POPULARITY
9 episodes with Germline
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4 episodes with Germline
2 episodes with Germline
2 episodes with Germline
Dr. Evan Noch interviews Dr. Marion Mateos about her and her team's recent manuscript entitled: "Germline analysis of an international cohort of pediatric diffuse midline glioma patients", published online in Neuro-Oncology in March 2025.
Dr. Paul Sieber and co-host Ashleigh Renitsky, Oncology PA, are joined by Dr. Morris from Urology Associates of Nashville to discuss how clinical guidelines have driven increased awareness of germline and somatic mutations in prostate cancer. They discuss how germline and somatic testing can help personalize treatment strategies and share real world case studies. The conversation also encourages the need for continued education in this rapidly advancing field and adoption of genetic testing in urology. Send us a text
Note: an audio narration is not available for this article. Please see the original text. The original text contained 169 footnotes which were omitted from this narration. The original text contained 79 images which were described by AI. --- First published: March 3rd, 2025 Source: https://www.lesswrong.com/posts/2w6hjptanQ3cDyDw7/methods-for-strong-human-germline-engineering --- Narrated by TYPE III AUDIO. ---Images from the article:
Ultrasound cosmetics technologies - with Dr. Nicholas Nikolov! -Pediatric melanoma germline mutations -Swearing for analgesia -Thin melanoma mortality -To sign up for Luke's atopic dermatitis CME activity, go to:impactedu.gathered.com/invite/4QbYEVpbzqWant to donate to the cause? Do so here! Donate to the podcast: uofuhealth.org/dermasphere Check out our video content on YouTube: www.youtube.com/@dermaspherepodcast and VuMedi!: www.vumedi.com/channel/dermasphere/ The University of Utah's Dermatology ECHO: physicians.utah.edu/echo/dermatology-primarycare - Connect with us! - Web: dermaspherepodcast.com/ - Twitter: @DermaspherePC - Instagram: dermaspherepodcast - Facebook: www.facebook.com/DermaspherePodcast/ - Check out Luke and Michelle's other podcast, SkinCast! healthcare.utah.edu/dermatology/skincast/ Luke and Michelle report no significant conflicts of interest… BUT check out our friends at: - Kikoxp.com (a social platform for doctors to share knowledge) - www.levelex.com/games/top-derm (A free dermatology game to learn more dermatology!
Germline melanoma mutations -Treating venous insufficiency -Dermasphere clip show: Episodes 141-150! -To sign up for Luke's atopic dermatitis CME activity, go to:impactedu.gathered.com/invite/4QbYEVpbzqWant to donate to the cause? Do so here! Donate to the podcast: uofuhealth.org/dermasphere Check out our video content on YouTube: www.youtube.com/@dermaspherepodcast and VuMedi!: www.vumedi.com/channel/dermasphere/ The University of Utah's Dermatology ECHO: physicians.utah.edu/echo/dermatology-primarycare - Connect with us! - Web: dermaspherepodcast.com/ - Twitter: @DermaspherePC - Instagram: dermaspherepodcast - Facebook: www.facebook.com/DermaspherePodcast/ - Check out Luke and Michelle's other podcast, SkinCast! healthcare.utah.edu/dermatology/skincast/ Luke and Michelle report no significant conflicts of interest… BUT check out our friends at: - Kikoxp.com (a social platform for doctors to share knowledge) - www.levelex.com/games/top-derm (A free dermatology game to learn more dermatology!
Dr. Jasmine Sukumar and Dr. Dionisia Quiroga discuss advances in adjuvant therapy for patients with early breast cancer and BRCA1/2 mutations, including how to identify patients who should receive genetic testing and the significant survival benefits of olaparib that emerged from the OlympiA trial. TRANSCRIPT Dr. Jasmine Sukumar: Hello, I'm Dr. Jasmine Sukumar, your guest host of the ASCO Daily News Podcast today. I'm an assistant professor and breast medical oncologist at the University of Texas MD Anderson Cancer Center. On today's episode, we'll be exploring advances in adjuvant therapy for high-risk early breast cancer in people with BRCA1/2 germline mutations. Joining me for this discussion is Dr. Dionisa Quiroga, an assistant professor and breast medical oncologist at the Ohio State University Comprehensive Cancer Center. Our full disclosures are available in the transcript of this episode. Dr. Quiroga, it's great to have you on the podcast. Thanks for being here. Dr. Dionisia Quiroga: Thank you. Looking forward to discussing this important topic. Dr. Jasmine Sukumar: Let's start by going over who should be tested for BRCA1/2 genetic mutations. How do you identify patients with breast cancer in your clinic who should be offered BRCA1/2 genetic testing? Dr. Dionisia Quiroga: So, guidelines on who to offer testing to somewhat differ between organizations at this point. I would say, generally, I do follow our current ASCO-Society of Surgical Oncology (SSO) Guidelines, though. Those guidelines recommend that BRCA1/2 mutation testing be offered to all patients who are diagnosed with breast cancer and are 65 years old or younger. For those that are older than 65 years old, there are additional factors to really take into account to decide on who to recommend testing for. Some of this has to do with personal and family history as well as ancestry. The NCCN also has their own specific guidelines for who to offer testing to. For example, people assigned male at birth; those who are found to have a second breast primary; those who are diagnosed at a young age; and those with significant family history should also be offered BRCA1/2 testing. I think, very important for our discussion today, ASCO and SSO also made a very important point that all patients who may be eligible for PARP inhibitor therapy should be offered testing. So clearly this includes a large amount of our patient population. In my practice, we often refer to our Cancer Genetics Program. We're fortunate to have many experienced genetic counselors who can complete pre-test and post-test counseling with our patients. However, in settings where this may not be accessible to patients, it can also be appropriate for oncology providers to order the testing and ideally perform some of this counseling as well. Dr. Jasmine Sukumar: Thank you Dr. Quiroga. Let's next review where we are in current clinical practice guidelines. What current options do we have for adjuvant therapy specific to people with high-risk early breast cancer and BRCA1/2 genetic mutations? Dr. Dionisia Quiroga: Our current guidelines recommend adjuvant olaparib for one year for individuals with HER2-negative high risk breast cancer. This approval largely came from the data and the results of the OlympiA trial. This was a prospective phase 3, double blind, randomized clinical trial. It enrolled patients who had been diagnosed with HER2-negative early-stage breast cancer who also carried germline pathogenic or likely pathogenic variants of either the BRCA1 and/or BRCA2 genes. The disease also had to be considered high-risk and there were several criteria that had to be evaluated to deem whether or not these patients were high-risk. For example, those who are treated with neoadjuvant chemotherapy, if they had disease that was triple-negative, they needed to have some level of invasive residual disease at time of surgery. Alternatively, if the disease was hormone receptor-positive, they needed to have residual disease and a calculated CPS + EG score of 3 or higher. This scoring system is something that estimates relapse probability on the basis of clinical and pathologic stage, ER status, and histologic grade, and this will give you a score ranging from 0 to 6. In general, the higher the score, the worse the prognosis. This calculator though is available to the public online to allow providers to calculate this risk. For the subset of patients who received adjuvant chemotherapy, for them to qualify for the OlympiA trial, if they had triple-negative disease, they needed to have a tumor of at least 2 cm or greater and/or have positive lymph nodes for disease. For hormone receptor-positive disease that was treated with adjuvant chemotherapy, they were required to have four or more pathologically confirmed positive lymph nodes at time of surgery. From this specified pool, patients were then randomized 1:1 to get either adjuvant olaparib starting at 300 mg twice a day or a matching placebo twice a day after they had completed surgery, chemotherapy and radiation treatment if needed. Dr. Jasmine Sukumar: And what were the outcomes of this study? Dr. Dionisia Quiroga: The study ended up enrolling over 1,800 patients and from these 1,800 patients, 70% had a BRCA1 mutation while 30% had a BRCA2 mutation. About 80% of the patients had triple-negative disease compared to hormone receptor-positive disease. Interestingly, about half of all patients enrolled had received neoadjuvant chemotherapy while the other half received adjuvant chemotherapy. Looking at the outcomes, this was overall a very positive study. We actually now have outcomes data from a median of about 6 years out. This was just reported in December at the 2024 San Antonio Breast Cancer Symposium. There was found to be a 9.4% absolute difference in six-year invasive disease-free survival favoring the olaparib arm over the placebo arm. What was also interesting is that this was consistent across multiple subgroups of patients and the benefit was really seen whether or not they had hormone receptor-positive or triple-negative disease. The absolute difference in distant disease-free survival was also high at 7.8% and additionally favored olaparib. Most importantly, there was found to be a significant overall survival benefit. The six-year overall survival was 87.5% in the olaparib group compared to 83.2% in the placebo group. This translates to about a 4.4% difference and a relative 28% overall survival benefit in using olaparib. Now, future follow up is going to be very important. Follow up for this study is actually planned to continue out until June 2029 so we can continue to observe if these survival curves will continue to branch apart as they have so far at each follow up. And I think this is especially important for those patients diagnosed with hormone receptor-positive cancers because we know those patients are at particular risk for later recurrences. As an additional side note, the researchers also noted that there were fewer primary malignancies in the olaparib group, not just of the breast but also primary ovarian or fallopian tube cancers as well, which is not completely surprising knowing that this drug is also heavily used and beneficial in different types of gynecologic cancers. Ultimately, the amount of adverse events reported have been low with only about 9.9% of patients receiving olaparib needing to discontinue drug due to adverse events, and this is compared to 4.2% reported in the placebo group. Dr. Jasmine Sukumar: You mentioned that the OlympiA trial showed an overall survival benefit, but interestingly the OlympiAD trial looking at olaparib versus chemotherapy in patients with advanced metastatic HER2-negative breast cancer did not show a significant overall survival benefit. Could you discuss those differences? Dr. Dionisia Quiroga: I agree, that's a very good point. So OlympiA's comparator arm was, of course, a placebo. So while this isn't the same as comparing to chemotherapy, it does still potentially suggest that there is a degree of benefit that olaparib can provide when it's introduced in the early local disease setting compared to advanced metastatic disease. I think we need more future trials looking at potential other combinations to see if we can improve the efficacy of PARP inhibitors in the metastatic setting. Dr. Jasmine Sukumar: For patients who do choose to proceed with use of adjuvant olaparib due to the promising efficacy, what side effects should oncologists counsel their patients about? Dr. Dionisia Quiroga: The most common notable side effects, I would say with olaparib and other PARP inhibitors are really cytopenias. Gastrointestinal side effects such as nausea and vomiting can occur as well as fatigue. There are some less common but potentially more serious side effects that we should counsel our patients on. This includes pneumonitis. So counseling patients on if they're short of breath or experiencing cough to let their provider know. Venous thromboembolism can also be increased rates of occurrence. And then of course myelodysplastic syndromes or acute myeloid leukemia is something that we often are concerned about. That being said, I think it should be noted that interestingly in the OlympiA trial so far, there have been less new cases of MDS and AML in the olaparib group than actually what's been reported in the placebo group at this median follow up of over six years out. So we'll need to continue to monitor this endpoint over time, but I do think this provides some reassurance. Dr. Jasmine Sukumar: Since the initiation of the OlympiA trial, other adjuvant treatments have also been studied and FDA approved for non-metastatic HER2-negative breast cancer. So for example, the CREATE-X trial established adjuvant capecitabine as an FDA approved treatment option in patients with triple-negative breast cancer who had residual disease following neoadjuvant chemotherapy. So if a patient with triple-negative breast cancer with residual disease is eligible for both adjuvant olaparib and adjuvant capecitabine treatments, how do you decide amongst the two? Dr. Dionisia Quiroga: If a patient's eligible for both, I honestly often favor olaparib, and I do this because I find the data for adjuvant olaparib a little bit more compelling. There are also differences in toxicity profile and treatment duration between the two that I think we should discuss with patients. For example, olaparib is supposed to be taken for a year total, whereas with capecitabine we typically treat for six to eight cycles with each cycle taking three weeks. There are some who may also sequence the two drugs in very high-risk disease. However, this is very much a data free zone. We don't have any current clinical trials really comparing these two or if sequencing of these agents is appropriate. So I don't currently do this in my own clinical practice. Dr. Jasmine Sukumar: Nowadays, almost all patients with stage 2 to 3 triple-negative breast cancer will be offered neoadjuvant chemotherapy plus immune checkpoint inhibitor therapy pembrolizumab per our KEYNOTE-522 trial data. With our current approach, pembrolizumab is continued into the adjuvant setting regardless of surgical outcome, so that patients receive a year total of immunotherapy. So in patients with residual disease and a BRCA germline mutation, do you suggest using adjuvant olaparib concurrently with pembrolizumab? Do we have any data to support that approach? Dr. Dionisia Quiroga: I do. I do use them concurrently. If a patient is eligible for adjuvant olaparib, I would use it the same way as if they were not on pembrolizumab. That being said, there are no large studies currently that have shown what the benefit or the toxicity of pembrolizumab plus olaparib are for early-stage disease. However, we do have some safety data of this combinatorial approach from other studies. For example, the phase 2/3 KEYLYNK-009 study showed that patients with advanced metastatic triple-negative breast cancer who were receiving concurrent pembrolizumab and olaparib had a manageable safety profile, particularly as the toxicities of these drugs alone don't tend to overlap. Dr. Jasmine Sukumar: And what about endocrine therapy for those that also have hormone receptor-positive disease? Dr. Dionisia Quiroga: Adjuvant endocrine therapy should definitely be continued while patients are on olaparib if they're hormone receptor-positive. An important component of this will also likely be ovarian suppression, which should include recommendation of risk reducing bilateral salpingo oophorectomy due to the risk of ovarian cancer development in patients who carry BRCA1/2 gene mutations. In most cases, this should happen at age 40 or before for those that carry a BRCA1 mutation, and at age 45 or prior for those with BRCA2 mutations. Dr. Jasmine Sukumar: And do you also consider adjuvant bisphosphonates in this context? Dr. Dionisia Quiroga: Yes. Like adjuvant endocrine therapy, adjuvant bisphosphonates were also instructed to be given according to standard guidelines in the OlympiA trial, so I would recommend use of bisphosphonates when indicated. You can refer to the ASCO Ontario Health Guidelines on Adjuvant Bone-Modifying Therapy Breast Cancer to guide that decision in order to utilize this due to multiple clinical benefits. It doesn't just help in terms of adjuvant breast cancer treatment but also reduction of fracture rate and down the line, improved breast cancer mortality. Dr. Jasmine Sukumar: Particularly in hormone receptor-positive breast cancer, another adjuvant therapy option that was not available when the OlympiA trial started are the CDK4/6 inhibitors, ribociclib and abemaciclib, based on the NATALEE and monarchE studies. So how do you consider the use of these adjuvant therapy drugs in the context of olaparib and BRCA mutations? Dr. Dionisia Quiroga: Yeah, so we are definitely in a data-free zone here. And that's in part because the NATALEE and the monarchE studies are still ongoing and reporting data out at the same time that we're getting updated OlympiA data. So unlike some of our other adjuvant treatments that we discussed, where olaparib could be safely given concurrently, the risk of myelosuppression and using both a CDK4/6 inhibitor and a PARP inhibitor at the same time would be too high. In some cases, even if a patient has a BRCA1/2 mutation, they may not meet that specified inclusion criteria that OlympiA set for what they consider to be high-risk disease. And we know from the NATALEE and the monarchE trial there are also different markers that they use to denote high-risk disease. So it's possible, for example, in the NATALEE trial that looks specifically at adjuvant ribociclib, they included a much larger pool of hormone receptor-positive early-stage breast cancers, including a subset that did not have positive axillary lymph nodes. In cases where patients would qualify for both olaparib and a CDK4/6 inhibitor, I think this is worth a nuanced discussion with our patients about the potential benefits, risks and administration of these drugs. I think another point to bring up is the cost associated with these drugs and the length of time patients will be on for, because financial toxicity is always something that we should bring up with patients as well. When sequencing these in high-risk disease, my practice is to generally favor olaparib first due to the overall survival data. There is also some data to support that patients with BRCA1/2 germline mutations may not respond quite as well to CDK4/6 inhibitors compared to those without. But again, this is still outside of the purview of current guidelines. Fortunately, we have more potential choices for patients, and that's a good thing, but shared decision making also needs to be key. Dr. Jasmine Sukumar: And while our focus today is on adjuvant treatment for people who carry germline BRCA mutations, what about other related gene mutations such as PALB2 pathogenic variant? Dr. Dionisia Quiroga: That's a great question. Clinical trials in the advanced metastatic setting have shown that there is efficacy of olaparib in the setting for PALB2 mutations. This is largely based on the TBCRC 048 phase 2 trial and that provided a Category 2B NCCN recommendation for patients with these PALB2 gene mutations. However, we're really still lacking enough clinical data for use in early-stage disease, so I don't currently use adjuvant olaparib in this case. I am definitely eager for more data in this area as the efficacy of PARP inhibitors in PALB2 gene mutations is very compelling. I think also, in the same line, there's been some data for somatic BRCA1/2 mutations in the metastatic setting, but we still have a lack of data for the early stage setting here as well. Dr. Jasmine Sukumar: Thank you Dr. Quiroga, for sharing your valuable insights with us today on the ASCO Daily News Podcast. Dr. Dionisia Quiroga: Thank you, Dr. Sukumar. Dr. Jasmine Sukumar: And thank you to our listeners for your time today. You'll find links to the studies discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you. Disclaimer: 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. Follow today's speakers: Dr. Dionisa Quiroga @quirogad @quirogad.bsky.social Dr. Jasmine Sukumar @JasmineSukumar @jasmine.sukumar.bsky.social Follow ASCO on social media: @ASCO on X @ASCO on Bluesky ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Dionisia Quiroga: No relationships to disclose Dr. Jasmine Sukumar: Honoraria: Sanofi (Immediate Family Member)
