversity Plan. Another is the Food and Drug Omnibus Reform Act of 2022 where the US FDA can require sponsors to have plans that include diverse populations in their clinical trials. These efforts are pivotal steps in the direction of making biomedical research more accessible and inclusive and lead to promoting health equity across the country. Thank you for listening to JCO Precision Oncology Article Insights and please tune in for the next topic. Don't forget to give us a rating or review and be sure to subscribe, so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.  

Editor’s Choice Paper: Associations between modifiable lifestyle factors and health-related quality of life among endometrial carcinoma survivors - A cross-sectional study Hosted by:Gregg Nelson, MD, PhD, Social Media Editor of Gynecologic OncologyFeaturing:Ane Gerda Z. Eriksson, MD, Oslo University Hospital, NorwayS. J. Kitson, MD, University of Manchester, UK

Dr. Shannon Westin and her guest, Dr. Ash Alpert and Spencer Adams, discuss the paper "Debunking Sex and Disentangling Gender From Oncology" recently published in the JCO. TRANSCRIPT The guests on this podcast episode have no disclosures to declare. Shannon Westin: Hello and welcome to JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, Social Media Editor and GYN oncologist by trade. I'm so excited to be discussing a very important manuscript. This is "Debunking Sex and Disentangling Gender from Oncology," which was published in the JCO Online on May 26, 2023. So I'm joined by two of the authors here today on the podcast. First is Dr. Ash Alpert. They are an instructor of medicine and hematology at Yale Cancer Center. Welcome. Dr. Ash Alpert: Thank you. Shannon Westin: And we also have Spencer Adams. They have a bachelor's in public health, are a certified health education specialist, and are currently pursuing a master's in public health at Western Michigan University. Welcome, Spencer. Spencer Adams: Thank you for having me. Shannon Westin: So let's get into it. I'm so excited. First off, I just want to say thank you because I learned a ton from this paper, and I'm hoping to be able to implement some of these changes that we're going to discuss over the next few minutes at my own institution. So I wanted to just make sure we kind of level set and everyone's on the same page. So let's start off by discussing ontological oppression. Can you explain to the listeners what this means and how it relates to sex and gender and oncology? Dr. Ash Alpert: Sure. So, ontological oppression is actually a concept from one of my colleagues at Yale, Robin Demroff, who's a philosopher. Ontology is a way of thinking about what exists and how we categorize what exists. And so ontological oppression is discrimination or stigma that happens because of the ways people imagine us fitting or not fitting into social categories. For example, if we think that people are women or men based on their sex assigned at birth, then it makes sense that we would think of transgender people and nonbinary people as abnormal, weird, or pathologic. In oncology, if we think of ovarian cancer as something that happens to women and a man with ovarian cancer comes into our clinic, we may be confused or uncomfortable. We may respond to those feelings by denying his identity, for example, thinking he's actually a woman or using the wrong pronouns or name for him or even potentially denying him care. And we have some data to suggest that clinicians respond to lack of knowledge about transgender people by treating them as abnormal, weird, or bad in some way.  Spencer Adams: Yeah. And to add to that, when we consider how we classify people, first, there's a problem within that. There's an ethical problem within that, but it's an idea or a construct that society has created and wants people to fit into these nice little boxes just because it's easier to digest, or you make the person more palatable if they're able to do these things. And life is not like that. We have differences, and we have things that make people fit outside the box. And I believe that when we keep reminding people that a box exists or a social construct exists, you're stifling who they are, their personality, their guiding light. You're stifling a lot of things about that person and ignoring something that's incredibly important to them. Shannon Westin: I think that along those lines, kind of taking that to the next step, it would be really helpful to discuss a little bit more around this interaction between sex assigned at birth and gender and what assumptions are made. And I think you kind of started along this, like, how that impacts oncology care. But in your paper, you did, I think, a really great job of really laying out a lot of the problems that happen in this space, and I'd love to explore that more right now. Dr. Ash Alpert: So sex is a designation made when a baby is born by somebody viewing that baby's external genitalia. And so I think we all, as doctors, know that that designation doesn't necessarily tell us what that person's karyotype is, what their later hormonal milieu will be, what their internal anatomy is, and it certainly can't tell us anything about their gender, which is how someone sees themselves as a man, woman, nonbinary, or something else, and usually develops around the age of four. And even though I think that we all know that, we're so used to sex and gender being used interchangeably, not just in the ways that we talk to each other, but in everything about the way that we do our work. And so it becomes very difficult to disentangle these concepts for ourselves.  And we have used sex in particular as a proxy for so many other factors where it doesn't necessarily function. And parts of medicine are based on that. So it's very hard to start to unpack and disentangle those things. For example, the ways that we talk about certain types of cancer can be linked with gender, like we were talking about earlier, women with ovarian cancer, men with prostate cancer. And that's the way that we talk to each other. But it's also in our clinical trial eligibility criteria, sometimes, it's in our patient facing materials, it's in the ways that we name our clinics, the ways that we talk about our work. So then even just sometimes occupying space to get oncology care can be a form of being misgendered.  Spencer Adams: Yeah, I think it's dangerous to conflate the two, sex and gender. As Ash was saying, that one is a visual inspection, the other is who the person is. And if we claim to be an institution that does patient-centered care, how can we be patient-centered if we are not properly respecting the patient? And to do that, you have to respect their gender as well. I see also one of the things that I want to add to the list is clothing that the patient is offered, especially going to a "women's clinic." We can change that to "reproductive health clinic," but usually the clothing is pink and that may be dysphoria-causing for some of our transgender and gender nonconforming friends. So it truly is in everything that is client facing, that is how the structural building is made. It truly is not just how we talk to each other, but how society runs.  Shannon Westin: Yeah, let's talk a little bit more about training because I think that will be pretty important as we try to change these things. So the way we're trained in medicine and oncology, regarding sex, regarding gender, how does this negatively impact the health? We've talked a lot about the mental health, definitely impacts, but also, I think, overall physical health. Dr. Ash Alpert: Well, I think something that we started to talk about, but didn't talk about in detail is not just the conflation of sex and gender, but the ways that this concept of sex is used as a proxy for a number of other factors, including anatomy, hormonal milieu, karyotype, and body size. One of the ways that this becomes problematic is in our laboratory values for example. Laboratory values are developed, as far as I understand it, based on looking at large studies of people that are categorized as women or men and looking at averages. So, averages are helpful, but they can't necessarily tell us about disease or no disease. So, for example, if a large number of cisgender women have iron deficiency that is undiagnosed, and we use their averages, then we're going to continue to underdiagnose iron deficiency anemia going forward.  So, the ways that we've tried to use sex as a proxy for a number of things doesn't just hurt trans people, but potentially leads to very imprecise data in general. Specifically for trans people, we know that many trans people have negative experiences with care, that this leads to people avoiding care and likely leads to decreased screening for cancer and delayed cancer diagnoses. So we don't have a lot of data about this, but we do have some data to suggest that transgender people may present later with later stage cancers, be less likely to be treated, and have poorer outcomes than cisgender people. Spencer Adams: And I think it's important to add that there are physicians who will - we call it like, “the trans illness" - but they will blame everything that you're experiencing on the fact that you're transgender or the fact that you're on hormones or the fact that you had the surgery, and say that you need a specialist. So you can't just go to your primary care physician anymore for the flu because they'll just blame it on your medical transition. When we take that into consideration, I think there's a whole host of physical ailments that come from just being denied care. I don't know if that is from the physician's own personal stigma around trans people or just them not being trained in trans healthcare to where they feel confident in going into that room. So it's a twofold attack. First, we need to make doctors who are competent in trans healthcare, and then second, we need to have more inviting spaces for trans and gender nonconforming people. Shannon Westin: I think the next step is really better understanding this idea around degendering care, specifically in oncology, but I could really talk about medical care as a whole, but let's focus on what you all brought forward in the paper. I would love to hear how we think this idea of degendering care will promote better healthcare. And then, I think, some practical actions. What can we do on a day-to-day basis? And you've already started peppering this through this discussion but I'd love to like bullet point it out for the listener.  Dr. Ash Alpert: Yeah. So the way we described it on our paper was: “disentangling oncology is a conscious and explicit disentanglement of gender, anatomy, hormonal milieu, karyotype, and other biological factors. In oncology, diagnoses, epidemiology, and knowledge production. As well as,” - and I think this is an important part and that's maybe the harder part of the paper - “eliminating sex from our conceptual framework of bodies and disease”. So, in other words, we're really trying to say that not only do we need to disentangle gender and sex, but we need to debunk the idea that sex is an immutable fact of the body that says something important about a person and their biology. Instead of thinking about sex as this immutable fact of the body, can we really break down and think about what exactly are we measuring? Is it anatomy, hormones, karyotype, size, or stigma?  In terms of practical actions, some of the things we had in our paper include that oftentimes, the words "woman" or "man" can be replaced with the word "people." So like a very easy change. And actually, ASCO and the NCCN, both in the last few years, have worked to degender their guidelines by doing just this simple change. Then we also need to do this on our websites, in our patient education materials, and in our clinical trial eligibility criteria. Because if you have a trial for prostate cancer that says that one of the inclusion criteria is being male, then whether or not you actually mean that as an inclusion criteria, a transgender woman or her physician may see that as a barrier to enrollment.   Ensuring that, as Spencer was saying, that gowns, binders, and wigs are available that are gender-neutral are available for all genders. Ensuring that people have access to bathrooms, so making sure gender-neutral bathrooms are available. And often, this is as simple as taking a one-style bathroom and putting a sign on it that says "gender-neutral." Ensuring the names of clinics, mammography suites, and titles do not contain gender. Ensure that intake forms don't conflate gender with biological factors. For example, in a clinic I used to work in, one of the questions on the intake form was, "If you are a woman, when was your last menstrual period?" Which if I'm a man and I have a period, it might be hard to figure out how to answer that question.   Spencer Adams: One of the biggest barriers for trans and gender nonconforming people is that intake form. It is the first person that you meet or see when you go to any healthcare establishment because that sets the tone for whether or not this establishment is trans-friendly. If you have, as Ash said, a "for women only" box or descriptor on your intake form, that is a sign that maybe they're not as trans-friendly as they could be. Or if you see "women's clinic" instead of "reproductive health clinic" or whatever, that could be a sign that they may not be as gender-friendly as they could be. These little changes actually make such a big impact on the trans community, and it's something that I believe would be very much appreciated and would close the gap between trans and gender nonconforming people and the medical community. Dr. Ash Alpert: I know that for me, going to a doctor's office, these small moments, although they may seem small to other people, really add up in terms of stress. People talk about microaggressions, and I think that's really a good way of conceptualizing what it's like to have these little irritations or hits that happen over and over again throughout a clinical encounter. And I think in particular, for folks who are dealing with a cancer diagnosis and treatment, which can be experienced as a traumatic event, having these recurrent denials of identity on top of that can lead to additive trauma in a way that can be very distressing and have negative sequelae for patients. Shannon Westin: Yeah, we're trying to look around this idea of allostatic load and how we can actually measure this because I think when we talk to policymakers about this, around not just the trans community, but also around underrepresented minorities, and the stresses that impact their risks of cancer, and how it's not just their race or ethnicity that's driving it, it's all of these microaggressions and everything. We get a lot of like, "Really? That's not science." So, I definitely think doing a better job around being able to objectively measure these other things and move forward in a very objective direction is going to help. Because if one of those things we know it's there, but for people who aren't as ready to believe or understand that, it helps to have and embed that objective data. So that gets into the epidemiologic potential and cancer prevention. Dr. Ash Alpert: Yeah. In some ways, we can't do much about the data that have been collected in the past, but we can start to think about them more critically and describe what we think is really going on in what we were calling sex or gender categories. But going forward, we can really think about collecting data on our clinical trials and in our large population-based surveys that actually speak to biological factors. So, if what we're concerned about is whether or not someone has ovaries, we can ask for an anatomy inventory. And when we're interested in hormonal milieu, we can check hormone levels. When we want to know about chromosomes, we can check a karyotype. And if what we're interested in is stigma, then we can ask about stigma, or we can ask about things that we think may cause someone to infer stigma. Once we have data that's much more nuanced and granular, we'll be able to better extrapolate it to all people in a much more rigorous and precise way, including trans people. Spencer Adams: When it comes to cancer treatment and diagnosis within the trans community, it's such a unique thing because we have to consider also the social determinants of health. And this built environment that we've created, such as a hospital or cancer wing, or whatever you want to call it is directly impactful. As you were saying before, this microaggressions that add on and on to our trans friends. So, I think that when we look at the data and we look at stigma, we also have to look at where people are– We have to meet people where they are. It's going to be very difficult to bridge the gap between the medical community and the trans community when it comes to stigma. But if we have competent doctors trained in trans care and not always pushing off for a specialist, then I think we'll get better data.  One thing that happens to trans people is doctors feel as if they cannot diagnose because being trans is seen as a disorder that they see as out of their wheelhouse. First, they classify it as a disorder, and secondly, they think it's outside of their wheelhouse. So they would refer to an endocrinologist or someone else to provide the care that the person is seeking. We call it the "trans disease" or the "trans injury,” because if I come in with a broken leg and the first thing you say to me is to go to an endocrinologist because we don't understand how hormones work, that's not care, and that's not patient-centered care. And that's what we're all moving towards, I believe. All hospitals are moving towards this patient-centered care. And to do that, to be patient-centered, you have to understand the person as a whole, and you have to be able to treat the whole person and then make a treatment plan that is specialized and custom to that person. This may involve different routes people take in order to feel comfortable or achieve what outcome that they wish to achieve. But it's really a patient-centered approach that we have to drive home in order to make some change.  Shannon Westin: My last question is, what's next, and how do we get this information out? How do we actually enact? I mean, obviously this podcast reaches a lot of listeners, but beyond that, how can we educate people so that we can make these changes? This is something that hits close to home for me. I recently took over the gynecologic cancer center, which is where we house all below the belt malignancies. But there's work in progress, and we're discussing an overarching center to cover breast and gynecologic malignancies. And there's a discussion around how to title that. One of the suggestions was that it should be a "women's center," or something like that and that is not in line with what we've just been speaking about. So I think, certainly, that kind of individualized, like boots on the ground, people that are willing to speak up and say things and try to change these types of things, and I fully intend to do that - fingers crossed that it won't be me just waving my tiny fists in the air.   But more broadly, I'd love to see more education at ASCO, large oncology symposia and conferences. It needs to go to the people who are not aware. It can't just be an echo chamber of people who have already been talking about this and are already knee-deep. It needs to reach the broader oncology community so that people realize that this is an issue that involves all of us and that we all need to be addressing. And like you said, even simple things around replacing language and saying people and making sure that the trial eligibility are broad, those simple things that individuals can do can. But I also think like NCCN and ASCO, we have to do something around the organizational levels to really make an impact.  Dr. Ash Alpert: Yeah. And I think that the things that we talked about the we can do as individual clinicians, there's the things that large institutions like NCCN and ASCO can do to sort of send out the inclusive messaging that is needed. And I think in the middle, we can create teams that are institutions of folks who we can be in allyship with to think about what are the most urgent changes that need to happen and the most feasible changes and start with those and then just keep going. Some of the changes that we make now will help us in the years to come, so I think being focused on the now and the future at the same time is helpful.  Spencer Adams: I think that the teams within our individual institutions is really a great approach to this. When it comes to figuring out the next steps to be more gender-inclusive, I really think that institutions should get data from their community. They should understand the makeup of their community and see if that is something that aligns with the makeup of their hospital. Because we can go and talk about doctors getting training in trans care or more doctors of color being in your hospital to make the BIPOC community feel more accepting. But if we don't have teams whether it's diversity, equity, and inclusion teams, or whatever you want to call it, that are willing to push to make policy change within the hospital, then there will be no movement. So, we really need to get people within their hospitals to give them the power to really push what has been taught for so long and really challenge the status quo and allow us to move forward with gender equity. Shannon Westin: Well, I think that is the perfect mic drop moment, and I just want to thank both of my guests. Spencer, this was awesome and I always take copious notes when I talk with you all because I learn so much. It inspires me to try to do what I can at my institution and within the field of gynecologic oncology to make things better. So I hope that others who are listening are just as inspired as I am. And to our listeners, thanks again for tuning into another episode of JCO After Hours. Please check out our other podcast offerings wherever you get your podcasts. Have a wonderful day. The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and should not be used for the diagnosis or treatment of individual conditions.    Guests on this podcast express their own opinions, experiences, and conclusions. These opinions do not necessarily reflect those of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an endorsement by ASCO.      