Dr. Evan Yu presents the new evidence-based guideline on genetic testing for metastatic prostate cancer. He discusses who should receive germline and somatic testing with next-generation sequencing technologies, what samples are preferred for testing, and the therapeutic & prognosistc impacts of genetic testing. Dr. Yu emphasizes the need for awareness and refers to areas of active investigation and future research to improve personalized therapies for patients with metastatic prostate cancer. Read the full guideline, “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline” at www.asco.org/genitourinary-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02608 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Evan Yu from the University of Washington and Fred Hutchinson Cancer Center, lead author on “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline”. Thank you for being here today, Dr. Yu. Dr. Evan Yu: Thanks for having me on. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the entire guideline, including Dr. Yu, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, Dr. Yu, to start us off on the content of this guideline, could you first provide an overview of both the purpose and scope of this guideline? Dr. Evan Yu: Yeah, absolutely. So I think the one key thing to recognize is that prostate cancer is the highest incidence of all cancers in males. Additionally, it's the second highest cause of mortality in males, and that's about 35,000 deaths in 2024. So with that being said and done, it's a disease where we need to do better. And part of that is recognizing that we now have many targeted therapies, precision medicine type of therapies, but unlike a lot of other cancers out there, prostate cancer patients are not always getting sequencing, next generation DNA sequencing, let's say, to identify both inherited and also spontaneously develop what we call somatic mutations in their tumor. And I suspect that's partially because other cancers like breast cancer, we're so used to- in the first line, you present the patient, you throw out their estrogen receptor status, progesterone receptor status, HER2, ER/PR HER2; in lung cancer it's EGFR, ALK, ROS1, etc. In things like prostate cancer, things like BRCA2 have major important patient treatment implications and potentially family counseling and downstream cascade testing implications. But it hasn't made their way into that first-line presentation yet. And for that reason, there are some studies out there that show that testing in the community may be as low as 15% of patients with metastatic prostate cancer. We want to bring awareness to that and hopefully increase testing down the road so that we can better help our patients with metastatic prostate cancer. Brittany Harvey: Absolutely. It's important to get these targeted therapies to the patients who can benefit most. Using that context, I'd like to next review the key recommendations of this guideline across the six clinical questions that the panel addressed. So, starting with: Who should receive germline testing with next generation sequencing technologies? Dr. Evan Yu: Yeah. We think that it's common enough that everyone with metastatic prostate cancer should receive germline genetic testing. And the reason for that is there have been studies that have looked at this and have shown that 12% of men with metastatic prostate cancer have some sort of inherited germline mutation in a gene, mostly DNA repair genes. But 12% have something that is inherited and that loved ones, first degree relatives, siblings, offspring might have also inherited. Now, most of these are in the DNA repair genes, but that being said and done, there's not only treatment implications for the patient, where there are newer drugs that that patient could get treated with, but other loved ones that might have inherited these gene mutations, that these things can cause other cancers as well - not just prostate cancer, but breast cancer, endometrial cancer, ovarian cancer, pancreatic cancer. So, it's very important to test, with as high of an incidence as 12%, to test, and if you identify it in a patient, it's our job to talk to the patient about it and talk to them about the pros and cons of family counseling and talking to their loved ones and potentially having their loved ones get tested. Because if they test positive, then their doctors may want to know and may screen them very, very aggressively and differently for a whole host of other cancers. And the whole idea is you find the cancer very early and cure the patients before the cancer really takes hold and has the ability to spread so we can save a lot of lives down the road. Brittany Harvey: Absolutely. This germline testing is important not just for the patient, but has wider implications for their families as well, as you mentioned. So then, beyond those recommendations for germline testing, which patients should receive somatic testing with next-generation sequencing technologies? Dr. Evan Yu: So let's talk a little bit about somatic testing. So germline again, as we know, is inherited. The patient inherited it in every single cell in their body, then it becomes very easy, many of these are cancer predispositions for them to lose the other allele and then to have biallelic loss and then develop the cancer. Now, somatic just means it spontaneously occurred. Certainly, it's not going to occur in every cell in the body, but you can get one hit, lose one allele and then lose the other allele. And if that gene is truly carcinogenic and leading to that cancer, then that can have implications potentially for treatment as well. So we recommend that all patients with metastatic prostate cancer also undergo somatic next-generation sequencing testing. We recognize that at this point in time it's only those with metastatic castration-resistant prostate cancer or hormone-resistant prostate cancer, which is a later disease state where there are drugs that may target those mutations, for instance, like PARP inhibitors, but that early identification for a patient population that's fit and that can benefit from these therapies makes sense so that you know it's in place already and you have your treatments outlined and mapped out for the future. So we recommend it for everybody - somatic testing also for everyone with metastatic prostate cancer. Brittany Harvey: Understood. And then when patients are receiving that somatic testing, what is recommended for somatic testing? Primary tumor archival tissue? Fresh metastatic biopsy tissue? Or circulating tumor DNA testing? Dr. Evan Yu: We recommend that in the initial setting when you're first diagnosed, that archival tissue samples are fine and preferred. But circulating tumor DNA is good when there's no accessible archival tissue, or if the archival tissue, let's say, is very old and it's been sitting around for a long time, or you can't get it anymore because it's many years back when maybe a patient had a prostate needle biopsy. So if it's not accessible, then we recommend ctDNA. We believe that is preferred and also that ctDNA is recommended in a situation where you can't easily biopsy a metastatic site. Sometimes it's just not in a safe area to go after. Sometimes it's just a small lesion. So in general, we recommend tissue when available, and when we think that the tissue sample will yield clean results, if not, then we recommend doing ctDNA at that point in time. Brittany Harvey: So you have described who should get germline and somatic genomic testing. But what are the therapeutic impacts of this germline or somatic testing for single gene genetic variants? Dr. Evan Yu: We pulled this panel together and we met like every single month for like 12 months straight, and part of it was to review the literature. And as part of this literature review, we were able to pull a whole bunch of different trials. I think there was like 1713 papers we identified in the literature search. Eventually, we narrowed it down because with ASCO, we want to present the data with the highest level evidence, level 1 evidence, randomized controlled prospective data. And after reviewing 1713 papers, we narrowed it down to 14 papers. With those 14 papers, if you look at it, there are a lot of things that we think may have implications for treatment or prognosis, but we didn't feel was the highest level of evidence that we could support. So the things that have the highest level of evidence that we can support are certain DNA repair gene alterations, especially BRCA2, and treatment with PARP inhibitors because there are many PARP inhibitor prospective trials that show progression-free survival benefit and even overall survival benefit. And so that's the type of study that achieved the level of evidence that we could include. So I would say BRCA1 and BRCA2 highest level of evidence and PARP inhibitor use also is included in that. Brittany Harvey: Understood. I appreciate you reviewing those therapeutic options. So then, the last clinical question, which you just touched on briefly, but what are the prognostic impacts of germline and/or somatic testing? Dr. Evan Yu: Whenever you do testing, especially if you use panel testing, you find a lot of information. There's a lot of different mutations and some of which are VUSs (variants of unknown significance) where we don't quite know what it means yet, but we can track that, especially if it's germline. But with somatic, we find lots of things that have implications, but maybe just not treatment implications. A perfect example is p53. p53 is one of the most common tumor suppressor gene mutations on all cancers, but in prostate cancer they can occur and they can usually occur late, although there can even be germline inherited p53 alterations. There's no treatment that targets p53 right now, but we know that if you have a p53 mutation that those patients may have more aggressive disease and that prognostic information is important to give to the patient. And I think it's important for future clinical trial design and direction. So we do not recommend making treatment recommendations or changes based on these prognostic only biomarkers at this point in time. But we do recommend that, based on this, we can design intensification trials for those patients who have these poor risk biomarkers and de-intensification trials for patients who may have a good risk biomarker. So for instance, SPOP is a gene where we think these patients may have better outcomes, they might respond better to certain hormonal therapies like abiraterone. I say might because the level of evidence isn't quite there. But what I would say is that these prognostic only biomarkers, we just don't think they cut the mustard yet to be able to make treatment decisions. But we do think that they can drive counseling for the patient and potential selection and trial design for the future to say, “Okay. This is a patient population that has a more aggressive cancer. We need to be more aggressive in treating these patients.” “This patient population might have a less aggressive cancer. Maybe we can de-intensify and say side effects and quality of life may be better for the patients.” Brittany Harvey: Definitely. It's important for thinking through how to personalize care for these patients. So then you've talked about this a little bit in talking through the recommendations, but could you expand on what is the importance of this guideline and how it will impact both clinicians and patients with metastatic prostate cancer? Dr. Evan Yu: Yeah, I think the number one thing is awareness. I think the data's out there and people that are in my field, they know this. But by evidence of the fact that it's not first-line presentation lingo that everyone's talking about things like BRCA status, it means it hasn't necessarily disseminated all the way through. So it's increasing awareness of the fact that both germline and somatic alterations can occur and that these may have impacts on the patient for their treatment and their prognosis, and basically to increase testing for the future. I really think that in the future, there'll be other reasons that we may want to serially even retest and we may find that there may be mutations that develop as mechanisms of resistance that might guide therapy down the road. So we need to get people to start doing this for everyone with metastatic prostate cancer, because someday we might be doing it not just once, but over and over again. Brittany Harvey. Absolutely. We hope this guideline reaches a wide audience and that these recommendations can be put into practice. Finally, you've talked about how not all the data in the field has yet risen to the level of evidence that made it into the guidelines. So what are the outstanding questions in future research areas for both germline and somatic genomic testing for metastatic prostate cancer? Dr. Evan Yu: It was in our discussion, but it clearly- it's not common enough for there to be randomized prospective trials that would reach that level of evidence to make it in this guideline recommendation. But we all know that for any solid tumor, you can get mismatched repair deficiency, microsatellite instability leading to hypermutation or high tumor mutational burden. And that happens in maybe 3 to 5% of patients with metastatic prostate cancer as well. There is evidence and data that these patients can potentially benefit from immunotherapies like pembrolizumab. But again, it's just not common enough for there to be those randomized prospective controlled trials out there. But we mention it because we know it's FDA-approved across all the tumor types, so we felt like we have to mention it because that's something that has treatment implications for the patient. But also, I alluded to this earlier, I think an area of active investigation is the tried and true number one driver of prostate cancer, which is androgen receptor. Testosterone binds to androgen receptors, stimulates it. That's how androgen deprivation therapy works. That's how abiraterone and the amides like enzalutamide, apalutamide, darolutamide, that's how they all work. But even beyond that, we're starting to identify that maybe 15%, 20% of patients with metastatic castration resistant prostate cancer have androgen receptor mutations. And there are newer classes of therapies like androgen receptor degraders like CYP11A1 antagonist that lead to complete adrenal annihilation of other steroid hormones that might promiscuously stimulate these androgen receptor mutants. These things develop as mechanisms of resistance, and in the future, we might want to serially test- and that's an active area of investigation in the future, to say you've been treated, let's say, with androgen deprivation therapy and abiraterone for years. There are certain mutations that might develop as a resistance mechanism. We might need to serially test somebody because you didn't have that mutation earlier on, but later in the disease course you might. And then there might be a new drug X out there that we would want to use. Again, we need the data, we need the randomized prospective controlled trials, but they're happening out there. And somewhere down the road we may rewrite this guideline and have a lot more recommendations to add to it. Brittany Harvey: Yes, we'll look forward to more research in this field to better provide targeted therapies for patients with metastatic prostate cancer across the treatment paradigm. And we'll look forward to report outs from those trials that you mentioned. So I want to thank you so much for your work to develop this guideline and thank you for your time today, Dr. Yu. Dr. Evan Yu: Thank you so much. It's wonderful to be here today. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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.
BUFFALO, NY - December 30, 2024 – A new #editorial was #published in Oncotarget's Volume 15 on December 24, 2024, titled “Pitfalls and perils from FDA-approved germ-line cancer predisposition tests." Authored by Dr. Wafik S. El-Deiry, Editor-in-Chief of Oncotarget, and Dr. Eli Y. Adashi from Brown University, the article highlights concerns about the risks of a newly approved genetic test for cancer risk. This test, called the “Invitae Common Hereditary Cancers Panel," was approved in 2023 and examines 48 genes linked to inherited cancers, including breast, ovarian, and Lynch syndrome-related cancers. Although the test increases access to genetic information, the authors warn that using it without professional guidance may lead to confusion, stress, and potential harm. One concern is that people can order this test online without consulting healthcare professionals or genetic counselors. Without expert help, users might struggle to understand their results especially if they indicate risks that are unclear or difficult to act on. This can cause unnecessary anxiety and confusion. “The DTC option of germ-line testing for cancer susceptibility should be discouraged given the risks of anxiety, lack of adequate interpretation for variants not strongly associated with cancer, potential for minors to be tested outside the healthcare system and potential for loss of follow-up if test results are not shared with health care professionals or never make it into the medical record.” The editorial also points out ethical and medical issues when minors use these tests. If a child's test is done without medical oversight, results might not be added to their health records, making follow-up care harder to manage and potentially risking their long-term health. Cost is another issue. These tests are often not covered by insurance, which can place a financial burden on families who might need additional testing or medical advice. The researchers emphasize that genetic testing for cancer risk should always include healthcare providers and genetic counseling. This ensures users fully understand their results and receive proper guidance. The authors also call on the US Food and Drug Administration (FDA) to provide clear rules for using these tests, particularly for minors. In conclusion, while genetic testing holds great potential for improving cancer prevention and care, its benefits must not come at the cost of safety and public health. Responsible use of these tests will require collaboration between regulators, healthcare professionals, and testing companies to address the risks and ensure these tools are used effectively. DOI - https://doi.org/10.18632/oncotarget.28677 Correspondence to - Wafik S. El-Deiry - wafik@brown.edu Video short - https://www.youtube.com/watch?v=DjKpiBNDWHo Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM
In this JCO Precision Oncology Article Insights episode, Miki Horiguchi summarizes two articles: “Germline Susceptibility to Renal Cell Carcinoma and Implications for Genetic Screening,” by Dr. Kate I. Glennon et al. published on August 01, 2024, and "Incidental Pathogenic Variants in Renal Cell and Urothelial Carcinoma: Is It Time for Universal Screening?” by Dr. Salvador Jaime-Casas, et al. published on August 01, 2024. TRANSCRIPT Miki Horiguchi: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Miki Horiguchi, an ASCO Journal's Editorial Fellow. Today, I'll be providing summaries of the article titled, "Germline Susceptibility to Renal Cell Carcinoma and Implications for Genetic Screening,” by Dr. Kate Glennon and colleagues. In the accompanying editorial titled, “Incidental Pathogenic Variants in Renal Cell and Urothelial Carcinoma: Is It Time for Universal Screening?” by Dr. Salvador Jaime-Casas and colleagues. Renal cell carcinoma (RCC) exhibits distinct clinical characteristics across its histological subtypes. Clear cell RCC accounts for approximately 75% of cases while the remaining non-clear cell RCC encompasses a diverse group of histology. Although a family history has been known to double the risk for RCC, genetic susceptibility, particularly across different histological subtypes and defined operations, has not been investigated well. Dr. Glennon and colleagues sought to identify risk genes for RCC within the Canadian population and investigate their clinical significance in comparison to cancer-free control populations. The authors conducted targeted sequencing of 19 RCC related genes and 27 cancer predisposition genes for 960 RCC patients in Canada. DNA samples were collected through the Ontario Tumour Bank between 2005 and 2019. For comparisons across histological subtypes, the cohort was divided into 759 patients with clear cell RCC and 201 patients with non-clear cell RCC, including all histological subtypes other than clear cell RCC. Non-cancer control data were obtained from a publicly available database which included over 118,000 cases from the European population. A total of 39 different germline pathogenic variants were identified in 56 patients representing 5.8% of the Canadian cohort. There was no significant difference in the overall number of germline pathogenic variants between the two groups. The most commonly identified germline pathogenic mutations were CHEK2, ATM/BRCA2 and MITF in the clear cell RCC group, and FH and CHEK2 in the non-clear cell RCC group. Compared to the non cancer control data, germline pathogenic variants in CHEK2 and ATM were significantly associated with an increased risk of developing clear cell RCC, while those in FH were significantly associated with non clear cell RCC. According to the bivariate association analysis between the presence of germline pathogenic variants and clinical characteristics, patients with metastatic RCC were strongly associated with pathogenic variants in BRCA1, BRCA2, and ATM. No other significant associations were observed. The authors then evaluated variations in germline pathogenic variants among RCC patients across the world using similar studies conducted in Canada, Japan, the United Kingdom, and the United States. Specifically, they compared the gene burden for significantly mutated genes in each of the cohorts against all other cohorts combined. Compared to the other cohorts, RCC patients from Japan were enriched for pathogenic variants in TP53 and depleted for pathogenic variants in CHEK2. The United States cohorts showed higher frequencies of patients with pathogenic variants in BAP1 and FH genes compared to other cohorts. In contrast, RCC patients from Canada and the United Kingdom were not enriched for any specific genes when compared with the other cohorts. After characterizing germline susceptibility to RCC, the authors evaluated how many of the RCC patients in the Canadian cohort did not meet existing referral criteria for genetic screening based on current clinical guidelines, aiming to help refine these guidelines. Among the 56 RCC patients with identified germline pathogenic variants in the Canadian cohort, 73% did not meet the referral criteria for genetic screening under current Canadian guidelines. The authors also applied the UK guidelines and the US American College of Medical Genetics guidelines to the same 56 RCC patients. Under these criteria, 80% and 64%, respectively, were not eligible for genetic screening. In an exploratory analysis, the authors examine the impact of raising the Asia onset threshold from less than 45 years to less than 50 years. This revision captured an additional five patients with pathogenic variants. In addition to more inclusive genetic screening guidelines, the study results suggest that expanding the current list of genes to include additional relevant genes such as BRCA1, BRCA2, CHEK2 and ATM could help identify more RCC patients who are affected by rare germline pathogenic variants in Canada. The authors concluded that these revisions would enable the identification of a higher number of at-risk patients and improve the management of RCC patients. In the associated editorial accompanying this research article, Dr. Salvador Jaime-Casas and colleagues emphasized that the findings from Dr. Glennon and colleagues' study are particularly worrisome as most RCC patients with incidental pathogenic variants are not being referred for genetic screening. Building on results from previous studies, the authors suggested the need to revisit and update the current screening guidelines for RCC patients. The authors also highlighted findings from other studies showing the prevalence of pathogenic variants in CHECK2, BRCA1, and BRCA2 at up to 6% in RCC patients and 11% in upper tract urothelial carcinoma patients. They noted that these rates are comparable to those of ovarian cancer and pancreatic cancer, which already have universal screening guidelines. The authors also discuss some challenges. While the prevalence of pathogenic variants is crucial for evaluating the impact of germline genetic testing, it's only one factor in devising screening guidelines for RCC and urothelial carcinoma. They emphasize the need for robust clinical trials to evaluate therapeutics targeting these pathways, as well as the importance of characterizing incidental pathogenic variants to guide patient selection for these trials. 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. 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.
How can we make many humans who are very good at solving difficult problems? Summary (table of made-up numbers)I made up the made-up numbers in this table of made-up numbers; therefore, the numbers in this table of made-up numbers are made-up numbers. Call to actionIf you have a shitload of money, there are some projects you can give money to that would make supergenius humans on demand happen faster. If you have a fuckton of money, there are projects whose creation you could fund that would greatly accelerate this technology.If you're young and smart, or are already an expert in either stem cell / reproductive biology, biotech, or anything related to brain-computer interfaces, there are some projects you could work on.If neither, think hard, maybe I missed something.You can DM me or gmail [...] ---Outline:(00:12) Summary (table of made-up numbers)(00:45) Call to action(01:22) Context(01:25) The goal(02:56) Constraint: Algernons law(04:30) How to know what makes a smart brain(04:35) Figure it out ourselves(04:53) Copy natures work(05:18) Brain emulation(05:21) The approach(06:07) Problems(07:52) Genomic approaches(08:34) Adult brain gene editing(08:38) The approach(08:53) Problems(09:26) Germline engineering(09:32) The approach(11:37) Problems(12:11) Signaling molecules for creative brains(12:15) The approach(13:30) Problems(13:45) Brain-brain electrical interface approaches(14:41) Problems with all electrical brain interface approaches(15:11) Massive cerebral prosthetic connectivity(17:03) Human / human interface(17:59) Interface with brain tissue in a vat(18:30) Massive neural transplantation(18:35) The approach(19:01) Problems(19:39) Support for thinking(19:53) The approaches(21:04) Problems(21:58) FAQ(22:01) What about weak amplification(22:14) What about ...(24:04) The real intelligence enhancement is ...The original text contained 3 images which were described by AI. --- First published: October 8th, 2024 Source: https://www.lesswrong.com/posts/jTiSWHKAtnyA723LE/overview-of-strong-human-intelligence-amplification-methods --- Narrated by TYPE III AUDIO. ---Images from the article:Apple Podcasts and Spotify do not show images in the ep
In this week's episode we'll discuss how CD8+ T-cell differentiation and dysfunction inform treatment response in acute myeloid leukemia; learn more about the effect of ATM germline pathogenic variants on the outcomes in children with ataxia-telangiectasia and hematological malignancies; and discuss the preclinical efficacy of a potent, selective menin-KMT2A inhibitor JNJ-75276617 in KMT2A- and NPM1-altered leukemias.Featured Articles:CD8+ T-cell differentiation and dysfunction inform treatment response in acute myeloid leukemiaATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematologicalmalignanciesPreclinical efficacy of the potent, selective menin-KMT2A inhibitor JNJ-75276617 (bleximenib) inKMT2A- and NPM1-altered leukemias
BUFFALO, NY- August 26, 2024 – A new #editorial was #published in Oncotarget's Volume 15 on July 10, 2024, entitled, “Genotype matters: Personalized screening recommendations for germline CHEK2 variants.” Recognized as a moderate-risk gene, CHEK2—responsible for encoding the CHK2 protein, which plays a crucial role in the repair of DNA double-strand breaks—is associated with a 20–40% lifetime risk of breast cancer (BC) by age 85. While CHEK2 pathogenic variants (PVs) were previously linked to an increased risk of colorectal cancer (CRC), two recent studies have not observed this association. In their recent work, researchers Adela Rodriguez Hernandez, Rochelle Scheib, Judy E. Garber, Huma Q. Rana and Brittany L. Bychkovsky from Dana-Farber Cancer Institute and Harvard Medical School in Boston, found that a CHEK2 PV does not increase the CRC risk compared with controls (odds ratio 0.62 (0.51–0.76), p < .001). The cancer risks associated with CHEK2 PVs vary depending on the variant type, and risk management strategies should reflect this variability. The CHEK2 c.1100del is the most studied truncating variant and has been crucial to our understanding of the cancer phenotype. Cancer risks seem to be higher with truncating variants compared to missense variants. “In our study, we postulated that these differences were driven by three common low-risk (LR) missense variants: p.I157T, p.S428F, and p.T476M, all of which have a BC odds ratio of
Genectic Innovations: From Gene Therapy to Germline Genome Editing Evaluation and Credit: https://www.surveymonkey.com/r/MedChat69 Target Audience This activity is targeted toward primary care physicians and advanced providers. Statement of Need This program will provide an overview of recent innovations in genetics, highlighting gene therapy and germline genome editing. The discussion will include a review of what it is as well as applications andfuture trends in gene therapy. Objectives At the conclusion of this offering, the participant will be able to: Define gene therapy, germline genome editing and precision medicine. Review the applications of gene therapy and germline genome editing. Explain the differences and clinical implications of whole genome sequencing and whole exome sequencing. Discuss future trends of gene therapy and germline genome editing. ModeratorMark McDonald, M.D., FAAP Medical Director Norton Children's Hospital and Norton Children's Medical Center Professor Department of Pediatrics, Critical Care UofL School of Medicine Louisville, Kentucky SpeakerKyle B. Brothers, M.D., Ph.D. Pediatrician and Bioethicist Chief Scientific Officer Norton Children's Research Institute affiliated with the UofL School of Medicine Louisville, Kentucky Moderator, Speaker and Planner Disclosures The planners and moderator of this activity do not have any relevant financial relationships with ineligible companies to disclose. The speaker Kyle Brothers, M.D., Ph.D., discloses a relevant financial relationship with Invitae in research. This relationship has been mitigated. Commercial Support There was no commercial support for this activity. Physician Credits Accreditation Norton Healthcare is accredited by the Kentucky Medical Association to provide continuing medical education for physicians. Designation Norton Healthcare designates this enduring material for a maximum of .50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. For more information about continuing medical education, please send an email to cme@nortonhealthcare.org. Nursing CreditsNorton Healthcare Institute for Education and Development is approved with distinction as a provider of nursing continuing professional development by the South Carolina Nurses Association, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation. This continuing professional development activity has been approved for .50 contact hours. In order for nursing participants to obtain credits, they must claim attendance by attesting to the number of hours in attendance. For more information related to nursing credits, contact Sally Sturgeon, DNP, RN, SANE-A, AFN-BC at (502) 446-5889 or sally.sturgeon@nortonhealthcare.org. Resources for Additional Study: Changes in opinions about human germline gene editing as a result of the Dutch DNA-dialogue project https://pubmed.ncbi.nlm.nih.gov/35551502/ Altered lipid metabolism and the development of metabolic-associated fatty liver disease https://pubmed.ncbi.nlm.nih.gov/38484227/ Also listen to Norton Healthcare's podcast Stronger After Stroke. This podcast, produced by the Norton Neuroscience Institute, discusses difficult topics, answers frequently asked questions and provides survivor stories that provide hope. Hear from stroke survivors and medical specialists about being stronger after stroke. Listen on your favorite podcast platform. Norton Healthcare, a not for profit health care system, is a leader in serving adult and pediatric patients throughout Greater Louisville, Southern Indiana, the commonwealth of Kentucky and beyond. Five Louisville-based hospitals and three hospitals in Southern Indiana, provide inpatient and outpatient general care as well as specialty care including heart, neuroscience, cancer, orthopedic, women's and pediatric services. A strong research program provides access to clinical trials in a multitude of areas. More information about Norton Healthcare is available at NortonHealthcare.com. Date of Original Release | Aug. 2024; Information is current as of the time of recording. Course Termination Date | Aug. 2026 Contact Information | Center for Continuing Medical Education; (502) 446-5955 or cme@nortonhealthcare.org Podcast editing and production by: www.unmuteaudio.com
Ms. Charité Ricker, MS, CGC and Dr. Nadine Tung, MD, FASCO share updates from the new ASCO guideline on selection of germline genetic testing panels in patients with cancer. They discuss highlights on family history collection, when and how multigene panel germline genetic testing should be used, which genes are generally recommended for testing, and how germline genetic testing interfaces with somatic genetic testing. Ms. Ricker and Dr. Tung also note the importance of the guideline and the impact of these new recommendations on clinicians and patients with cancer. Read the full guideline, “Selection of Germline Genetic Testing Panels in Patients with Cancer: ASCO Guideline” at www.asco.org/molecular-testing-and-biomarkers-guidelines. TRANSCRIPT GDL 24E13 This guideline, clinical tools, and resources are available at www.asco.org/molecular-testing-and-biomarkers-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00662 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts My name is Brittany Harvey, and today I'm interviewing Dr. Nadine Tung, a medical oncologist from Beth Israel Deaconess Medical Center in Boston, and Ms. Charité Ricker, a cancer genetic counselor with the Norris Comprehensive Cancer Center at the University of Southern California and Los Angeles General Medical Center, co-chairs on, “Selection of Germline Genetic Testing Panels in Patients with Cancer: ASCO Guideline.” Thank you for being here, Ms. Ricker and Dr. Tung. Dr. Nadine Tung: Pleasure. Ms. Charité Ricker: Thank you. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Tung and Ms. Ricker, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to start us off first, Dr. Tung, could you provide us a broad overview of both the purpose and scope of this guideline? Dr. Nadine Tung: Sure. A main impetus for creating the guideline is that oncologists are increasingly being tasked with ordering genetic testing for hereditary cancer risk for their cancer patients. More and more now, they may find themselves sending the test and then seeking guidance from genetic experts to interpret the result. And these panels range from focused tests with just a few genes to comprehensive ones that include over 100 genes. So it can be very overwhelming for an oncologist to be able to understand ordering these tests and explaining them to their patients. So, we believe that it was important to offer some guidance and direction on the use of these multigene panels. Brittany Harvey: Thank you for setting the stage for this guideline and the recommendations that come from it. So then, Ms. Ricker, this guideline addresses four overarching clinical questions. I'd like to review the recommendations based on each of those questions for our listeners. So starting with that first question, what is the importance of family history collection in the setting of germline multigene panel testing and which elements of family history are the most important? Ms. Charité Ricker: Thanks. As a genetic counselor, this is probably one of my favorite questions. I love the opportunity we have to sit with families and really dig into family history. But family history collection can be overwhelming and a big lift sometimes in busy clinics where genetics is not the focus. So, what we tried to do was to break down the key elements of what components of family history are most relevant to informing which test to do, and also the interpretation of those test results. And I like to think about the key pieces of family history as being the who, what, and when of somebody's family cancer history. Who was diagnosed with cancer within their close relatives? And usually we're most focused on first and second degree relatives. So parents, siblings, grandparents, aunts, and uncles. But sometimes relevant history might go into third degree relatives like cousins or more distant. So the who being who has cancer on both sides of the family? And then the what: what kind of cancer was it? Or where did that cancer begin? And the when: how old was that individual at the time they were diagnosed? Often we ask patients maybe not to fixate on the exact age, but to give us a sense. So was this somebody who was diagnosed young, in their 20s or 30s or older, in their 60s or 70s? Because that at least gives us a ballpark around what might be relevant for understanding the genes that should be included on somebody's test. When we are thinking about the purpose of this history, as Dr. Tung said, often the range of multigene panels might be from a few very focused genes to a very broad panel. Family history can help us understand if we need to step beyond the very focused genes that might be relevant for the patient's history of cancer and include other genes that might be indicated based on that family history. So I think about the role that family history has at the time of identifying which test to do and then its role when interpreting what those results mean for the patient and their family. Again, Dr. Tung touched on the fact that we are often testing very large panels. However, we still don't know everything. And so a negative genetic test result does not mean that somebody does not have additional cancer risk. And family history becomes our kind of guiding star for understanding if there is still a need to change the cancer screening and prevention management for that individual and their family members. Brittany Harvey: Absolutely. Those are key points to understanding the important role of family history for each individual patient. So then moving to the next clinical question, Dr. Tung, what does the panel recommend regarding when and how multigene panel germline testing should be used, when germline genetic testing is indicated? Dr. Nadine Tung: Well, anytime multiple genes need to be tested, as Ms. Ricker said, because of the patient's own personal cancer history, or their family history of cancer and close relatives, it's appropriate to consider a multi-gene panel. And in truth, we rarely ever just order one gene these days. Perhaps we do if there's a known gene like a BRCA gene in the family, and a relative just wants to know if they have that. But it's not all that common. And to be clear, as Ms. Ricker is going to cover a bit later, we are recommending that the appropriate minimal panel at least include the genes relevant to the patient's own cancer and the cancers in their relatives. But it's worth thinking about what are some of the pros and cons of ordering genes beyond that, beyond the patient's own cancer or their relatives? Well, for pros, since a patient's awareness of their family history may be incomplete, testing for a larger number of cancer risk genes does ensure that significant pathogenic variants won't be overlooked. And sometimes, even if the family history is well known, pathogenic variants in important cancer risk genes can be found even when the family history would not have prompted testing for them. But it is important for clinicians to appreciate that bigger isn't necessarily better. Some larger panels may include genes for which management of pathogenic variants is not entirely clear and that can create anxiety or unnecessary screening. And if the clinician receiving the information is not well informed about the significance of the finding, that can lead to unnecessary treatment and sometimes even unnecessary surgeries. And I'd add one final point that clinicians must have a system for communicating reclassification of these variants, the ones with uncertain significance that we call VUS. Because as the number of genes tested increases, so does the likelihood of encountering these VUS. So I would say those are some of the main points about when to use the panel and when to think about larger or smaller panels. Brittany Harvey: Yes, I appreciate you reviewing both the pros and cons of expanding the genes included in multi-gene panel testing and the importance of variants of uncertain significance. So then Dr. Tung just touched on this, but speaking of minimal panels and which genes should be included, Ms. Ricker, what are the recommendations on which genes are generally recommended for germline genetic testing? Ms. Charité Ricker: I think this is one of the harder questions that our group took on as we were working on this guideline. I don't think there is a one size fits all and one easy answer to this question. However, we chose to approach it by selecting the more common solid tumors that oncologists see in their clinics and the ones where the role of genetic testing is most well defined, as well as some very rare tumors where they're kind of easy. So we know that all individuals with certain types of cancers, even though they are rare, should merit genetic testing regardless of age of diagnosis, family history. And so as we approached it, and I really appreciate ASCO's support in helping us develop some tools and tables that hopefully will be important aids for clinicians who are trying to make these decisions, we took the approach of, as Dr. Tung mentioned, selecting kind of a minimal set of recommended genes where most individuals who are informed in this area would agree that if nothing else was done, these genes should be done, but then also acknowledged that there is an expanding understanding about the impact of certain genes on cancer risk, and so then also provided a kind of a next level if somebody wanted to be more expansive, what we would recommend less strongly, but would be reasonable to consider. Then I think the other last piece that the committee felt was important to acknowledge is that given how common, in comparison to some of these genetic conditions that we work with, pathogenic variants in BRCA1 and BRCA2 can be, and also the important clinical impact of those genes along with the genes associated with Lynch syndrome, we felt that those were important to think about in the setting of all cancer patients. So if you're approaching a panel and thinking about what genes to include, looking at that kind of minimally recommended based on the patient's personal and family history, maybe the next level, which might include some additional genes that we have included in kind of the less strongly recommended category for those tumor types. And then consideration of the BRCA1 and 2 genes and genes associated with lynch syndrome, if they weren't already encapsulated by your other personal and family history considerations. Brittany Harvey: Definitely. This was a big lift for the panel to tackle, and the tools and tables that you mentioned are all available online with the publication in the Journal of Clinical Oncology. So listeners who are looking for more specifics on that can definitely refer to those tools and tables there. Dr. Tung, the last clinical question: which patient should be offered germline genetic testing, who will have or who have previously had somatic genetic testing? Dr. Nadine Tung: Identifying which genes identified through the tumor testing should trigger germline testing is really important for assessing our patients' future risk of cancer and their relatives. So during the development of our guidelines, the ASCO expert panel became aware that the ESMO Precision Medicine Working group had updated their recommendations for this topic, namely germline testing in response to tumor test findings. And these recommendations were based on the Memorial Sloan Kettering IMPACT registry, which consists of nearly 50,000 tumors and paired germline testing. Given the sheer volume of that data and the methods that ESMO used, our group decided to use that as a framework to develop our recommendations. The ASCO guideline provides a list of genes that, if found in the tumor, a pathogenic variant in those genes may prompt germline testing. And we offered or proposed two different approaches. The first approach, which is broad and perhaps simplest, involves doing germline testing if a pathogenic variant is found in any of the genes listed. But then we offer a conservative approach to test the germline for all highly actionable genes, like BRCA1 and 2, or lynch genes that are found in a tumor, but for less actionable genes, testing the germline only if the pathogenic variant is found in a tumor relevant to that gene. So, for example, ATM, if found in breast cancer or pancreatic cancer, would trigger germline testing with this approach, but not if found in lung cancer, whereas with the permissive first approach, you would simply test the germline if any pathogenic variant is found in any of the genes on the list. This latter, more conservative approach, while less sensitive for identifying every germline pathogenic variant, increases the likelihood that a pathogenic variant found in the tumor will actually be germline. That approach considers the limited resources available, such as genetic counselors, and respects trying not to overwhelm a system already stressed. Brittany Harvey: Thank you for reviewing both of those approaches and to you both for discussing all of the recommendations included in this guideline. Finally, to wrap us up, in your view, Ms. Ricker, what is the importance of this guideline and how will it impact both clinicians and patients with cancer? Ms. Charité Ricker: I hope that this guideline can open the door for more expansive and appropriate utilization of germline genetic testing. For me, I think about, from both the clinical and patient side, for example, all ovarian cancer patients have had a recommendation for germline genetic testing for many years. Nonetheless, data from multiple research studies has shown us that ovarian cancer patients still are not being tested universally, and this has important implications for their treatment plans and for their family members. And so even in the setting where genetic testing, if I can use the phrase, has been simple in that it didn't require family history, it didn't require even a specific age criteria, it was just broad, testing is not utilized as much as it should be, and then you step into the world of more complex decision making around genetic testing for other tumor types. And so we hope that this provides a framework to simplify that decision making process for providers to increase appropriate utilization. And then from the patient perspective, I also think about the lack of access of genetic testing in underrepresented communities and minoritized patient populations where there's many barriers that patients face in accessing genetic services. And so if we can help reduce the barriers for this piece of the genetic testing process, my hope is that that opens up better avenues for access to testing, not just for patients with certain tumor types, but for all patients from all communities and backgrounds. Brittany Harvey: Yes, those are key points. We hope that this guideline helps all patients access the appropriate testing to better inform their cancer prevention and treatment. So I want to thank you both so much for your work on this comprehensive guideline on germline genetic testing and all of the work that you put into it. And thank you for your time today. Ms. Ricker and Dr. Tung, Dr. Nadine Tung: Thank you. Ms. Charité Ricker: It was a pleasure to be here. Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/molecular-testing-and-biomarkers-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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 week's episode we'll learn about fitusiran prophylaxis in patients with hemophilia A or B, with or without inhibitors. Next we'll hear about new findings that heterozygous germline variants in the NBN gene that are linked to increased risk of B-cell acute lymphoblastic leukemia in children. Finally, we'll explore new insights on the histone demethylase PHF8, which has been identified as a master regulator of cell-intrinsic immune responses in acute myeloid leukemia. Featured Articles:Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trialGermline genetic NBN variation and predisposition to B-cell acute lymphoblastic leukemia in children Epigenetic control over the cell-intrinsic immune response antagonizes self-renewal in acute myeloid leukemia