JCO PO author Dr. Amit Mahipal shares insights into his JCO PO article, “Tumor Mutational Burden in Real-world Patients with Pancreatic Cancer: Genomic Alterations and Predictive Value for Immune Checkpoint Inhibitor Effectiveness.” Host Dr. Rafeh Naqash and Dr Mahipal discuss real world evidence of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma. TRANSCRIPT Dr. Rafeh Naqash: Welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center, University of Oklahoma. Today we are joined by Dr. Amit Mahipal, Professor of Medicine and Director of GI Oncology at the Case Western Reserve University in Seidman Cancer Center. Dr. Mahipal is also the author of the JCO Precision Oncology article titled "Tumor Mutational Burden in Real World Patients with Pancreatic Cancer: Genomic Alterations and Predictive Value of Immune Checkpoint Inhibitor Effectiveness."  Our guest disclosures will be linked in the transcript. For the sake of this conversation, we will refer to each other using our first names. So Amit, welcome to our podcast and thank you for joining us today. Dr. Amit Mahipal: Thanks for having me here. Dr. Rafeh Naqash: Excellent. We came across your article in JCO Precision Oncology and it really aroused my interest because the topic and the audience that it caters to is very important in the current times. Because immunotherapy generally is considered- pancreas cancer the graveyard in immunotherapy in essence, based on what I have seen or what I have encountered. And now you're the expert here who sees people with pancreas cancer or has done a lot of work in pancreas cancer research side. So can you tell us the context of this work and why you wanted to look at immune checkpoint inhibitors in pancreas cancer? Dr. Amit Mahipal: Absolutely, Rafeh. As you mentioned, pancreatic cancer is considered a what we call "cold tumors." They don't typically respond to immunotherapy. And when we talk to our patients or patient advocates, as you know, patients are very excited about immunotherapy. Immunotherapy has transformed the treatment for a lot of different cancers and not only has increased survival, but the quality of life is so much different than with chemotherapy. This work came from based on the KEYNOTE-158 trial, which was a tumor-agnostic trial which accrued patients who had TMB high tumor. What that means is that tumor mutation had more than 10 mutations per megabase. And what happens is because of that trial, more than 200 patient trial, the FDA actually approved this immunotherapy or pembrolizumab as a single agent pembrolizumab for any patient with a solid tumor who has high TMB. Again, tumor mutation burden, more than 10 mut/Mb. This question comes in now. Does this apply to our pancreatic cancer patient groups? Especially as we know these are "cold tumors" that typically do not respond. There have been multiple trials looking at immunotherapy, single agent, dual immunotherapy agents, as well as combinations with chemotherapy, with somewhat very, very limited success. So that was kind of the basis. So we wanted to look at this retrospective kind of review of a big database to see how many patients we can find who have high TMB and see in that patient population is immunotherapy really active based on the FDA approval or is pancreatic cancer not a tumor where we should try immunotherapy unit as a selective group.    Dr. Rafeh Naqash: Thank you for that explanation. Taking a step back again, since you see these individuals with pancreatic cancer I imagine day in and day out in the space of drug development, what is the general current standard of care approach for individuals with pancreas cancer in your clinic? I'm talking about what are the most common approaches that you utilize that seem to be working or have FDA approvals in the pancreas cancer space. Dr. Amit Mahipal: As with any tumor, the first thing is obviously staging. So depending on whether we're dealing with early stage or advanced stage and what are the goals of treatment. At this point, the only thing that can cure pancreatic cancer patients that would be considered conventional therapy is surgical resection. So any patient who is a candidate for surgical resection is in a different bucket compared to advanced patients. For early stage patients, we try to do what we call neoadjuvant treatment or neoadjuvant chemotherapy. We shrink the tumor or at least maintain it, look at the biology of the disease, and then take them to surgery, which typically involves a Whipple procedure if it's a head of the pancreatic mass.   Moving on to advanced patients, that's where we know the goal of treatment is palliative to increase survival, but unfortunately, most of the times we cannot cure them. And there the standard of care options include systemic chemotherapy. We have two typical regimens that we use, one is called FOLFIRINOX, which is a three-drug regimen of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan. And another regimen is gemcitabine plus abraxane, which is a two-drug regimen of gemcitabine plus abraxane. These are considered the standard of care. Unfortunately, the median survival even with the best standard of care chemotherapy is only about a year, 12-13 months, depending on what trials we look at.  Dr. Rafeh Naqash: I still remember some of these regimens from my fellowship, where we had to decide which to give to each individual based on their performance status and clinical status, etc. But now I can see a lot of ongoing drug development in the space of pancreas cancer. I'm guessing that's why you wanted to assess both the molecular genomic landscape of pancreas cancer in this study and also look at the immune biomarker aspect. Could you tell us a little bit about the Foundation Medicine Clinical Genomic Database? How did you identify the patients, how many patients did you identify, what you narrowed down in the criteria, and the eventual sample size of what you were looking at?  Dr. Amit Mahipal: FoundationOne has a rich database. They have two or three things. One is a genomic database only. So in our clinical practice, I think it's some sort of next-generation sequencing or mutational testing for all patients with advanced solid tumors. All of these goes into their database. All of the samples that are sent to FoundationOne that goes into their database where they know the diagnosis of the patient and the know the sequencing results of these patients. In addition, they also have a clinical database called Flatiron. Basically, they collaborated with them. Flatiron has about 280 or so cancer clinics throughout the country, so a lot of community settings and some academic sites as well. They did not only have a genomic database, but they actually have a clinical database. They have demographics, clinical features, baseline clinical features, comorbidities, what kind of treatment they received, what would be the stage of the cancer, how many months of treatment they received, and their overall survival, and so on. So from that perspective, the FoundationOne has access to this partnership with Flatiron, clinical genomic database where they have both clinical data as well as genomic database for a lot of these patients.  In our study, we only focused on patients with advanced pancreatic cancer. We excluded a lot of patients who did not have sequencing results available, they cannot be performed due to lack of tissue. So the first we talked about the genomic database and we found about about 21,932 patients, so almost 22,000 patients and there we had the sequencing and we also had the data on TMB or tumor mutational burden. So here, we classified them into two groups: high TMB and low TMB. High TMB was seen in 1.3% of the patients, and about 98.3% of the patients had low TMB. Here we looked at the genomic alterations between the two groups. So these are like our genomic group, so to speak of about 22,000 patients. And among them, as mentioned, that the clinical data was available for about 3300 patients or 3279 patients to be exact.   After excluding some of those patients, we found about 51 patients who received immunotherapy. And when we say immunotherapy, it is single agent immuno checkpoint inhibitor like pembrolizumab or nivolumab. And then we classified them into high TMB versus low TMB and then we also looked at patients with high TMB and compared them to who received immunotherapy versus other therapies. Just to recap, we had about 22,000 patients where we have the genomic database and about 3300 or so patients who we have both genomic and clinical data for this patients. One of the key findings was that high TMB was present in only 1.3% of the patients, or about 293 patients out of 21,932.  Dr. Rafeh Naqash: Definitely an interesting sample size that you had utilizing this resource, which, of course, is more or less real-world. It is important to gather real-world outcomes that you did.   So, going to the TMB story of this paper, where you looked at immune checkpoint inhibitor use in these individuals, was there a reason why some of the individuals with low TMB were also given immune checkpoint inhibitors? From my understanding, I did see some checkpoint inhibitor use there. What could be the explanation for that? Dr. Amit Mahipal: So this data is from 2014 to 2022. So from the span of about eight or so years. And as you know, immune checkpoint inhibitors were approved in the last decade. And there were a lot of not only trials, but even in the non-trial setting, people had tried immune checkpoint inhibitors in, frankly, different tumor types because of the success in some of the common tumor types, like melanomas, lung cancer, and so on. So I agree, as of today, we probably would not use immune checkpoint inhibitors in patients with low TMB or MSS. But at that time, I think that information was not available. So people with low TMB and MSI-stable tumors also received immune checkpoint inhibitors. But those numbers are again low. So it's not very high numbers. Dr. Rafeh Naqash: Understandable. That makes it a little more clear.  Now, you looked at the TMB aspect. I'm guessing you also looked at the MSI aspect of PDAC. What is your understanding, or what was your understanding before this study, and how did it enhance your understanding of the MSI aspect of PDAC? And I'm again guessing, since TMB high individuals are on the lower side percentage, so MSI high is likely to be low as well. Did you see any interaction between those MSI highs and the TMB highs on the PDAC side?  Dr. Amit Mahipal: Yeah, absolutely. So we are very excited in general about MSI-high tumors for solid tumors because of their response to immunotherapy. Although I would do a caveat because we still don't know how MSI-high pancreatic cancer responds although there have been some real-world, very, very small series as well. In this study, one of the things is, is high TMB totally driven by MSI-high? That's a question that comes up, and TMB high may not matter. It's only the MSI-high that might matter. So definitely when we look at this patient population, we found that the patients who were 35-36% of patients who were TMB high also had MSI-high patients. So we do expect MSI-high patients to have a higher TMB compared to MSS patients. But there were about 66 or two-thirds of the patients who did not have MSI-high tumors and still had high TMB, as defined by, again, ten mutations per megabase. So we did see patients with MSI-stable tumors who had high TMB. And I think that was one of our biggest questions. I think MSI-high patients, we all tend to think that we would try immunotherapy even if it's in pancreatic cancer. I think what is not clear, at least from the real-world or any of the trial data, is if we were to give MSI-stable patients who have high TMB, if we give immunotherapy, are there any responses or any disease control that we see? And that was one of the reasons for this study.  Dr. Rafeh Naqash: Now, one of the things that comes to mind, and again, I think you based it on the FDA approval for TMB high, which is ten mutations per megabase, as you defined earlier. I do a lot of biomarker research, and oftentimes you come across this aspect of binary versus a linear biomarker, in this case being TMB, where about ten, less than ten. Do you think, in general, an approach where you maybe have tertiles or quartiles or a biomarker, or perhaps a better approach in trying to stratify individuals who may or may not benefit from immunotherapy? Dr. Amit Mahipal: That's a great point. I think when we use ten mutations per megabase as a biomarker, as a binary endpoint, do we apply it to all tumor types? I don't think that's a fair comparison, frankly speaking. We do know that high TMB, even in different tumor types, do tend to respond a little bit better to or do have better outcomes for patients treated with immune checkpoint inhibitors in different tumor types. But what that cutoff is not known in most of the tumor types. And also, one of the problems is how do you measure TMB and is it standard across different platforms? Like I'm just giving some names like FoundationOne, Tempus, Caris, and some obviously like MSKCC and some other university-owned panels as well. And frankly, I think if you look at different panels and if you send the same tumor tissue, you will get different measurements. So I think standardization is a problem as well.  In one of the studies involving cholangiocarcinoma, for example, we found that a TMB of 5 was enough to have an additive effect of immunotherapy, same with chemotherapy, so to speak. But again, this needs to be validated.  So you're absolutely correct. I don't know why we use the binary endpoint, but on the same token, the binary endpoint is easy to understand as a clinician. Like, “Hey, someone has this, do this, not this.” And when we look into a continuous range, I think the benefit obviously varies between high and low, different tertiles, and becomes somewhat challenging. How do you classify patients and what treatments to give? So I think in clinical decision-making, we like the cutoffs, but I think in reality, I don't know if the cutoff is a true representation. And maybe with the more use of AI or computing, we can just input some values, and then it can tell us what the best treatment option might be for the patient. But that's way in the future. Dr. Rafeh Naqash: That would definitely be the futuristic approach of incorporating AI, machine learning perhaps, or even digital pathology slides in these individuals to ascertain which individuals benefit.  Going back to your paper, could you highlight some of the most important results that you identified as far as which individual is better, whether it was immunotherapy, and you've also looked at some of the mutation co-mutation status. Could you highlight that for our listeners? Dr. Amit Mahipal: So the first thing we looked at was the genomic database of almost 22,000 patients, and then we classified them into high TMB and low TMB, with about 300 patients in the high TMB group and the rest in the low TMB group. And what we found was, talking about again in the genomic database, that patients who have high TMB actually have low KRAS mutation. So if we think about KRAS mutation, pancreatic cancer, almost 85% or so of patients have KRAS mutation who have pancreatic adenocarcinoma. So patients in this subgroup, so in the high TMB group, only about two-thirds of the patients had KRAS mutation, compared to 92% of the patients with low TMB who had KRAS mutation. So just giving that perspective. So KRAS mutation, which is the most common mutation in pancreatic cancer and is a driver mutation, their rates vary differ from the high TMB group versus the low TMB group.   And then in addition, in the high TMB group, we found higher rates of BRCA mutation, BRAF mutation, interestingly, and then obviously from the DNA damage repair genes like PALB2 mutation, MSH2 or MSH6, MLH1, and PMS2. So all these mismatch repair protein mutations were higher. As I mentioned before, one-third of the patients with high TMB also had MSI-high. So it's not a totally unexpected finding. I think the biggest finding was that we found more KRAS wild-type pancreatic adenocarcinoma in the high TMB group, almost a third. And those tend to have different targetable mutations like BRCA2, BRAF, and PALB2 mutations. So I think one of the interesting findings is that patients in the high TMB group actually tend to have KRAS wild-type or less KRAS mutations. So they're not necessarily KRAS-driven tumors, and they have a higher chance of having other targetable mutations like BRAF and so on, for which we have therapies for. So it's always something to keep in mind. Dr. Rafeh Naqash: Would you think that from a DDR perspective, the mutations that you did  identify that were more prevalent in individuals with high TMB, do you think that this is linked to perhaps more DNA damage, more replication stress, more neoantigens leaning toward more tumor mutation burden perhaps? Or is there a different explanation?  Dr. Amit Mahipal: For sure. As we said, MSI-high tumors have mutations in the DNA damage repair pathway and they definitely tend to have higher TMB. So I don't think that is very surprising that we found PALB2, or other MMR genes like MSH2, MSH6, MLH1, and PMS2 at much higher rates. I think the interesting finding is the fact that the KRAS wild-type and having BRAF alterations at least that's not suspected to definitely increase TMB. Although if we look at colorectal cancer, BRAF mutation and MSI are somewhat correlated to patients with BRAF mutations and to have high rates of MSI-high tumors. But that's not the case in pancreatic cancer. We also found an increase in BRCA2 mutations as well. So I agree that the DNA damage pathway repair gene alteration is not unexpected because they tend to increase TMB, but I think the other mutations were interesting. Dr. Rafeh Naqash: And I think one other aspect of this, which I'm pretty sure you would've thought about is the germline implications for some of these mutations where you could very well end up screening not only the individual patient, but also their family members and have measures in place that we're trying to enhance screening opportunities there. In your current practice, you are at an academic center but I'm talking about in general with your experience, how common is it to sequence broad sequencing panels in individuals with pancreas cancer? The reason I asked that is I do a lot with lung cancer and even now despite having all those targets in lung cancer which sort of paved the pathway for targeted therapy in many tumor types, we still don't see a full uptake for NGS Phase I drug development. And I get a lot of referrals from outside and I often see that it's a limited gene panel. So what is your experience with pancreatic cancer? Dr. Amit Mahipal: We kind of changed our practice. Similar to you, I'm involved in drug developments. I've been a big proponent of NGS for almost a decade now, when didn't even have targeted therapies but these companies first came in and they're like, “Okay. We're very very low chance.” But now obviously, we transformed the treatment for a lot of different cancers. Especially lung cancer, you don't sometimes even start treatment before you get an NGS panel like you said in situ. So what we're finding, at least for pancreatic cancer, as you know, the targetable mutations are there but they are somewhat not that common, I would say, in the 10-15% range. So many people would get dissuaded and then it's like, what's the point of doing it?   But I think for those 10% to 15% of the patients, firstly we can really change their treatment course and their prognosis. Secondly, if you don't do it and they cannot go in a different clinical trials, now we have trials targeting KRAS G12C, but not only that, KRAS G12D which is the most common mutation we see in pancreatic cancer and so on. So it's becoming very very important. One thing, at least with our practice we adopted last two or three years is sending liquid biopsies or liquid based NGS or blood-based NGS testing. Otherwise, what's happening I would send a solid tumor NGS from the tissue. And pancreatic cancer as you know has sometimes a very small amount of tissue obtained from FNA. And inevitably after four weeks, we'll get the result that there's not enough tumor to do NGS testing. And then the patient comes one or two months later and then we order the test, and that just delays everything.  So now we adopted a practice where we are trying to send both blood based NGS and solid tumor NGS at the same time the first time of diagnosis when we see the oncologist for the first time. And that has really increased the rate of NGS testing results for our patient population. And it's not 100%, even in blood-based NGS, sometimes they may not be able to find enough circulating tumor cells to do this blood-based NGS testing, but at least they're having these. But you're correct. I think we still see about one third of the patients who had not had NGS testing or referred for phase I clinical trial and have gone through more than two or three line of therapies which is unfortunate for our patients.  Dr. Rafeh Naqash: That's a very interesting perspective on how important it is to sequence these individuals. As you said, it may not be that all of them may benefit, but the ones that have those important alterations, especially BRCA, PALB, and KRAS could benefit from novel precision medicine-based approaches.  A question that came to my mind, I saw that you were trying to look at MYC and turmeric low tumors as well. So what is the role of MYC in the context of these individuals? Is there any drug development that's going on? Because I see small cell lung cancer. MYC is an important target there. These are two different tumors, but it looks like there was a hint of some correlation with respect to some of the findings that you showed. Is that something that you're currently looking at or planning to look at?  Dr. Amit Mahipal: I think that if we just talk about MYC in general, it is present at somewhat lower rate. I think we found MYC amplification in about 5% or so of TMB-low patients who had that and not really seen in the TMB-high patients. So right now, I am not aware of any trials targeting MYC in pancreatic cancer. But as you said, if it's successful in lung cancer, maybe that's when we can transform into the pancreatic cancer group. Dr. Rafeh Naqash: Of course we can all learn from each other's specialties.We learned a lot from melanoma with respect to therapy. Hopefully, other fields can also benefit from each other's experiences in the space of drug development.  Thank you so much for this interesting discussion. The last few questions are more or less about you as an individual researcher. So could you tell us briefly on your career trajectory and what led you into the space of GI oncology, pancreas cancer, even for that matter, drug development? And some of the advice that you may want to give to listeners who are trainees or early career individuals? Dr. Amit Mahipal: Sure. So I have gone through some different institutions. During my fellowship, that's when I really decided that I wanted to do GI oncology. Prior to that, I actually have a Masters in Public Health, where I learned about epidemiological research and how to design clinical trials, how to design cohort studies. My focus was on, actually there was somewhat a lot, but one of my mentors was working on colorectal cancer, and they had this huge database called the Iowa Women's Health Study Database of 100,000 patients. So that's where I started by clearly getting into colorectal cancer and GI cancer in general and how to learn from this database, how to mine these databases, how to do analyses, which seems easy but is actually quite complicated.  During my fellowship, I think the key to it is finding a good mentor during the fellowship. And I worked with one of the top GI oncologists in the country who's practicing. And I worked under her and learned a lot not only from the clinic side but also from the research perspective and how sometimes you'll come up with the ideas during the clinic itself.Like, “Hey, this patient had this and why aren't we looking into this.” And she would even do some of the therapies based on phase II trials and she was a part of a lot of these trials and learning from those experiences.  And following my fellowship, I joined Moffitt Cancer Center, where I led the phase I program there. So I was heavily involved in drug development programs, all training programs I've been to, NIH in Bethesda, an observership in the CTEP program, and also did the ASCO/AACR Vail workshop, where you really learned a lot in just like one week. So those are kind of opportunities present for fellows and even the early investigators and attendings as well in the first few years can go there, have your proposal. And really they are the world experts in trial design and they'll talk about how to design trials, how to add collaborators, improve your trial, and basically learn the whole protocol in a week so to speak.   And then I was at Moffitt Cancer Center for about five, six years. My home was GI so I did both GI oncology as well as phase I. And in terms of the GI oncology, my main focus was pancreatic cancer and liver tumors. Then I was at Mayo Clinic in Rochester for about seven or so years. I kind of did the same thing and solidified my career at GI oncology, looking at liver tumors, and pancreatic cancer and then being a part of the phase I division program. And now, most recently, about a year or so ago, I joined Case Western to lead the GI program here. Dr. Rafeh Naqash: Are the winters in Cleveland better than the winters in Minnesota? Dr. Amit Mahipal: For sure. I always say, you don't know cold until you go to Minnesota. It's a different kind of cold. I'm sure people in Dakota might say the same thing, but the cold in Minnesota is very brutal and different compared to any other place I've been to.  Dr. Rafeh Naqash: Well, it was great learning about you. Thank you so much for spending this time with us and for sharing your work with our journal. We hope you'll continue to do the same in the near future.  Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ascopubs.org/podcasts. Dr. Amit Mahipal: Thank you for having me here, Rafeh. Good luck. Take care. Dr. Rafeh Naqash: Thank you so much. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   The guests on this podcast express their own opinions, experiences, and conclusions. Their statements do not necessarily express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Dr. Mahipal: Consulting or Advisory Role:QED TherapeuticsAstraZeneca/MedImmuneTaiho Oncology Speakers' Bureau:AstraZeneca Research Funding:Taiho Pharmaceutical"

Dr. Shannon Westin and her guests, Dr. Judy Garber and Dr. Geoffrey Oxnard, discuss the paper "Germline EGFR Mutations and Familial Lung Cancer" recently published in the JCO. TRANCRIPT The guest on this podcast episode has no disclosures to declare.   Shannon Westin: Hello, and welcome to JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for the JCO and Gynecologic Oncologist by trade. And it is my great pleasure to speak today with you about an amazing manuscript entitled, “Germline EGFR Mutations and Familial Lung Cancer.” It was published in the JCO on August 14, 2023.  The authors have no conflicts of interest, and they are Dr. Geoffrey Oxnard, he's a Thoracic Oncologist and Associate Professor, Hematology and Medical Oncology at Boston Medical Center.  Welcome, Geoff. Dr. Geoffrey Oxnard: Hi, Shannon. Thanks. Shannon Westin: And Dr. Judy Garber, the chief of the Division of Cancer Genetics and prevention at the Dana-Farber Cancer institute in Boston. Welcome, Judy. Dr. Judy Garber: Thank you. Hi, Shannon. Hi, Geoff.  Shannon Westin: So excited you both could be here. Let's get started. So first I just want to levelset for our audience. Can you speak just a little briefly about the incidence and mortality of lung cancer and how that's been changing over time? Dr. Geoffrey Oxnard: Sure. Lung cancer is common and it's deadly, more than 200,000 cases a year in the United States, more than 100,000 deaths a year in the United States. But I think importantly, it's evolving. Its biology is evolving as smoking incidence goes down. We've identified these genomic subtypes of lung cancer that are sort of increasingly apparent and important as we think about its treatment. Outcomes are changing with emerging therapies, presentation is changing with lung cancer screening and with a growing ability to now find cancers early and prevent them. And so it's in that setting of a very dynamic disease that we chose to study a really unique little slice of it, which is germline risk. Shannon Westin: So let's take that one step further because I think that's really interesting. You mentioned the genomic aberrations and kind of how you're using that to target. Can you expand upon that a little bit more for me? Dr. Geoffrey Oxnard: Lung cancer that I've long studied is different than breast cancer when Judy has long studied because we think about its somatic alterations, we've always thought about KRAS mutations, EGFR mutations, and smaller and smaller splice limit. ALK, RAS, RET HER2, etc. And so tumor testing in lung cancer has one of the first to be standard across on solid tumor oncology. And the germline genetics was kind of an afterthought and is the flip, I think, of how genetic testing evolved in the breast cancer space for example. Dr. Judy Garber: I might argue a little bit if breast cancer was earlier and it was subtyped some molecularly it doesn't have as many molecular subtypes yet perhaps as lung cancer. But we've all been studying the somatic space to look for targets for therapy. And the germline space, certainly in breast cancer, came much earlier. And everybody knows about BRCA1 and 2. Now, we hope everybody knows about Lynch Syndrome, but certainly not everybody's thinking about inherited lung cancer risk. Dr. Geoffrey Oxnard: Yeah, these have converged. I think 10 years ago when this kicked off, I felt like a super outlier for thinking about, wait a second, what about the genetics behind all this that is leading to this strange variable presentation of lung cancer? For example, we know that in Asian populations, one type of lung cancer, EGFR mutant lung cancer, is more common. There must be some geneticness that leads to that. What explains the sort of pattern of presentation of these genetic subtypes in the populations we see in the US, that's pretty unclear?  Dr. Judy Garber: So, I think, Shannon one of the clues about all this came from the fact that the EGFR mutations were being identified in the tumors. And then I really should let Geoff tell this story, but as the amateur thoracic person in the room here, to me, it was so interesting that there were the EGFR mutations, then there was treatment exploiting EGFR mutations, and the most common resistance mutation was this T790M variant. But when labs started testing EGFR, there was a small group of people who had that resistance variant without ever having been treated at all. So that was the obvious question, what was it doing there? And that's where Geoffrey came in.  Dr. Geoffrey Oxnard: Yeah, this is a patient I met more than a decade ago at my fellowship in MSKCC. She'd been living with a T790M mutation in her tumor for years and years and years. I was like, “Well, I don't understand. Why is this sitting there?” And she had this sort of slightly mysterious history of lung cancer in her family. And we realized, wait a second, this T790M was behind her cancer from the beginning, and in fact, might have been the basis of why she developed lung cancer. And so that actually motivated a career development award I submitted to the Conquer Cancer Foundation of ASCO, a grant I received, and that then led to a program that I led at Dana-Farber under Judy's mentorship, where over the past decade, we sort of focused in and studied this strange, rare syndrome, really to dig into inheritedness as a kind of different flavor of lung cancer genetics.  Dr. Judy Garber: Well, and now it's really a good time to think about this because we're recognizing there are younger cancers, colon cancer, like an epidemic, and lung cancers, and we're not sure how many of them are genetic or come from other exposures. Geoff talked about the differences in Asia, some of which are certainly genetic, some which may be environmental, especially in the lung, where that's such an issue. But trying to sort these things out, you have to be willing to think a little bit differently. And that was fun when Geoff came from the lung program, interested in the germline, we said, “Oh, we have to do this.”   Shannon Westin: Well, let's talk about what you did. I would love to hear and I know the audience would as well about the design of this study, so called INHERIT study. Very good name. I love a good name. This is a good one.   Dr. Geoffrey Oxnard: Yeah. So that stands for Investigating Hereditary Risk of T790M, INHERIT. I forget where we coined that. Let me give you a case example. A patient presents in his 40s. I remember this man. He has an EGFR mutation in his tumor. He has a T790M in his tumor as well. He had routine tumor testing that lung cancer patients were getting. And he says, “Oh, also, my brother had lung cancer in his 40s just a couple of years ago. He was a smoker, though. He never had genetic testing.” And so this patient we test on the study, we hypothesized that when patients present with T790M at diagnosis, that it would be a representation of an underlying germline EGFR mutation. Our hypothesis was that about 50% of the time T790M at diagnosis would be explained by a germline behind the doll. And that that could then empower families like this one to understand the kinds of lung cancer they're getting in their family, the kinds of treatment they should be getting, and the kinds of testing they should be getting to look for lung cancer at risk early on.   It really saddens me that in a family that doesn't know about this condition, the brother would never get testing and would never think that I might be getting or might never get testing, might not be disposed to getting testing, and might not realize there's a therapy available to target that EGFR mutation if he died young without even much treatment. But this individual, we tested his lung cancer, we found him a therapy, we put him on a pill therapy that could last a very long time. And so we set up a program with a consortium alchemy, the Addario Lung Cancer Medical Institute, where we enrolled at three sites, both at Dana-Farber in Boston, Vanderbilt, and Ohio State, with some motivated investigators there that we appreciate their collaboration.  But also, again, this is now more than 10 years ago, set up shop where people could enroll remotely, that if you found a T790M in your tumor, for whatever reason, you could reach out to the team at Dana-Farber centrally and get consented online and even get counseling. And this is one of the early ways of getting this remote participation. And you can imagine, over the course of the study, we quickly ran out of individuals at any given site, but that remote enrollment accelerated and really allowed us to get to the large population of remote study. Dr. Judy Garber: We were lucky that things were happening. The things you don't expect. So EGFR testing was not routine at that time. And the EGFR testing that had developed in Dana-Farber and NGH became standard of care at Dana-Farber so we were finding those patients, and then grew outside as well, at institutions and testing labs. And these people would somehow emerge so we were very lucky that we were able to set up remote testing. We could send and get a saliva sample and be able to test. Or these were people who got tested through their own doctors, found out they had this mutation and then went online and said, “Who knows anything about this?”  I would say that we and our amazing genetic counselors who spoke to all these patients, took their detailed family histories, got their other information, and were able then to really build out these cohorts so we can understand them. And to look at, for example, Geoff's question, it was really his question, “Why did we have such clusters in certain parts of the country? Could it be that there were the so-called founder mutations that somebody had this mutation and they spread their genes around so that they're around the country and that turned out to be true. Shannon Westin: It's so fascinating, and I love how you kind of almost crowdsourced getting these patients to you because I was mystified because it's such a rare aberration and you had so many patients. Let's talk a little bit maybe about your patient population and who volunteered, and is it reflective of kind of you do think, the general population? Dr. Geoffrey Oxnard: I want to give a shout out to the GO2 Lung Cancer Foundation. That really was a lot of the ‘rah rah', getting people to know about this, having some word of mouth and spreading the word. And so certainly there are physicians around the country that have been like found patients that I've got to know because they sent us patients to study over the years. We ended up getting germline testing on 141 individuals who presented eligible for testing because of either a relative or a mutation that was suspicious for inherited. Most of those were enrolled remotely, in the end, as you might expect. We found what you might expect, that this was Mendelian in its inheritance, that if you had a first degree relatives, they had 50% chance of having this. And so we sort of slowly built these pedigrees of individuals who once they were positive, would refer in their relatives and say, “Please go get testing. Let's describe our family and help understand our risk.”   It ended up boiling down to six individuals with a germline EGFR mutation from 39 different families. I remember one family where two different cousins presented separately to the program, not knowing each other was participating. And so, of course, there's not that many of these families around the United states, but we're really very lucky to have touched so many different individuals. What did we find? That if you had a germline EGFR mutation, your tumor almost always had an EGFR mutation. That really is the dominant biology of lung cancer that presents in these affected individuals, that it presents young, that the likelihood of developing lung cancer is around 55% by age 40 to 50. So it really is– I'm trying to make sure I'm quoting that right, actually, Shannon, I'm looking at the numbers here, but it was a really broad range of diagnosis.  We had a 28-year-old who was affected and an 83-year-old who was affected. I saw a family where the grandson had lung cancer, but his father and grandfather who had germline EGFR mutations, did not. So variable penetrance. Judy, of course, told me, “Geoff, this is the way families present. Come on, Geoff.” But other families, incredible penetrance– not everyone having lung cancer, many of them smoking, some of them not smoking. But for these families, what a sense of empowerment to say, “Oh, this helps explain what's going on in our family, why this is happening at a younger age.” And helps explain the therapies that we had some concern about giving these potent EGFR inhibitors originally, understanding every cell in their body has this EGFR mutation. Are we going to somehow cause toxicity? No. These potent therapies can be effective, can be tolerated, and can work for many years. So we really feel hopeful that we've described a syndrome that's out there that people see and that has a distinct presentation, a distinct treatment pattern, and a clear association with lung cancer risk. Dr. Judy Garber: And I think that now the opportunity is to say, can you find these people before they get their lung cancers? Some of them have abnormalities on scans. Think of it's like the APC, the polyposis coli of lung cancer. You can see these adenomas forming, but we can't really predict exactly who's going to develop tumor when. And that, I think, is a challenge that families have to help us with because we need to continue to identify some of these people who have not had cancer. They have children. They want to know what to tell them besides not smoking adamantly and maybe with some hopes that we're going to do some screening.  I am afraid there probably is not good data that EGFR inhibitors could be used for prevention, but it's tempting to think that way. So there's plenty of work to do still to sort out the questions. This is the nature of genetics. We often find inherited susceptibility and people want to know, “Well, why would I want to know? What am I going to do about it?” And here I would say, “We're going to figure out what's your risk more specifically, and how can we help reduce that risk, in addition to telling you not to smoke.” Dr. Geoffrey Oxnard: I do want to allude to Judy's comment about founder effect. I didn't tell you exactly about the presentation, but these families, first off, we only found germline EGFR mutations in Caucasian individuals and in black individuals, and it was mostly in the United States and in fact, enriched in the southeast United States. And don't get me wrong, we had enthusiastic participation from Vanderbilt. But still it seemed like there was more southeast United States prevalence. And even families I met in the Boston area would say, ‘Oh yeah, I have relatives going back to Arkansas.”   And so we ended up with a bit of a suspicion for this geographic enrichment, studying the genomes of these affected individuals, and in fact did find a very large region of chromosome 7 that was shared in more than 90% of the folks we tested, suggesting a founder effect in the southeast United States, probably white and black. And that goes back hundreds of years, maybe 200, 300, 400 years, as far as we can estimate, making me think that this is a fairly unique syndrome that we're seeing in North America, but actually may not be prevalent in other parts of the globe. Though we did identify a single individual in Australia, it might be a unique phenomenon in North America. Dr. Judy Garber: At least more common. But these days, people travel, so hard to know. Shannon Westin: I don't know if you've gotten a chance to do this - any other cancer type seeming to be associated with this mutation? Dr. Judy Garber: No, fortunately not. Shannon Westin: Okay, very interesting. And what about outcome? What was the association, or was there any association of these mutations with cancer related outcomes? Dr. Geoffrey Oxnard: I would say the survival of these cancers isn't that different than EGFR mutant lung cancers. If they get to effective therapy, they can live for years on therapy. If they don't, they can do quite poorly. One interesting finding is that they can present in a multinodular fashion that might be multiple primaries. And so you can kind of use an approach of eliminating individual clones. Sometimes it's been described these different tumors have different mutations, and so you might treat them like a stage IV lung cancer, but actually they lived for a long time because actually they had multiple stage I lung cancers, so it can present a little bit differently. And then we tried to collect CT scans on affected carriers who did not yet have lung cancer to see if they might develop lung cancer. It was not required on study, and it's sort of an area of future investigation. But as you can imagine, lots of lung nodules and certainly anecdotes of individuals where we found early precancers through the screening effort, motivating the investigation that Judy was alluding to. Dr. Judy Garber: I think this is what you expect in inherited predisposition that you have an earlier chance. So some of them are younger, not the 84-year-old, but that they could be younger, that they could have multifocal disease, that their biology could be different, but could be the same, maybe accelerated, maybe not. Some of these are slower. And I think that's why we're excited to be able to continue this work with the group at Dana-Farber.  Now, Jaclyn LoPiccolo is going to lead the INHERIT study, but much of the team is the same. And now the focus will be even more on trying to really quantify the risk and help think about prevention strategies and screening for these patients. It's a little tricky to want to do too much chest CT screening. On the other hand, there are lower dose CTs now, and we hope the guidelines will clarify the role of inherited risk. At ASCO this year there were a lot of talks about inherited lung cancer risk, but nothing is quite as well characterized as, I think, the T790M population. Shannon Westin: Well, thank you all so much. This was fascinating. I learned a ton and I know our listeners did as well. And thank you to our listeners. This was “Germline EGFR Mutations and Familial Lung Cancer.” Again, published in the JCO August 14, 2023. So go check it out and check out our other podcasts on the website or wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