In this episode, Kimary Kulig, PhD, MPH dives into the topic of cancer biomarkers. Kimary explains the difference between genes and proteins, germline versus somatic gene testing, and the critical importance of testing for both as biomarkers for treatment selection. She also describes the world of lung cancer biomarkers and the implications for treatment decisions. The conversation highlights the need for patients and their families to understand biomarkers and the impact those biomarkers have on treatment options. Biomarker testing in cancer patients is crucial for personalized treatment, but there are significant challenges and delays in the current system. The long turnaround time for biomarker testing can be harmful to patients with aggressive cancers who need immediate, targeted treatment. Kimary highlights that patients and their families need to be aware of the importance of biomarker testing and advocate for it. Key Highlights: 1. Biomarker testing should encompass both germline and somatic gene alterations. Germline testing is sometimes called “genetic testing” and identifies inherited mutations that appear in every cell in the body, whereas somatic gene testing detects mutations just in cancer cells, some of which can be targeted with specific drugs. 2. There can be significant delays in biomarker testing results, which can be particularly harmful for patients with aggressive cancers. These delays often result in patients beginning chemotherapy while awaiting results, potentially impacting the efficacy of targeted therapies. 3. Kimary discusses the lack of “reflex” testing in the current system, where biomarker tests are not automatically ordered based on the type of cancer. Implementing reflex testing could speed up the process, ensuring timely and appropriate treatment for patients. About our guest: Kimary Kulig's professional career has spanned the academic, non-profit, large pharma, start-up, and healthcare technology ecosystems. Kimary is currently Owner and Principal of Kulig Consulting, providing advice and service to biotech start-up, pharmaceutical, and medical device companies who develop oncology products. She also provides individual Biomarker Navigation services to cancer patients as My Biomarker Navigator™. Kimary applied her unique training in immunology, molecular oncology, and epidemiology for 12 years at both Pfizer and Bristol Myers Squibb. Her pharma career is highlighted by research on lung cancer biomarkers which are now standard of care companion diagnostics. Kimary was also Vice President at the National Comprehensive Cancer Network (NCCN) where she oversaw all operations of its Outcomes Research Database. At Verily Life Sciences, Kimary was Head of Oncology Clinical Research and led digital pathology machine learning and wearable device oncology application development. Kimary continues in her goal to bring AI tools to clinical practice as a member of the Friends of Cancer Research Digital Pathology Working Group. Kimary received her PhD from New York University's Institute of Graduate Biomedical Sciences and her MPH from Columbia University's Mailman School of Public Health. Visit the Manta Cares website Disclaimer: This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this podcast or materials linked from this podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions. --- Support this podcast: https://podcasters.spotify.com/pod/show/manta-cares/support
On this episode, Nate is joined by ER doctor, nuclear power advocate, and podcast host Chris Keefer for a broad ranging conversation including the basics of nuclear energy, how he engages with opposing opinions, and hypotheticals for a future medical system. Coming from a broad background, Chris understands what it means to have a human to human conversation and put together the pieces of our systemic puzzle in a clear and compelling way. What role could nuclear play for our future energy needs - and how are different countries making use of it today? How can we prioritize the health and safety of people under energetic and resource constraints? Most of all, how do we listen to others that we don't agree with - regardless of the issue - to foster the diverse perspectives necessary to navigate the coming challenges of the human predicament? About Chris Keefer: Chris Keefer MD, CCFP-EM is a Staff Emergency Physician at St Joseph's Health Centre and a Lecturer for the Department of Family and Community Medicine at the University of Toronto. He is also an avid advocate for expanding nuclear power as the President of Canadians for Nuclear Energy and Director of Doctors for Nuclear Energy. Additionally, he is the host of the Decouple Podcast exploring the most pressing questions in energy, climate, environment, politics, and philosophy. PDF Transcript Show Notes 00:00 - Chris Keefer works + info, Decouple Podcast, Canadians for Nuclear Energy 04:45 - Egalitarian hunter gatherer society, infant mortality 05:12 - Bow drill fire 07:10 - Yukon 07:30 - Humans and livestock outweigh wild mammals 50:1, not in the Yukon 08:10 - Dr. Paul Farmer 08:45 - Most humans use to work in agriculture, ~15% now involved in healthcare 10:56 - Ontario nuclear power, one of lowest electric grid in the world 12:01 - Justin Trudeau 12:24 - Simcoe Clinic, Canadian Center for Victims of Torture 14:01 - World population over time 14:36 - Paleodemography 14:59 - Degrowth 15:19 - Infant mortality in developed countries 15:55 - Tight link between energy, materials and GDP 20:54 - Duck and Cover Drills 21:05 - Environmental Movement and Nuclear 21:21 - Nagasaki bomb radiation injuries 21:49 - High dose radiation is deadly, low dose radiation less so 21:05 - Strontium-90 found in the teeth of babies 21:10 - Atmospheric weapons testing ban 22:33 - Fukushima meltdown, health impacts are negligible 23:09 - 20,000 people died from the Fukushima earthquake and following tsunami 23:47 - Fukushima contaminated water has been filtered out and is safe 24:24 - How radiation is measured 26:02 - Health effects from alcohol 26:16 - Drinking culture in the U.S. 27:22 - Nuclear energy density, land footprint 28:23 - Best nuclear applications and limitations 30:01 - Those who live in nuclear powered areas fare better 30:33 - Price of nuclear energy over the lifetime 30:45 - Nuclear power in France 31:18 - Canada energy history, center for nuclear research outside of the Manhattan Project 32:23 - 1000 people die prematurely every year due to coal 33:25 - Ontario population 33:38 - Candu Reactors 34:15 - Levelized cost of electricity, skewed with renewables 37:01 - Lazard Graphs 38:09 - Mark Jacobson 41:07 - Carbon emissions by power source 41:23 - Lifespan of nuclear plants 43:11 - Land use change impacts 43:31 - Nuclear and job creation 46:05 - US spending on military vs healthcare 48:49 - Meiji Restoration 49:33 - Vaclav Smil 50:42 - AI electricity demands 50:55 - AI risks 51:29 - Meredith Angwin 52:42 - Nuclear fuel 53:10 - 46% of uranium enrichment happens in Russia 54:15 - Known Uranium Reserves 54:25 - Haber Bosch 54:55 - Breeder Reactors 55:42 - Uranium in seawater 56:14 - Slow vs Fast Neutrons, fertile elements 57:04 - Sodium Fast Reactor 58:45 - China built a nuclear reactor in less than 4 years 1:00:05 - Defense in depth 1:01:11 - EMP, solar flare 1:01:30 - HBO's Chernobyl, wildlife thriving in chernobyl area 1:03:13 - Death toll from radiation in Chernobyl 1:05:13 - Scientific literature and confirmation bias 1:08:12 - Chernobyl Children's International 1:08:44 - Genome sequencing of highest exposures to radiation from chernobyl 1:09:09 - Germline mutations if the father smokes 1:10:02 - The Great Simplification animated video 1:10:32 - Peak Oil 1:12:10 - Complex 6-continent supply chains 1:12:30 - I, Pencil 1:15:19 - Nuclear Fusion 1:16:24 - Lawrence Livermore 1:17:45 - Tomas Murphy, Galactic Scale Energy 1:18:11 - Small Modular Reactor 1:19:26 - Cost saving in nuclear comes from scaling 1:19:34 - Wright's Law, economies of multiples 1:23:33 - Biden administration policies and advances on nuclear 1:24:00 - Non-profit industrial complex 1:24:24 - The size of the US non-profit economy 1:24:44 - Sierra Club, anti-nuclear history 1:25:14 - Rocky Mountain Club 1:27:15 - Hans Rosling 1:27:32 - Somalia infant mortality rate 1:27:42 - Cuba 1990s economic shock and response 1:27:42 - Vandana Shiva + TGS Episode 1:30:27 - Cognitive Dissonance 1:31:45 - Jonathan Haidt + TGS Podcast, Righteous Mind 1:32:48 - Fatality and hospitalization statistics for COVID for first responders 1:33:22 - Truckers protest in Ottawa 1:34:15 - The problem with superchickens 1:36:54 - How social media tries to keep you online 1:37:12 - Paleopsychology 1:37:55 - Tristan Harris and Daniel Schmachtenberger on Joe Rogan 1:39:45 - John Kitzhaber + TGS Episode, Robert Lustig + TGS Episode 1:39:55 - US healthcare 20% of GDP, 50% of the world's medical prescriptions are in the US 1:41:55 - Superutilizers 1:42:37 - Cuban medical system, spending, life expectancy, infant mortality 1:43:06 - Cuban export of pharmaceuticals 1:44:08 - Preventative medicine, chronic disease management 1:44:25 - Cuban doctor to person ratio, rest of the world 1:48:47 - Social determinants of health 1:49:20 - Cement floor reducing illness in Mexico 1:50:03 - Hygiene hypothesis 1:50:28 - Zoonotic disease and human/animal cohabitation 1:50:50 - Roundworm life cycle 1:52:38 - Acceptable miss rates 1:53:16 - Cancer screening effectiveness 1:53:58 - Drugs produced from nuclear plant byproducts 1:58:18 - Timothy O'Leary 2:02:28 - Superabundance 2:02:40 - Julian Simons and Paul Ehrlich bet 2:02:15 - Malthusian 2:06:08 - Pickering Plant Watch this video episode on YouTube
Germline and somatic testing for in prostate cancer can improve outcomes and promote early detection and prevention, yet many patients are not aware of testing and the impact it can have on treatment options. In this episode, CANCER BUZZ speaks with David Gill, MD, medical oncologist at Intermountain Healthcare's Intermountain Cancer Center and Lindsey Byrne, MS, LCGC, licensed certified genetic counselor at The Ohio State University Comprehensive Cancer Center, who discuss how genetic counselors and increased patient education can help cancer programs close the practice gap and promote guideline-concordant testing among patients diagnosed with prostate cancer. “I'd really advocate—even in your patients with a negative NGS panel—please still consider getting germline testing in those patients.” –David Gill, MD “We know that individuals, yes, they're dealing with a diagnosis of cancer, but the first thing people say to me when I sit down with them is, ‘All right, I have this figured out, but what does this mean for my family?' They're really worried about their family, and that's where our focus is, to help take care of that.”—Lindsey Byrne, MS, LCGC David Gill, MD Medical Oncologist Intermountain Healthcare - Intermountain Cancer Center Salt Lake City, Utah Lindsey Byrne, MS, LCGC Licensed Certified Genetic Counselor The Ohio State University Comprehensive Cancer Center – The James Columbus, Ohio This episode was developed in connection with the ACCC education program Germline and Somatic Testing for Mutations to Optimize Outcomes in Metastatic Prostate Cancer and is supported by AstraZeneca, Johnson & Johnson, and Pfizer. Resources: Germline and Somatic Testing for Mutations to Optimize Outcomes in Metastatic Prostate Cancer - ACCC Abstract: Homologous recombination repair gene mutation (HRRm) testing patterns and treatment selection from a real-world cohort of patients with metastatic castration-resistant prostate cancer (mCRPC) Abstract: Utilization of genetic counseling and testing for patients with prostate cancer following integration of a genetic counselor into a genitourinary cancer clinic
In this JCO PO Article Insights episode, Miki Horiguchi provides a summary on the article, “TARGET: A Randomized, Noninferiority Trial of a Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing and explains what a non-inferiority trial is. TRANSCRIPT Miki Horiguchi: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Miki Horiguchi, an ASCO Journal's Editorial Fellow. Today, I'll be providing a summary of the article titled "TARGET: A Randomized Non-Inferiority Trial of a Pre-Test, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing" by Dr. Stacy Loeb and colleagues. To help you understand the TARGET study design, I'll first explain what a non-inferiority trial is. One of the most common clinical trial designs we see in clinical papers is the superiority trial. A superiority trial is designed to demonstrate that a new treatment is superior to a control, such as a placebo or a standard treatment, in terms of a primary outcome that is relevant to the study's purpose. In a superiority trial, a statistical test is performed for the null hypothesis that there is no treatment difference between the two arms. If a significant p-value, which is conventionally less than 0.05 is observed, we consider that the probability that the null hypothesis being true is very low, and thus conclude that there is a treatment difference between the two arms. On the other hand, if the p-value is larger than 0.05, we cannot conclude that there is a treatment difference because the probability that the null hypothesis being true is not low enough. Here, it's very important for us to keep in mind that a non-significant p-value does not mean no difference between the two arms. Therefore, if the study objective is to show that a new treatment has a similar treatment effect to a control treatment, the standard statistical testing approach used in a superiority trial is not appropriate. To meet this specific study objective, utilizing a non-inferiority test is more appropriate. The formulation of a hypothesis in a non-inferiority test is distinct from that in a superiority test. In essence, the null hypothesis is that the new treatment is inferior by more than the predefined margin, whereas the alternative hypothesis argues against this, suggesting that the new treatment is not inferior within this margin. A significant p-value from the non-inferiority test indicates support for the alternative hypothesis, implying that the new treatment is at least as effective as the control treatment considering the predefined margin of non-inferiority. There are a couple of points to consider prior to designing a non-inferiority trial. The first is about the justification for using a non-inferiority study. The new treatment must offer a clear advantage other than the treatment effect, such as fewer side effects and lower cost, so that it can be a viable alternative to the control treatment as long as it maintains a certain level of treatment effect that is not inferior to the controls. The second point is about the non-inferiority margin. The non-inferiority margin defines the threshold below which the new treatment is deemed non-inferior to the control. The selection of an appropriate margin is pivotal as it profoundly influences the power and sample size of the study, as well as the interpretation of the statistical test results. To ensure the study's objectives are met, the non-inferiority margin must be established during the study design phase. This decision should be informed by clinical expert opinions, findings from previous studies, or regulatory guidelines. Now let me move on to the introduction of the TARGET study. The TARGET study was a multicenter, non-inferiority randomized trial to compare the effects of two types of interventions for pre-test genetic education in patients with prostate cancer. The authors developed a patient-driven, web-based education tool that consisted of nine modules with text and videos to deliver genetic testing education. They then assessed its non-inferiority to traditional genetic counseling and the decisional conflict about taking genetic testing. The primary endpoint was the change in the decisional conflict score between pre- and post-intervention. The authors estimated the difference in pre-post change of the score between the two arms and the corresponding one-sided 95% confidence interval. The non-inferiority of the web tool arm on the pre- post change of the score to the genetic counseling arm was assessed based on a pre-specified non-inferiority margin of 4. In this case, if the estimated upper confidence bound for the difference between the two arms is less than the non-inferiority margin, the study confirms the non-inferiority of the web tool to the genetic counseling in terms of the primary outcome. The non-inferiority margin for this study was determined based on a previously conducted similar study. For the TARGET study, several factors underscore the appropriateness of using a non-inferiority trial. First, the web-based education model is likely to significantly increase convenience compared to traditional genetic counseling, which is delivered in person or through telehealth appointments with the genetic counselor. The introduction of the proposed web tool is expected to reduce logistical burdens for patients, such as those related to transportation and scheduling. Second, from the perspective of healthcare providers, the adoption of the proposed web tool could reduce the workload of genetic counselors, offering a potential solution for a shortage of counselors. A total of 346 patients were randomly assigned in a 1:1 allocation to either of the two interventions. The primary analysis population was the modified intention-to-treat population, which included 153 on the web tool arm and 162 on the genetic counseling arm. The estimated difference in pre- post-change of the decisional conflict score between the two arms was -0.04 and the upper boundary of the corresponding confidence interval was 2.54, which was less than the predefined non-inferiority margin. The p-value for the non-inferiority test was 0.01. The authors reported results for the secondary endpoints, which included cancer genetics knowledge, attitude toward genetic testing, and satisfaction with genetic counseling. It was also reported that a total of 265 patients took genetic testing, and among the total, pathogenic variants were identified in 42 patients. The authors concluded that the study results support the use of a patient-driven web tool for expanding access to pre-test education for germline genetic testing among patients with prostate cancer. The authors also mentioned some limitations of this study, one of which is the limited racial and ethnic diversity among the study population. Some requirements to access the web-based tool, such as a computer and Wi-Fi access, may raise concerns about widening disparities in access to genetic services for cancer patients. Further studies to examine ways to address these limitations are needed. 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 the 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.