 JCO PO author Dr. Mary Redman shares insights into her JCO PO article, “Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP)” Host Dr. Rafeh Naqash and Dr. Redman discuss the background of LungMAP and how it was developed to accelerate drug development and biomarker-driven therapies in lung cancer. Dr. Redman shares the initiatives undertaken to increase participant diversity in LungMAP and invites junior investigators to get involved in the project. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Stevenson Cancer Center. Today I'm delighted to be joined by Dr. Mary Redman, Professor of the Clinical Research Division at the Fred Hutch Cancer Center and also Senior Author of the JCO Precision Oncology article, “Representativeness of Patients Enrolled in the Lung Cancer Master Protocol” or the Lung-MAP. Our guest disclosures will be linked in the transcript. Dr. Rafeh Naqash: Dr. Redman, welcome to the podcast, and thank you for joining us today. Dr. Mary Redman: Thank you very much for the invitation. Dr. Rafeh Naqash: And for the sake of this podcast, we'll just use each other's first names. If that's okay with you. Dr. Mary Redman: Please. Dr. Rafeh Naqash: And since you and I know each other through the lung working group, we've worked on some things, or planning to work on some things, this article was something that I came across recently that you published with some very well-known folks in the field of lung cancer. And I wanted to utilize the first few minutes of this discussion to understand what was the background behind Lung-MAP because I think it's very important for people to understand why this kind of an approach was started in the first place and how it has successfully created a mechanism for master protocol. So, if you could dive a little deeper into that for us, since you've been there, you've done that, and it would help our listeners understand the genesis or the origination of this whole process of Lung-MAP. Dr. Mary Redman: Happy to do so. So, Lung-MAP, the original concept goes back to February of 2012. And in February of 2012, the Thoracic Malignancy Steering Committee, the FDA and the NCI had a workshop. And the focus of the workshop was how we could accelerate drug development in lung cancer, and in particular, how we could accelerate biomarker driven therapies within lung cancer. And the outcome of that meeting was that master protocols or studies that set up infrastructures to evaluate multiple therapies, all within one infrastructure, were the way to go. And so born out of that, there were three master protocols. The Lung-MAP trial, the ALCHEMIST trials to evaluate studies in adjuvant therapy setting, and then the MATCH trial, which, of course, isn't just in lung cancer, it looks across different cancer types and looks on biomarker targets that transcend across.  So, when the Lung-MAP trial was being thought of, the idea was that while in non-squamous, non-small cell lung cancer, we had seen some advances with targeted therapies, that squamous cell lung cancer had essentially no targeted therapies that had been successfully evaluated. And therefore, there was an unmet need that squamous cell lung cancer being a more aggressive form of lung cancer than non-squamous lung cancers, and in particular in the second line setting, after patients had received platinum-based therapy, there was pretty much nothing other than docetaxel.  And so, the study was initially conceived of by Vassiliki Papadimitrakopoulou, who was at MD Anderson at the time and Roy Herbst who we had at Yale. And so therefore, we thought second line squamous cell lung cancer was an unmet need and that we could potentially have targeted therapies, given now that we had the genome atlas, the TCGA understanding of what all the potential biomarkers or targets that exist in squamous cell cancer. Concurrently, we also had the developments and improvements in next-gen sequencing. So, the technology improved for us to be able to detect these different genomic alterations that were present in these cancers. So, all of that together - an unmet need of an aggressive cancer, a better understanding of the biology and the potential to have these targeted therapies - led to the development of Lung-MAP. But in addition, what we had seen and I think most of you who have studied cancers across the country know, patients who live in urban areas or are financially more well off are more able to access therapies, whereas patients who are less well off, more rural areas, and then just in general, different race ethnicities, didn't have the access that other patients from other settings had. And so, when we conceived of Lung-MAP, it wasn't just about meeting the unmet need in terms of treatment, it was also about an unmet need in terms of accessibility of these types of studies for all types of patients who get lung cancer. And so, utilizing the National Clinical Trials Network system that has sites all over the country, I think there's something like 2500 sites around the country, which include community oncology sites and of course academic sites.  Dr. Rafeh Naqash: Excellent. Thank you so much Mary, for explaining that. Now, as you highlighted, this dates back to 2011-2012, when things were just picking up from a broad sequencing platform standpoint, rather than limited gene testing, which has been more and more, there's been more and more uptick of NGS, especially in the space of lung cancer. So, you and several others came up with this idea and eventually implemented it. And there's a significant process of thinking about something and implementing something. So, what were some of the challenges that you encountered in this process and successfully circumvented or dealt with appropriately over these years, some of the lessons or some of the processes that you were able to understand and navigate around. Dr. Mary Redman: We could spend the next hour probably talking on that topic. Anytime that you're setting up a big infrastructure, and I really do think the best way to describe Lung-MAP and a master protocol is that it's an infrastructure because the goal is to set up something where we can bring in new studies and so that everything is modular. And you complete one study, you add a new one. Things can be added while things are ongoing. And by things, I mean studies evaluating investigational therapies.   And so, anytime you're setting up an infrastructure that's never been done before, well, first of all, the complexities of different partners that had never worked together, so just understanding how best to work together, the infrastructure in terms of how to build it within our systems, the statistical and data management center had many complexities. The infrastructure in terms of how our systems at the statistical and data management center spoke to the NCI had challenges. How the NCI evaluated this protocol that had all these different studies that were coming and going.  The studies oftentimes involved therapies that were very new in their development. And so oftentimes you'd have some new safety signal that came up which required a rapid amendment. And how do you do that when you have this infrastructure, and you don't want to stop one thing for other studies to be moving forward. And that because it's a public-private partnership and the pharmaceutical partners that are partially supporting financially and scientifically, some of these studies, learning to work with them, they have a little bit more say because they are more financially involved with the studies than a study that's typically funded by the NCI. And maybe the company is only supplying drug. So, contracting had its challenges, budgets, how do we actually budget things appropriately in this new infrastructure? I talked about all of that. And then a challenge about running such a study is how do you educate the sites so that when they're approaching patients, how can they talk to a patient about, “You're going to have your tissues submitted to be tested, and then on the basis of that tumor testing you're going to be assigned to get to an investigational treatment study.” And how do you describe all of that? Dr. Rafeh Naqash: So definitely lots of lessons and experiences that you and your team have had. And the way I describe or look at Lung-MAP is one of those success stories that has redefined the way to run clinical trials from an NCTN and a SWOG cognitive group network standpoint. And going to this paper that you have published in this, your Precision Oncology, there's one aspect of clinical trials where we are always very focused on responses and survival and other clinical outcomes data. And then there is this important component that you and your team have looked at is, what is the distribution of the different kind of clinical trial participants? What kind of people are we getting in? What kind of people are we trying to cater to, and what is the unmet need gap that we still have not completely met? Could you tell us how this project started, the idea behind this project, and then some of the results that you can highlight for us today? Dr. Mary Redman: So, Lung-MAP also has a company advisory board, and we meet with them either quarterly or biannually. And one of the conversations that we were having with our industry partners or collaborators was especially after the FDA came out with some of their work saying, we think it's really important that industry does better that they enroll a more representative patient population in their studies. You see some of these studies in lung cancer with 1% or a very small percentage of Black participants, for example, whereas the US population has significantly higher levels. And so, one of the major objectives, as I said about Lung-MAP, was to enroll a more representative patient population to provide access. And as part of these conversations, we kept saying, “Well, we've done a better job.” And I was thinking, well, we actually could evaluate how we have done. And so, in thinking about that, I proposed within some of the researchers that are part of the SWOG Statistical and Data Management Center that we look at this question in particular, I approached Dr. Riha Vaidya, who is here at Fred Hutch with me, and she's a Health Economist with this idea. And she was very excited to look at this. And my initial thought was just to look at race, ethnicity, gender. And she took it one step further where she wanted to look at not only that, but also area deprivation index and then rural versus urban. So, getting at some of those other very important aspects of representativeness when we think about patient populations. And so that was how it came about.  Dr. Rafeh Naqash: Going back to some of the interesting things that you and the authors have done, is not only looked at the gender, age, but also looked at the socio-demographic representativeness. Now, there's definitely some things that you guys looked at and that Lung-MAP study did better on, and some things where maybe there's more room for improvement. Could you highlight some of those results for us today? Dr. Mary Redman: Happily. And one thing I think that it's important if one goes and looks at this paper, and as I talk through the results, so Lung-MAP opened to enrolling patients in June of 2014. And from June of 2014 to January of 2019, we exclusively enrolled patients with squamous cell histology. And then in 2019, we expanded the study to enroll all histologic types of non-small cell lung cancer. And so, in this paper that's published here in JCO Precision Oncology, we compare our patient population and Lung Map to other patients enrolled within advanced non-small cell lung cancer trials. So that's all-histologic types. And then we compared it to the SEER population, the US population evaluated by SEER. And that also is all histologic types of non-small cell lung cancer.  And so, one of the major results, as you pointed out, is that while we did well in certain areas, for example, we did not enroll as many females as the other SWOG trials and then the US population. And I think that is probably, I would attribute all of that to being the case that squamous cell lung cancer patients tend to be more male than female. So therefore, those results, I don't know that if we looked at only the data since 2019, we might actually see that we were comparable. Going through the results, as you were just asking about, compared to previous SWOG trials, we did better in terms of enrolling older patients, not as well as the SEER data. Some of the challenge is I'm not 100% clear that we'll ever be able to get perfectly there, in part because Lung-MAP, for the majority of the time, only enrolled patients who had performance status 0 or 1, and older patients tend to have higher performance status, and so they might just not have been eligible. And I do think, especially with these investigational treatments, particularly with immunotherapies, for safety reasons, we do need to enroll patients with performance status 0 or 1. We talked about the female sex versus male sex percentages and that our numbers were smaller. But if you look at SWOG trials versus SEER trials, they're pretty much identical numbers. So, I think that if we just looked at the later part of Lung-MAP, you'd see that they match. In terms of race ethnicity, the earlier part of Lung-MAP, we enrolled close to 15% of patients of nonwhite race or ethnicity. Historically, SWOG trials were slightly higher, but in the US population, it's around 21.5%, based on this year's data. And so, we did better than industry sponsored trials. So, if you look at those data, but there's definitely room for improvement. And that just in part, has to do with getting more sites, better outreach, more education, and better access.  And so, I think we have an accrual enhancement committee that does include patient advocacy groups. And I think that that is just going to be an area that we need to continue to work on. And then, as you mentioned, that we did better in terms of enrolling more patients from rural areas. We enrolled more patients from socioeconomically deprived neighborhoods, and more patients that were using Medicaid or no insurance for those who are under 65. Dr. Rafeh Naqash: Absolutely. I think those are very important results. Me, as somebody who sees people on clinical trials, both phase I and late phase, of the questions that I get commonly asked if somebody refers a patient from the community is, “Am I going to be treated on a placebo?” It's one of those common things. And the second question ends up being like, “Is my insurance going to cover some of the costs associated?” And I think understanding those concepts, whether it's from an educational standpoint or a financial barrier standpoint, is extremely important in clinical trials because at the end of the day, these are things that people use as metrics for enrolling or not enrolling themselves on a clinical trial. There are certain aspects or sensitivities associated with enrolling people, let's say, of Native American ethnicity or American Indian ethnicity, where outreach is extremely important. From a Lung-MAP standpoint, could you talk about some of the outreach initiatives that are being implemented or have already been implemented to potentially help decrease this gap of representation?  Dr. Mary Redman: I think that one of the major- and this isn't exactly outreach, but to start out with one of the things that we have, in addition, I mentioned that we had an accrual enhancement committee. We also have a site coordinators committee. And when we set up the site coordinators committee, we make certain that we have representation from the geographic regions within the country and different types of sites. And the major goal for our site coordinators committee is to give us input about how it is to implement Lung-MAP within their own institutions. And so, we want to be able to overcome any type of barriers or perceived barriers that are out there, and we want to hear it directly from those people who are working closely to enroll the patients. And so that's been a key part of everything that we've done. And so, part of that is that we've just developed educational materials. We have modified the protocol based on input that we've received from them. So that's, I think, been a major approach that we have used to try to reach more patients.  We do have a newsletter that we put out. The accrual enhancement committee has also contacted different sites to really have more conversations, one on one, just more, I guess, almost like focus type groups where you try to understand, really understanding what's coming on, what are the challenges from their perspectives. And then we've had webinars where we try, and we've had hundreds of attendees for these webinars, where we let the sites have direct access to those of us who are running the study to ask their questions. So those have been our major approaches. And I think that we're always trying to figure out how we can do better.  Dr. Rafeh Naqash: I agree with you, and I think as both physicians, providers, and the clinical trial staff as such become more and more cognizant of increasing diversity, these conversations end up happening earlier and earlier in an individual's patient's journey, where trying to see feasibility, trying to see financial aspects, getting a patient enrolled on a clinical trial gets evaluated earlier and earlier. And hopefully, with some of the measures that the SWOG or the Lung-MAP group is implementing, these percentages will see more spike in the long run for better clinical trial enrollment approach. So, Mary, now going to the science part of Lung-MAP for maybe some of the fellows or the investigators, early career investigators, who might be listening to this podcast, could you briefly explain what is the process of getting involved in Lung-MAP? Because for me, as a junior faculty a few years back, I was a fellow, and I remember at that point I hardly had any knowledge of corporate groups. SWOG, for example, was one of those that I'd heard about, but didn't necessarily know how to get involved. So, for trainees, for junior faculty, could you briefly say, what's the process? What does it involve? How would somebody propose something to Lung-MAP?  Dr. Mary Redman: Yeah, thank you for that question. And I really do hope that this actually is a way to get people to understand, and we'd love to have more engagement from more junior faculty and that's a major objective for the study. Because this infrastructure is in place, we are actually well suited to be able to mentor and bring junior faculty in. And so, the process is basically, you contact any of us that are in leadership within Lung-MAP and talk to us and we'll see if we can figure out a way. If you have an idea of a new study, wonderful. Our drug selection committee chair is Saima Waqar. She's a member of ASCO as well. I mean, one could find her and send her a note. The study chairs for Lung-MAP are Hoss Borghaei and Karen Reckamp. You can send them a note. You can send me an email, maryredman@fredhutch, and we will make certain that you are engaged and brought into the direct conversations that would lead to something.  So, it would be wonderful to have more junior faculty proposing ideas and leading sub studies, being a sub study chair. Each of our sub studies, as I mentioned before, are conducted independently, and then you are responsible for the development, conduct of the trial and writing of the paper and presenting. And so, we want all of that to happen. But we also would love to have ideas. If you think of this infrastructure as just being an amazing resource of data, we are happy to and would love to receive proposals for data analysis that could result in publication and presentation as well. So, if there's something that somebody sees as a question that they think we could answer, again, contact any of us and we will happily figure out a way how to work with you. We have a great team and a lot of capacity to be able to work with new people.   Dr. Rafeh Naqash: Thanks, Mary. And for all those listeners, trainees listening, you did get Mary's email, so try to send her an email, and hopefully she won't be complaining that there was a lot of requests. But I think all things considered, the Lung-MAP is a great data resource. As you mentioned, it's a great resource for junior investigators who are trying to build a career around clinical trials, precision medicine, and it's also a great resource, as you've shown, regarding diversity equity research from a clinical trial standpoint. So, I think it has all the components that are needed to run and create some interesting questions and answer those questions using the data set.  So now, Mary, going to the last part of the discussion here, one of the key components, we try to ask a few questions of the investigator, which in this case is yourself. Could you tell us briefly about your career trajectory, how you ended up doing what you're doing now, and what are some of the things that you've learned from and maybe advice to all the junior people listening to this podcast?  Dr. Mary Redman: Wow. Okay. Well, so if you hadn't already guessed, I'm a biostatistician. I started out in mathematics as an undergrad and then learned about biostatistics and thought that it sounded perfect for me. After I finished my doctorate, I did a year of postdoc and was starting to look for faculty positions. And if you haven't already inferred, I am a Seattle native. And so, when a position became available at the Fred Hutchinson Cancer Center here in Seattle, I applied for it, and the job happened to be with the SWOG Statistical Center. And so, you probably already guessed as well that I got the job. And so, I have been here at Fred Hutch since 2005. And when I joined Fred Hutch and the SWOG Statistical Center, which is co-located here and at Cancer Research and Biostatistics, just a mile west across Lake Union here in Seattle, the person who had been the lead statistician for the Lung Cancer Committee in SWOG, John Crowley, he was also the director of the SWOG Statistical Center and had been doing that for over 20 years, and he was ready to take some things off of his plate. And so, when I joined, they thought that I would be a great fit for the lung committee, in part because I had shown an ability to work with vibrant personalities, let's just say, which the lung community has in spades.  And so, when I started in the lung committee, David Gandara was the chair of the lung committee. And so, I worked for many, many years very closely with David, and we established a very close and really wonderful working relationship. And I learned a lot from him. I learned a lot from a lot of the other lung cancer researchers in the country and around the world. I pretty quickly became involved with the International Association for the Study of Lung Cancer and have attended most of the World Congress on Lung Cancer meetings and have gotten to know people around there. So as a biostatistician, obviously, I enjoy my mathematical and statistical skills, but I also just really enjoy learning and thinking about what I can bring to the problem where I come from a certain point of view and I love collaborating with the other people doing clinical research, in particular in lung cancer. And basically, my focus has always been on doing the best to answer our questions the most efficiently and effectively so that we can move the field forward and help people live longer. Dr. Rafeh Naqash: Thank you so much, Mary, for your time and giving us insights into your professional and personal journey. Also, thank you for listening to this JCO Precision Oncology conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Shannon Westin and her guest, Dr. Michael Anne Kyle and Dr. Nancy L. Keating, discuss the paper "Prior Authorization and Association With Delayed or Discontinued Prescription Fills" recently published in the JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast that goes in depth on articles and manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the Journal of Clinical Oncology. And as always, I'm so excited that you've joined us, and none of the authors have any conflict of interest today. We are going to be discussing a very exciting piece of work, “Prior Authorization and Association with Delayed or Discontinued Prescription Fills,” recently published in the Journal of Clinical Oncology. And I'm thrilled to be joined by the two authors of this important work. The first is Michael Anne Kyle. She's a PhD research fellow in the Department of Healthcare Policy at Harvard Medical School.  Welcome, Michael Anne.  Dr. Michael Anne Kyle: Hi. Thanks for having me. Shannon Westin: We're so excited. And the second is Dr. Nancy Keating. She's Professor of Healthcare Policy at Harvard Medical School and Professor of Medicine at Brigham and Women's Hospital in Boston.   Welcome. Dr. Nancy Keating: Thank you. It's great to be here.  Shannon Westin: So, we'll get right to it. First, I always like to level set because we have such an interesting and diverse audience. Can one of you describe the process and goals of prior authorization? What does this mean for our groups that maybe haven't experienced this? Lucky them.  Dr. Michael Anne Kyle: Prior authorization is- the process can take many forms. Basically, what we're describing is before you can be prescribed a treatment, in this case, we're looking at medications, you have to submit a request to the payer, to the insurance company, asking for approval to receive that treatment, or in this case, that drug. The doctor's office does have to do a ton of work, but very often, the patient also receives a lot of the communication. So, there's a lot of work for everybody in prior auth often. And the uses of it- in principle, the purpose of prior authorization is to confirm that the reason this medication or this treatment is being prescribed is because the patient meets the criteria for need. So that can mean, you want to confirm that you have the right tumor markers for the drug that's being prescribed. You want to confirm that you are aligned with guidelines. And then I think the thing that's often on many people's minds is that in the US, we don't have a lot of controls on drug pricing, but drug prices are very high. And so, I think we often think about prior auth as being a mechanism to try and contain costs.  Shannon Westin: And this isn't new, right? So, this is a process that's been going on for a while. I'd love to hear you speak a little bit about, maybe, some of the changes, like how have the requirements for prior authorization been changing over time, especially for patients with cancer? Dr. Michael Anne Kyle: That's a great question. And that was the first step we took in this work because we've heard from oncologists, from patients, from researchers, that prior auth has been increasing. And we did find, looking at Medicare data, that that is true, that the use of prior authorizations for oral oncology drugs, so that will be Part D outpatient drugs you get at the pharmacy, has been rising over the past decade. And I think what's really interesting to point out here is we found the use of prior authorization increasing both for branded drugs and for generic drugs, and for specialty drugs, which are high cost, as well as non-specialty drugs, which are typically lower cost. So, across the board, prior auth is increasing. And why is this happening really is the million-dollar question. Some of it is surely like we have accelerated approvals happening predominantly in oncology. So, you could imagine that you do need to verify some evidence of these newer treatments, but some of it is a little bit harder to interpret. And that was one of the things in our paper that we were very interested in because we also see a lot of prior auth on drugs that have a very well-established record of efficacy. And we know our first-line therapies often now include some generics, and yet we still see that they have prior auth. And the reason for that is less clear. Shannon Westin: Yeah. Just as a gynecologic oncologist, coming from this standpoint of PARP inhibitors, which have long been established as a standard of care and for years now have been a frontline treatment, we're getting so much pushback around that, and it's a huge issue because that impact of delays and things, and I know that's your work. So, I think that's one of the reasons I was very enthusiastic about this because I think it has such broad-based impact across all of our patient populations.   So, I think that kind of definitely transitions into this. What are the potential negative impacts in this process of patients? And I would say not only patients with cancer, but what do we know also in patients with other disease types that are facing this prior authorization issue as well? Dr. Michael Anne Kyle: What we were curious about is there's a sense that prior auth is increasing, the trends show it's increasing. And we were wondering, does that matter for patient care? And we could think about the benefits of prior authorization being like double-checking that you're getting the right treatment. But the negatives are that you can be delayed in getting treatment, and that can either be because you're going through the initial process or there can be some error or denial or dispute in a prior auth process that delays your access. And the clinical implications of that would vary by drug, how that would affect your treatment. In this case, in this paper, we're talking about drugs, but for any treatment, the implications would depend on what the treatment is and what the patient's condition is. But I really want to draw attention to this other piece, which is that it's stressful not to have your cancer medicine. And so even if you ultimately end up getting it, the time that you're on the phone trying to figure it out is time taking you away from other things. It's stressful. And very often, patients with cancer are taking multiple drugs and have complex health issues. So, they may be dealing with this for multiple parts of their care. And that can add up. Shannon Westin: Perfect. Thank you. So, I guess next is to talk about how you address this. Let's talk a little bit about the overall objectives of the study that you just published and maybe briefly kind of go through the design for our listeners. Dr. Michael Anne Kyle: What we were interested in doing, like I said, was trying to figure out what happens with prior authorization at the point of care. And our study looks at 11 oral anticancer drugs in Medicare Part D. And the reason for that is because data available to look at prior auth is fairly limited. And Medicare Part D for the outpatient formularies does have indicators for whether a drug has a prior auth. So, we were able to use that. The next piece is we're not inside the office understanding why these treatment decisions were made. So, what we decided to do was say, “Okay, let's look at patients who've been consistently taking this drug.” And we said, “Okay, let's say you've had to have at least three fills in the past four months.” And we sort of take that as an indicator that you're able to access this drug and it seems to be working for you. And then what we do is we look at who are patients in plans, same drug, same plan, where the plan introduced a new prior auth on this drug they're taking, as compared with patients in plans who did not have a change in their prior auth policy. And we said, “Okay, there's this new prior authorization introduced, does that affect whether you get that next fill or how long it takes to get it?” Dr. Nancy Keating: I want to emphasize Michael Anne's point about these are patients who are already successfully filling and regularly taking their drugs. And unfortunately, due to data limitations and the inability to see prescriptions that aren't filled, we would love to look at the same question with people that are starting on a new drug but weren't able to do so but would imagine that you might even see bigger impacts in those patients. We both recognize from a health policy standpoint that there could be benefits of prior authorization policies. But it's also very unlikely to think that for a patient that's regularly filling an anticancer drug over a long period of time, that there's a reason that that patient should not be on that drug. And so, this is an area where we think that there may be really limited benefits of prior authorization, but potential harms.  Shannon Westin: Yeah, it makes sense. And of course, it would be. There's always the ideal way to set research up, and then a practical way. So, I was struck by what you chose. I thought it was really very practical and rational and made a lot of sense. And certainly, there are inferences that we can make based on what you found. So, let's talk about that. Let's talk about your primary findings. What did you see as the impact of a new prior authorization policy on patient care? Dr. Michael Anne Kyle: We found that for the patients who had a new prior auth policy introduced in their plan, compared to patients who didn't have a prior auth change, their odds of discontinuation within the next 120 days increased by about 7.1 times higher odds of discontinuation. And then for delays, we found that people were delayed an average of 9.7 days from when we last saw that they were expected to run out of their drugs based on their last fill, we said, “Okay, what's the last day we expect you to have meds on hand, and then when do we actually see you fill again if we see you fill? And the average delay there was 9.7, about 10 days. And that's a fairly conservative estimate that we decided to make. And I'm sure you and Dr. Nancy Keating can elaborate on how that's not just passive time. There's a lot of people scrambling around, probably in that interval, trying to close the gap. Shannon Westin: I mean, you said it, like, 10 days. It's a huge time. And it's not just time sitting there twiddling your thumbs. They're probably stressing, anxious. They might be having side effects related to stopping their medication. They might be taking other medications and reduce the efficacy of the combination. I mean, there's so many implications here of the impact. Dr. Nancy Keating: They're also calling the office, trying to get through to the office. Then the doctors are calling, trying to get through. People are like, what's going on here? Why isn't this medicine there? And so, there's a lot of individual patient and clinician effort that's happening at this time as well. Shannon Westin: And I think, of course, you were limited by the databases that you were using and what you're able to access, but I think it really does make me wonder, what's the impact on cancer related outcomes. We know about delays in certain therapies and things and how that can negatively impact survival and response and all of those types of things. And I wish we did have access to that kind of data because obviously the time and the things that you've been able to demonstrate are important, but the more objective data we can get around patient outcomes, I think will help us impact the actual policies that are being implemented here.  Dr. Nancy Keating: Right. And just to underscore too, Michael Anne highlighted the delays, but also there was a substantial increase in discontinuation within 120 days. So, there are some people that seem to not be able to get the med, maybe found another way to get it, or maybe were able to get samples from a drug company that we couldn't observe, but that's also concerning that there might be some people who fell through the cracks.   Shannon Westin: A very good point. I think that it's hard to know, but the potential there of losing the drug that's actually working for you is really distressing for providers and patients both.   One other thing I noticed that was interesting. Can you speak a little bit about some of the other factors that were associated with these findings with the treatment delays and what other things may be impacting these outcomes? Dr. Michael Anne Kyle: We looked at some patient characteristics and insurance characteristics that may be associated with delays. And I just have to note here that our sample is fairly small because prior authorization is so prevalent. There aren't a lot of switchers. So, this sort of limited the amount of depth we could go into. But here's what we can tell you, which is that people who are under 65, so in Medicare that will typically be people who have eligibility through disability, were filling about a day later than that 9.7 average people, female sex also filling 0.7 days, nearly a full day later. Similarly, and this is compared to males and then compared to white, non-Hispanic patients, patients who are black and patients who are Hispanic Latino are filling about 0.6, 0.7 days later, which is, of course, quite concerning, given our desire to have a more equitable health care system. And then finally, we linked our data to census data. And for patients living in a residential zip code with higher rates of poverty, we found that for each 10-percentage point increase in proportion of residents in that zip below the federal poverty level, the delay was about 2.5 days. So, what you can sort of take from that is the risk factors in particular are in Medicare being younger, which I would say is having a disability, female sex, non-white, and people living in high poverty zip codes. And given what we know about racial segregation, I think the odds are likely that the patients themselves would potentially also be low income. Shannon Westin: That's what's so important about this work, is it raises an awareness of, really, who's being impacted by this. Because I just want to draw back to kind of what you said at the beginning, that this is meant to do cost containment. It's meant to help the healthcare system. But what we're seeing in practice is it may be helping in some specific areas, but it's certainly creating quite a detriment. So perhaps there are other mechanisms that we could be exploring from a policy standpoint to try to work on cost containment, but not put the burden on the patients or on the people that are giving this health care. So, I think that's why I was so struck by this work.  I guess the next question is, what are your next steps for the research, and how can we use these data to help the patients?   Dr. Michael Anne Kyle: What a great question. I'll start, and then I'll let Nancy give her thoughts too. We're lucky that prior authorization is a very active policy area right now, both at the state and federal level. There's a great deal of interest in sort of certainly improving a lot of the information systems. Perhaps we can move away from the fax machine finally in 2023. I think there's a lot of policy relevant action happening around trying to make prior authorizations electronic, and you can automate them and make a lot of this move faster. There are also larger questions about what is the right price for a drug and how do we distribute it to people that I think are a lot more fundamental than any one study, but I think this is just another way. When we think about financial toxicity, there's just many challenges that come back to some way to this root cause of care is very expensive, and this is, I think, prior auth is one of the side effects of that.  And so, hopefully, to help patients, we can get this data in the hands of policymakers who are trying to bring us to a more modern prior auth system. And hopefully also to payers, I would be very excited to see a little bit more examination of, like when is prior auth appropriate versus when is it not. I think there are cases where prior authorization is very appropriate, and we shouldn't take it away. But one of the drugs in our study is generic imatinib, and perhaps that is a lower value prior auth. And so, I'd be very interested in seeing payers think more strategically about when is prior appropriate, both to improve access and improve equity, and then also to improve the provider burnout and the poor docs who are really struggling under the weight of this. Dr. Nancy Keating: Yeah, I couldn't agree more with everything that Michael Anne said, but really, we'll underscore that last point. The prior auth policy seems like it's this very broad policy and the way that it's implemented, it's sort of like, let's just hit everything and not take a nuanced, thoughtful approach. But just like Michael Anne said, generic imatinib, really? And then back to this point of patients that are doing well on a drug, people are not going to be taking anti-cancer therapies if they don't need to. And so there just doesn't seem to be any reason to implement a prior authorization policy on a drug that is being well tolerated. And so really, I think there could be a lot more thought and nuance put into applying these policies within health plans. Shannon Westin: Yeah, I think that's a perfect way to end this. I would just add, I think this is beyond anticancer therapy for our patients with cancer. I mean, we're seeing it now with supportive care medications. And to your point, I mean, generic antiemetics, and you're like, come on, this is ridiculous. So, I think that this type of work is- the best type of work always spurs more questions and gets us fired up about what to do next. So, I just want to again commend you on all of this important work, and we need to add more data here so that policy will change. And so, thank you both for your hard work in this area and for taking the time to educate our listeners. I'm sure we're going to hear a lot of intriguing questions for you about this work, and hopefully that'll move our policy forward.   And thank you, listeners, for checking in again with JCO After Hours. Again, we were discussing prior authorization in association with delayed or discontinued prescription fills. I'm so grateful to Dr. Kyle and Dr. Keating for joining me today, and I hope you all will listen to our other podcast offerings wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and it is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

What is the significance of gender and masculinities in understanding conflict? Through an ethnographic study conducted between 2013 and 2016, Amya Agarwal's book Contesting Masculinities and Women's Agency in Kashmir (Rowman & Littlefield, 2022) explores the politics of competing and sometimes overlapping masculinities represented by the state armed forces and the non-state actors in the Kashmir valley. In addition, the book broadens the understanding of women's agency through its engagement with the construction, performance, and interplay of masculinities in the conflict. Combining existing elements of both feminist research and critical scholarship on men and masculinities, the book highlights the significance of foregrounding the interplay of men's identities in conflicts to understand agency in a meaningful way. Through the focus on the simultaneous play of multiple masculinities, the book also questions the oversimplified and monolithic usage of masculinity being associated only with violence in conflicts. The empirical data in the book includes interviews and narratives of multiple stakeholders belonging to diverse vantage points in the Kashmir conflict. Some of these include activists, widows, wives of the disappeared, ex-militants, surrendered militants, participants of the stone-pelting movement, mothers of sons killed in the conflict, women representatives of the village Halqa Panchayats, and army personnel. The book also draws from alternative material in the form of graffiti, folk songs, poetry on graves, and slogans. Through anecdotal reminiscence, the author reflects on the challenges of field research in Kashmir that served as an opportunity for self-contemplation. Dr. Amya Agarwal is a senior researcher at the Arnold Bergstraesser Institute in Freiburg, Germany. She also teaches at the University of Freiburg and University College Freiburg. Her research interests include gender, conflict and security in South Asia; critical masculinities studies and visuality, and aesthetics in war and resistance. Tusharika Deka is a PhD student in International Relations at the University of Nottingham. Currently, she serves as an Editor-at-large for E-International Relations and as the Social Media Editor for Commonwealth and Comparative Politics, a peer-reviewed journal published by Taylor and Francis. Previously she was the Assistant Editor for the Asia Dialogue, an online journal affiliated with the Asia Research Institute at the University of Nottingham. On Twitter: @Tusharika24. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/new-books-network

What is the significance of gender and masculinities in understanding conflict? Through an ethnographic study conducted between 2013 and 2016, Amya Agarwal's book Contesting Masculinities and Women's Agency in Kashmir (Rowman & Littlefield, 2022) explores the politics of competing and sometimes overlapping masculinities represented by the state armed forces and the non-state actors in the Kashmir valley. In addition, the book broadens the understanding of women's agency through its engagement with the construction, performance, and interplay of masculinities in the conflict. Combining existing elements of both feminist research and critical scholarship on men and masculinities, the book highlights the significance of foregrounding the interplay of men's identities in conflicts to understand agency in a meaningful way. Through the focus on the simultaneous play of multiple masculinities, the book also questions the oversimplified and monolithic usage of masculinity being associated only with violence in conflicts. The empirical data in the book includes interviews and narratives of multiple stakeholders belonging to diverse vantage points in the Kashmir conflict. Some of these include activists, widows, wives of the disappeared, ex-militants, surrendered militants, participants of the stone-pelting movement, mothers of sons killed in the conflict, women representatives of the village Halqa Panchayats, and army personnel. The book also draws from alternative material in the form of graffiti, folk songs, poetry on graves, and slogans. Through anecdotal reminiscence, the author reflects on the challenges of field research in Kashmir that served as an opportunity for self-contemplation. Dr. Amya Agarwal is a senior researcher at the Arnold Bergstraesser Institute in Freiburg, Germany. She also teaches at the University of Freiburg and University College Freiburg. Her research interests include gender, conflict and security in South Asia; critical masculinities studies and visuality, and aesthetics in war and resistance. Tusharika Deka is a PhD student in International Relations at the University of Nottingham. Currently, she serves as an Editor-at-large for E-International Relations and as the Social Media Editor for Commonwealth and Comparative Politics, a peer-reviewed journal published by Taylor and Francis. Previously she was the Assistant Editor for the Asia Dialogue, an online journal affiliated with the Asia Research Institute at the University of Nottingham. On Twitter: @Tusharika24. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/gender-studies

What is the significance of gender and masculinities in understanding conflict? Through an ethnographic study conducted between 2013 and 2016, Amya Agarwal's book Contesting Masculinities and Women's Agency in Kashmir (Rowman & Littlefield, 2022) explores the politics of competing and sometimes overlapping masculinities represented by the state armed forces and the non-state actors in the Kashmir valley. In addition, the book broadens the understanding of women's agency through its engagement with the construction, performance, and interplay of masculinities in the conflict. Combining existing elements of both feminist research and critical scholarship on men and masculinities, the book highlights the significance of foregrounding the interplay of men's identities in conflicts to understand agency in a meaningful way. Through the focus on the simultaneous play of multiple masculinities, the book also questions the oversimplified and monolithic usage of masculinity being associated only with violence in conflicts. The empirical data in the book includes interviews and narratives of multiple stakeholders belonging to diverse vantage points in the Kashmir conflict. Some of these include activists, widows, wives of the disappeared, ex-militants, surrendered militants, participants of the stone-pelting movement, mothers of sons killed in the conflict, women representatives of the village Halqa Panchayats, and army personnel. The book also draws from alternative material in the form of graffiti, folk songs, poetry on graves, and slogans. Through anecdotal reminiscence, the author reflects on the challenges of field research in Kashmir that served as an opportunity for self-contemplation. Dr. Amya Agarwal is a senior researcher at the Arnold Bergstraesser Institute in Freiburg, Germany. She also teaches at the University of Freiburg and University College Freiburg. Her research interests include gender, conflict and security in South Asia; critical masculinities studies and visuality, and aesthetics in war and resistance. Tusharika Deka is a PhD student in International Relations at the University of Nottingham. Currently, she serves as an Editor-at-large for E-International Relations and as the Social Media Editor for Commonwealth and Comparative Politics, a peer-reviewed journal published by Taylor and Francis. Previously she was the Assistant Editor for the Asia Dialogue, an online journal affiliated with the Asia Research Institute at the University of Nottingham. On Twitter: @Tusharika24. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/anthropology

What is the significance of gender and masculinities in understanding conflict? Through an ethnographic study conducted between 2013 and 2016, Amya Agarwal's book Contesting Masculinities and Women's Agency in Kashmir (Rowman & Littlefield, 2022) explores the politics of competing and sometimes overlapping masculinities represented by the state armed forces and the non-state actors in the Kashmir valley. In addition, the book broadens the understanding of women's agency through its engagement with the construction, performance, and interplay of masculinities in the conflict. Combining existing elements of both feminist research and critical scholarship on men and masculinities, the book highlights the significance of foregrounding the interplay of men's identities in conflicts to understand agency in a meaningful way. Through the focus on the simultaneous play of multiple masculinities, the book also questions the oversimplified and monolithic usage of masculinity being associated only with violence in conflicts. The empirical data in the book includes interviews and narratives of multiple stakeholders belonging to diverse vantage points in the Kashmir conflict. Some of these include activists, widows, wives of the disappeared, ex-militants, surrendered militants, participants of the stone-pelting movement, mothers of sons killed in the conflict, women representatives of the village Halqa Panchayats, and army personnel. The book also draws from alternative material in the form of graffiti, folk songs, poetry on graves, and slogans. Through anecdotal reminiscence, the author reflects on the challenges of field research in Kashmir that served as an opportunity for self-contemplation. Dr. Amya Agarwal is a senior researcher at the Arnold Bergstraesser Institute in Freiburg, Germany. She also teaches at the University of Freiburg and University College Freiburg. Her research interests include gender, conflict and security in South Asia; critical masculinities studies and visuality, and aesthetics in war and resistance. Tusharika Deka is a PhD student in International Relations at the University of Nottingham. Currently, she serves as an Editor-at-large for E-International Relations and as the Social Media Editor for Commonwealth and Comparative Politics, a peer-reviewed journal published by Taylor and Francis. Previously she was the Assistant Editor for the Asia Dialogue, an online journal affiliated with the Asia Research Institute at the University of Nottingham. On Twitter: @Tusharika24. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/sociology

What is the significance of gender and masculinities in understanding conflict? Through an ethnographic study conducted between 2013 and 2016, Amya Agarwal's book Contesting Masculinities and Women's Agency in Kashmir (Rowman & Littlefield, 2022) explores the politics of competing and sometimes overlapping masculinities represented by the state armed forces and the non-state actors in the Kashmir valley. In addition, the book broadens the understanding of women's agency through its engagement with the construction, performance, and interplay of masculinities in the conflict. Combining existing elements of both feminist research and critical scholarship on men and masculinities, the book highlights the significance of foregrounding the interplay of men's identities in conflicts to understand agency in a meaningful way. Through the focus on the simultaneous play of multiple masculinities, the book also questions the oversimplified and monolithic usage of masculinity being associated only with violence in conflicts. The empirical data in the book includes interviews and narratives of multiple stakeholders belonging to diverse vantage points in the Kashmir conflict. Some of these include activists, widows, wives of the disappeared, ex-militants, surrendered militants, participants of the stone-pelting movement, mothers of sons killed in the conflict, women representatives of the village Halqa Panchayats, and army personnel. The book also draws from alternative material in the form of graffiti, folk songs, poetry on graves, and slogans. Through anecdotal reminiscence, the author reflects on the challenges of field research in Kashmir that served as an opportunity for self-contemplation. Dr. Amya Agarwal is a senior researcher at the Arnold Bergstraesser Institute in Freiburg, Germany. She also teaches at the University of Freiburg and University College Freiburg. Her research interests include gender, conflict and security in South Asia; critical masculinities studies and visuality, and aesthetics in war and resistance. Tusharika Deka is a PhD student in International Relations at the University of Nottingham. Currently, she serves as an Editor-at-large for E-International Relations and as the Social Media Editor for Commonwealth and Comparative Politics, a peer-reviewed journal published by Taylor and Francis. Previously she was the Assistant Editor for the Asia Dialogue, an online journal affiliated with the Asia Research Institute at the University of Nottingham. On Twitter: @Tusharika24. Learn more about your ad choices. Visit megaphone.fm/adchoices Support our show by becoming a premium member! https://newbooksnetwork.supportingcast.fm/south-asian-studies

Dr. Shannon Westin and her guest, Dr. Nanda Horeweg and Dr. Carien Creutzberg, discuss the paper "Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer" recently published in the JCO. TRANSCRIPT  The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host Shannon Westin, Social Media Editor for the JCO and GYN Oncologist by trade. And I'm so excited about today's topic because it is a GYN Oncologist dream. Before I start, please note that none of the authors have any conflict of interest. We are going to be discussing molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early-stage endometrioid endometrial cancer. And this was published in the JCO on September 20th, 2023. And we're going to be speaking to two of the lead authors. First is Nanda Horeweg. She's a senior researcher in the Department of Radiation Oncology at the Leiden University Medical Center in the Netherlands. Welcome. Nanda Horeweg: Thank you. Happy to be here. Shannon Westin: And Dr. Carien Creutzberg. She's professor at the Department of Radiation Oncology at the Leiden Medical Center as well. Carien Creutzberg: Thank you. Shannon Westin: So, let's get into it. And I want to really level set because we have a mixed audience here. So, why don't you start by speaking about the incidents and mortality of endometrial cancer? Nanda Horeweg: Yes, of course. Endometrial cancer is the sixth most common cancer in women with around 400,000 new diagnoses made globally each year. And a woman's lifetime risk to get endometrial cancer is around 3%, and the median age, the diagnosis is 61 years. Most of the women who are diagnosed with endometrial cancer are diagnosed at an early stage, around two thirds, and they have an excellent prognosis. Actually, the five-year survival rates are around 92%. For stage 2 disease, this is actually already going down a bit to 74%. Therefore, stage 3 disease is only 48%. Women that are diagnosed with advanced disease have only a five-year survival, 15%. Shannon Westin: So, given that we know the majority of endometrial cancers are diagnosed at this early stage, prior to your evaluation, what was known about the optimal way to treat this early-stage patient population? Carien Creutzberg: Well, of course, the PORTEC trials were done … were started PORTEC-1 in the 19th of the last century, and PORTEC-2 in 2002. So, at that time, there were still many, many women treated adjuvantly with external beam radiation therapy. And we just developed risk factors to decide on their risk and the incidents for radiotherapy. And in PORTEC-2, because in PORTEC-1 we had seen that most of the recurrences in these early stage cancers were in the vaginal fold, we compared local vaginal brachytherapy only three sessions within full course of pelvic radiotherapy and showed that it had similar pelvic control and survival. Of course, this study, which Nanda conducted, was a long-term analysis with many new factors known from the translational research in the tissue samples of these patients who participate in PORTEC-1 and 2. And in the meantime, we've developed much more knowledge on the molecular factors and other important factors such as LVSI, which tell us much more about the individual prognosis to patients. So, the treatment has been developing greatly in the past 20 years. Shannon Westin: Yeah, and I think this is a great case of less is more, right? We were doing so much for so many people that really didn't need it. And so, really tailoring who needs less treatment, who doesn't need any treatment, and then also, conversely, who may need more treatment that would be missed by the traditional risk factors that you're speaking of. So, I think that brings us right into my next question, which is just bringing the audience up to date on the cancer genome atlas and how that's changed the way we classify endometrial cancer. Nanda Horeweg: Yes, I think the molecular classification of the TCGA has shaped the way we think about endometrial cancer, and has huge impact on decisions on adjuvant treatments in the years to come. The TCGA performed an extensive characterization of the endometrial cancers and found that in fact, this disease exists of four different groups. And the first of the groups I'd like to discuss is the ultra-mutated group, which is characterized by POLE mutations. And this group is shown to have an excellent prognosis in many independent studies. A second group that also has a high mutational burden is characterized by microsatellite instability, and mismatch repair deficiency and has shown to have an intermediate prognosis. Then there's another group that has a low mutational burden with high copy number alterations and frequent TP53 mutations, and these have a poor prognosis. And then lastly, there's a group that does not have any of the classifying features and is often called non-specific molecular profile or TP53 wild type. And this group also has an intermediate prognosis. And then finally, there's a small group of cancers that has more than one of these classifying features, the so-called multiple classifiers. And the WHO 2020 has developed an algorithm which can be used to classify them into the four groups. And that's first on the POLE status. And for the POLE wild type tumors, they are assigned according to mismatch repair deficiency status. And for those that are mismatch repair proficient than POLE wild type, they are classified according to the TP53 status into NSMP or p53 abnormal. Carien Creutzberg: Yeah, that is because of in the ultra-mutated and hyper mutated groups, many of the other mutations are secondary mutations in the context of the ultra-mutated stage, and they behave like the first molecular group. Shannon Westin: Yeah. So, that POLE mutation is going to trump anything else, and it's so important. And I will just say as a sidebar, it's been challenging with the price of next gen sequencing sometimes to get that for everyone. So, sometimes for us when we see a p53 mutation, we actually go back and do the full next gen sequencing to make sure that we're not going to act on that core prognostic feature when it really is in the setting of that more simplistic or that more positive prognostic place. So, this is great, we already kind of highlighted a little bit PORTEC-1 and 2, but if you don't mind, I would love to get the audience a little bit more information just maybe about the populations that were included as we were figuring out how aggressive to be with radiation just to remind people of that, or to teach them that if they haven't gotten a chance to look at those studies. Carien Creutzberg: Yeah, that's important to know because PORTEC-1 was still in the era that we also treated intermediate risk stage 1 endometrial cancer patients. So, deep invasion with grade 1 and 2 or superficial invasion with grade 2 and 3. That's what we defined at that point. Then we compared external beam radiation or no further treatment, showing no survival difference, but a higher risk of recurrence with higher risk being older age over 60, grade 3 for deep myometrial invasion. And we kept those high intermediate risk factors as also similarly found by GOG-99 at the time to do PORTEC-2. So, at the time, about 50% of patients did not have an indication for adjuvant therapy anymore, and with a high intermediate risk population for PORTEC-2, we compare external beam or vaginal brachytherapy and found the benefit of vaginal brachytherapy. A simple outpatient treatment, very short with almost no side effects ensuring local control. And nowadays, using the molecular classification of PORTEC-4a, we've compared achieving treatment with or without use of the molecular factors to designated treatment. So, the standard arm is vaginal brachytherapy and investigational arm is first, a molecular risk profile. And then we give no radiotherapy for those with a favorable profile, then a brachytherapy for the intermediate ones, and for the small group is either extensive LVSI or TP53 mutation or L1 chem overexpression external beam. And we hope to show that less overtreatment and less undertreatment will benefit these patients. Shannon Westin: Yeah, I'm very much looking forward to the results of PORTEC-4a. But let's circle back and talk a little bit about your amazing work here. So, how did you leverage those patient populations from PORTEC-1 and 2 for the current study? Nanda Horeweg: Yes. Well, the PORTEC-1 and 2 study provided a unique opportunity to look into differential treatment effects for radiotherapy. And that is because these are randomized trials, so the groups are comparable, and we have long-term follow-up data that's of very high-quality. In addition, as Carien said earlier, she had the vision already back in the nineties to directly ask the patients permission for the collection of the tissue. So, we have a broader complete biobank for both of these trials, which is quite unique. And our colleagues, Professor Smit and also Charlene Goseff from the pathology department, they have done extensive work on molecular classification, and have molecularly characterized all these cases. So, this allowed us to include 880 patients in this study, which is the largest so far. And besides like the very good starting point that we have of PORTEC-1 and 2 is that we also chose a design that was optimized to conduct like real causes, the causal effects of the molecular class on radiotherapy response. So, we tried to preserve this randomization effect, the exchangeability of the groups as much by working with the intention to treat population and not excluding any patients, except for when they did not have the molecular classification assessed. And also, we looked at areas in the body that were irradiated in one group and not in the other one to really observe the effect of radiotherapy as much as possible. So, looking to the entire pelvis, so local and regional recurrences in PORTEC-1 and looking at pelvic recurrences in PORTEC-2. Shannon Westin So, how were the intervention outcomes in this study different based on the TCGA classifiers? Nanda Horeweg: Before I tell you the results of biomolecular group, I think it's good to have the starting point of the analysis here. So, the no hypothesis of my study was to see whether there was any difference, and no hypothesis is that there's no difference. So, if we find a significant effect, then we can actually say that we found something. And if we start with the POLE group, we did not find any significant difference between the groups allocated to radiotherapy or not. But we did see not a single recurrence in any of the patients that we included from both of these trials. So, technically speaking, we did not find a predictive effect of the molecular classifier, but a prognostic effect. There's no one's having recurrence, so we can deduct from that, that radiotherapy is probably over treatment. Then for the MMRd group, we did observe some recurrences, but these were not significantly different between these three groups. So, based on this study, we cannot draw conclusions on which type of radiotherapy we should give to the patients or whether we should give radiotherapy at all. This was very different for the p53 group. There, the patients had lots of recurrences, unfortunately, as we expected, but we saw a big difference in outcome compared between no radiotherapy at all if it's vaginal brachytherapy where we still had lots of recurrences, and EBRT where we hardly saw any recurrences in the pelvis. And that difference was significantly different. So, that's an indication that these patients need more than just vaginal brachytherapy, even though it's only stage 1 endometrioid endometrial cancer. And then in the last group, the NSMPs, we saw even a different pattern where patients who had had external beam radiotherapy or vaginal brachytherapy, both had an excellent local regional control, and the ones that did not receive any treatments had more recurrences. And this was also very significant. So, there, you would conclude that both therapies are appropriate, but of course, the toxicity profile for vaginal brachytherapy is much more favorable than that of EBRT. Shannon Westin: We really are getting kind of consistent data around p53 needing more treatment. And I think the natural question that comes here, for me at least, and I know we can't answer it with the work, is would chemo be — would that be that extra treatment, when we saw with PORTEC-3 that the group needed the chemotherapy the most. So, I think we'll have to continue to work through that and determine is any more treatment what we need or specific treatments really the best. So, this is so intriguing and it's nice that it's consistent, that we're seeing that across these different studies that really kind of lends strength and validity, I think to what we're finding. So, one of the actions that we're kind of moving towards and that you advocate certainly in your paper is omitting therapy for patients with POLE mutations. Are there any ongoing studies around that that will help us confirm that this is safe for our patients? Nanda Horeweg: Yeah, that's a very good point. I think the evidence is strong enough now to conduct prospective trials. And of course, these are ongoing, the PORTEC-4a trial was already briefly mentioned there. The patients with poor mutations will be randomized between observation and vaginal brachytherapy. So, that will give us a good indication whether in this high intermediate risk early-stage group omission is safe. And in addition to that, we are also conducting with the RAINBO Consortium, the RAINBO-BLUE trial, wherein patients also with high-risk features, so non-endometrioid isotypes, LVSI and higher stages are included. And also in those patients, we investigate whether the de-escalation of treatment is safe. So, we're definitely looking forward to those results to be able to transfer this knowledge to clinical practice later on. Carien Creutzberg: And maybe it's nice to add that RAINBO BLUE is connected to the Canadian Taper trial. Taper being a general de-escalation trial where the POLE patients in that trial are also feeding into the RAINBO-BLUE. And I know that in North America, many centers will participate in the Taper trial. Shannon Westin: Yes, I think everyone is very excited and I think it'll be nice to have these two very strong studies that will help us really confirm that that is 100% a test that needs to be done, cost are not — and that will help avoid overtreatment of patients. So, in line of that, have you all experienced any challenges with implementing molecular testing across patients with endometrial cancer? Any thoughts on how we could potentially simplify? You talked about the rational promise algorithm, which I think is excellent, but I'm just curious to hear your thoughts on this. Nanda Horeweg: The implementation of the molecular classification can be challenging. We have to be honest about that. And usually, it's the assessment of the POLE status that's causing the problems because that's usually done with NGS, which is quite expensive. It requires a lot of knowledge in the laboratory and it's also a bit time-consuming. So, that is the bottleneck for most laboratories and for most settings. But this is already changing in a couple of places, like in the UK and the Netherlands, it's being reimbursed by healthcare insurances, and also, in many tertiary care centers in other countries, they're already systematically performing this test. But of course, there will always be places where this is not feasible. And luckily, there are also cheaper alternatives coming up and are already available at the moment. So, one of them is, for example, standard sequencing, which is not so expensive, but a bit labor intensive. Some colleagues we work with from India have implemented that in their clinical practice and are perfectly able to molecularly classify the endometrial cancers in daily practice. Another alternative is a test that we've developed in Leiden that's called the QPOLE test, which is based on qPCR, so that's a technology which we use for our COVID test around the world, so that can be done almost anywhere. And with that, you have a very high accuracy to detect unknown pathogenic variants. And this is also published in JCO Global Oncology, and can be implemented in any center after a local validation step. And even like more companies nowadays are realizing that this is important. So, I think commercial tests are already becoming available and very more on the market soon. So, I am really hoping that it'll be more available to endometrial cancer patients. Carien Creutzberg: And they'll offer them at a very low cost and also a rapid turnaround because NGS can take like 10 days. But realizing on a more national level, if you have found one patient with a POLE mutation, the omission of cycles of chemotherapy with all of the patient care around in the hospital is worth much more than just a few POLE tests. So, we have to look at this and that's I think why our healthcare reimbursement came through that if you look at a population level, it is cheaper, and we'll do an extensive cost analysis in PORTEC-4 just to show this. Shannon Westin: That is such a good point. I love that and all of the downstream issues that happen potentially with radiotherapy or with chemotherapy, that's really brilliant. And I'm going to take that back, I love these podcasts. I always learn stuff that I immediately start to use. So, I guess then the last question is, what's next for this particular research and how might we validate what you found? Nanda Horeweg: Yes. Well, as mentioned earlier, for POLE, we have already put the next step in place. So, PORTEC-4a has completed accrual almost two years ago, and we're very much looking forward to do the final analysis within one to one and a half years. So, that will be one of the important next step. And of course, the POLE-BLUE trial is open at the moment, and within a couple of years, we also hope to learn more about this group. So, that's very exciting. Then for the mismatch repair deficient group, while we did not find any particular sensitivity for radiotherapy, and I also don't think that we will conduct another large randomized radiotherapy trial in this group — I think the results that we've observed in the metastasized setting, were really impressive results with immunotherapy are the way forward for this molecular class. And I think the next thing we should do now is prove whether this works or not in the adjuvant setting. And if that's starting with the high-risk patients, which is something we are currently doing in the MMRd-GREEN trial, which is ongoing in the Netherlands, and soon, will open internationally. And from there on, we can work forward if we see that also in this setting the immunotherapy works well. Shannon Westin: And I think GY020 also — NCI trial is also looking at the addition of immunotherapy to radiotherapy in that irony at risk. Carien Creutzberg: Absolutely. Nanda Horeweg: Yeah. And the KEYNOTE-B21 as well — oh, well, already complete accrue. Shannon Westin: The B21, yeah. So, I think those are good. Yeah, that's a really good point for that MMRd group that the immunotherapy really is the way to go, and then more work to be done with the no specific molecular profile. Nanda Horeweg: The NSMP, I think like for the early-stage group, it's quite clear that vaginal brachytherapy is a therapy of choice. But you can of course, try to identify those at such a low risk that you could deescalate treatment. And that's of course what's being done in the Taper trial and also in part, investigated in the PORTEC-4a trial. Carien Creutzberg: And those with higher risk NSMP that we are revisiting hormonal treatments because 90% are estrogen receptor positive, and they have a clearly better prognosis than those with estrogen receptor negative tumors. So, those with estrogen receptor positive tumors can in RAINBO-ORANGE, which will be run led by the UK group, see if we can improve quality of life with less intensive adjuvant treatment. And then you came to the p53 group, that's a good one to stop with. Nanda Horeweg: Yeah, we have very good indications that radiotherapy and chemotherapy is working well for this group. And this is also in line with the guidelines that have been issued in the last few years by many societies. So, I don't think we should change this base of the treatment consisting of radiotherapy and chemotherapy. But since the prognosis is still rather poor, we need to add systemic agents to reduce the risk of metastasis. And preferably, this should be like well-designed based on a proper biological underpinning, plus something that's not too toxic since we're combining the three therapies together. So, this is what we try to do in the RAINBO-RED trial where we will investigate the addition of a PARP inhibitor to chemoradiation in the p53 group. Shannon Westin: Oh, I love that. That's been my whole career, is adding PARP inhibitors wherever I can. Carien Creutzberg): We might also want to mention the HER2 inhibitors, which are also in about 20% of the p53 group has HER2 overexpression. And there is a trial being set up in NCI with trastuzumab and pertuzumab. Shannon Westin: My only concern with that one is I think that the antibody drug conjugates are so much more powerful, the TDX data that we just saw from DESTINY is so impressive. And so, I do wonder, like if we need to move on from kind of some of the older HER2, and get with the program and use some of these more powerful drugs. But with that, I just want to thank Dr. Creutzberg and Horeweg. This was such a great discussion, and obviously, near and dear to my heart talking about endometrial cancer, but I hope our audience enjoyed as well. Just as a reminder, this was a discussion on molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early stage endometroid endometrial cancer, published in the JCO on 9.20.23. I am your host, Shannon Westin, and I hope you'll check out more JCO After Hours wherever you get your podcasts. Have an awesome day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