Amander Clark, Ph.D., delves into crafting artificial ovaries for fertility and aging research. She stresses the importance of diversity in stem cell studies to ensure comprehensive findings. By assembling ovarian models from various genetic backgrounds, her team aims for inclusive representation in biomedical research, potentially offering insights into reproductive health and disease. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 38334]
Amander Clark, Ph.D., delves into crafting artificial ovaries for fertility and aging research. She stresses the importance of diversity in stem cell studies to ensure comprehensive findings. By assembling ovarian models from various genetic backgrounds, her team aims for inclusive representation in biomedical research, potentially offering insights into reproductive health and disease. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 38334]
Amander Clark, Ph.D., delves into crafting artificial ovaries for fertility and aging research. She stresses the importance of diversity in stem cell studies to ensure comprehensive findings. By assembling ovarian models from various genetic backgrounds, her team aims for inclusive representation in biomedical research, potentially offering insights into reproductive health and disease. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 38334]
Amander Clark, Ph.D., delves into crafting artificial ovaries for fertility and aging research. She stresses the importance of diversity in stem cell studies to ensure comprehensive findings. By assembling ovarian models from various genetic backgrounds, her team aims for inclusive representation in biomedical research, potentially offering insights into reproductive health and disease. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 38334]
Host: Daniel Kwon, MD Between patient anxiety and insurance implications, there are several challenges associated with delivering germline testing to veterans with advanced prostate cancer. Learn more about these challenges and proposed solutions with Dr. Daniel Kwon, who presented the “Challenges in Patient-Centered Germline Testing Delivery for Veterans with Advanced Prostate Cancer” session at the 2024 ASCO Genitourinary Cancers Symposium.
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.
Dr. Isabelle Bedrosian and Dr. Mark Robson discuss the new guideline from ASCO and SSO on germline testing in patients with breast cancer. They discuss the framework for which patients should be offered BRCA1/2 testing, and what additional moderate- and high-penetrance genes may be considered for inclusion in germline testing. They highlight key aspects of personal and family history, recommendations surrounding counseling for genetic testing, and the impact for patients and their families. They close the conversation with a discussion of gaps in the research. Read the full guideline, Germline Testing in Patients with Breast Cancer: ASCO-SSO Guideline TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02225 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Isabelle Bedrosian from the University of Texas MD Anderson and Dr. Mark Robson from Memorial Sloan Kettering Cancer Center, co-chairs on “Germline Testing in Patients with Breast Cancer: American Society of Clinical Oncology – Society of Surgical Oncology Guideline.” Thank you for being here, Dr. Bedrosian and Dr. Robson. Dr. Mark Robson: My pleasure. Dr. Isabelle Bedrosian: Thank you, Brittany. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bedrosian and Dr. Robson, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content of this particular guideline, Dr. Bedrosian, could you give us a general overview of both the scope and the purpose of this guideline? Dr. Isabelle Bedrosian: Yeah, sure. So, in the last decade or so, the whole area of clinical cancer genetics has become incredibly complicated, driven, I think, predominantly by the development of extended gene testing. And in the midst of this complexity, our goal here was to try to give providers a framework through which they can think about the application of germline testing within their patient population. And really, this framework was to help them think through how testing can best be applied to patients that were both newly diagnosed with breast cancer or had a history of breast cancer, and also to help them think through the scope of that testing as well, be it BRCA testing or testing in a more extended fashion that may help inform longer-term decisions such as risk management. Brittany Harvey: Absolutely. We appreciate your efforts to provide recommendations in this framework in this complicated space. So then, I'd like to review the key recommendations of this guideline developed by the expert panel. So first, Dr. Robson, who should be offered BRCA1/2 testing? Dr. Mark Robson: Thank you. I think this is perhaps one of the most important things that comes out of the guideline is that we, and the group, are now recommending that anyone who is either newly diagnosed with breast cancer at or before the age of 65, or if they're over 65 and have suggestive personal or family history criteria, or alternatively, if they are eligible for PARP inhibitor therapy, that they all be offered BRCA1 or BRCA2 testing. And the same would hold for women who had a personal history of breast cancer but were not currently under active treatment if their diagnosis had been made at or before 65 or older than that, with certain criteria then they should be offered testing. This is a much simpler way to look at things than the rather complicated existing criteria, which are perhaps a bit both difficult to remember and unfortunately inadequately sensitive in a setting where there is such critical, both therapeutic and risk management implications to the identification of a BRCA mutation. Dr. Isabelle Bedrosian: Yeah, I would just also add there's one other, albeit a much smaller group of women for whom BRCA testing could be considered, and those are women who develop a second primary breast cancer. That's another group that I think we can think about offering BRCA1/2 testing to. Brittany Harvey: Understood. I appreciate you both reviewing those recommendations for BRCA1/2 testing. So, Dr. Bedrosian, which additional genes does the panel recommend including in germline testing? Dr. Isabelle Bedrosian: Yeah. So, in this area, outside of BRCA genes, Brittany, I think the panel didn't make any definitive recommendations or any specific genes that should be tested for. I think the panel felt that the decision to test for additional high penetrance genes and also for some moderate penetrance genes should be guided by the specifics of the individual case, whether the identification of germline mutations makes sense in the context of the patient's personal history and family history. So, in other words, is there a worrisome pattern in the family that might warrant more in-depth testing beyond BRCA, and also considerations around the implications of those test results. Would it change the management for the patient themselves? Either in the treatment of the index malignancy, which, in the case of most of these non-BRCA genes, there really is not changes to the management of the breast cancer that would be offered based on the finding of non-BRCA germline mutations. But potentially, the finding of a non-BRCA germline mutation in a breast cancer patient might help better understand risks of second malignancies that would then be addressed. And certainly for families as well of the patients, identifying those that are carriers could offer opportunities for risk assessment, risk mitigation. Dr. Mark Robson: I totally agree with Dr. Bedrosian. One thing I think it's important to understand is that most commercial testing done in the United States now does involve panels of genes. And the group certainly did not intend to suggest that that practice not continue. So, I think if somebody has a history of breast cancer, I think the panel felt that it would at least be reasonable to test for breast cancer susceptibility genes. However, this issue of do you test for all of the high penetrance genes when the family history doesn't suggest it, was certainly something we left open and we did not want to imply that it was obligatory to test for a large number or large panel of genes that weren't related to the patient's personal and family history. So, in other words, didn't want to imply that it was obligatory to do an extremely large panel just as a target of opportunity, if you will. Dr. Isabelle Bedrosian: I think really a key part of these guidelines was that we wanted to afford the oncologist flexibility. It's very difficult beyond BRCA to be prescriptive. There are so many considerations about testing, and those considerations will be applied differently in every patient context. So, we really wanted to let providers know that while they have to think about these other genes, and oftentimes there'll be good reason to do these other genes as part of the overall germline testing, again, that it's not obligatory to do so. It's not a fixed set that needs to be tested for. And really, the understanding of the patient's personal history, family history, therapeutic goals, and risk assessment goals should be used to determine kind of the ultimate scope of the testing. Brittany Harvey: It sounds like these decisions will be individualized, based on patient characteristics and with working between both patients and their clinicians. So that leads into my next question. But, Dr. Robson, how should patients with breast cancer considering genetic testing be counseled? Dr. Mark Robson: With this recognition and emphasis on the therapeutic implications for patients with breast cancer, both surgical and potentially systemic using PARP inhibitors, the approach has gradually moved away from the concept of testing for personal utility, in other words, just wanting to know, and more towards the idea of this being a clinically useful test that's to some extent necessary for the appropriate management of a fair number of patients. And so the counseling is usually- the pre-test counseling is perhaps more educational than we have used in the past, rather than this extensive discussion of whether or not somebody wants to know. Obviously, it's always the patient's ultimate decision whether or not to be tested, and we have to give them the same elements of education that we would have given back in the day. But it can be delivered in a more didactic type of context rather than necessarily the back and forth that takes place with formal genetic counseling. Now, for patients who have complicated or extensive family histories or who have histories that may suggest predispositions other than those for breast cancer, the type of thing that Dr. Bedrosian was talking about earlier, they could certainly benefit, again, from a more formal evaluation by a provider experienced in cancer genetics to help select what the scope of the testing should be, for instance, and also to help interpret those results. And certainly anybody who had a pathogenic variant or a likely pathogenic variant identified should be considered for meeting with somebody who's experienced in clinical cancer genetics both to interpret and also to help with family expansion when appropriate. Brittany Harvey: Excellent. Thank you for reviewing those recommendations from the expert panel. So, Dr. Robson just touched on this a little bit, but Dr. Bedrosian, how will these guideline recommendations affect patients with breast cancer and their families? Dr. Isabelle Bedrosian: Yeah, so from a patient perspective, I think there are two ways that these recommendations can impact care. For those women that are identified as germline carriers, specifically with BRCA, it will open the door for receipt of PARP inhibitors, which are currently recommended for patients that are high-risk primary cancer or those with metastatic disease. The other ways that patients will be affected by a germline testing is really in this idea of second cancer risks. Some of these germline mutations are well established to carry risks of either second primary breast cancer or non-breast malignancies. And understanding those risks will allow the patients and their providers to create management strategies, be they surgical or with more intensified screening that will help them mitigate the effects of that germline-driven risk. And I think similarly for the families of patients, the ones the proband has identified, I think that family now has a very real opportunity to better understand their cancer risks and again be able to more effectively manage those risks through either surgical or non-surgical means. And it would really underscore the family component of this. I think oftentimes oncologists are very much focused on the patient and admittedly so that is the person that has the most immediate needs. But I think there's a real opportunity to extend efforts at prevention and early detection by identifying the at-risk family members and allowing them the opportunity to access care that mitigates their cancer risks and hopefully will improve survival outcomes in so doing. So, I think the opportunities for families here to understand risks of germline testing is a really important one to underscore from these recommendations. Dr. Mark Robson: Just to expand a little bit on what Dr. Bedrosian was saying, I think this is a very important place for collaboration between the oncology community and the clinical cancer genetics providers because the oncologist is pretty occupied taking care of all of their cancer patients, and the approach to people who are unaffected is a little bit different. People who are unaffected perhaps do need a little bit more pretest counseling to understand the pros and cons of choosing to be tested for the familial mutation. And certainly that idea of family expansion is something that's well known to clinical cancer genetics providers and that's really very much something that they can help the primary oncologists do. Brittany Harvey: Absolutely, these recommendations have impacts beyond just the individual patient, but also for their families as well. So then, finally, Dr. Robson, what are the outstanding questions regarding germline testing in breast cancer? Dr. Mark Robson: Oh, there are so many. Where should I start? I think over the years we've become, as a community, pretty comfortable managing individuals who have BRCA1 or BRCA2 mutations. There are certainly some questions left, but there's a lot of familiarity with that. I think the challenges expand into these what we call moderate penetrance genes and how to guide people with alterations in those genes. Because except for PALB2, which is relatively uncommon, many of the other genes don't really have the same implications for therapy because it's not clear that they confer PARP sensitivity. It's not at all clear that they have high risks of contralateral breast cancer. And even in the unaffected setting, we know that there's a wide distribution of risk for people who carry these alterations. And some individuals with these alterations probably are not at increased risk at all because they have protective factors. So the management of breast cancer susceptibility genes beyond BRCA1 and BRCA2 is still very much in evolution. They can't be handled exactly the same way as a woman with a BRCA carrier. And then, of course, this issue of how much should we test and what do we do with some of the alterations that we find, if you will, out of context, what are the implications for that and what's the most appropriate management? Those still remain very much open questions. So I think there's still plenty of work to do. Dr. Isabelle Bedrosian: Yeah, I agree. I think one of the enormous challenges has been the disconnect between how rapidly our technology has advanced and can sequence alterations, and our ability to really understand the biologic and clinical implications, which really is a time-dependent issue. We need to see over time how patients do for us to understand the implications of some of these germline findings. So that disconnect is a very difficult one to bridge, particularly, I think, for surgical oncologists because they are oftentimes referred patients who don't have a cancer history, necessarily, or have a distant history, and really the concern is “I'm at risk and I would like to reduce my risk.” And it becomes very difficult to counsel patients as to the benefits of risk reduction when we don't have such a great handle on the degree to which they are actually at risk. So that really is a significant gap, I think, for surgeons in particular to have to contend with. Brittany Harvey: Definitely. We'll look forward to answering some of those questions as we learn more and get more data to address those gaps. So I want to thank you both so much for your work to develop this framework for genetic testing in breast cancer, and thank you so much for your time today, Dr. Robson and Dr. Bedrosian. Dr. Isabelle Bedrosian: Thank you, Brittany. Dr. Mark Robson: Thank you for having us. Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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.
The AUA Expert Exchange Podcast: Discussions in Managing GU Cancer: Germline Testing and Novel Approaches to Targeting Genetic Mutations in Prostate Cancer CME Available: auau.auanet.org/node/39487 Release Date: December, 2023 Expiration Date: December, 2024 LEARNING OBJECTIVES At the conclusion of this activity, participants will be able to: 1. Identify the indications for germline testing in prostate cancer patients. 2. Explain how germline testing is used to identify genetic mutations in genitourinary (GU) cancers, specifically focusing on prostate cancer. 3. Analyze the potential advantages and challenges associated with using germline testing and targeted therapies in the management of prostate cancer. ACKNOWLEDGEMENTS: Support provided by independent educational grants from: Astellas and Pfizer, Inc AstraZeneca Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC Lantheus Medical Imaging Merck & Co., Inc.
Germline Testing in GU Cancers – How I Do It CME Available: https://auau.auanet.org/node/39544 ACKNOWLEDGEMENTS: This series is supported by independent educational grants from: AstraZeneca Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC Lantheus Medical Imaging Merck & Co., Inc. LEARNING OBJECTIVES: At the conclusion of this activity, participants will be able to: 1. Differentiate between germline and somatic testing in the context of GU cancers, understanding the fundamental differences in the types of genetic alterations detected and their implications for patients and their families. 2. Describe the genetic counseling process and the importance of pre-test counseling to discuss the benefits, limitations, and potential implications of germline testing. 3. Evaluate the clinical significance and impact of germline testing results on treatment decisions, surveillance recommendations, and family management.
This episode includes content provided on behalf of Myriad Genetics as part of ACRO's Corporate Partnership Program: In recognition of Family History Month, the latest ACRO podcast is a conversation between ACRO's host Dr. Albert Attia from the Mayo Clinic and Dr. Christopher Lee from Cancer Care Northwest about how germline and somatic tests are transforming patient discussions. Dr. Lee shares how genetics are playing a role not only in the diagnosis and treatment of cancer, but in how families are making decisions about genetic testing.
JCO PO author Dr. Sanjeevani Arora shares insights into her JCO PO article, “Exploring Stakeholders' Perspectives on Implementing Universal Germline Testing for Colorectal Cancer: Findings from a Clinical Practice Survey” Host Dr. Rafeh Naqash and Dr. Arora discuss germline genetic testing for all colorectal cancer (CRC) patients and advantages and barriers of implementing universal germline testing (UGT). TRANSCRIPT 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 OU Health Stephenson Cancer Center at the University of Oklahoma. Today we're excited to be joined by Dr. Sanjeevani Arora, assistant professor at Fox Chase Cancer Center, and author of the JCO Precision Oncology article, Exploring Stakeholders' Perspectives on Implementing Universal Germline Testing for Colorectal Cancer: Findings From a Clinical Practice Survey. At the time of this recording, our guest's disclosures will be linked in the transcript. Dr. Arora, welcome to our podcast and thank you for joining me today. Sanjeevani Arora: Hi, thank you so much for having me. It's a pleasure to be here. Rafeh Naqash: As it happens, you were in Vegas for your meeting, which is relevant to this publication since this was, I believe, presented at the meeting as well. Is that correct? Sanjeevani Arora: Yes. Rafeh Naqash: Great. So, Dr. Arora, for background purposes, could you tell us what is the main theme of this project and what was the reasoning for doing this project in this important space of germline testing for colorectal cancer? Sanjeevani Arora: So, we were interested in understanding what the stakeholder's perspectives would be for support as well as implementation of universal germline testing in all colorectal cancer patients. We know that colorectal cancer is one of the leading types of cancers in the United States as well as in the world. And from what we understand is that the prevalence of mutations that would increase risk of colorectal cancer, that can vary in an unselected population, so somewhere about 15%. The criteria, however, to identify who might be harboring a variant that would predispose to colorectal cancer, there are various methods to do that. However, I think an important point to consider here is that many patients who harbor such variants do not meet established criteria for genetic testing. The problem with that is that that is a missed opportunity to not only manage a patient who may carry such variations, so that can impact their clinical management as well as in their family as well. So, missed opportunity for risk reduction and early detection with enhanced surveillance. So, really if you think about this is based on these, the NCCN itself has now recommended universal germline testing for individuals who are diagnosed with colorectal cancer who are younger than 50 years of age. And in June 2022, they also suggested to consider testing for those who are older than 50 years of age. But in spite of this, there is lack of data from stakeholders and lack of data on advantage of and barriers to implementing universal germline testing at different clinical practices. So, this was really the main reason why for us to go ahead and do this study so that we can understand what the challenges are related to universal germline testing and especially coming from the stakeholders and also to try to understand what the overall broad support is from the stakeholders. Rafeh Naqash: Thank you so much for that explanation. I personally work in the early phase clinical trial space. So, for me, genomics makes a huge difference for people with cancer and not just from a testing standpoint, but also from a target standpoint drug discovery standpoint. And I think as I've gradually progressed in my career, I have felt that catching individuals with germline predispositions can make a huge difference for their families, especially. Prevention is better than cure in most respects. So, this is a very relevant and a very timely topic. And outside of this study, from a logistics perspective, could you tell us, since our listeners are not just academic clinicians or geneticists, but perhaps a bunch of them are probably community oncologists also and hopefully other disciplines that are not in the academic setting, how does it work for you in your current setup at Fox Chase of how people get this germline testing, people with colorectal cancer? Sanjeevani Arora: The main challenge here is trying to, at least in terms of the perspectives of genetic counselors, is that currently they see all patients and eventually if there is implementation of universal setting in the way, they will perhaps only end up seeing those who truly are at high risk. So, that would really be a huge change in their own practice as well, like who they're seeing in the clinic. In terms of how this could be implemented, obviously there are multiple challenges here. So, for example, it would go on from not only just the who would order and who would consent, but also then who would be disclosing the results because there would be a big demand for this. So, the idea would be trying to really streamline if non-genetics providers could get the training to be involved in this. So, this system can be streamlined, I should say, that genetic providers would be more involved in the phase where they are truly required. So, perhaps that would be in the result disclosures or on a case-by-case basis. Rafeh Naqash: I think you bring an important point as far as testing and who is responsible for discussing the implications of the results. And I know you touched into that aspect in your survey. Could you elaborate a little more on the results section side of what you found that had clinical relevance or meaningfulness from your survey standpoint? Sanjeevani Arora: So, when we surveyed our respondents on support for the kind of providers who could be involved in ordering and consent for universal germline testing, the majority obviously supported genetics providers. So, here genetics providers were genetic counselors, medical genetics geneticists and genetic nurses. However, there was also broad support for medical oncologists, gastroenterologists, and surgeons. There was even a minor part of our respondents also supported other providers as well. So, it's good to see that while there is broad support for genetics providers, there is room for other providers to be involved in this aspect of universal germline testing in a program. We also looked at the opinions and how and when genetics education should be provided in such a program for universal germline testing. The majority of our respondents, said that pre-test genetic education is necessary. So, they all felt that this is an important aspect of a universal germline testing program. However, there were nuances on what materials could be provided as well as who could potentially be involved in this. So, based on what the respondents said in their survey, it looks like this could be a good place for non-provider staff to be involved in this. However, when we also asked them what the non-genetics providers in the knowledge that they have potentially when we directly ask them this, do they have the knowledge to consent for genetic testing? Going back to the consent point, again, the majority did not agree with this. However, there was a percent that also felt that they do have this knowledge, but when we asked them that if they have the knowledge to disclose results, there was a strong disagreement there. So, there definitely is room for non-genetics providers to get the right training or to be involved in this aspect if needed. But it looks like at least for the consent, there is more support. Rafeh Naqash: So, the more one thinks about this topic from a broader perspective, not just colorectal cancer but other tumor types. What comes to my mind as you have elaborated in your discussion and in your survey, is the education part of it that you just mentioned about. If you were to think out of the box, do you think that the NIH has a potential role in creating mechanisms to help facilitate some of that? Since I think the bigger question comes back to funding at the end of the day. Institutions need to invest time, energy, resources in trying to educate and expand on this aspect of genetic testing, which I think is immensely important for individuals with strong family history of cancer, or even find out that they don't have high risk features, but they end up having some germline variants that are potentially actionable for them or their family. So, have you as part of your association, the CGA, been able to think on some of those lines to get a stakeholder like the NIH to help facilitate fund some of these educational initiatives at institutions? Perhaps maybe to start with NCI-Designated institutions and then expand in the community. Sanjeevani Arora: I think NIH would have a big role in this or NIH as well as other funding agencies because I think this effort for a universal germline testing program in academic centers and then eventually going on to community-based centers or maybe both at the same time, this will require a collaborative effort between genetics and non-genetics providers that we identify is going to be really very important going forward. So, there is not only a big role for the institutions and the community itself, but also for the NIH as you mentioned, where this would be really necessary to really help us identify who is a high-risk individual and when the pre-test education and other post-test is required. Rafeh Naqash: I think because in the bigger picture it does play out into the amount of funding that a government agency like the NIH spends in individuals with advanced cancer, which they could potentially prevent if some of these programs are well implemented early on and help with reducing morbidity and mortality when these events do happen later on. But I guess these are discussions beyond the scope of this project in this podcast, but I was just thinking from an out of the box perspective, could that be an opportunity that your group can perhaps work with the NIH on? So, going back to the project, the publication, tell us a little bit more about the genes that were tested. You talk about the single gene versus the multi-gene panel. Could you elaborate a little more on that and what are the advantages of one or the other? Sanjeevani Arora: We did survey our respondents on what they thought would be the best way to move forward in a universal germline testing program. And you can see that the majority really supported a standardized multi cancer gene panel. And I thought that was really interesting because if you look at the data here is that while 46% support that, there's also a smaller majority, about 26% that only support colorectal and some common cancer genes. So, in terms of the large multi cancer gene panels, so this would be not only just the colorectal cancer genes, so these would be high risk, moderate risk or limited evidence, colorectal cancer genes, plus it would be all other genes that we test currently for hereditary cancer types. So, this would be a lot of data that would come about in a universal germline testing program. And then I think the idea would be how would this be managed? Because many of the genes currently, we don't understand if they would increase colorectal cancer is, so how would be manage the risk for perhaps other cancer types if there is a positive result? I think that's something to think about. The other would be how would the variance of uncertain significance would they be reported and how would that work about? So, those two would be really important as well to think about going forward in such a program. Rafeh Naqash: Now from a cancer standpoint, my experience with germline testing has been when I see individuals for clinical trials especially, and I do broad next generation sequencing the tumor tissue or on blood and identify something that has a very high variant allele frequency that triggers a question in my mind whether this is germline. Unfortunately, these days we don't do a great job in taking history from the individual where you ask them about family history extensively. Some clinicians are better in this perspective than others, but I think there's a gap there. And then you go back to the patient, you ask them whether they have a history, had a recent individual recently that had uveal melanoma, and then I identified a very high variant allele frequency in a gene called BAP1, which you might be aware of. And then went back to the patient asked them and they said, well yes, they have family history of mesothelioma, family history of this cancer that cancer, and that triggered germline testing, which was positive. So, from your perspective, since a bunch of these individuals would have first-line contact, I would imagine with oncologists, mostly medical oncologists rather than surgeons, what should one look out for? Let's say a program does not have universal germline testing implemented yet. If me or my colleagues sees an individual with colorectal cancer, what would be the three or four red flags that we should consider to focus on germline testing in those individuals? Let's say we're in the community and I'm someone who's not necessarily on the genomic side, I'm a clinician treating colorectal cancer. What would some of those things be that should prompt me to consider germline testing in that individual with colorectal cancer? From your perspective. Sanjeevani Arora: Once the universal germline testing program is implemented, and you wouldn't necessarily need those questions actually, but without such a program, obviously family history is a major red flag that is very important to consider. And another would be, for example, in terms of tumor set testing for Lynch, if there is any mutations in Lynch genes or MSI High that could at least trigger test if that came from the germline. Rafeh Naqash: I think those are important points. And in the clinical setting it does often happen that you see so many individuals and sometimes some of this thought process can get lost in translation. But I think it's important to emphasize, like you pointed out, asking for family history if the universal program for testing of these individual's not implemented, then inquiring on family history and these days we see a lot of young onset colorectal cancers. Interestingly enough, my colleagues talk about it all the time and I think those aspects of it should ideally prompt people to go for germline testing. Now, from an implementation standpoint, you also looked at that in your respondents which individuals would be the ideal candidates for this testing. Could you elaborate on that? Sanjeevani Arora: Which individuals would the ideal candidates, I mean, I think the idea here was what is the support overall for testing everybody? So, the idea is to move away from having certain criteria. Now it would be the NCCN recommends testing any colorectal cancer patient who is younger than 50 years for a germline multi-gene panel testing. And then the consideration is for those who are older than 50, I hope the NCCN will eventually decide to recommend it for all. But this way there would be no need for any criteria as such, but just test all patients. Rafeh Naqash: I absolutely agree with you, and I think organizations such as NCCN, NCGA should ideally partner on creating some of this framework so that everybody's on the same page. Because I think that does play into the fact that how payers consider reimbursement for some of this testing. Did you encounter that in your respondents as one of the reasons why it could be challenging to implement universal germline testing, from a payer standpoint, insurance standpoint? Sanjeevani Arora: One of the things that we did factor into the survey as one of the barriers that ... so, we had about 11 questions for what the clinical practice barriers would be in a universal germline testing program. And this was one of the questions that the respondents did majorly agree on that the insurance may not cover the cost of testing for all patients. So, I think obviously the things do have to modify in terms of coverage guidelines to include all patients. Rafeh Naqash: Right. Because that again plays into logistics of ordering this for individuals and those individuals not having to see several thousand dollars bills resulting in financial toxicity. So, Ithink having these discussions, in your collaborative group is leading, I think extremely important from that perspective. What would be the next step for this? You did the survey, you understood what are the pros, the cons, the limitations, the benefits, what is the next step that your group is planning to take to implement some of this, create the second stage for some of this work, if there is something that you would like to highlight. Sanjeevani Arora: In terms of just in general speaking about this, I think as we finished this survey and we got it through publishing this, some of the things that we thought about and not necessarily that we may be doing this as a group or it might be just individuals, but just to talk about what we think could be the next steps here is obviously, this survey, the stakeholders here were those who are experts in hereditary GI cancers. The idea would be to also see what the thoughts are for those who are not, because they would be big stakeholders in this as well. So, it would be good to understand what they also perceive as the barriers associated with this and how we could get this implemented and also see what their support is. So, I think that's one thing. The other thing that's I think really important to point out here is that we don't have patient perspectives on a universal germline testing program. And what do they think about this? What do they perceive could be potential barriers even for them? I think that would be very important so that there is really a real uptake in the real world. I think that's very important to do, that the patient focus is very important. Now, I'm not sure if we would be doing this, I would love to do this, but I think it's really important to really consider that going forward. Another thought that I had that was based on a question that I got asked when I presented this at the CGA-IGC meeting in Vegas just last week was that how one of the things that was pointed out were that the majority of our respondents were, and I've already kind of touched on this too, were genetics providers. So, perhaps the results could be for some of the perceived barriers for how non-genetics providers could be involved, could be skewed because the survey majorly had results from genetics providers. So, I think again, just pointing out that there is a real need for collaborative efforts between genetics and non-genetics providers to understand where are the areas that they could need help so that this could be realized. Rafeh Naqash: Absolutely. I think as you pointed out there are definitely limitations associated, but I think your work and this publication lays some very important groundwork to initiate the discussion, at least. It's understood that community providers take care of at least 60% of individuals. There's maybe more with cancer. So, having stakeholders from different aspects is important, but can be challenging also since your group is just starting this work. So, I think the patient perspective, the community perspective is definitely important and hopefully that'd be something that you and your group can further work on and hopefully in the years to come, maybe publish it again in JCOPO as you did this time. Sanjeevani Arora: Yeah, that would be the hope to really get even broader perspectives. Yeah. Rafeh Naqash: So, Dr. Arora, a couple of quick questions on you as a researcher now since you've touched upon your work. Could you tell us a little bit about your background, your professional background, your interest in genetics and your current role at your institution? Sanjeevani Arora: So, my background, I have a PhD in biochemistry and cancer biology, as a postdoc I really expanded into molecular genetics. That's what really led for me to work in this area. So, currently I have a research lab at Fox Chase Cancer Center, and I'm in the Cancer Prevention and Control program. And a major part of my research program is looking at the genetics of colorectal cancer. And I'm very interested in understanding what could be the other genetic risk factors that is really leading to this alarming rise in incidents, especially in the young population. So, that's one of the aspects of my work that I'm interested in. But another aspect of my work that I'm working on is looking at are there genetic factors in the germline that could potentially impact how individuals respond to their treatment? And so, yeah, I do have a big stake in knowing more about overall genetics of colorectal cancer. Rafeh Naqash: Excellent. Well, thank you so much. It was great talking to you about this topic and hopefully our listeners find this interesting as well. 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 ASCOshows 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.