In this "Podcast Takeover," Dr. Lidia Schapira guest hosts to discuss with Dr. Shannon Westin her own JCO paper, which reports on the DUO-E Trial. Dr. Ramez Eskander also joins in this lively discussion. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor of the JCO and Gynecologic Oncologist by trade. And actually, I'm super excited today because we are going to have a podcast takeover because we are discussing my own work, which was simultaneously presented at the European Society of Medical Oncology 2023 Congress and published in the Journal of Clinical Oncology on October 21st, 2023. And this was the DUO-E trial, “Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer.” Because we're discussing this work and we wanted you to have an unbiased podcast discussion, Dr. Lidia Schapira, who is a Professor of Medical Oncology at Stanford University and an Associate Editor of JCO and the Art of Oncology podcast host, is going to take over this podcast and really just pepper me with questions about this exciting work.  Welcome, Dr. Schapira.  Dr. Lidia Schapira: Thank you so much. It's such a pleasure to be with you. Dr. Shannon Westin: And before I turn over the reins, I also want to introduce one of my colleagues, who's going to be providing quite a bit of insight on this topic, Dr. Ramez Eskander, who is Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego. And you will know he's the principal investigator of the GY-018 study, which established pembrolizumab and chemotherapy as the new standard of care in endometrial cancer. Welcome, Ramez.  Dr. Ramez Eskander: Thank you. Thank you, Dr. Westin. It's a pleasure to be here. And congratulations again to you and your study team for this exceptional work.  Dr. Shannon Westin: Thank you. And congratulations to you.  Dr. Schapira, thank you for being here and please do take it away. Dr. Lidia Schapira: So let's start by having you tell us a little bit about the standard of care for women with endometrial cancer and advanced endometrial cancer prior to this study. Ramez, I'm going to direct this question to you first. Dr. Ramez Eskander: For many years, actually since about 2012, carboplatin and paclitaxel, which ironically is a chemotherapy backbone really across all of our gynecologic tumors, emerged as the preferred doublet chemotherapy regimen for the management of advanced-stage metastatic or recurrent endometrial cancer. It evolved through a series of different clinical trials, in fact taking us from whole abdominal radiation, systemic chemotherapy, comparing single agents to doublets and then triplet regimen of TAP to carboplatin and paclitaxel, which ultimately, then, following the presentation of GOG Protocol 209 and its publication, as the chemotherapy backbone, being carboplatin and paclitaxel. And it's been that way for many, many years. Dr. Lidia Schapira: And how effective is the regimen? Dr. Ramez Eskander: The response rates to carboplatin and paclitaxel are actually quite reasonable in the patients who have advanced-stage disease, particularly if they haven't had prior systemic chemotherapy. Response rates in the 50% to 60% range. The issue is that the responses tend to be limited and disease recurrence is an expectation in these patients who have advanced-stage disease. And so that really highlighted the importance of trying to continue to advance therapeutic opportunities in these patients to improve long-term outcomes.  Dr. Lidia Schapira: As we think about improved long-term outcomes, we're thinking about a better treatment and also a kinder treatment, perhaps one that is also less toxic. Can you talk a little bit about the population of women with endometrial cancer? Are these older women? Do they have comorbidities?  Dr. Ramez Eskander: What we're seeing is, interestingly, there has been an evolution a bit in this space. Historically, we used to think about endometrial cancer as—the phrases we used to use are type I and type II. These type I tumors, we would say, are estrogen-driven malignancies; they tend to be seen in overweight or obese patients. And we would identify them in a theoretically younger patient population. And then we had these type II, or what we termed estrogen-independent malignancies, that we would see in an older patient population. Of course, with obesity came metabolic syndrome and other cardiovascular comorbidities, etc. But really, that narrative has evolved dramatically, and that's really something that will be highlighted in, I think, our discussion of these studies today, where the nomenclature that we used to historically use has evolved because of our understanding of the molecular characterization of this disease. So we've really gone away from that, and now we understand that we're seeing all of these different heterogeneous endometrial cancer types amongst patients of different ages, different comorbidities, different races and ethnicities. And so it's created a more complex picture for us. But certainly, there are comorbidities that these patients face, and that's important as we look to identify treatments strategies that are both effective and tolerable. Dr. Lidia Schapira: My final question before we jump into this very exciting study is about the Cancer Genome Atlas work. Can you tell us how that's changed the thinking and the design of the studies? Dr. Ramez Eskander: It was a seminal publication, really, back in 2012/2013 looking at an assessment of endometrial cancers to try and determine whether or not all of these "endometrial cancers" that we used to enroll on a single study are similar or divergent. And it's important because the study I referenced that really established the standard of care, GOG Protocol 209, as carboplatin and paclitaxel, there was no real consideration of molecular characterization at all. We enrolled all patients onto this study without thinking about these variables, of course, because it was designed, conducted, and completed before the TCGA data emerged. But what we learned from the TCGA is there appeared to be four distinct molecular subgroups. There were the POLE-mutated patient population. There was the mismatch repair deficient or MSI-high endometrial cancer population. There was the copy number-high or what we say are the p53-mutated. And then the last cohort was called the NSMP (no specific molecular profile). But now, that's even evolved; some people term it TP53 wild type. That's a bit of even a heterogeneous cohort amongst itself. So we're going to take these subsets, independent of POLE and an MSI-high, and we're going to look at TP53 or copy number-high, and that will probably be divvied out further, and the NSMP, and that will probably be subdivided. But really, it gave us these four components, which has then evolved. Many of you may have heard of the ProMisE algorithm or ProMisE Plus, which looked to take the data from TCGA so that we can start to really look at it in clinical practice. So it's really revolutionized how we think about these patients, how we think about the disease, and how we design trials.    Dr. Shannon Westin: And I just want to add to that because I think that it's so important, what Ramez said about the way we were developing trials, the way we were designing trials. We knew that these classifiers—we were learning these classifiers are prognostic. Now what we're really trying to hone in on is how predictive they are. And certainly, one of the major classifiers that we're going to talking about today is mismatch repair status, and that is most definitely predictive of response to therapies. But we're still learning about the other classifiers and how we might adjust the way we treat people, even deescalating care for certain patients. That is still being proven in clinical trials, although we suspect that it's going to be borne out as other clinical trials report. Dr. Lidia Schapira: It's a perfect segue to this current trial. Tell us a little bit about the objectives and the design of DUO-E. Dr. Shannon Westin: As Ramez said, the standard of care was chemotherapy. And so we wanted to see if there was a way to improve outcomes for these women with advanced and recurrent endometrial cancer in a really clinically relevant, meaningful fashion for patients. And so we knew that this TCGA classifier, the mismatch repair, was so important, and we thought that the addition of immunotherapy to chemotherapy would most certainly work in that population but could even work in the entire population because, generally, endometrial cancer seems to be a little bit more responsive to immunotherapy and to activation of the immune system than, say, some of our other gynecologic malignancies. And so we set out to see what the addition of durvalumab, which is a PDL-1 inhibitor, would add to chemotherapy. And this was two chemo as well as followed by durvalumab maintenance.  But even further, we had some really kind of exciting science data from our lab that said that if we combined a PARP inhibitor with immunotherapy that we could accentuate on the response to therapy and we could get more benefit. And there's kind of a lot behind that, but essentially, what we thought was that the damage that's caused by the PARP inhibitors would create an activation of different immuno-pathways, like STING pathway and activating cytokine release, and that we would get this synergistic activity. So one of the other objectives was to see if the addition of the olaparib, the PARP inhibitor, to durvalumab in that maintenance setting could even further improve benefit. So we had a dual primary endpoint looking at progression-free survival, so the amount of time people live without their cancer coming back. And that endpoint was first, the durvalumab-alone arm to control, and then the second portion of that was the durvalumab/olaparib arm back to control. Dr. Lidia Schapira: So before you tell us about the results, tell us a little bit about the study itself. I mean, I was very impressed that you did it in so many different locations. Tell us about that effort.  Dr. Shannon Westin: This was a huge collaborative effort both with the GOG Foundation, the Gynecologic Oncology Group Foundation, as well as ENGOT, which is our European colleagues that do amazing clinical trials. But in addition to that, we really worked very closely with our industry partner to really make sure we spanned the globe. And so we had groups from all over the world that participated and really were exceptional. The care that was taken and the hard work that went into this type of study across the world really can't be overstated. We were very lucky to have a wonderful infrastructure group. We met weekly for a long time, just keeping an eye on the data and making sure that everything was as positive as possible and, of course, that we were watching the outcomes of the patients very closely and making sure that there was no evidence of harm or issue. And so it really did take a village, truly, to run this study and to ensure that at the end of it, we got really great data that we can trust. Dr. Lidia Schapira: So tell us the results. Dr. Shannon Westin: So DUO-E was positive for both of its primary endpoints, which was very thrilling. So for the first analysis, which is the durva-alone arm to control, we saw a reduction in the risk of progression of 29%, so a hazard ratio of 0.71. And then the addition of olaparib seemed to further enhance this benefit, so a 45% reduction in the risk of progression for a hazard ratio of 0.55. But what's really exciting is our follow-up time was pretty long; it was about 17 months, so we were able to look at a couple of different analyses, including an 18-month landmark analysis where we saw approximately 50% of the patients were still alive progression free at 18 months, as compared to only 21% of patients being alive progression free in the control arm. So there was a doubling in that progression-free survival time point at 18 months, which is thrilling. Dr. Lidia Schapira: So Ramez, as an expert in the field, what was your reaction when you read or heard these results?  Dr. Ramez Eskander: It's exciting, honestly. So we have gone a long time without seeing really significant successes in the endometrial cancer space, a testament to the fact that we hadn't yet developed our understanding of how we could move this needle forward. But Dr. Westin and the DUO-E team conducted an exceptional clinical trial, as you mentioned, international study, rational and important hypothesis to adjudicate. And what we saw here was both now we had other studies—the RUBY trial, the GY018 trial, the  AtTEnd—and now here DUO-E, which added this hypothesis of PARP maintenance in addition to checkpoint to try to augment response and consistent, really provocative data, exciting, in line with what we've seen and hopefully will continue to drive the science in this space, most importantly. Dr. Lidia Schapira: So let me ask you a follow-up question to that. What kind of scientific questions are in the air now as a result of this trial and what the trial found? Dr. Ramez Eskander: Oh, goodness. Shannon and I could both take this, I'm sure. But I think in the dMMR population, we recognize that there's a ton of data that is supportive of the fact that these tumors are immune responsive, particularly in dMMR endometrial cancer, whether it's an epigenetic promoter hypermethylation, or a mismatch repair gene mutation. I think the data has emerged that immunotherapy is here to stay for these patients in the newly diagnosed advanced stage, even chemo naïve, who need adjuvant therapy.   The pMMR population, this is where we're seeing more and more questions emerge because we realize that that may be a cohort of different cancers. And I'll let Shannon speak to this briefly, but even the incorporation of the PARP inhibitor, in addition to the checkpoint, there's a biologic rationale for combining those two together to augment response. And to see the benefit in that trial—arm three and arm two, we can look at descriptively and look at the differences, but who are those patients? Where is the PARP and the checkpoint most effective? How do we expand that to a larger population of patients potentially? These are questions that emerged because, as Dr. Weston will allude to, I know we also talk about HRR mutations, which are captured, but we even have a lot to understand about that in endometrial cancer, where we've had more research in the ovarian cancer space. Dr. Shannon Westin: Being mindful of time, because I have, like, 1,000 hypotheses that have been generated by this study, which, I think, shows it's a great study, right? Because you get some answers, and as our colleague Brad Monk says, “The only definitive study is the negative studies.” This most certainly was not that. But just kind of expanding on what Ramez said, the interesting thing about DUO-E is that really the biggest benefit for the combination of the durvalumab and olaparib was in that mismatch repair proficient group. And I personally thought that we were going to see accentuation of the impact in the mismatch repair deficient group based on the science, but that just wasn't borne out by the data. It doesn't seem that the combination has that much to add in that mismatch repair deficient group. And when we tease out the mismatch repair proficient group, I think that's where a lot of interesting information is going to come because, to Ramez's point, we're going to tease out: Is it driven by the P53-mutant population? Is it driven by the population that has homologous recombination deficiency? How do we even measure homologous recombination deficiency in endometrial cancer? So I'm super excited about what we found and how that may help us to make those decisions for the patient in front of us.  The other thing I think needs to be made mention of—and this was something we saw in DUO-E as well as AtTEnd—we had a large population of patients that were recruited in Asia, 30%. Interestingly, when we look at the forest plot, that group doesn't seem to benefit as much from the addition of the olaparib. So we really need to tease out what's different about that population because what Nicoletta Colombo presented around AtTEnd, it looked like they didn't benefit from the atezolizumab either in that study. So there's clearly something different about that population, and we have a really big opportunity to look at that since we had such a large proportion of patients that were enrolled there. So that's another, I think, really intriguing question. Dr. Lidia Schapira: So how does this fit in the context of endometrial cancer treatment, and what are we going to do with patients in the clinic? I'd love to hear both of your perspectives, starting with you, Ramez. Dr. Ramez Eskander: It's an evolving answer, to say the least. What we can say definitively is that we have a United States FDA approval for the regimen of dostarlimab plus carboplatin and paclitaxel in the mismatch repair deficient, advanced-stage/recurrent or metastatic patient cohort. And again, that's because the magnitude of benefit that we saw in the RUBY trial, which looked at that, was actually analogous to what we saw in 018, AtTEnd, and DUO-E, again, consistently highlighting the benefit of the IO and the dMMR. We have yet to see how this is going to evolve the landscape in the larger patient population, which is the pMMR patient population. And it may be that based on the data that we have, we will see immunotherapy plus carboplatin and paclitaxel as the new standard of care in the pMMR cohort, or it may not. That's yet to be defined. And I think Dr. Westin will add to this, but I think that's also going to depend on the perception of how we view the cohort. Is it one group of patients? Are we going to have to think about subsets within the pMMR population? That is an active conversation. Dr. Shannon Westin: I would just add, having treated patients on this combo regimen with the durvalumab and olaparib, I have multiple patients that still remain on study, and this—we're looking at three and four years out. I just never saw anything like that before with standard chemotherapy, so there's definitely something here. So I want to know who those patients are, who benefits really the best from the combination, and who could we just give the immunotherapy to and get that same benefit. So we obviously always want people to live as long as possible. That's the bottom line. But we don't want to overtreat. And so I think balancing that is really important. Dr. Ramez Eskander: The point that was made earlier: We have yet, aside from MMR response to checkpoint, within the pMMR population, we understand that there may be subsets, but we have yet to prospectively validate that these molecular cohorts within the pMMR population are truly defining response to a particular therapeutic strategy. So we have to be cautious not to limit the treatment opportunities for these patients without having the data that we need to do so because, as Dr. Westin mentioned, for us—whether it was the Gy018 trial, the RUBY, the DUO-E trial—what we saw is there are pMMR patients who have a dramatic response even though they are “biomarker negative.” They're pMMR, they're TMB low, they're not POLE mutated, but yet they still derive a dramatic benefit. And so that goes back to the hypothesis about why we're even combining checkpoint with chemotherapy in which, for example, in lung cancer, there's been established success and approval. So I think we're all eager to see these strategies emerge as treatment opportunities for the pMMR patients as we work to still develop additional effective opportunities. Dr. Lidia Schapira: So, based on all of this and sort of the new twists on the scientific hypotheses that are now generated, what are the next steps? Dr. Shannon Westin: Well, I think we have to see if these drugs are available for patients. So looking at things like compendium listing and regulatory approvals obviously is going to be very important. But from the things that I can control, we are looking at the different molecular subtypes and understanding the different mutation status and trying to tease out who may be driving the biggest benefits so that we can help advise and make sure that we're doing the right thing for the patients. Dr. Lidia Schapira: And wearing my supportive care hat, I have to ask you, Shannon, about the tolerability. We often find that the quality of life and studies come out after, sometimes months or years after, the original trials are published. So let me take this opportunity to ask you now: How did women tolerate these drugs? Dr. Shannon Westin: The bottom line, Lidia, is, as expected, when you add additional drugs, you see additional side-effects. I think the good thing is that we're very comfortable with immunotherapy and we're very comfortable with PARP inhibition in gynecology because we have had access to these agents and so we know how to manage the toxicities. And so, from a standpoint of incidence, there was a higher incidence of grade three and higher adverse events in the group that had durvalumab/olaparib. But this was primarily driven by anemia, which is as expected and is usually pretty time-limited at the start of olaparib. From a long-term standpoint, there was a slightly higher proportion of patients that discontinued therapy, but it actually wasn't as much as I was worried about. So we saw a 19% discontinuation rate in the group that was just the control arm, and that went up to 24% in the dual arm, so definitely higher, but not that much higher. And when we moved to maintenance, which is really where—that's where the arm becomes unique, it was much lower at about 12%. And so that's exciting to me, that patients were able to stay on a drug and were able to tolerate it.  And then, to your other point, we do have a very nice patient-reported outcomes plan, and that is actually being analyzed as we speak with the hope of presenting it at the next major meeting, our Society of GYN Oncology meeting in March. So not right away, but I think in a pretty timely fashion, we'll have those data. Dr. Lidia Schapira: Congratulations, Shannon, on leading and presenting this wonderful study. So it's been a real pleasure to chat with the two of you. Dr. Ramez Eskander: Thank you. Dr. Shannon Westin: Thanks so much, Lidia. I really appreciate it. Thanks, Ramez, for being here.  And I will just say thank you to all of our listeners. We really hope you enjoyed this episode of JCO After Hours, where we discussed the DUO-E trial, which is a phase III trial evaluating durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer. And again, please do enjoy this publication that was online at the Journal of Clinical Oncology on October 21st, 2023. And do check out our other podcast offerings wherever you get your podcasts. Have a wonderful day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Do strange and spooky things happen while hunting?  In this Halloween special episode of the Ducks Unlimited podcast, hosts Chris Jennings and Dr. Mike Brasher are joined by Kyle Philson and Cam Hale from the Expanded Perspectives Podcast. This episode explores a few spooky hunting destinations, bizarre stories and some of the folklore associated with them. The hosts talk about these locations, share their reactions, and Dr. Mike takes on the role of debunking and searching for facts. Get ready to have some fun and be spooked by stories of ghosts, ghouls, and more!Make sure you also check out the Expanded Perspectives podcast here… www.expandedperspectives.comwww.ducks.org/TheDUPodcast

Quick programming note: We recorded this episode before recent events unfolded. It doesn't address the current war in the Middle East but we believe this episode still holds value so we're sharing it today as planned. Then we'll be back with an added bonus episode this week with a family therapist on how to care for ourselves in an emotionally taxing world and how to address what's going on with our kids. Be sure to subscribe to the Do Gooders Podcast wherever you listen to podcasts and you'll be the first to know when that episode drops this week. What would it mean to you to see the scenes of Scripture, the places where Jesus walked and talked and performed miracles, right in front of you? To survey the land and picture the people, to take in the detail of a setting we so often study? How would it affect your understanding of the Bible? Of the legacy you want to leave as a follower of Jesus? Emily Anderson is here to answer these questions after recently returning from the Holy Land. Emily is the Social Media Editor for Caring Magazine. So while she's usually behind the screen, interacting with you on our Facebook, Instagram or Pinterest, today she's sharing more about her time seeing the setting of Scripture come to life. And she's reflecting with us on what the experience means for her moving forward. After the episode, be sure to follow Caring on Instagram and send us a DM with your favorite Holy Land experience or what you would most want to see if you go in the future. EPISODE SHOWNOTES: Read more. BE AFFIRMED. Get the Good Words email series. WHAT'S YOUR CAUSE? Take our quiz. STUDY SCRIPTURE. Get inside the collection. BE INSPIRED. Follow us on Instagram. FIGHT FOR GOOD. Give to The Salvation Army.