Drs. Shaalan Beg and Priyanka Kanth discuss the readiness, logistics, and barriers to implementing universal germline multigene panel testing for colorectal cancer (CRC) following new guidelines from the National Comprehensive Cancer Network that recommend genomic testing for all individuals with CRC younger than age 50. The experts also address other areas of unmet needs as new data emerge on moderate-risk genes and their association with CRC. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm the vice president of oncology at Science 37 and an adjunct associate professor at UT Southwestern Medical Center in Dallas. Last year, the National Comprehensive Cancer Network, or NCCN, updated its guidelines on colorectal cancer (CRC), recommending that all patients with colorectal cancer who receive a diagnosis before the age of 50 have multigene panel testing and that multigene testing should also be considered for patients 50 years of age and older with colorectal cancer, regardless of a personal or family history or other criteria. This represents a huge paradigm shift in the screening and care of patients with inherited cancers. And today, I'm joined by Dr. Priyanka Kanth, an associate professor of medicine and the director of the GI Cancer Prevention Program at MedStar Georgetown University Hospital in Washington, DC, to discuss new research that explores the readiness, logistics, and barriers associated with the implementation of universal germline testing in clinical practice. You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod. Dr. Kanth, it's great to have you on the podcast today. Dr. Priyanka Kanth: Thank you, Dr. Beg. It's wonderful to be here today and discuss this very exciting topic. Dr. Shaalan Beg: As a gastroenterologist who sees patients and families with a high risk for GI cancer, including medically underserved populations, can you comment on the significance of the expanded NCCN guidelines for colorectal cancer? Dr. Priyanka Kanth: Yes, absolutely. So this is, I would say, a big change from NCCN recommending pretty much every colorectal cancer patient can undergo multigene panel testing or universal. So everyone who's younger than age 50 and has colon cancer should get multigene panel testing. But we are also expanding it to pretty much anyone who may have colorectal cancer, and we can offer multigene panel testing. So, we are broadening the pool of patients who can get tested, and this will bring in more patients from very different demographics. So I think it will expand to every arena of patients with different insurance profiles, underserved, and, as more insurance companies and Medicare/Medicaid picks up, I think this will help a lot more patients in not only following on their genetic testing, but also their family members. Dr. Shaalan Beg: Medical oncologists are very familiar with the challenges of implementing somatic molecular testing for people who have cancer. I can only imagine that implementing universal germline testing also has significant logistical challenges and barriers. You recently published a study in JCO Precision Oncology along with your colleagues and captured some interesting perspectives from clinicians on their practice of implementing universal genomic testing for colorectal cancer. Can you tell us more about this? Dr. Priyanka Kanth: Absolutely. So I would first like to thank the lead authors and senior authors of this study. They are Linda Rodgers-Fouche and Sanjeevani Arora and Rachel Hodan, who literally wrote the study and created and did all the legwork. And as you know how hard it is to do these big survey studies, so really thank them. The study is a cross-sectional survey of the members of this Community Collaborative Group of America, IGC, which I would say comprises a lot of genetic counselors, gastroenterologists, oncologists, and colorectal surgeons who take care of these patients. So these are highly specialized groups that work in the field of GI genetics. Roughly 300 plus members were sent the survey to get their take on how they think [multigene panel testing] can be implemented for all colorectal cancer patients. So to give you a synopsis of the study, the majority of members who participated, 70% or more, they supported this universal germline testing for colorectal cancer patients. But interestingly, more than 50% also thought that it will require a change in their practice or how this will be delivered. So that's the major takeaway, I would say. We are all supportive but how to really deliver to the patient would be the biggest challenge or barrier for us in the future. Dr. Shaalan Beg: So, your study reported concerns on knowledge among non-genetics providers. I would assume that includes a lot of clinicians who are the first people to be in contact with potential patients who would require testing. How can the field mitigate this problem? And what are some alternate delivery service models for increasing awareness and making the process of ordering and following up on the results more efficient for practices? Dr. Priyanka Kanth: We all know the biggest barrier I would say is resources like who's going to deliver the added pool of patients that get genetic testing. So most of the current scenario, they're all seen by genetic counselors, but we have a limited number of genetic counselors and they cannot truly deal with this big influx. So how to educate non-genetic providers would be the biggest barrier. But also implementing in the system itself, like can we do pretest counseling as the first contact with the patient to deliver to discuss like you should undergo genetic testing. So that contact, can that be done with a non-genetic provider or even by other modes like telemedicine? Or can we do something like an online chat box or something which could just not only go over all the types of testing but opens the door for the patient to ask questions. So if there are alternate modes of delivery where the pretest is taken care of, that would be one big change required. The other part is like when the test is done, who returns the results? So where does it go and who explains the results? So at that point, we surely need more genetic and even non-genetic providers if they are comfortable. So how to educate them would be the biggest barrier. At that point, I think, we are still figuring out the biggest change is in the system and requiring a take from all the stakeholders who are part of taking care of these patients. So not only genetic counselors, but oncologists, gastroenterologists, pathologists who are taking care of this patient to be on board and have a really clear-cut flow of how these are delivered, how these results are returned, and how they are explained to family members. Dr. Shaalan Beg: The workflows and the resources that you have in a high-risk GI clinic at a center like Georgetown's, I think it's safe to say, are much more than what typical resources a practicing provider will have in the clinic. How do you envision clinics resourcing for this type of test either through training or retraining their existing staff or by adding additional resources? Dr. Shaalan Beg: At the community setting, it is really hard to educate essentially everyone as well. So, I feel like taking the load off the genetic counselor at the pretest level is the biggest implementation or change that can be done. And if we can remove that because not every patient is going to be positive for the gene mutation either; it does filter many patients who eventually will need returns. So at that place, how do you implement and where do you implement is the key and it is so system-based that I cannot even pinpoint. But I agree, bigger academic centers have better advantages and a knowledge base as compared to smaller community cancer centers or practices. Dr. Priyanka Kanth: Yeah, and I noticed that many of the respondents in your survey agreed with offering multigene panels, but there was variability by profession, and I was wondering if that resonated with you and that was an expected finding or not. Dr. Priyanka Kanth: Yes, and it was more so in terms of standardized multigene panel versus customized panel. So, this is fairly understandable because the genetic counselor is so well versed in offering which genes should be tested based on family history, but a non-genetic provider may not be fully equipped with the knowledge. So for example, myself, I do GI genetics, but if I have a patient with a lot of breast cancer in the family, I do defer them to a high-risk breast team. So there are nuances, too. The major difference here was also in standardized multigene panel, most of the gastroenterologists, oncologists were all for it compared to customized, which were more heavily leaned by the genetic counselor based on family history. And I can see why it's different because standardized, I would say, is much easier to implement and compared to customizing, which is based on family history or other cancer history and family. That's the major difference in the study. It comes down to education and experience and the follow-up based on what comes back from it. Dr. Shaalan Beg: You've highlighted many factors, both from the pre-test, sort of preparing and selecting the right individuals, to ordering the right test based on the participant's risk factor profile and then optimal ways of following up on the results of these genomic tests. What are other areas of unmet needs when it comes to genomic testing for colorectal cancer? Dr. Priyanka Kanth: We know a lot about high-risk genes that are associated with colorectal cancer. We still are finding and learning about many genes, many moderate-risk genes, and their association with colorectal cancer. We don't have enough data or long-term cohort data to understand how they truly affect their lifetime risk for colorectal cancer and how do we truly surveil these patients. So that's one of the big barriers. Genetics still cannot explain all colorectal cancers. So as we get more data, we may discover more things and more genes that may be associated. But understanding these moderate-risk genes and their association with colorectal cancer would be, I think, one of the key areas to be looked into in the future. Dr. Shaalan Beg: And I would imagine as new biomarkers are identified, there will need to be a strategy to retest people who may have had genomic testing in the past. Dr. Priyanka Kanth: Absolutely. We are already encountering that in a practice. I have patients who have been tested maybe 10 years ago and just had Lynch mutation tested and were negative for that or so, and now we have so many other genes which are associated and also to understand family history changes. So, as family history changes, there might be clues to say that, “Okay, we should expand the panel or we should add these patients.” So it is a very dynamic situation. There could be a scenario in which we have a lot of patients who may need to be retested based on their current situation or even based on changing family history and the availability of genetic information. So, when I see a patient, I also tell them if we don't find anything or we are not doing anything major, we say, “Let's regroup in 3 to 5 years, let's see where we are,” or even with the risk mutation for some of the moderate-risk genes, we may change in a few years. So, revisiting that with these patients is highly useful. Dr. Shaalan Beg: So, is it safe to say that as of 2023, if we're seeing people in our clinic who have not had testing in the last 3 to 5 years, that they should have a discussion for repeat testing today? Dr. Priyanka Kanth: Yes, in terms of certain, I would say, newer polyposis genes in the GI world that have been included, some other moderate gene mutation which we have a little bit more sense of now and it has not been tested, I think that can be expanded. Five years is a safe bet. Last 2 to 3 years, maybe not so much, but you can revisit this. Also, some patients were tested for a smaller gene panel. So not 2 genes, but maybe 10 genes were included. That would probably still stand true. They may not need 70 gene panels, so it's still good to review that in the current scenario, and every few years, every 5 years, I would say. Dr. Shaalan Beg: Whenever I think about any type of new test that has logistical challenges, has costs associated with it, and has operational demands of the clinic, I think about its disparate effect across different populations based on race, ethnicity, geography, demographics. Can you talk a little bit about how these guideline changes, what type of impact they may have, positive or not, for comprehensive genomic testing for colorectal cancer across different populations? Dr. Priyanka Kanth: Yes, I think this is more positive than negative. This will include more patients and include more family members who were not being included, who were being missed. As we know that one of the reasons to do this multigene panel testing was the criteria, the family history criteria or the risk prediction models are not perfect. And the recent studies have shown that not every family member, every patient, is going to fit in these criteria. So we are getting more and more data in recent years that I think the much better, long-term option is to do a multi-chain panel and find it because we are missing patients. So it will increase the pool [of patients to be tested], and that will surely increase patients from all demographics. And as we do it more, there will be more buy-in from the payers and hopefully, this will decrease disparity. The problem, I think the negative part is how do we deliver it to everyone? If it is there but we are not able to deliver and that there is disparity on who gets the test and who does not, then that will create another disparity in a sense that it's there and we could have used it, but it's not being delivered. So the pros are we can include everyone, but how to include everyone is the big question. Dr. Shaalan Beg: So, Dr. Kanth, there are indeed challenges ahead in our pursuit for universal germline testing for colorectal cancer. I'd like to thank you for sharing your valuable insights with us today on the ASCO Daily News Podcast. Dr. Priyanka Kanth: Thank you very much for having me here. It was great to talk to you, Dr. Beg. Dr. Shaalan Beg: And thank you to our listeners for your time today. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: 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. Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Priyanka Kanth @priyanka_kanth Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Priyanka Kanth: Patents, Royalties, Other Intellectual Property: Methods and Compositions for Predicting a Colon Cancer Subtype
Dr. Corey Watson is an Associate Professor at the University of Louisville. His work focuses on characterising and cataloguing antibody genetic diversity in human and mouse to better understand disease susceptibility and clinical health outcomes. Dr. William Lees is a researcher at University of London. His work focuses on developing Adaptive Immune Receptor (AIR) reference sets for diverse species and the annotation of experimental sequence data. In this episode we talk about the recent work by the Germline Database Working Group of the AIRR-Community. The accuracy of V and J gene segment assignment improves with the quality of the reference germline set. The accurate assignment is critical for characterization of somatic hypermutation. We discuss the challenges in creating a database to hold all relevant and potentially relevant germline information, especially in the light of increased discovery rate through technological advances and improved analysis pipelines. We also reflect on the complexity in handling personalised germline reference sets. The episode is hosted by Dr. Ulrik Stervbo and Dr. Zhaoqing Ding. Comments are welcome to the inbox of onairr@airr-community.org or on social media under the tag #onAIRR. Further information can be found here: https://www.antibodysociety.org/the-airr-community/airr-c-podcast. Website of the AIRR-C Germline Database Working Group https://www.antibodysociety.org/the-airr-community/airr-working-groups/germline_database/ Papers mentioned Collins, Andrew M., Mats Ohlin, Martin Corcoran, James M. Heather, Duncan Ralph, Mansun Law, Jesus Martínez-Barnetche, et al. 2023. “AIRR-C Human IG Reference Sets: Curated Sets of Immunoglobulin Heavy and Light Chain Germline Genes.” BioRxiv. https://doi.org/10.1101/2023.09.01.555348 Rodriguez, Oscar L., Yana Safonova, Catherine A. Silver, Kaitlyn Shields, William S. Gibson, Justin T. Kos, David Tieri, et al. 2023. “Genetic Variation in the Immunoglobulin Heavy Chain Locus Shapes the Human Antibody Repertoire.” Nature Communications 14 (1). https://doi.org/10.1038/s41467-023-40070-x Lees, William D., Scott Christley, Ayelet Peres, Justin T. Kos, Brian Corrie, Duncan Ralph, Felix Breden, et al. 2023. “AIRR Community Curation and Standardised Representation for Immunoglobulin and T Cell Receptor Germline Sets.” Immunoinformatics (Amsterdam, Netherlands) 10 (100025): 100025. https://doi.org/10.1016/j.immuno.2023.100025 Jackson, Katherine J. L., Justin T. Kos, William Lees, William S. Gibson, Melissa Laird Smith, Ayelet Peres, Gur Yaari, et al. 2022. “A BALB/c IGHV Reference Set, Defined by Haplotype Analysis of Long-Read VDJ-C Sequences From F1 (BALB/c x C57BL/6) Mice.” Frontiers in Immunology 13. https://doi.org/10.3389/fimmu.2022.888555 Ford, Easton E., David Tieri, Oscar L. Rodriguez, Nancy J. Francoeur, Juan Soto, Justin T. Kos, Ayelet Peres, et al. 2023. “FLAIRR-Seq: A Method for Single-Molecule Resolution of near Full-Length Antibody H Chain Repertoires.” The Journal of Immunology 210 (10): 1607–19. https://doi.org/10.4049/jimmunol.2200825 Omer, Aviv, Ayelet Peres, Oscar L. Rodriguez, Corey T. Watson, William Lees, Pazit Polak, Andrew M. Collins, and Gur Yaari. 2022. “T Cell Receptor Beta Germline Variability Is Revealed by Inference from Repertoire Data.” Genome Medicine 14 (1). https://doi.org/10.1186/s13073-021-01008-4 Rodriguez, Oscar L., Catherine A. Silver, Kaitlyn Shields, Melissa L. Smith, and Corey T. Watson. 2022. “Targeted Long-Read Sequencing Facilitates Phased Diploid Assembly and Genotyping of the Human T Cell Receptor Alpha, Delta, and Beta Loci.” Cell Genomics 2 (12): 100228. https://doi.org/10.1016/j.xgen.2022.100228 Tools mentioned TIgGER (Immcantation) https://tigger.readthedocs.io/en/stable IgDiscover https://github.com/NBISweden/IgDiscover Partis https://github.com/psathyrella/partis MiXCR https://mixcr.com
Since 2014, the widespread use of germline and somatic testing in gynecologic oncology has dramatically increased. The use of genetic testing can support actionable changes which may influence treatment decisions. Test results can inform risk for other malignancies and prompt preventive screenings for at-risk relatives. Despite an increasing awareness of the benefits of genetic testing, many patients are not receiving consistent or equitable testing. CANCER BUZZ spoke to Melissa Frey, MD, MS, Assistant Professor, Division of Gynecologic Oncology, and Director, Genetics and Personalized Cancer Prevention Program, Weill Cornell Medicine in New York, New York, and Leigha Senter, MS, CGC, Professor, Clinical Internal Medicine, Associate Director, Division of Human Genetics, and Licensed Genetic Counselor, The Ohio State University in Columbus, Ohio. Listen as we discuss germline and somatic testing for patients with ovarian cancer. “Ovarian cancer is probably one of the most exciting examples of the way genetics and genomics can inform treatment, and also improve patient care, and patient outcomes.” Melissa Frey, MD, MS “While we are putting a lot of effort into making sure patients get the testing they need, we also need to have a support web in place for their family members too. And that is actually a service to our patients.” Leigha Senter, MS, CGC Melissa Frey, MD, MS Assistant Professor, Division of Gynecologic Oncology Director, Genetics and Personalized Cancer Prevention Program Weill Cornell Medicine New York, New York Leigha Senter, MS, CGC Professor, Clinical Internal Medicine Associate Director, Division of Human Genetics Licensed Genetic Counselor The Ohio State University Columbus, Ohio Resources: Cancer Support Community This project is supported by AstraZeneca and GlaxoSmithKline.
In this week's episode, we'll learn that Germline pathogenic variants of the DDX41 gene are relatively common in the general population and linked to higher risk of AML and MDS, discuss the birtamimab plus standard of care in light chain amyloidosis, and review new insights on rare movement and neurocognitive toxicities that are observed after BCMA-directed CAR T cell treatment.