Dr. Shannon Westin, Dr. Stephanie Wheeler, and Dr. Caitlin Biddell discuss the paper "Economic Evaluation of a Non-Medical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer," a simultaneous publication, podcast, and presentation at the ASCO Quality Care Symposium. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, Social Media Editor of the JCO and GYN Oncologist. And I am so excited that today we have a simultaneous publication in JCO and presentation at the 2023 ASCO Quality Care Symposium here on 10/28/2023. And this is going to be the manuscript “Economic Evaluation of a Nonmedical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer.” Very exciting work. And I'm thrilled to tell you I have two of the authors here with me today. First is Dr. Caitlin Biddell. She's a Health Services Researcher at Mathematica Policy Research.  Welcome, Caitlin.  Dr. Caitlin Biddell: Thank you. Happy to be here. Dr. Shannon Westin: And we also have Dr. Stephanie Wheeler. She is the Michael S. O'Malley Distinguished Professor in the Department of Health Policy and Management at the University of North Carolina, Chapel Hill, as well as being the Associate Director of Community Outreach and Engagement at UNC Lineberger Comprehensive Cancer Center.  Welcome. Dr. Stephanie Wheeler: Thank you. Happy to be here as well. Dr. Shannon Westin: Please note that our authors and participants have no conflicts of interest.  Let's get started. So first I would love to level set. Can you speak a little bit about what financial toxicity is and how common it is among patients with cancer?  Dr. Stephanie Wheeler: Sure, Shannon. I'm happy to take that one. This is Stephanie. So we know that financial hardship is often reported by patients and survivors who've experienced cancer. And as many as 50% of people with cancer have trouble with financial toxicity. There has been prior work that has conceptualized financial toxicity in three domains. So there's the material hardship, kind of the out-of-pocket material costs associated with cancer, which include both medical and nonmedical expenses. There is the stress and the psychosocial effects of that material hardship. And then there's coping behaviors that patients and their caregivers may employ to help deal with the high cost of cancer care. And as we've seen, cancer care increases in cost over time, and these expenditures really have very burdensome effects on patients and their families. We've been interested in looking at ways that we can try to mitigate that harm and really thinking about interventions in addition to the health policy changes that are needed to really ensure that this doesn't become a barrier to patients seeking and receiving the best quality care that they can. Dr. Shannon Westin: I think that kind of leads pretty nicely into my next question, which is really: How does this toxicity potentially impact equitable cancer care delivery?  Dr. Stephanie Wheeler: Yeah, I'm happy to talk about that a little bit as well. So we know from prior research, including some of our own, that patients of color, those from rural areas, and those who are uninsured or underinsured face the largest financial burdens associated with their cancer care. So to the extent that those financial hardships influence people's ability to seek and continue with and complete their cancer care that's been recommended, this actually is directly in the pathway and a mechanism through which patients are not able to get recommended treatment and therefore can contribute to differences in cancer outcomes. So there's direct health impacts in terms of their ability to receive and respond to cancer treatment.   In addition to that, we know that this financial hardship contributes to household-level harms both economic and psychosocial in nature. And in some other work, this financial hardship has translated to worse quality of life, worse economic outcomes, things like being able to stay employed and seeking changes in employment or remaining within a particular position because you don't want to lose your insurance—this is referred to as “job lock”—or can also contribute to higher mortality. So there's been some really important work showing that financial toxicity is directly linked with cancer mortality.  And so, as we think about ways that we need to address this, it's really key to ensuring cancer health equity that we are thoughtful about multiple solutions implemented at multiple levels that can deal with not only the contributors to high cancer costs but that can also start to affect both the nonmedical and the medical components of this cost burden. And by nonmedical, I mean things like the cost associated with transportation and seeking care, accommodations for people who need to receive radiation therapy multiple days in a row at a different healthcare facility than where they live, childcare costs. These things really start to add up in addition to the medical costs associated with cancer treatment. Dr. Shannon Westin: I really was intrigued by the intervention here that you all are studying around this Cancer Patient Assistance Fund. Can you tell me a little bit more about exactly what that was or is? Dr. Caitlin Biddell: Yeah, absolutely. So this is a program at the North Carolina Basnight Cancer Hospital, located within the Lineberger Comprehensive Cancer Center, and it started back in 2013, actually, and has really grown in size. But the main goal of this program is to ensure that patients do not face the nonmedical financial barriers to care that Dr. Wheeler was just talking about. So thinking about giving patients gas cards so that they are able to drive to and from treatment. Lineberger has a catchment area of the entire state, so many people are coming a long distance to come for cancer treatment. They also provide things like lodging and accommodations, as Stephanie mentioned, and then even paying patients' utility bills, things to keep them housed with electricity, the lights on, while they're undergoing cancer treatment. So just last year, in 2022, they distributed almost $350,000 to over 700 patients, and most of this is funded by philanthropic grants to ensure that patients can access the care they need. And it is a program that's really targeted to patients with low incomes. So they target patients with household incomes less than 250% of the federal poverty level. Dr. Shannon Westin: And how does a patient get connected to the fund? How do they find it and get hooked up?  Dr. Caitlin Biddell: Yeah, there's a couple different ways. So one path is through the outpatient social work team. So they often perform distress screening for new cancer patients. So they use the Distress Thermometer, which was developed by the National Comprehensive Cancer Network. And it measures a variety of different factors that may be contributing to distress, but that does include financial stress, job stress, and the expense of daily living stress. And so, when a patient scores a certain amount on that thermometer, a social worker will meet with them for a full assessment. And then part of the referral pathway from that assessment includes the Cancer Patient Assistance Fund. Patients who are in inpatient will often be screened with the Social Determinants of Health Module, which is housed in the electronic health record. And so that can also generate referrals for assistance. And then beyond the kind of standard pathways, there's also many other ways that a patient may express concerns to a nurse, a care coordinator, an oncologist, and then that provider can reach out directly to the Cancer Patient Assistance Fund. Dr. Shannon Westin: Your objective was to basically try to formally assess the impact of this fund on missed radiation or chemotherapy appointments. And so what was kind of your rationale for choosing this endpoint? And kind of take us through the design. Dr. Caitlin Biddell: Yeah, absolutely. So the idea for this study actually came about from the program coordinator of the Cancer Patient Assistance Fund several years back. We were just having a conversation about the program. I was commenting how important I thought it was, how interesting it was. And she was saying, “You know, I know anecdotally that this program makes a difference, but we've never really known how to quantify that.” And that's becoming increasingly important as they apply for philanthropic grants and really need to show that their program is having an impact. So that's what originally started our plan for evaluating the program.  And then, in thinking about endpoints, of course we imagined this program could have an impact on a range of different endpoints. So missed appointments is quite practicable. We also imagine it could influence patient health-related quality of life, patient symptoms associated with their cancer treatment, even potentially other long-term outcomes like mortality. But for the purposes of this evaluation, we needed to identify an endpoint that we believed could be measured, the association could be measured, in the data we had. And so we had electronic health record data. Missed appointments is something that is routinely captured in the electronic health record data because it's an endpoint that matters financially to health systems. So they are regularly tracking missed or no-show appointments. And it's also an outcome that matters financially to the health system, so they want to reduce this.  So we thought if we measure the impact of this program on missed appointments, there's potentially an opportunity to kind of align financial incentives so that if we show that the program has an impact on missed appointments, then that could be something that could get decision makers at the health system level to say, well, that's also an endpoint that we want to reduce, and so let's think about ways that we can align resources to reduce missed appointments through potentially the Cancer Patient Assistance Fund and other mechanisms. Dr. Shannon Westin: It's interesting because it definitely caught my eye because we give radiation, obviously, for gynecologic malignancies, and there's some pretty decent data that longer treatment duration for radiation has worse outcomes, with the implication that patients have missed appointments and so then, to finish their work, it takes longer, or to finish their treatment plan, it takes longer. So I definitely would be really intrigued to see the cancer-related outcomes. But I completely agree, like something practical, straightforward, and something easily obtained was the right way to start. I was just curious. So that's really interesting. So why don't you just walk us through the design of how you laid this out? Dr. Caitlin Biddell: Yeah, absolutely. So we conducted a retrospective evaluation between 2015 and 2019, and we chose that time point to end before the COVID-19 pandemic since we know that had many impacts on missed appointments. And we compared the proportion of missed appointments in the six months following treatment initiation between patients who were receiving Cancer Patient Assistance Fund assistance and then propensity-weighted comparators. And this is really just a method to make the pool of potential comparison patients look as similar to those receiving Cancer Patient Assistance Fund assistance as possible so that we can really tease apart that direct effect of the Cancer Patient Assistance Fund and separate it out from other characteristics that may be influencing missed appointments.  So we had stratified our analysis by treatment type. We looked at radiation therapy, and then we also looked at oncology infusion, so specifically immunotherapy and chemotherapy. And to evaluate these endpoints, we used a couple of different data sources that we linked together. So the first and the primary data source was the electronic health record. So at UNC, we have EHR data for research purposes stored in a data warehouse that we were able to pull from. And then we also linked in UNC Health's portion of the North Carolina Cancer Registry to get that really important information on cancer stage, cancer type, and treatment start date. And then, of course, we pulled in program records from the Cancer Patient Assistance Fund to identify which patients were receiving assistance, how much, and at what time points. And so, essentially, using that data and thinking about missed appointment outcomes in those six months following treatment initiation, we created a couple different models. So we looked at the high versus low no-show proportion using a logistic regression. And then we also looked at just the continuous no-show proportion in the sample to see if there was an effect on that as well. Dr. Shannon Westin: And what did you find? What was the impact of the fund's support on your outcomes? Dr. Caitlin Biddell: For radiation therapy, which I'll start with, the radiation therapy had a higher number of encounters, as we might expect, than immunotherapy/chemotherapy. There were a mean of 37 total radiation therapy encounters in the six-month follow-up period, and about 53% of the sample had one or more no shows. And so, then, when we looked at the impact the Cancer Patient Assistance Fund on radiation therapy missed appointments, we found that receipt of any assistance was associated with an eight-percentage-point decrease in the probability of having a no-show proportion in the highest quintile.  And then, when looking at continuous no-show proportion, we found it was associated with a 2.1-percentage-point decrease in the overall proportion of no shows, which corresponds to a 51% decrease in the overall mean no-show proportion. So a really substantial effect on radiation therapy missed appointments. And unsurprisingly, when we stratified the analysis by the amount of assistance received, we did see a greater impact of the program among patients receiving higher amounts of assistance.  Moving on to the oncology infusion cohort, this sample had a lower number of encounters in the follow-up period and less no shows, so only about 14% had one or more no shows. And so it potentially wasn't as surprising that we did not see an impact of the Cancer Patient Assistance Fund on infusion oncology missed appointments, though, of course, with the additional power and alternative analyses, it's not to say that there wasn't an effect, but in our population, we were not able to detect that. Dr. Shannon Westin: Yeah, and that makes a lot of sense. I mean, radiation is so much more time intensive and having to come back and forth. And when you were describing the fund and saying, like, housing assistance, I was like, “Oh, well, there you go.” Because that, I feel like, is one of the major issues. At MD Anderson, we also kind of take care of a very large catchment area, and it can be a huge burden for patients to have to come for that 15-minute appointment every day. So, yeah, when I saw your results, I thought that was likely what you were hypothesizing was the reason. And certainly, the impact on radiation is so impressive. It's just a hugely successful study and a hugely successful fund. So congratulations.  So, I guess, any other variables? You spoke a little bit about the amount of financial assistance received. Was there anything else that impacted the number of missed appointments in your study? Dr. Caitlin Biddell: Yeah, because of our propensity-weighting design, we really didn't focus as much on other patient-level contributors to missed appointments. So we attempted to control for all of those things through the waiting and then kind of didn't add those into the final model. So that was really the main focus, was looking at the impact of the Cancer Patient Assistance Fund and then, of course, looking by amount of assistance. That was a really important finding and also, of course, needs to be taken in the context that every patient has different needs and so the amount of assistance may differ for every patient. And so there's always a need to kind of really assess what a patient's needs are and base the amount of assistance on that. Dr. Stephanie Wheeler: It's probably worth saying again that the level at which we dichotomized these results was $180, which was sort of the median level of assistance provided. As you can imagine, there's a long tail, with some people receiving considerably more financial assistance. But I think it's really noteworthy that in the grand scheme of things, $180 per patient is a very small amount of money to provide to assist with things like housing support, transportation support, gas cards, and so forth. And the program does not have strict rules about how those funds are used. So, in our setting, where we've got a lot of rural patients potentially traveling hours across state in their own vehicles, gas cards are really important for them. But in other settings—more urban settings, for example—having flexibility in how those funds are used could be really helpful for people who need bus assistance or other public transportation beyond kind of having to drive a private vehicle to appointments.  Dr. Shannon Westin: It is a great point, and it is incredible how much you can do with a fairly little amount of money. And when we were talking about healthcare spending, obviously, that's a lot of money to an individual or a family. But in the grand scheme of what we spend on healthcare, that is a very, very small amount. So really, again, congratulations.  So I think the last question I'll ask is just kind of what are the next steps? And really should we be making sure that we have these programs everywhere? Do I need to go back and make sure that this kind of situation is set up in my institution? Dr. Stephanie Wheeler: Well, we also should share a little bit more about the economic evaluation results. Caitlin, why don't you describe that? Dr. Caitlin Biddell: Yeah, absolutely. And this speaks exactly to what you were talking about in terms of the amount of assistance that can go a really long way for a patient and is a drop in the bucket for a health system. So we did want to look at what the cost-effectiveness, or the cost consequence, of this program was from the health system perspective. And so we conducted a decision tree analysis, which is a method used in economic evaluation research, using kind of a hypothetical cohort of 350 patients, that mean number of radiation therapy encounters, 37 encounters over a six-month time horizon. And we did find that under the current funding of the model, which essentially is that philanthropy covers all of the financial assistance and then UNC Lineberger covers the cost of the staffing and the indirect cost of housing the program, we found that this program was estimated to save the health system $153 per missed appointment averted.  And then, in kind of an additional threshold analysis we conducted to see how much could the health system chip into this program in some way, whether it's through indirect cost or direct financial assistance, while still kind of breaking even from the perspective of no shows averted, and it was around $100 per patient. So, of course, that would be split across patients in different ways. Not everyone might receive that same amount. But there is opportunity here for health systems to make investments in reducing patient nonmedical barriers to care in a way that will come back in the form of saved revenue from averting missed appointments. Dr. Stephanie Wheeler: And the only thing I would add to that is this obviously was focused on those no-show appointments, but we anticipate that there's other financial benefits to the health system, like retention in care, patient satisfaction. There's a whole host of quality-of-life and clinical outcomes that are probably also benefited through use of this kind of nonmedical financial assistance program that we weren't able to measure. But I think part of our goal with this analysis is to start to make the case to hospitals and health systems that providing direct nonmedical financial assistance helps their bottom line as well. Dr. Shannon Westin: We, as clinicians and researchers, always want the benefit to the patients. But I agree, when you're dealing with administrators, we also need to show that. So I think that is super clever and a really nice part of the design.  So what's next steps for your research? Dr. Caitlin Biddell: Yeah, so I think we're currently kind of disseminating these findings within our own institution, so disseminating them back to the Cancer Patient Assistance Fund program so that they can use them in additional grant applications, but also really trying to get these findings in front of the health system administrators who might be able to make funding decisions surrounding this program. And then I think we are also thinking about ways to measure other endpoints beyond missed appointments. So we've kind of created this data set that involved some complicated linkages upfront, and now I do think there's opportunities to pull in other endpoints and even potentially some patient-reported endpoints as our electronic health records get better at collecting patient-reported data and even social determinant of health data, opportunities to really think about other impacts of this program.  And then I'll also add that there is talk among other groups at our institution about using this kind of approach to measure other similar programs. For example, we have a pretty large AYA program that does a lot of similar types of assistance and also psychosocial assistance. And so they're thinking about ways to use a similar methodology to evaluate some of their own work. So I think it's just kind of starting to open the door to thinking about how we can use the data we have within our institutions to really underscore the impacts that the programs that already exist are having on patients. Dr. Stephanie Wheeler: I would only add to Caitlin's fabulous answer that dissemination of this is really critical because we know that NCI-Designated Conference of Cancer Centers, the vast majority of them provide some kind of direct medical and nonmedical financial assistance, but many of them have restrictions on who can access those funds and eligibility criteria that preclude patients with certain cancers from accessing those funds or patients with still what we would consider to be relatively high financial vulnerability to not be able to access those funds. In addition to that, we know that community oncology practices less often have access to these kinds of financial support resources. And so what often happens—and this is an extremely fragmented space for patients and their caregivers to be navigating—is that when nonmedical financial needs present, people are left to their own devices to have to search out, seek out, and identify programs for which they're eligible in the community. And these are often funded by philanthropic organizations, really wonderful healthcare support organizations. But oftentimes these types of financial supports are not directly provided through the hospital, or if they are, they're in the form of “charity care provisions,” which are often opaque to patients and their caregivers to even find. And then the eligibility requirements for those programs, again, are often preventing access for a number of patients in need.   So what I would like to see, as a person who does a lot of research in this space around financial hardship, is for that burden to be shifting away from patients and caregivers and more towards the systems that are treating these patients and that are supporting the caregivers so that people can focus on what's important during their cancer care, which is getting treatment that's recommended, staying in treatment, and attaining the best possible health that they can. When patients and their families spend hours and hours and days and weeks trying to understand existing financial support programs in the community and then those disappear or evaporate, as they do when funding and contributions subside, that really has a very detrimental impact on the patient's entire care experience. And I think it's on us, as people who are part of the healthcare system, to ensure that that doesn't happen. And the financial case to hospitals is clear, I think, from this analysis, but the moral case to all of us, as providers, should be clear and should be compelling in itself.   Dr. Shannon Westin: On that note, I think that's a perfect way to end. Thank you so much. This was such an intriguing discussion, and I really hope people are listening that are making the decisions for their hospitals and will see how they can implement something like this in their institution.  Again, this was a discussion of “Economic Evaluation of a Nonmedical Financial Assistance Program on Missed Treatment Appointments Among Adults with Cancer,” simultaneous publication in the JCO and presentation at the 2023 ASCO Quality Care Symposium on October 28th. It was great to have you all here. This was amazing, and I hope our listeners had a good time. And please do check out our other podcast offerings wherever you get your podcasts.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the Podcast do not express the opinions of ASCO. The mention of any product, service, organization, patient activity or therapy should not be construed as an ASCO endorsement.      

JCO PO author Dr. Bryson Katona shares insights into his JCO PO article, “Outcomes of the IMMray PanCan-dTM test in High-Risk Individuals Undergoing Pancreatic Surveillance: Pragmatic Data and Lessons Learned.” Host Dr. Rafeh Naqash and Dr. Katona discuss IMMray PanCan-d:  A Blood-based Test for Early Detection of Pancreatic Cancer. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO Precision Oncology articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Stephenson Cancer Center.  Today, we are thrilled to be joined by Dr. Bryson Katona, Director of Gastrointestinal Cancer Genetics Program and Assistant Professor of Medicine at University of Pennsylvania Abramson Cancer Center, and also lead author of the JCO Precision Oncology article, “Outcomes of the IMMray PanCan-d tm Test in High Risk Individuals Undergoing Pancreatic Surveillance: Pragmatic Data and Lessons Learned.”  At the time of this recording, our guest disclosures will be linked in the transcript.  One of the other unique things about this article is that this will be a concurrent podium presentation at the 2023 CGA-IDC Meeting and also concurrent publication in JCO Precision Oncology. Bryson, welcome to our podcast and thank you for joining us today. Dr. Bryson Katona: Thank you so much for the invitation and I'm looking forward to discussing the findings of our recent study. Dr. Rafeh Naqash: So, one of the unique things about this topic or this publication is surveillance, which we often talk about a lot in lung cancer, breast cancer, colorectal cancer, but not so much in pancreas cancer. For a listener who might be a community oncologist or for a trainee out there, fellow, who may not be as specialized in cancer genetics, what are the kinds of individuals that you would screen for pancreatic cancer? What are the high risk populations where there's a decent pretest probability that you could catch something early? And what are the implications of catching something early in people with pancreas cancer? Dr. Bryson Katona: The whole field of pancreatic cancer screening and high risk individuals, which we'll refer to as pancreatic surveillance, has just been an area of increasing growth and increasing data over the last five years or so. For individuals that we would consider pancreatic cancer surveillance in, really, we try to target those individuals that have a lifetime risk of pancreatic cancer of about 5% or more. And so those fall in two main groups. So one of those groups are individuals that would have what we would define as familial pancreatic cancer. That's where there's a very strong family history of pancreatic cancer without a known genetic susceptibility. And so by strong family history, what we typically refer to is having two members of that family with pancreatic cancer. And those two members of the family have to be directly related to one another, and your patient would then have to be directly related to one of those individuals. So, say your patient has a father and a brother or a mother and a maternal grandfather. Those would kind of fit the criteria.  The other big group of patients that we consider doing pancreatic cancer surveillance in are those with genetic susceptibility to pancreatic cancer. And this can come in multiple different forms. Some more of the common cancer risk syndromes, such as Lynch Syndrome, and carriers of a BRCA1 or BRCA2 mutation. Typically in the presence of one family member with pancreatic cancer, those individuals could be eligible for surveillance. But there are other rarer syndromes as well, such as carriers of an ATM or PALB2 mutation, individuals with Peutz-Jeghers syndrome or hereditary pancreatitis as well.  Dr. Rafeh Naqash: My understanding of these mutations is they have to be germline in these individuals. Could you shed a little more light on germline mutations, what they are, how potentially to recognize them? Because in the current setup, at least, most patients with advanced cancer get next generation sequencing, which is not the same as germline testing. So, for somebody who sees these reports, I do early phase clinical trials primarily and do a lot of sequencing, and find a lot of interesting things which lead to germline testing in individuals, could you shed some light on the differences between NGS testing and germline testing, since you do this day in and day out? And in what scenarios would you test for germline things that could lead to downstream implications for individuals?  Dr. Bryson Katona: Oftentimes, this is a point of some confusion or uncertainty. And so when we think about germline testing, basically we're looking for gene mutations that are going to be present in every cell throughout the body. When patients who have a tumor undergo somatic sequencing of that tumor, of course, we expect to find lots of gene mutations in the cancer itself. But then, typically, if there is a mutation in all cells in the body or i.e., a germline mutation, that mutation will oftentimes be picked up in the cancer as well. And so I think when you're looking at somatic sequencing reports, sometimes some of these mutations that you see in there in cancer predisposition genes may not be a cancer specific gene mutation, but may be germline and may merit kind of more additional testing. That's always one way that we can identify individuals that if one of these gene mutations is picked up on the somatic sequencing, they can get referred.  Now, if we think about the population who may not have cancer yet but may have a strong family history, in those cases, those individuals are typically getting referred directly for germline testing since they don't have any tumor or anything like that that has been tested. So that also is another opportunity where, ideally, we would identify all these gene mutations in the ideal world just because we, of course, like to know about these before an individual actually does develop any cancer. Dr. Rafeh Naqash: I think the important point you brought out is doing this before the individual develops cancer is a huge opportunity for us in the cancer field to improve outcomes for certain cancers. As you pointed out in your paper, like pancreas cancer, survival outcomes in the later stages are not that great, and we haven't had any significant breakthroughs in treatments. Could you tell us a little bit more about how pancreas cancer screening could help change some of those aspects where you could see an opportunity where individuals who get screened timely, diagnosed timely, could also benefit in the long term?  Dr. Bryson Katona: For pancreatic cancer, really, we know that if it can be detected at stage 1, that's really our only opportunity to meaningfully intervene and impact survival. And so when we talk about screening for pancreas cancer, basically our goal is that we either want to find very high risk lesions that are almost at the stage of cancer, or potentially stage 1 pancreatic adenocarcinomas. We know that for stage 1 disease, especially stage 1a, a five year survival is over 80%. And once you get to stage 2 disease, the five-year survival decreases dramatically. And so I think that if we're going to screen patients, really, our goal should be to detect these cancers at stage 1, where there's an opportunity for surgical intervention. Even stage 2 pancreatic cancers or any that are not surgically resectable, our ability to cure these patients essentially evaporates, and so really, screening should be done to detect things at a time when we can surgically intervene.  Dr. Rafeh Naqash: In your program, from a practical standpoint at UPenn, is it the cancer geneticist, or is it the medical oncologist who makes the referral and determines need? Or how do you go about it so that other programs or individuals who might be listening to it would understand how a screening program for pancreas cancer actually works?  Dr. Bryson Katona: I pretty much serve as the referral point for all of our pancreatic cancer early detection studies. We have a great collaborative group here and a lot of our oncologists who may be following these carriers with genetic susceptibility, oftentimes, if the patient is very convinced and wanting to go forward with screening, the oncologist will just order the screening tests themselves, and then me and my team will enroll individuals in studies once they come in for screening. So patients who are interested in screening oftentimes will come in for a full office appointment to really discuss the pros and the cons of screening and decide if this is something that they want to pursue themselves. Regardless of how patients get into the process, whether they get directly referred from oncologists or they come through our high risk pancreatic clinic through which I see patients, it's important that these individuals be offered the opportunity to enroll in pancreatic cancer early detection studies as really capturing data on all individuals who are getting screened is really our only hope of continuing to move this field forward. Dr. Rafeh Naqash: I totally agree, and I think, as you mentioned in the manuscript, EUS, MRIs are decent tests, but nevertheless, one is invasive, the other one is probably not cheap, may not even be available outside of North America to a large extent. So you definitely need something that's easy, less invasive, perhaps can be implemented in a broader scale.  Now, from a payer standpoint in the current landscape, do payers actually reimburse for pancreas cancer screening? Is that something that is easy to come by, or do you actually end up requiring, like, peer to peer prior auth, which is something that has become a theme, an unfortunate theme in the oncology space these days. What is your experience with the pancreas cancer screening aspect?  Dr. Bryson Katona: I think that the landscape has been getting much more favorable towards payer reimbursement. Since the National Conference of Cancer Network, or NCCM, guidelines have included pancreatic cancer screening in one of their high risk guidelines, individuals who meet those criteria, we really haven't been having any issues getting their screening covered. Now, of course, there can be copays and deductibles and things like that that may still provide a financial barrier, but the insurance companies have fortunately been much more amenable to covering the screening procedures.  But you make a great point that doing an annual EUS or MRI is a pretty involved endeavor. It's expensive, it's time intensive. And in the pancreatic cancer screening space, what the studies have shown is that you probably have to screen 100 or a little bit over 100 individuals in order to find a high risk lesion. So you end up doing a lot of screening to identify a very small minority of individuals who will develop a high risk lesion. And I think that's important as well because even in these high risk populations, pancreatic cancer is still not an incredibly common cancer. It's still diagnosed at a fairly low rate. So, any individual who is undergoing screening, I think they have to be ready to embark on a long journey where they're sticking to this annually, but in the majority of cases, we will not identify a high risk lesion. Dr. Rafeh Naqash: And from a genetic susceptibility, germline susceptibility standpoint, is there an age cut off where you mandate that these individuals should have pancreas cancer screening? Let's say if somebody's a BRCA1 or BRCA2, or is it irrespective of the age? Dr. Bryson Katona: We know pancreas cancer is a cancer that affects older individuals. And so typically for the gene mutation carrier, so for like the BRCA1s and 2s and Lynch syndromes, those individuals in whom we're doing screening, usually we say to start at around age 50. 50 may still be a little bit on the early side, and the only reason we would ever consider starting earlier than 50 was if there was a very young pancreatic cancer in the family. One of the more difficult discussions to have with patients is when should they stop screening? And we don't have a really great answer for that, but I think that each year that we do screening, we always address that or think about those factors with patients.  Technically, a patient who would not be a surgical candidate, if a pancreatic cancer were to be identified, that individual probably should continue to screen, but that ends up being a very individualized decision between the patient and the provider. Now, apart from the BRCA1 and 2 and Lynch and those type of high risk patients, there is the familial pancreatic cancer patients where there's no known genetic mutation. Those individuals, we typically start around age 50 as well. Some of the rare syndromes, such as Peutz-Jeghers syndrome, and carriers of a CDKN2A mutation, we would start at earlier ages, but those syndromes are overall fairly rare.  Dr. Rafeh Naqash: Going to another aspect of biomarkers in the pancreas cancer setting, something that we regularly, routinely do. In fact, I was on service a couple of weeks back. A fellow of mine saw a patient with pancreas mass, he ordered a CA 19-9, and it was kind of elevated. You mentioned some very important aspects of limitations associated with this CA 19-9. Could you elucidate a little more about some of those aspects? Dr. Bryson Katona: Definitely. So finding a biomarker, a blood based biomarker that we could use for pancreatic cancer early detection would really be the holy grail and would solve so many issues that come up in the field. And so CA 19-9 has definitely been the one that has been studied the most in this space. With CA 19-9, we know that it's a good marker for pancreas cancer once it develops. The issues that arise in the pre cancer stage when it's used as more of a screening type tool, is that, one, 10% to 20% of patients actually are Lewis antigen null and don't express CA 19-9. And so you have a pretty decent amount of at risk individuals who are not going to express CA 19-9 to begin with.  And then I think the other thing that makes it very difficult is the differing baseline levels of CA 19-9 that can be present. An individual who has a CA 19-9 that's checked and say it's 5 or 10 above the upper limit of normal, that could just be their baseline level or that could be something of concern. And oftentimes in those situations, it's a lot of worry and angst for the patient, but then also a lot of worry and angst for the provider as well, and individuals just don't quite know what the next best step is for evaluation in that case.  There is some data that's come out of Hopkins recently showing that there are a few genes where there are certain genetic mutations that may alter one's level, baseline level of CA 19-9. And so that may be a potential way to personalize or individualize what someone's baseline CA 19-9 level should be. But that's, of course, still kind of in the experimental stage and not something that's ready for widespread practice yet. Dr. Rafeh Naqash: And the other biomarker, as you've based the study around is the IMMray PanCan-d ™ test. Seems like a composite biomarker. Could you tell us a little more about what constitutes this biomarker and what are the different parameters associated with it?  Dr. Bryson Katona: The IMMray PanCan-d test, really just to give a little history on it. So this was the first commercially available pancreas cancer specific blood-based test. This was commercially available to patients starting in late 2021 and through the summer of this year 2023. This particular test looked at 18 protein biomarkers and in addition also factored in the level of CA 19-9. And basically what it would result in, it would give four possible results. It would either give a positive or a negative result, but also had the potential to give a borderline result. And then the fourth possibility was via test not performed result. And those were primarily for the individuals who were CA 19-9 non-expressors. Again, this was really the first commercially available pancreas screening blood based test that was available. Just for listeners, the company has, based on, I guess, their first 18 months worth of data, they temporarily pulled it off of the market to reevaluate some of the parameters. But while it was on the market, we were fortunate enough to collect this real world data. And I think that the data that we collected through this study really allowed us to learn some really important lessons about how a pancreas specific blood based biomarker, how it should work, and what are some important components of this biomarker that really need to be addressed in future versions of this test, but then also in future blood based pancreatic cancer biomarkers that are developed down the road as well.  Dr. Rafeh Naqash: Bryson, can you tell us a little bit about the inclusion exclusion for this study, the kind of individuals that you incorporated in the study, and then we can go on to some of the results? Dr. Bryson Katona: Sure. So for this study, what we did was we ran an IMMray PanCan-d test on individuals who were coming in for their normal, their regular pancreatic cancer surveillance. So these were high risk individuals, lifetime risk of pancreatic cancer of 5% or higher who were already enrolled in a surveillance program. And so we had had baseline imaging of their pancreas. And in addition to those individuals who were offered this test, who were undergoing surveillance, we also spiked in several patients that had a known diagnosis of pancreatic cancer. And this was done such that the company was blinded to the results of who had a known diagnosis of pancreatic cancer. So what this did was it provided us really with the first real world data on the use of this test in clinical practice and also, because we utilized some spike in samples, allowed us to utilize and calculate some performance metrics of this particular pancreatic cancer early detection test.  Dr. Rafeh Naqash: And some of the important metrics that you mentioned in the manuscript is this test having a very high negative predictive value, but a low to medium positive predictive value, partly from some of the testing aspects related to some of the results. So could you tell us a little bit more why the negative predictive value was so high, but the positive predictive value was not as high? And what are the things that could be done in the near future to perhaps improve upon the positive predictive value? Dr. Bryson Katona: Yeah, you're right. As you do mention, the negative predictive value was very strong. The issue with the positive predictive value came out of the fact that this test had a borderline result that was used. And when you have the option of not just a positive result or a negative result, but you have a test that can offer this borderline result, how this borderline result is characterized can really alter the performance characteristics. So just to give some numbers, about 7% of the patients who had the test performed came back with a borderline result.  Now, if people were comfortable with just brushing off the borderline result and not doing anything additional, then that would be fine, that wouldn't be a problem. But I think most providers, and probably most patients as well, if they see a borderline result, they're probably not going to be okay with just brushing it off and they're going to want to either do some additional testing, whether that be additional blood testing or potentially a sooner imaging study. And so, although it's a borderline, it's not a true positive, it's in the borderline region, I think it's probably going to raise a level of concern enough that most people are probably going to act on it like it may actually be a positive test. And so how those were characterized, the borderlines, it really altered the performance characteristics. And if you considered those borderlines to actually be positive tests, given that people are probably going to want to act on those results differently, it made the positive producing value of the IMMray PanCan-d very suboptimal.  And I think that probably is one of the most important lessons that we learned from looking at this data is that any future pancreatic cancer early detection tests probably should not have a borderline result and should be designed so that it either comes back as a positive or a negative without having kind of that ambiguity of a borderline result in the middle. Dr. Rafeh Naqash: I think this is an aspect that touches every aspect, every side of biomarker assessment. One size does not fit all. There's a lot of borderline results we get. I do a lot of immunotherapy. Of course, immunotherapy biomarkers is a huge thing and so far we have not been able to narrow down something that is just one sole marker.   Now from a pancreas cancer standpoint, I think in your data set you had a few individuals with IPMNs, a few with pancreatic adenocarcinomas, and a couple, I think, with neuroendocrine tumors. Do you think that actually impacts the type of the lesion, actually impacts the outcome or the positive predictive value associated with the test? Dr. Bryson Katona: We did find a couple incidental pancreatic neuroendocrine tumors in these patients. The test itself was not designed. It was designed and trained on pancreatic adenocarcinomas. And so the tests in the patients with pancreatic neuroendocrine tumors did not come back as positive or borderline. And then in terms of IPMNs, IPMNs are so incredibly common. I mean, most series have shown that probably around 30% of individuals who are undergoing pancreatic cancer surveillance have an IPMN that's identified. And so again, I don't think it was trained to necessarily pick those up. Although talking to patients about the frequency of IPMNs on surveillance is really important because I always counsel patients that you have about a 30% chance or that something's going to be found in your pancreas. Granted, most of these are inconsequential and just things that we continue to monitor, but they are found incredibly frequently. Dr. Rafeh Naqash: And one of the other aspects I guess, is you mentioned this as a limitation in your manuscript, is the fact that the study had a majority of individuals that were of Caucasian ancestry or ethnic ancestry. So from an ethnicity standpoint or racial diversity standpoint, is there a plan to incorporate other ethnicities in a bigger, broader data set to validate whether a similar pattern of high NPV negative predictive value could be identified in non Caucasian individuals also? Dr. Bryson Katona: That's a great point and at this point, unfortunately, it's not an issue that is specific to this particular study, but it is one that affects really the entire literature in the pancreatic cancer early detection space. Diversity amongst individuals who are undergoing pancreatic cancer surveillance enrolled in these pancreatic cancer surveillance studies is really limited. So most of the data that we have on outcomes of pancreatic cancer surveillance really in all of the major publications is primarily limited to individuals who identify as white. And so this is an area where the whole field I think needs to think of ways and create new innovative ways to get more diverse populations into surveillance. And so again, I think until we fix the bigger problem of getting more diverse populations into surveillance, we won't have populations big enough to validate this particular test on those individuals.   So I think one other point that is really important that came out of this data was having a pancreatic cancer early detection test that requires CA 19-9 to be expressed is also a major limitation. In this particular study that we did, we found that about 14% of our high risk individuals got a ‘test not performed' result back because they were not CA 19-9 expressors. And with 10 to 20% of the general population not expressing CA 19-9, that really limits the individuals that would potentially be eligible for this type of a test. And so I think one of the other lessons that we learned from this is that any type of pancreatic cancer early detection test that is developed in the future, I think it ideally needs to be developed such that it can be run regardless of CA 19-9 expression. Otherwise you run the risk of developing a test that up to a fifth of at risk individuals may not even be able to benefit from. Dr. Rafeh Naqash: I think those are very important points, and as the biomarker field advances, I think taking into account, one, different races ethnicities because biomarker expression could be different based on genetic ancestry, and then taking into account the fact that, for example, for pancreas cancer, as you mentioned specifically, CA 19-9 may not be a universally expressed biomarker. So trying to overcome some of those limitations by designing things that are more universal is probably the way to go and I guess more to come in this field. So Dr. Katona, what is next for this project to perhaps expand on this pilot proof of principle project into a bigger, broader population or a validation cohort of some subtype? Dr. Bryson Katona: Immunovia, who is the company that developed the IMMray PanCan-d test, they're working to retool this test to hopefully release a second generation test in the near future. And I think that the hope will be that the second generation test will not have some of the issues such as dependence on CA 19-9 and use of a borderline result that this first version had. So we'll certainly be excited to help test and validate a second line test once it comes out.  And I think that just the pancreatic cancer biomarker field is an exciting one. I know there's several other commercial tests that are also currently being developed a little bit earlier in the development stage, but it's exciting to see so much effort and research being put into this area of just really great need. And so I'm really excited to see where the field goes over the next couple of years.  Dr. Rafeh Naqash: A couple of quick questions about yourself. Tell us a little bit about your journey, what led you into this specific field and how have things gone for you as an early career investigator in the last several years? Dr. Bryson Katona: Great. Yeah, I'm a physician scientist, so I see high-risk individuals in the clinic. I have a basic science lab and I run a lot of clinical research and early detection studies. Really, I knew I was interested in digestive cancers very early on and as a gastroenterologist, I found that I could probably have the most impact in the early detection space. And so ever since I was a fellow, this has been kind of my area of interest and expertise and I think taking the highest risk individuals, so those with strong family histories, those with genetic predisposition, I think you really have the opportunity to make the biggest impact with early detection strategies. And so that was one thing that always really motivated me in this field. Dr. Rafeh Naqash: Bryson, thank you so much for indulging with us. Thank you for choosing JCO Precision Oncology as one of the destinations, the final destination for your work and hopefully, more to see from you and your group in the near future. Congratulations on your concurrent publication presentation and the podcast, and thank you again for joining us. Dr. Bryson Katona: Thank you so much for the opportunity. It's been a great discussion. Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Shannon Westin speaks with Holly Prigerson and Alfred Neugut about their thought-provoking editorial, "You Get (Offered) What You (Can) Pay For: Explaining Disparities in End-of-Life Cancer Care." TRANSCRIPT The guest on this podcast episode has no disclosures to declare.   Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast. And this is where we get in-depth on manuscripts and editorials that have been published in the Journal of Clinical Oncology. As always, I am your host, Shannon Westin, Gynecologic Oncologist and Social Media Editor for the Journal of Clinical Oncology, and I'm so excited to be here today. We are going to be talking about a very compelling editorial that is called “You Get (offered) What You (can) Pay for: Explaining Disparities in End-of-Life Cancer Care." And this was published on June 20th, 2023, in the Journal of Clinical Oncology as an editorial on an article entitled the "End-of-Life Systemic Oncologic Treatment in the Immunotherapy Era: The Role of Race, Insurance, and Practice Setting." So a very timely topic and very exciting for us to discuss today. I'm joined by two of the authors of the editorial, Dr. Holly Prigerson, Professor of Sociology and Medicine, the Irving Sherwood Wright Professor in Geriatrics Medicine at the Weill Cornell Medical College and the Director of Cornell Center for Research on End-of-Life Care. Welcome, Dr. Prigerson. Dr. Holly Prigerson: Great to be here. Dr. Shannon Westin: And also accompanied by Dr. Alfred Neugut, the Myron M. Studner Professor of Cancer Research and Professor of Medicine and Epidemiology at Columbia University and the former Associate Director for Population Science and Racial Disparities Program for the Herbert Irving Comprehensive Cancer Center at Columbia. Welcome, Dr. Neugut. Dr. Alfred Neugut: Thank you very much. Dr. Shannon Westin: Very excited to talk about this topic today, and I like to always start with a little bit of level setting. So I'd love for one of you to discuss: How common is the use of systemic anticancer treatment at the end of life? Dr. Holly Prigerson: So, based on the article, it looks like the rates within the last 30 days of death, it was 34% on average overall. So that was sort of the—you say level setting—the base statistic. Within 14 days of death, it dropped to 13% overall. So all the associations that are described are really disparities from that level.  Dr. Neugut: Speaking as an oncologist, I don't think any of my clinical colleagues will be surprised that it's that high. There is an effort made really to, in desperation, try to help. Patients want it. Families want it. So there really is efforts made to try to do that to prolong life or palliate or whatever. Dr. Holly Prigerson: The design also, which is probably going to be a question that's coming up, does raise a question for me that I'm wondering if Al could enlighten at least me on. They did select patients who were getting treatment for metastatic or advanced cancer starting in 2011 and then who died four years later. Does the selection for the fact that they were getting treatment initially—because everyone, that's how they sampled the study—does that increase the likelihood that they'll get treatment later on so that the rates are somewhat inflated is my question.   Dr. Alfred Neugut: Yeah, no, for sure. People who start chemo tend to continue partially because there is a certain amount of those who do well do well. If you respond to chemo initially, you tend to respond to the second-line therapy, you tend to respond to third-line therapy. If you didn't do well on first-line chemo, you're not likely to respond to a second line or a third line, so you don't have the enthusiasm to continue with it, and the patient certainly tends to lose interest in it. So you're right; there is a certain, call it, momentum or inertia in going forward with chemo once you've started. Dr. Shannon Westin: I mean, I think this just always highlights some of the issues we have, right, with any kind of retrospective data is how well can we design a population without—because we can't always do randomized control trials, and certainly not in this kind of setting. That would not be acceptable, I think, to providers nor patients. And I do agree that it can be tricky. Any other kind of, maybe just to help the listeners if they haven't gotten a chance to read this Canavan study, about the design, exactly what they were looking at in this population?   Dr. Holly Prigerson: Basically, they took these patients who were getting systemic therapy and had advanced metastatic cancer prior, and then who died. So there's always a question about the sampling on death issue, that they had to have died to be in the sample. So those are methodological issues, but there's really very little way around that. If you want to know what treatments people received in the last month of life, they have to die for there to be a last month of life.  So then the treatments were divided into chemotherapy alone, chemotherapy with immunotherapy, and then immunotherapy with and without targeted therapy. So there were three types of treatment, which is sort of an important update because Al and I had published something in 2015 on chemotherapy and the outcome of what was called palliative chemotherapy at that time. And this was sort of a very refreshing–well, not—I shouldn't say refreshing, but important update to our study, which had said that there are questionable outcomes of palliating someone with palliative chemotherapy so far along in the disease. And then the question became, well, is it different? Is it different with immunotherapies? Is it different with targeted therapies? And that's why I was delighted to see this paper, because it answered…  Dr. Alfred Neugut: I'd have to say there are probably differing views on this, but Holly and I are probably relatively nihilistic in terms of thinking that chemotherapy in late stages or near terminal patients is probably not all that helpful. Third-line, fourth-line therapy probably not going to get you very far. And maybe it's best to be thinking more about hospice care and supportive care. And now we have terrific palliative care programs at most or all cancer centers, and we really should be taking advantage of this. I think a real benchmark study was the Temel study from 2010 or 2011, which really—for those of your listeners who haven't read it or seen it, they should really take a look at it. It really changes the playing field and makes you realize that treatment is not really always the best thing for patients, and there are other options. And we go to hospice care or palliative care really, I think, too late in the game a lot of the time, and we really should be thinking otherwise.  Dr. Holly Prigerson: That is one of the outcomes that we had looked at before. So we had looked at palliative chemo, and not only does it not palliate, and we didn't show that it significantly enhanced survival; we also showed that it resulted in a lower likelihood of earlier enrollment in hospice, a higher likelihood of not dying where your family members thought you would have wanted to die, a higher likelihood of dying in the ICU or getting some kind of aggressive care. So it's not only what the chemo does or doesn't do in terms of treatment or survival or quality of life; it also seems to exacerbate and put someone at risk for very burdensome interventions that having avoided it might have enabled patients to avoid getting very burdensome care that's largely futile. But as Al said, we are probably more the nihilistic type.  Dr. Shannon Westin: Well, I think you bring up a couple of good points because you've got objective data, and these studies that you're mentioning are just some of them that show that early hospice care and early enrollment and even just a palliative care program or a supportive care program or whatever terminology we want to use, people do better, right? They live longer actually from that piece rather than necessarily the more “aggressive measures” of chemotherapy and things. Dr. Holly Prigerson: When there was an extra analysis of the Temel data, I believe they had shown that some of the survival advantage was explained by avoiding toxic chemo. So that's directly relevant. Dr. Alfred Neugut: There is an on the other hand, as always, which is that patients and families often don't want to do that. I mean, they realize that doing that is giving up, so they're reluctant to take hospice care or palliative care as an alternative to another cycle of chemo or another type of chemo. And as you say, you never know; maybe the next one is going to be the winner and there'll be a miracle or there'll be at least some substantial benefit. And then there's always experimental therapy, and now immunotherapy, which is the topic of this article, is the new winner on the block. And it has bright lights around it, and everybody has great hope for it. And it's the new kid on the block, and everyone hopes that that's going to be the big savior.  Dr. Shannon Westin: Right, and I think everyone knows of a story of somebody that was “on death's door” and got immunotherapy or the newest targeted therapy or the newest ADC, so that definitely colors it. And that also colors, I think, the physicians that are offering it, right? Because, yes, I've definitely heard this, and I'm sure you guys have too: nobody should die with such and such cancer without receiving immunotherapy once or without receiving such and such targeted therapy. I hear people say this all the time, and I don't necessarily disagree. It's more that when are we giving it, right? So we should be thoughtful about when we're placing those things. But you're right; there's so many factors that go into these decisions, and it's not cut and dry around what the patients and the family members and the physicians are going to decide. Dr. Holly Prigerson: And I think that Al hits on a really key issue when he used the word “hope” because that seems like what the negotiation appears to be all about. You don't want to disparage someone or not offer them hope if there might… No one wants to say that there isn't hope. No one wants to be the bearer of that kind of bad news. And I guess it leads to—I think that that's part of the driver that ends up providing the gas that drives people to getting more aggressive therapies is because no one wants to be the person to be the wet blanket and disparage hope. And so it might affect how treatments are sold to patients or at least communicated to patients.   There was this one finding in this report that was curious, and it was that patients with undocumented performance status were the ECOG group most likely to get treatment. And so, in terms of what could be done going forward to make people more realistic and not offer hope where it's really, really unlikely, maybe employing more decision rules about requiring the documentation of performance status and ensuring that it's what the ASCO guidelines permit for administering another line of treatment. Because that might be a way to sort of use data to help correct what in psychology we call cognitive distortion, so correct the distortion of this hyper-optimism. It might help correct some of that. We don't want to overcorrect and make people hopeless or depressed, but we want to offer realistic options.  I think that's part of why this paper is so important, and it sort of informs future research to try to unpack some of the findings that they didn't have data on physician characteristics or communication discussions between patients and their oncologists. And maybe that's where the money is. Maybe that's where offering hope in a realistic way or different forms of hope, what to hope for, might be better communicated through more effective communication strategies and ways to enhance patients' abilities to understand what they're agreeing to or not agreeing to.  Dr. Alfred Neugut: And I would add that it's easy for us to sit here and be dispassionate or scientific interlocutors and saying, you know, “It doesn't work, and therefore we're not going to offer it or you shouldn't get it or go on to hospice.” But it's different when you're on the other side of the table. And even us doctors or healthcare professionals or scientists, when you're sitting on the other side of the table and you're the one who's got the cancer or your mother or child, you're not going to be so easily dismissive of getting third-line chemotherapy and having your 5% chance that the tumor will respond to some cocktail of who knows what and you never know. I don't want to say anybody's wrong or that it's stupid. Everybody has to do what they have to do, and we at least have to think about it and know what we're doing and have realistic—at least some idea of the realism of what we're putting people through and the costs and the toxicities and what to expect. Dr. Shannon Westin: I think you guys brought up some really great points, and I do think that there is a huge impact around the communication piece. And we actually just did a podcast on discussion of goals of care at the end of life for adolescents and young adults and how those conversations can be different.  I think the other thing that really caught my eye and, of course, caught your eye when you did the editorial around the Canavan study was this idea that the patients with insurance—with all other things being equal, that the patients with insurance were more likely to receive end-of-life systemic treatment. And it's interesting because typically I feel like we think having insurance and having that support is always a positive thing and has a positive impact on our health, and it most certainly does. So that's not up for grabs. But then this particular study showed that it could potentially have been negative because of all the things that you all just said about the negative impact of care in this 30 days or even 14 days near the end of life. What are the opportunities for intervention at the insurance level? You talked a little bit about provider level and communication. Are there opportunities at the insurance level that we could address? Dr. Holly Prigerson: It does seem like having insurance companies determine what is reasonable and not reasonable to reimburse for. So including things, I would think, like having performance status factored in. What are the criteria for determining whether it's high value care or not? And I'm not an oncologist, so I really am going out on a limb, and I really want Al to respond to that question. But from my perspective, it seems like the ASCO guidelines determine when it's—“low-value care” is how they put. It's wasteful and futile and burdensome. And they have guidelines of performance status, having not responded to multiple lines of chemotherapy, so that there could be guidelines for when there is value and when there isn't and that it could be more values driven in terms of guidelines of what they would reimburse. Because, as our title implicated, it seems like you get offered what insurance companies are willing to pay for, and that leads to potential disparities in equity if you have different insurance than other people and fairness and justice. Those seem like valid questions to raise. Dr. Alfred Neugut: I mean, I think if we're following randomized trials and evidence-based medicine, then I think we're in a reasonable area of what should be done and could be done and needs to be done. And almost always, insurance will follow those. You don't usually end up then having to argue with a peer-to-peer call to the insurance company under those circumstances. Where things get sticky is when you want to treat someone off-label or go off the reservation. I don't know if that's to some degree what this paper talked about. And there you probably don't get much benefit from treatment if it's not a data-driven use of the drug. So that's really, I think, where the line needs to be drawn. I don't think there you'll have an insurance problem if you've stated those sorts of guidelines. If you want to use NCCN or the ASCO guidelines, all good and reasonable. The problem is when someone's desperate and you're trying to make them happy, so you give them something even though there's no reason on God's earth why it should work, but just so they feel like you're getting something and you're not being abandoned, which sometimes you do feel pressured to do that, and very commonly you do. And maybe that's where racial disparities save the uninsured from being tortured for something that's not likely to really be very helpful.  Dr. Holly Prigerson: But as someone who's a disparities researcher as well, it raises the question were Black patients—which these data couldn't answer: were they offered different treatments than the White patients? And I think we all agree that low-value treatments shouldn't be offered or received, but the fact that Black patients receive less of the expensive stuff, the newer cutting edge, is problematic. And I think there does need to be more research into equity in terms of the options presented to patients with similar diagnoses. That was the troubling aspect of it, not that they weren't getting, in essence, better end-of-life cancer care, but that's beside the point. In terms of ethics, it would be nice to have known whether they were offered the same things and declined it. I think all of us are a little suspicious that maybe they weren't.  Dr. Shannon Westin: Yeah, that definitely—I like how you said it. It struck a nerve. Like, when I was reading through both the article and your editorial, that was something that caught my eye is this evidence of how implicit bias is impacting what people are offered. And yes, it ended up being an overall benefit to underrepresented minority patients. However, that wasn't necessarily the intention or why that happened. So I would be interested to hear what you all think about what we know about how implicit bias impacts the care of patients with cancer, just for our listeners, and specifically what particular treatments are offered, not necessarily just at the end of life, but just across the cancer continuum.  Dr. Alfred Neugut: There are estimates—if you read the medical literature on health policy and things like that, there are estimates that we overdo a lot of things in medicine and give—I don't know. I've read that like 70% of what we do in medicine is unnecessary. I'm not saying in oncology necessarily, but screening and wellness care, etc. And so oncology probably is equally guilty of such things. And there are biases in that as well, so, you know, that's what happens.   Dr. Holly Prigerson: And in the article, they had cited, I think it's Penner. There was a study that showed that ratings of an oncologist's implicit bias were negatively associated with Black patients' willingness to undergo their treatment recommendations. So the dynamic between what's offered, what's heard, what's trusted. There's obvious history of Tuskegee and concerns about being denied treatment. So this article kind of feeds into why was the latest and greatest types of treatment not as common? That said, the actual differences, if you look in the tables, the actual differences weren't that disparate. They were statistically significant, but we're talking like 37% to 34%. So the disparity isn't as wide as to cause serious alarm bells to go off that people are being treated so differently. But it does raise a lot of underlying concerns that you would want to make sure that everyone's being offered the same things. So it does imply—that Penner article implied—it's basically medical mistrust may be interfering with a Black patient's willingness to undergo or accept some treatment offered. So if you follow the logic on that through, then the intervention would be: What are ways to enhance medical mistrust of their oncologist? What are the reasons for it? And how can patients feel that they are being treated by someone who treats them fairly and no differently than White patients? And so efforts in those directions seem like they might pay off in terms of enhancing and addressing implicit bias.  Dr. Shannon Westin: Well, this has been a really great discussion. I'd love to hear just kind of your last thoughts from each of you around some of the unmet needs. We've heard themes throughout the discussion, but maybe just sum it up for the podcast listeners, bring them back and where we need to go next here.  Dr. Holly Prigerson: Al and I have been working on a few different projects to address medical mistrust and leveraging things like healthcare chaplains, who might be liaisons within an outpatient oncology setting. We also have interventions that try to enhance clinical communication, like what we call a GIST, so that patients easily get the gist, the essential meaning of things like scan results to sort of level the playing field so that patients have adequate information to know what the harms and benefits of the treatments that they're being offered might be and have a better background to be engaged in those decisions in the first place.  Dr. Alfred Neugut: My own thing is that you should be telling patients right from the get-go that they have incurable diseases and not letting them meander along thinking that we can actually help cure them in some meaningful way. We know who's incurable, and even if they have two or three years of survival coming to them, colorectal cancer or breast and prostate, etc., it's still fair to tell them that we can't cure them. And then when the time does come two, three, four years later, they're not going to be shocked, and they'll deal with it, I think, in a better way because they've known all along that this day is going to come, and then they don't react badly in the last two weeks, three weeks, four weeks, because they've been prepared for all those years before. I think the real problem is no one ever tells them directly, or many doctors don't tell them directly upfront. And so, when it comes near the end, they don't tell them until they're almost semiconscious. Then it's a shock out of the blue. And then of course they want to be treated more aggressively at the end. And I think that's where some of the issues may come. Dr. Holly Prigerson: And with the immunotherapies, that probably raises a lot more questions, even from the oncologist's perspective, about what they can call incurable because maybe there is hope, maybe there are these outliers. That's where it seems like it's wonderful that there are advances, but if the rates are so low and people have a misunderstanding of their chances, I think we're on the side of understanding what the best data suggests are the likely outcomes. And I think all the new advances sort of undermine disparaging hope because that's what they're there to do. They're there to offer hope. Dr. Shannon Westin: And everybody wants to be the tail of the curve, right? They all want to be that person. So that's exactly—you're totally right. When we're trying to communicate, “Okay, this is the most common outcome.  Yes, there are people that are way over here but…”  Dr. Holly Prigerson: That's going to be me. Dr. Shannon Westin: Yes. They always say, “That's going to be my miracle.” Well, great. Well, thank you both so much. This was such a lively discussion, and I know the listeners learned a ton. I know I did.  Again, thank you all for listening to JCO After Hours. We were discussing "You Get (offered) What You (can) Pay For: Explaining Disparities in End-of-Life Cancer Care," published in the JCO 6/20/23. We're so excited that you took the time to listen. If you're looking for more podcasts, check out our website, or you can find us wherever you get your podcasts. Have a wonderful day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Editor's Choice Papers:  Improving genetic testing following abnormal mismatch repair immunohistochemistry results in endometrial cancerEditorial: Universal testing – Should it be that hard? Probably. If you're doing it rightHosted by:Gregg Nelson, MD, PhD, Social Media Editor of Gynecologic Oncology Featuring: Bhavana Pothuri, MD,NYU Perlmutter Cancer CenterLeigha Senter, MS, CGC, The Ohio State University College of Medicine

JCO PO author Dr. Jens Rueter Chief Medical Officer at The Jackson Laboratory and Medical Director of the Maine Cancer Genomics Initiative, shares insights into his JCO PO article, “The Maine Cancer Genomics Initiative: Implementing a Community Cancer Genomics Program Across an Entire Rural State.” Host Dr. Rafeh Naqash and Dr. Rueter discuss this successful initiative for patients and its implementation for access to precision oncology in rural settings.  TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the OU Stephenson Cancer Center. Today we are joined by Dr. Jens Rueter, Chief Medical Officer at The Jackson Laboratory and Medical Director at the Maine Cancer Genomics Initiative. Dr. Rueter is also the Associate Director for Regional Translational Partnerships at the Jackson Cancer Center and the lead author of the JCO Precision Oncology article titled “The Maine Cancer Genomics Initiative: Implementing a Community Cancer Genomics Program Across an Entire Rural State.”  Full disclosures for our guest will be linked in the transcript and can be found on the article's publication page.  Welcome to our podcast and thank you for joining us today, Dr. Rueter.  Dr. Jens Rueter: Well, thanks for having me. It's a pleasure to be here. Dr. Rafeh Naqash: For the sake of this podcast, we'll refer to each other using our first name if that's okay with you. Dr. Jens Rueter: That's great. Dr. Rafeh Naqash: So this article that your group published in JCO Precision Oncology has significant implications. It has broad outreach. It incorporates an aspect of Precision Oncology that is very important for not only academia but also from a community outreach perspective, which is one of the reasons why I chose this as one of our podcast highlights. So to start off, I would really be interested to know what are the current barriers to the implementation of Precision Oncology, especially in rural settings versus urban settings, that can impact cancer mortality. Dr. Jens Rueter: Yeah, that's a great question. Let me just go back a little bit in time here. When we first started with the Maine Cancer Genomics Initiative back in 2016, the problems were actually even more significant than they are today. Back in those days, I would say even access to testing was a problem in rural areas. And I think that is still the first thing to consider when thinking about barriers. Back in 2016, there were only a handful of testing companies. There were issues with reimbursement or patient out-of-pocket costs. So I think that's the first barrier. I would say that that has significantly changed in the last six years. There are more testing companies available. It appears that the out-of-pocket expenses for patients have dramatically decreased or the systems programs have improved. There are still some barriers, but I think it's a much smaller part of the population.  The second barrier to implementation, though, which remains to this day, and in fact, I would argue has actually become more complicated, is a quick and comprehensive, yet fast and deliverable interpretation of the test reports. The test reports contain a lot of information. It's often 20 to 30 pages long, multiple sections, and really understanding how to utilize that information for clinical care is a very significant issue for clinicians to this day. So that's the second barrier.  And I think then the third barrier that is still ongoing and I think, especially in rural areas, is the access to treatments through either a clinical trial or even through off-label prescriptions, that both of those require a lot of infrastructure, and that still remains a significant issue to this day. Dr. Rafeh Naqash: You touched up on some very important aspects and one being understanding of genomic reports and this has been something that I talk to fellows all the know. I finished fellowship a few years back. At that time, NGS testing was becoming more and more prevalent, even though, as you mentioned in your paper, CMS coverage for this didn't start until 2018, 2019 approximately. And from a phase one trial standpoint, which is what I do, I have probably a little more exposure to genomics and precision medicine than perhaps some of our community colleagues. But it does come up often when we get referrals from outside sites. We're trying to look through the report and see something that stands out, whether it's a varying allele frequency that's high enough to warrant testing, germline testing, or some other targets that were identified a few years back but probably were not acted upon.   So you had this very interesting approach, a three-pronged approach is what I understood, of how you tried to tackle this within your main precision oncology program. Before we go there, could you tell us what was the idea behind establishing something like this? Because I imagine bringing it to fruition is something much more complicated, but the idea is where it starts. So I imagine, like, you probably had a conversation with some of your colleagues or somebody else noticed this as a barrier in the clinic and came up with this sort of an approach. Could you touch upon that for the sake of our listeners? Dr. Jens Rueter: Yes. So back in 2016, or actually in 2015, when we started conceptualizing the Maine Cancer Genomics Initiative, the idea was to look at Maine as a state, as a very rural state. The Jackson Laboratory is an NCI-designated basic science cancer center in the state, the only NCI-designated cancer center in the state. And we feel like there is an obligation, if you will, to the state to do good for all of Maine. So it's a community approach that we felt was important. And we realized then at the time that, again, that testing genomic tumor testing, or NGS testing while available, was not being used effectively in the community. So I think those two ideas essentially made us think and believe that we should take the lead in starting such a program.  We felt that we had actually one significant advantage in that we are a non-patient care organization. So the Jackson Laboratory, even though we have an NCI-designated cancer center, we don't see patients at Jax. So we were not a competitor, if you will, for patients in the state. So we were an honest broker. We were sort of a neutral Switzerland, if you will, in Maine, and were able to convene the entire community around this concept. Even though Maine is a small state, there are a number of healthcare systems that are actually competing with each other for patients in certain areas. And when we sort of started this program, we said, look, we want to work with everyone, and it's important for us to work with everyone, and we want to include even the smaller, truly rural critical access hospitals that have small, very small oncology practices. They're just as important to us as the larger centers. So I think that was sort of the community idea behind this and this is what really started it all. And then also, again, the fact that testing was such an issue, it also happened that at the time, Jax had just started we had just started our own clinical laboratory, our own CLIA certified laboratory. So we felt like we actually had the expertise to bring a test to the community that would then engage them to utilize the technology more effectively. And that's how we proceeded with this.  Dr. Rafeh Naqash: Excellent. And I totally agree that this inclusive stakeholder approach that you had was probably one of the elements for success in this kind of an approach and led to a significant impact in the lives of patients. You mentioned three things that you targeted or three things that you identified and tried to implement as part of this Precision Oncology program. Could you tell us about those briefly, what they were, and why they were important to be included in this approach? Dr. Jens Rueter: Yes, absolutely. So the first and most important one and most impactful one was that we developed a genomic tumor board program through this initiative, which again we had a centralized yet hub-and-spoke type approach where we said, “Okay, we are going to organize these for all of the practices, for all of the studies. The patients that are enrolled in our study protocol, we will organize these and basically create an environment where we call on national experts from around the country and, in fact, around the world at this point, that call in and provide input on the different cases that the physicians had enrolled.” We left it up to the physicians to decide which cases they wanted to present because they had some patients that they enrolled where they felt like they didn't necessarily have to present the case. So there was a lot of buy-in for these genomic tumor boards because we really discussed cases that were probably the most challenging ones and the most relevant ones.  So I think the genomic tumor board program was really the most significant development and the most significant infrastructure that we built. And in fact, the work that we did in Maine actually enabled us to design a cluster randomized study that we're now running through the SWOG Cancer Research Network. I'm leading that effort with a collaborator from Columbia in New York, actually, Meghna Trivedi. And so that was really a great success, and we will hopefully in a few years know if this approach actually leads to changes in some patient outcomes. We have some indication that it does from our own work, but we will see that in a more rigorous fashion.  The second pillar, if you will, the second part of the approach was that we have a dedicated clinical education group at JAX. So JAX Laboratories, as I said, a basic science cancer center,  but we also have essentially an entire group dedicated to genomic education. And part of that group is focused on clinical genomics education. So we have a modular online program that clinicians can access, not just the physicians, but also the nurses and other people, other members of the patient care team. And in fact, in addition to the online program, we ran a few virtual educational sessions specifically for nurses, which we actually found was, nurses and clinical research coordinators were really one of the most important keys to success as well, that we get them on board and enable them to better understand the complexities of testing.  And then the third aspect, of course, was that we did provide the testing as well as part of this initiative, which we saw as kind of a method to really engage clinicians and take the pressure off the clinicians. “What if I order this testing? Are patients going to come back with significant out-of-pocket expenses?” Again, that was particularly relevant back in 2016, 2017, before the CMS coverage decision. So those three aspects were really what drove this program. Dr. Rafeh Naqash: Excellent. Now what I gather is for something like this to come to a full functional state, you need a team and you need funding. So how did you define or identify the core group of people that were most important for this initiative? And what was the funding source? Because these days, nothing gets done without the appropriate level of funding. So I wanted to ask you and see how you manage some of those logistical issues.  Dr. Jens Rueter: Great question. So this whole program was really enabled by a large philanthropic grant, or donation, if you will, from a foundation called the Harold Alfond Foundation. It's a very large philanthropic organization in New England, and they're very Maine-focused. They have historical or family ties actually to Maine, and it's very important to them to bring Maine sort of to the forefront, sort of out of the rural disadvantage, and turn that into an advantage, which is why they agreed to provide funding for this program. And I agree with you that that is a critical step. This program was always in between a traditional research program that could be funded by an NIH grant, for example. I think that initially you need some startup funding first to get this going, and then later on, as you can develop more concise research questions, I think you can also apply for NIH funding for something like this. But certainly, philanthropy goes a long way here. So that was sort of the funding source, and, I think, very important.  Now, in terms of the team, that's actually a great question. You need a few different functions represented here. So I think, first of all, having some clinical expertise is important. So I was actually specifically hired to JAX for this program. I'm a medical oncologist. I actually still have a small practice in Maine as well, but I was in full practice before I joined JAX. And I was hired specifically for this purpose so I could engage with the community and sort of understand my colleagues over the state. You need a very good and rigorous program manager, someone who can really– It's a complex project that there are many aspects you need to consider and you really need someone that kind of keeps track of all the different activities and makes sure that things are moving in the right direction.  Since we are a research organization, we decided to roll this out on a study protocol. So we hired a clinical research manager that would basically disseminate and enable the study protocol and make sure that it's actually done correctly. Even though it was a low-risk observational study, we still wanted to make sure that we collect good data on the patients and the number of publications that we've been able to produce from this initiative, I think, speak to the quality of the data. And then as the program has evolved, we have actually added on a couple of other key functions within the program, and actually one of them pertains specifically to the genomic tumor boards, which again, I think are really critical to this. So you really need one dedicated person to organize these and coordinate these. It's a lot of scheduling. There's a lot of, as you know, from your own clinical practice, clinicians have very specific schedules, and if you really want to make this successful, you really need to make sure that everyone's schedules are accounted for.  And then we also recently added another function to our program, another individual who is a genomic navigator. Actually, we call it the genomic navigator. And I think that this individual, her job is if there are additional questions, for example, after genomic tumor board, or if there are just some very specific about a test report from the entire- it could be from anyone on the team, the physicians, the nurses, the research coordinators, she can help identify some additional answers to some additional questions. She can also help clinicians if they're interested in finding a clinical trial for the patient or find some supporting evidence for off-label drugs, for example, she can provide them with additional references. We have crafted documents that basically summarize the available evidence that exists for using a specific drug in association with a genomic marker. So I think genomic navigators are also very important, and I think there are some other individuals on my team now, but I think those are the core functions that you really should consider. Dr. Rafeh Naqash: Thank you for giving us a detailed explanation of the team that I'm pretty sure has expanded over the last few years as you've tried to expand this program concurrently.  Now, going from the team to the platform, I was kind of interested to know a little more about the sequencing platform generally, as from my clinic, I do FoundationOne, or ERUS testing, or Tempus testing, etc., and I'm not very well versed with some of the platforms used. Could you tell us a little bit more about what these platforms are? How big the panels are from a DNA standpoint? And I see you did test for some RNA fusions as well. So could you tell us how that came about? Dr. Jens Rueter: So when we first started the initiative, we started with a single assay that we ran through the Jackson Laboratory, and it was at the time a fairly contemporary test. It looked at both SNVs, insertions, deletions, and so forth on the DNA level and on copy number variants as well. And it was 212, at the time, 212 cancer-related genes. It was a homegrown panel if you will. This was back in 2017, 2018, and we also had a fusion assay that looked at RNA already at the time. So we were already kind of ahead of the curve at that point because, at the time, many assays were still just looking at DNA for fusion. So we already figured that it would be better to look at the RNA level. And then we sort of grew the panel from there.  The last panel that we used specifically for this first phase of the initiative had grown to 501 genes. It was already done on a specific platform. I think it was one of the Illumina platforms at the time. So we figured the off-the-shelf solutions weren't necessarily the right approach. We also added in tumor mutational burden. We added in MSI. We did not yet have at the time LOH or HRD assessment, but we certainly offered TMB and MSI. And we had the usual sort of commodity testing for PDL-1, which we actually sent out because it wasn't necessarily what we do in-house. So that was during the program as it is described in the manuscript. I will say we continue this program. We're continuing the genomic tumor boards now. We've never stopped. We just continued after the study was over. We offer it essentially as a service now to the community, as an educational service if you will, and we now actually work with any test reports that the physicians provide. Again, I think the landscape has shifted dramatically and the testing itself doesn't seem to be as much of a barrier anymore. So we look at a lot of Tempus reports, KRAS foundation, every now and then we'll have something that's a little bit more unique, I would say.  There are obviously many other sequencing companies out there and we've actually found that this is– For our genomic tumor boards, we actually developed a template that is non-branded, that is just trying to put every test into the same table, front table, which I think has actually been very helpful for the clinicians because, again, sometimes you just can't find all of the relevant information on the front page. And we comb through every report and try to find every addendum that may have been generated and all kind of collate it in one single slide if you will, so that the clinicians have it right there and then we kind of talk it through as well. So that's essentially the evolution of the testing over the last six, seven years. Dr. Rafeh Naqash: So this more or less sounds like a very state-of-the-art, contemporary approach that was available more or less to other clinicians at that time. 200 gene panel seems pretty extensive for 2018, 2019 and, as you probably know, things have gone to whole exome at this point, but I think you seem to be doing what was most appropriate at that time.  Now, going to the results between 2017 to 2020, your precision oncology program enrolled around 1600 people. The results were simple but very impactful, is how I describe it. Could you tell us some of the highlights from the results, what you identified, both from an implementation standpoint, participation standpoint, and from an impact at an individual patient's level?  Dr. Jens Rueter: Yeah, I'm happy to do that. So, I think the most important for us, the most important metric was that we were able to, over time, engage all practices and engage all– When we finished with the initiative, at that point, every physician, every oncologist in the state had actually been enrolled in our program as a study participant, which was actually one of the unique features, by the way, of our program: we said we were going to study both the physicians and the clinicians. So we had enrolled on our study 100% of the oncologists. It took us about 18 months to get to all the practices, which I think is an important metric for anyone who wants to pursue something similar. You have to always keep in mind that, even if you come in with a fairly solid proposal and something that is clearly of benefit to patients, every institution that you work with, it's going to take a while before you can get all the agreements signed and the IRB issues settled.   So it took us about 18 months, which I think is still fairly quick actually. And we listed the enrollment as well, the enrollment curve of patients in the paper. And it certainly did take some ramp-up in the very beginning, but then we really very quickly sort of ramped up to a steady state after about a year or so. We discussed about a little bit less than, about a third of the cases actually, at our genomic tumor boards. Almost three-quarters of the physicians actually participated in the genomic tumor boards as well. We ran around 200 GTBs throughout the initiative, and we're currently looking at the clinical outcomes of these patients. It's currently under review what the clinical outcomes were, but I can already say that we are sort of, I would argue, in about the same place in terms of patients that actually went on a genome-match therapy as many other publications in that venue. And it is actually, as you can probably imagine, rather complicated to define what a genome-match therapy actually is. And that will be coming out soon, hopefully soon.  So the other findings are also quite interesting and they have been published in other publications over the last few years. So at baseline, for example, we actually asked the patients, “What are your expectations? What are you expecting from this enrollment, from the tumor testing?” And we actually identified that the patient expectations were very high, which I think is important, an important finding -  can be explained partially by precision oncology, it's a buzzword right now, and patients have certainly picked up on this and there are a lot of very high expectations in that it's going to change your outcomes. And physicians also at baseline felt quite confident, actually. There was a fairly good spread, but most of them felt quite confident that they would be able to utilize the information and actually explain it to their patients. They felt mch less confident, very on-point, in my opinion, that they would be able to put the patients on a targeted therapy or that their practice would have the infrastructure to support putting patients on therapy. So those are some of the other findings that we've identified over the last few years overall. Dr. Rafeh Naqash: Thank you. And just on a side note, I was looking at Figure 4, which shows the number of cases per physician, and one physician particularly stands out with 120+ cases. Dr. Jens Rueter: Yes. Dr. Rafeh Naqash: Did that individual physician get any kudos after doing this excellent job? Dr. Jens Rueter: Yes, actually this physician did. That's actually a really good point that you're bringing up. That's another important finding that I found quite fascinating, actually, that everyone is kind of the same at baseline. We offer the same thing to everyone. And you can see in Figure 4 in the paper that there is a significant spread in terms of how many patients each physician enrolled and also how many they presented at a genomic tumor board. And certainly that one physician is a very engaged member. We have a steering committee that we implemented very early on. That physician is also on our steering committee. And this really has contributed a lot of insights into what has worked well and maybe what hasn't worked so well. So it is a rather fascinating statistic, I agree. Dr. Rafeh Naqash: One of the things I also noticed from your summary was that the uptake of the genomic testing and being part of this initiative was more for rural areas than for urban areas. And I was trying to understand why perhaps one of the reasons could be that it does help the community physicians in that setting. Was that what you saw, or was there another side to it that perhaps may not necessarily be explained in this manuscript? Dr. Jens Rueter: Yeah. So, first of all, just to be very clear that the highest enrollment in rural areas was per capita so that's an important distinction in my opinion. So, it obviously goes that the more rural areas are more densely populated. And what's actually behind this is that the physicians that were working in those rural areas also just happen to be really engaged in the program and find a lot of value, especially, in the genomic tumor boards. So it was really very much a personable motivation. I would say, though, that the larger issue behind this, or the larger interpretation of these findings is that, especially at that time, I would argue that the– In Maine, you can always see that everything kind of moves from the south all the way to the north. It takes a little bit of time and it's the same in pretty much anything, but in medicine as well. And so, I think at that time, the NGS testing just wasn't really used all that much in the more rural areas. So I think the fact that we provided it– And again, there's also less infrastructure at these smaller hospitals or smaller practices. So running through the hoops of getting prior authorizations and still managing potential out-of-pocket expenses just aren't there and these were things back in the day for sure that were barriers. So I think us coming in and saying, “Look, all you have to do is you mention to your patients that there is this program called the Maine Cancer Genomics Initiative, and if you're interested, someone will contact you from the Jackson Lab and talk to you more about the study and see if you want to participate.” That's all they needed to do. And then everything else kind of went from there. I think that is really probably one of the reasons why we had such a significant accrual in those more rural areas. Dr. Rafeh Naqash: Amazing. And one of the things that I am very dreadful of is ‘tissue being the issue' where, despite the biopsy, despite everything you do, the pathologist comes back. Or you send the tissue to the sequencing company, they come back saying, not enough tumor cells. What were some of the things that you did or your group did to help the people involved in this process understand why tissue matters? Because that can add to further delays in treatment. So I'm very curious to know what some of those things were that you tried to help everybody understand from an educational perspective. Dr. Jens Rueter: We noticed that very much in the beginning, especially, of the program, so after about two or three months, we realized that there were a significant number of tissue failures and we realized we needed to address that. And we did that both by internal as well as external processes. So we actually looked back at our assay and said, "Look, maybe our requirements for DNA input are just too high. We need to rethink that and maybe there's a way to improve the laboratory processing so that we can actually work with less DNA." So I think that's a very important lesson.   And interestingly enough, I think this is still an issue to this day in a certain way with any of the testing laboratories, and we can get back to that in just a second. But I think the other aspect that was important here was, again, getting on the phone or on a Zoom call or whatever it was at the time, and really talk to the pathologist, talk to the clinicians, talk about, when you order a test, for example, think about beforehand as you're identifying the right specimen. Is this actually potentially enough tissue? If it's an FNA, maybe it's not enough. But if it's a good core biopsy, that's probably the better specimen. So that's certainly on the ordering physician side, but then also on the pathologist side, it was actually quite interesting. And one of the larger pathology practices in the state actually implemented something very smart, I think, as they sign out cases, and I think they do this universally on any case, as a pathologist signs out the case, he will actually indicate on the report which block should be used for sequencing. And they will actually indicate a tumor cell percentage, which I think is an excellent small step, but very impactful because it will reduce frustration on the side of the clinician, if a block is sent with not enough tissue, it will facilitate the workflow between the place where the tissue is stored, for example, and where it's cut, and it makes everything a lot simpler. And I think those are the kinds of things that you really have to think about. I think in the contemporary times now where it's become quite common for testing companies to weed out samples that have 20% or 30% neoplastic content. What's interesting there, though, is that I feel like sometimes they're almost a little bit optimistic. They're always very clear on the disclosures in the report. They will say that there was a low tumor cell purity and some of the results should be interpreted with caution. But again, I'm not sure that clinicians are actually reading the fine print. So the example has kind of flipped a little bit that nowadays you're getting a lot more information than you did six, seven years ago. But you have to understand better as to how the information was derived. Dr. Rafeh Naqash: I couldn't agree with you more as far as noting down in the pathology specimen which specimen is the most appropriate for NGS. It's a small thing to do, but I think it makes a huge impact when the research team or the nurses are actually trying to identify what specimen to send.  So now, Jens, coming to the last portion, I'd really like you to summarize in 30 seconds what are the future directions from this program? Where does it stand right now? And what are some of the things that you're trying to add on to the current format? Dr. Jens Rueter: Where we stand is we're continuing to run our genomic tumor boards in the state of Maine. And as I mentioned earlier, we're also running a national study where we're running an additional GTB per week just to really see how impactful it is on patient outcomes. In the future, we need to improve the processes. We need to streamline the processes with genomic tumor boards, involve more technology to scale it, essentially, and make it more broadly available. And lastly, what's really important is we also need to think more closely about treatment options and enabling rural areas to have more access to clinical trials. And I hope that with the current post-pandemic thinking, that we can actually enable that with technologies, with virtual visits, with virtual consent, and so forth. And then, one other point, we also need to educate patients so that they know what to ask for when they're meeting with the oncologist.  Dr. Rafeh Naqash: Thank you so much.  Now the last portion, a minute or two is going to be dedicated to you specifically. So, Jens, tell us a little bit about your career trajectory. Where did you start? You mentioned earlier that you did or currently do practice clinical oncology. And how did you get into the field of precision medicine that culminated into developing such an impactful program? Dr. Jens Rueter: We moved to Maine in 2010 after I completed my Hem/Onc Fellowship at the University of Pennsylvania, where I'd actually done quite a lot of translational and bench research. We came to practice. We moved to Bangor, and practiced here. And the Jackson Laboratory is really just on the road from where we are. We're at Mount Desert Island, right next to Acadia National Park, and I started collaborating with some of the scientists. Actually, early on, we built a tissue bank at the Northern Light Hospital here to facilitate translational research. And then when the funding became available, I received a call from the then CEO of Jackson Laboratory, and h, Ed Liu, and he said, "Jens, we're thinking about running this program and would you be interested?" And so that's how I joined JAX. And that's really when I started. I saw at the time already this gap that was widening and I saw how complicated it is to practice rural oncology. And I really saw this as a great opportunity to bring the field forward, to bring Maine forward, and to really address one of the major disparities that still exist to this day.  Prior to that, I spent quite a bit of time doing, as I said, bench research at the University of Pennsylvania. I also did my internal medicine residency at Tulane, and I always thought I was going to be a traditional physician-scientist. I actually feel great about this opportunity because I think it's addressing one of the major issues in contemporary oncology. So that's sort of how I got here. I'm originally from Germany, I went to medical school in Germany, did some research there, and then came to the United States about 20 years ago now for my postgraduate training, and I've stayed here ever since.  Dr. Rafeh Naqash: Excellent. Sounds like you're the right person for this job, with both a clinical translational bench kind of experience and having worked in different settings.  So thank you once again, Jens, for being a part of this conversation. I think at least I learned a lot. Hopefully, our listeners will find it equally interesting, intriguing, and perhaps implement some of the things that you have accomplished as part of this initiative.  Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Guest Bio: Jens Rueter, M.D. is the Chief Medical Officer of The Jackson Laboratory and Medical Director for the Maine Cancer Genomics Initiative.  Guest COIs: No Disclosures

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