Taking a look at someone's genes when they have cancer is more and more common. One type of testing involves looking at the variations in an individual's genes they've had since birth, so-called germline testing, to see if they are … If you have been diagnosed with cancer, have you had germline testing? Elizabeth Tracey reports Read More »
View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Wendy Chung is a board-certified clinical and molecular geneticist with more than 25 years of experience in human genetic disease research. In this episode, Wendy delves deep into the world of genetics by first exploring the historical landscape of genetics prior to decoding the human genome, contrasting it with what we know today thanks to whole genome and exome sequencing. She provides an overview of genetic testing by differentiating between various genetic tests such as direct-to-consumer, clinical, whole genome sequencing, and more. Additionally, Wendy unravels the genetic underpinnings of conditions such as PKU, breast cancer, obesity, autism, and cardiovascular disease. Finally, Wendy goes in depth on the current state and exciting potential of gene therapy while also contemplating the economic implications and ethical nature of gene editing. We discuss: Wendy's interest in genetics and work as a physician-scientist [2:45]; The genetics of phenylketonuria (PKU), a rare inherited disorder [5:15]; The evolution of genetic research: from DNA structure to whole genome sequencing [18:30]; Insights and surprises that came out of the Human Genome Project [28:30]; Overview of various types of genetic tests: direct-to-consumer, clinical, whole genome sequencing, and more [34:00]; Whole genome sequencing [39:30]; Germline mutations and the implications for older parents [45:15]; Whole exome sequencing and the importance of read depth [50:30]; Genetic testing for breast cancer [54:00]; What information does direct-to-consumer testing provide (from companies like 23andMe and Ancestry.com)? [1:01:30]; The GUARDIAN study and newborn genetic screening [1:06:30]; Treating genetic disease with gene therapy [1:18:00]; How gene therapy works, and the tragic story of Jesse Gelsinger [1:22:00]; Use cases for gene therapy, gene addition vs. gene editing, CRISPR, and more [1:28:00]; Two distinct gene editing strategies for addressing Tay-Sachs and fragile X syndrome [1:37:00]; Exploring obesity as a polygenic disease: heritability, epigenetics, and more [1:41:15]; The genetics of autism [1:48:45]; The genetics of cardiovascular disease [2:01:45]; The financial costs and economic considerations of gene therapy [2:06:15]; The ethics of gene editing [2:12:00]; The future of clinical genetics [2:21:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube
This week on the BackTable Urology Podcast, Dr. Bagrodia talks with Dr. Daniel Spratt, professor and chairman of radiation oncology at Case Western University in Cleveland, about the workup and treatment of high risk prostate cancer. --- CHECK OUT OUR SPONSOR Veracyte https://www.veracyte.com/decipher --- SHOW NOTES First, Dr. Spratt defines high risk prostate cancer and discusses how to evaluate non-specific PSMA PET findings. He notes the importance of standardized systems to avoid over-calling such findings and discusses the role of CT scans and MRI scans when necessary. Finally, the doctors emphasize the importance of synthesizing PSMA PET findings into their decision-making. Next, the doctors discuss the use of germline and genomic testing, specifically Decipher testing, to characterize the tumor. Germline testing can determine eligibility for neoadjuvant PARP inhibitor trials, and biomarkers have the potential to improve radiation therapy outcomes. Although they quickly summarize the NCCN guidelines, they also emphasize the importance of patient counseling to determine the right treatment plan. Then, the doctors move on to discuss the different radiation treatments available for treating high-risk prostate cancer, such as conventional fractionation, brachytherapy, and ultrahypofractionated radiotherapy. They also explain the use of protons in treating high-risk prostate cancer, which is difficult because of the lack of high-level evidence and financial benefit when using protons compared to conventional radiation treatments. Finally, they wrap up the episode by explaining the correlation between early PSA responses and the success of radiation therapy. Surgery and radiation are often used together in treating most cancers, and how combining both can cut down the chances of PSA recurrence. --- RESOURCES Veracyte Decipher: https://decipherbio.com/
Drs Sandhya Srinivas and Heather Cheng discuss PARP inhibitors, clinical trials, and germline vs somatic testing for patients with prostate cancer, as well as the optimal time for this testing. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/988734). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Germline Testing in Prostate Cancer: When and Who to Test https://pubmed.ncbi.nlm.nih.gov/34669358/ Germline and Somatic Mutations in Prostate Cancer for the Clinician https://pubmed.ncbi.nlm.nih.gov/31085765/ Genetic and Genomic Testing for Prostate Cancer: Beyond DNA Repair https://pubmed.ncbi.nlm.nih.gov/37207301/ Genome-Wide Association Study of Prostate Cancer-Specific Survival https://pubmed.ncbi.nlm.nih.gov/26307654/ Inherited DNA-Repair Gene Mutations in Men With Metastatic Prostate Cancer https://pubmed.ncbi.nlm.nih.gov/27433846/ NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Prostate Cancer https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf PARP Inhibitors in Metastatic Prostate Cancer https://pubmed.ncbi.nlm.nih.gov/37168382/ Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration https://pubmed.ncbi.nlm.nih.gov/32795228/ Olaparib for Metastatic Castration-Resistant Prostate Cancer https://pubmed.ncbi.nlm.nih.gov/32343890/ Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200043 Rucaparib or Physician's Choice in Metastatic Prostate Cancer https://pubmed.ncbi.nlm.nih.gov/36795891/ FDA Approves Olaparib With Abiraterone and Prednisone (or Prednisolone) for BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer https://pubmed.ncbi.nlm.nih.gov/36952634/ Talazoparib Plus Enzalutamide in Men With First-line Metastatic Castration-Resistant Prostate Cancer (TALAPRO-2): A Randomised, Placebo-Controlled, Phase 3 Trial https://pubmed.ncbi.nlm.nih.gov/37285865/
In this episode, we discuss the diagnosis and management/monitoring of Clonal Cytopenias of Unknown Significance (CCUS) with Dr. Uma Borate. We also discuss the emerging data on risk stratification and key trials in this space that are currently ongoing. Here are the shownotes:1. CCUS and risk of transformation to myeloid neoplasms:https://www.sciencedirect.com/science/article/pii/S0006497121013471 2. Prediction of risk for myeloid neoplasms in clonal hematopoiesis:https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200310 3. CHRS risk score:http://www.chrsapp.com 4. Germline predisposition to clonal hematopoiesis: https://www.sciencedirect.com/science/article/abs/pii/S0145212623006094?via%3Dihubhttps://www.nature.com/articles/s41586-020-2819-2 5. Cancer therapy shapes the fitness landscape of clonal hematopoiesis:https://www.nature.com/articles/s41588-020-00710-0 6. Canakinumab for the prevention of progression to cancer in patients with Clonal Cytopenias of Unknown Significance, IMPACT Study:https://clinicaltrials.gov/study/NCT05641831?cond=CCUS%20Clonal%20Cytopenia%20of%20Undetermined%20Significance&rank=3 7. Ivosidenib in patients with CCUS and mutations in IDH1:https://classic.clinicaltrials.gov/ct2/show/NCT05030441https://sites.wustl.edu/pimm/
In this week's episode, we'll discuss pembrolizumab after autologous stem cell transplantation in patients with peripheral T-cell lymphoma. Newly reported phase 2 study results show that blocking PD-1 with pembrolizumab had a favorable safety profile and demonstrated promising activity, supporting further confirmatory studies in this setting; germline genetic predisposition to myeloid neoplasms in patients with hypoplastic bone marrow. Researchers report mutations that are significantly associated with cytopenias in adulthood in these patients. And pathogenic or likely pathogenic variants were linked to severe cytopenias and advanced myeloid malignancies; and finally, if monocytes and their descendants are less plastic than previously thought. Investigators have identified four functionally specialized monocyte subsets that derive from specific myeloid progenitor lineages. They show that the fate of these monocyte subsets is epigenetically scripted, with little flexibility after differentiation begins, even under conditions of stress.
Dr. Shannon Westin and her guest, Dr. Andreana Holowatyj, discuss the paper "Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer," recently published in JCO. 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, the podcast where we get in-depth on manuscripts and interesting papers that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, and it's my pleasure to serve not only as a GYN Oncologist but as an Associate Editor for Social Media for the JCO. And as always, I'm super excited about the paper that we're going to discuss today. This is “Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.” This has been published in the JCO. And I am so excited to be accompanied by the last author, Dr. Andreana Holowatyj, who is an Assistant Professor of Medicine and Cancer Biology at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center. Welcome. Dr. Andreana Holowatyj: Thank you, Dr. Westin, for having me. I'm really excited to get to talk about this paper. Dr. Shannon Westin: So are we. And please note that we do not have any conflicts of interest with this work. So let's get started. First, early-onset colorectal cancer is any colorectal cancer diagnosed before age 50. So I just wanted to level set. Can you give us a bit of background on the incidence of early-onset colorectal cancer? Dr. Andreana Holowatyj: Sure. All of the attention recently has been drawn to the fact that in contrast to incidence of colorectal cancer decreasing among adults over age 50, we've seen over the last several decades, this uptick—alarming uptick, in fact, in colorectal cancers among individuals diagnosed younger than age 50 years, or, as you point out, we call early-onset colorectal cancer, largely with reasons that are unexplained overall, which has drawn a lot of concern and attention as to what are the factors driving this marked increase in early-onset colorectal cancer both in the United States and globally. Dr. Shannon Westin: And what do we know about the burden of early-onset colorectal cancer across different racial and ethnic groups? Are there disparities in survival like we've seen in some of the other cancer types? Dr. Andreana Holowatyj: Yeah. So recently, a paper published demonstrating this greater shift towards early-onset colorectal cancer, where now we're seeing approximately 1 in every 8 adults with colorectal cancer being diagnosed under age 50. Add to that prior studies have shown that the proportion of early-onset colorectal cancer cases or incidence is actually higher among individuals who identify as non-White compared to those who identify as non-Hispanic White. We previously published in JCO a paper that assessed disparities in survival among early-onset colorectal cancer patients and strikingly found that individuals who identify as non-Hispanic Black had poorer survival compared with non-Hispanic Whites, both in colon and rectal tumors, specifically for young individuals. However, and of striking interest, we did not see these survival disparities between Whites and individuals who identify as Hispanic, which further led us to question what may be some of the biological, environmental, and other factors that may actually be driving some of these disparities by race and ethnicity, both in incidence but also in outcomes. Dr. Shannon Westin: So that kind of brings us to this study. Will you walk us through what the objective of this study was? Dr. Andreana Holowatyj: Yeah. So the underlying question really is what could be the role of germline genetic features or germline predisposition in early-onset colorectal cancer disparities? We know from prior studies published in JCO and other journals that about 14%-25% of early-onset colorectal cancer cases have a germline predisposition. However, these populations have been of limited size and, more importantly, of limited diversity. So we really wanted to tackle that question to understand what is the prevalence and spectrum of germline genetic features in early-onset colorectal cancer by race and ethnicity. Are there differences? Where do these differences lie? And what can this information really tell us in better understanding the early-onset colorectal cancer burden? Dr. Shannon Westin: Well, now, well, just talk us through the design that you employed to achieve these objectives. Dr. Andreana Holowatyj: We were fortunate to partner with a nationwide clinical testing laboratory to identify individuals who were between the ages of 15 and 49 years when diagnosed with the first primary colorectal cancer over about a five-year study period. We were able to identify around 4,000, or specifically 3,980 individuals, who identified as non-Hispanic White, non-Hispanic Black, Hispanic/Spanish or Latino, Asian, or Ashkenazi Jewish who had clinical multigene panel testing uniformly for 14 genes that have a known susceptibility to colorectal cancer overall, to really examine the prevalence and spectrum of genetic features across these self-identified racial/ethnic groups. Dr. Shannon Westin: And what was the overall prevalence of germline mutations in this population? And did it differ kind of overall in the different racial and ethnic groups? Dr. Andreana Holowatyj: Overall, the prevalence of germline genetic features when assessing 14 colorectal cancer susceptibility genes in this population was pretty consistent with prior studies at 12.2%, seeing about 1 in every 8 patients present with germline genetic predisposition. However, when we teased these numbers apart across racial/ethnic groups, what we saw is the prevalence of these germline genetic features ranged from 9.5% in individuals who identified as Asian to 10.3% of individuals who identified as Black, 12.4% as White, 12.7% for individuals who identify as Ashkenazim, all the way up to 14% of individuals who identify as Hispanic within this population. So we saw a wide—a decently wide breadth of prevalence across these racial/ethnic groups overall. Dr. Shannon Westin: And of course, as a gynecologic oncologist, I'm always centering myself and thinking about Lynch Syndrome. So how did the prevalence of mutations in the mismatch repair gene differ between racial and ethnic backgrounds? Dr. Andreana Holowatyj: So really interesting question. Overall, about 7% of individuals in our cohort presented with a pathogenic or likely pathogenic variant in the mismatch repair gene. But what we saw is that the prevalence of Lynch Syndrome varied from 3% or so of Ashkenazim individuals all the way up to 9.9% of Hispanic individuals. We saw that variance in MLH1 strongly differed across racial/ethnic groups, particularly in the Hispanic population, that accounted for some of these differences. Dr. Shannon Westin: And then were there any differences in some of the other germline mutations that you explored? Dr. Andreana Holowatyj: Yeah, we also observed differences in the prevalence of APC mutations, although largely attributable to the p.I1307K variant in Ashkenazim individuals, as well as CHEK2, monoallelic MUTYH, and PTEN. Dr. Shannon Westin: Okay. Interesting. I was intrigued about those findings for the monoallelic MUTYH variants. Do you think we should be potentially doing increased screening in specific populations based on your results? Dr. Andreana Holowatyj: Yeah, so I think to kind of put this into context, most people probably know that biallelic MUTYH variants yield MUTYH-associated adenomatous polyposis and, of course, confer a strong increased risk of colorectal cancer development. In monoallelic carriers of MUTYH variants, there really is limited evidence to guide clinical management, and this is an evolving area. Per NCCN guidelines, unaffected individuals with a monoallelic MUTYH pathogenic variant and a family history of colorectal cancer in a first-degree relative are recommended to get colonoscopy screening every five years beginning at age 40 or 10 years prior to the age of that first-degree relative of colorectal cancer diagnosis. However, for individuals with a monoallelic MUTYH variant and no known family history of colorectal cancer, it's inconclusive as to whether specialized screening and surveillance are warranted. Current studies conducted in European or predominantly White populations have reported conflicting evidence as to whether there is an increased colorectal cancer risk for carriers of a monolithic MUTYH pathogenic variant. I don't think we're quite there yet to make a conclusive decision on whether increased screening is warranted in the population or not. I think the evidence is leaning towards potentially seeing not a strong increased colorectal cancer risk, but we'll have to wait and see on some additional studies to be conclusive in that area. Dr. Shannon Westin: I was also intrigued—the lack of difference in germline features between Blacks and Whites was stark. I mean, why do you—what do you think might have led to us not seeing a difference there? Dr. Andreana Holowatyj: I think there's potentially two avenues for this. I want to caveat the fact that this could be attributable to a limited sample size. Although we had about over 1,000—just over 1,000 individuals who identified as non-White, there's still potential selection bias in this cohort. However, we have included about a comparable number of individuals who identified Blacks and Hispanics herein, which does raise this question of we see differences in germline genetic features between Whites and Hispanics, but the lack of difference between individuals who identify as White and Black kind of yields possibly two avenues. If germline genetic features do contribute to racial/ethnic differences in early-onset colorectal carcinogenesis and outcomes, then there's a chance that we have not yet identified ancestry-specific variants associated with early-onset colorectal cancer. This has marked implications in the development and equitable design of multigene panel tests. However, we also know that beyond genetics, the interplay with biology, social determinants of health, and behaviors could also underlie these distinct patterns. We recently demonstrated in a separate paper that we see actually differences in the tumor mutation burden between individuals who identify as Black or White, which is supporting the idea that a distinct tumor biology may be driving early-onset colorectal cancer disparities. And if there are no germline genetic features, then the question is really how does that interplay of the environment—some of these other complex interrelated factors, how could that be driving disparities in early-onset colorectal cancer incidence and outcomes, particularly for individuals who identify as Black? Dr. Shannon Westin: And I guess that kind of leads to my next question. The testing platform that you studied, is it all-inclusive? Are there other mutations that might be relevant, or just we don't know yet? Dr. Andreana Holowatyj: Yeah. So I think one of the advantages of this study is that all individuals had clinical multigene panel testing for the 14 genes that we evaluated overall. However, while that's a strength of the study, it's also a limitation, given that we only queried 14 genes with unknown colorectal cancer susceptibility, which really is a first step, yet a key step, in further studies and supporting further discovery of potential ancestry-specific variants or genes associated specifically with early-onset colorectal cancer predisposition. Dr. Shannon Westin: That makes a lot of sense. And I guess that's the next kind of natural question is so what do we do next, right? Where do we go? How do we move this forward? Dr. Andreana Holowatyj: Yeah. So I think one of the advantages of this approach and being fortunate to partner with the clinical testing laboratory is that the study was nationwide among individuals who, of course, had multigene panel sequencing. But at the same time, we were able to accumulate a sufficient number of cases to be able to study these patterns across population groups. I think the natural next step from multigene panel testing is based upon these findings to move into clinical exome sequencing to be able to not only move towards identifying genetic ancestry, since that's, of course, the biological construct—and I would be remiss if I didn't acknowledge that race and ethnicity is a social construct but was all that was available in the context of this present study—but also will allow us to query the entire exome and understand and dive deeper into some of these questions: variants of uncertain significance and also potential ancestry-specific variants. Dr. Shannon Westin: Well, great. Well, this is super intriguing, and I know this is going to get a lot of excitement and attention from our readership. So I just want to thank you again for taking the time to review this really important paper, “Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.” Again, I'm Shannon Westin, and I'm just so grateful that everyone came to listen to JCO After Hours. Please do check out our website for other podcasts you might have missed. Have a great one. 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 episode of ASCO Educational podcasts, we'll explore how we interpret and integrate recently reported clinical research into practice. The first scenario involves a 72-year old man with high-risk, localized prostate cancer progressing to hormone-sensitive metastatic disease. Our guests are Dr. Kriti Mittal (UMass Chan Medical School) and Dr. Jorge Garcia (Case Western Reserve University School of Medicine). Together they present the patient scenario (1:12), review research evidence regarding systemic and radiation therapy for high-risk localized disease (5:45), and reflect on the importance of genetic testing and (10:57) and considerations for treatment approaches at progression to metastatic disease (16:13). Speaker Disclosures Dr. Kriti Mittal: Honoraria – IntrinsiQ; Targeted Oncology; Medpage; Aptitude Health; Cardinal Health Consulting or Advisory Role – Bayer; Aveo; Dendreon; Myovant; Fletcher; Curio Science; AVEO; Janssen; Dedham Group Research Funding - Pfizer Dr. Jorge Garcia: Honoraria - MJH Associates: Aptitude Health; Janssen Consulting or Advisor – Eisai; Targeted Oncology Research Funding – Merck; Pfizer; Orion Pharma GmbH; Janssen Oncology; Genentech/Roche; Lilly Other Relationship - FDA Resources ASCO Article: Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019 ASCO Course: How Do I Integrate Metastasis-directed Therapy in Patients with Oligometastatic Prostate Cancer? (Free to Full and Allied ASCO Members) If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org. TRANSCRIPT Dr. Kriti Mittal: Hello and welcome to this episode of the ASCO Education Podcast. Today we'll explore how we interpret and integrate recently reported clinical research into practice, focusing on two clinical scenarios: localized prostate cancer progressing to hormone-sensitive metastatic disease; and a case of de novo metastatic hormone-sensitive prostate cancer progressing to castration-resistant disease. My name is Kriti Mittal and I am the Medical Director of GU Oncology at the University of Massachusetts. I am delighted to co-host today's discussion with my colleague, Dr. Jorge Garcia. Dr. Garcia is a Professor of Medicine and Urology at Case Western Reserve University School of Medicine. He is also the George and Edith Richmond Distinguished Scientist chair and the current chair of the Solid Tumor Oncology Division at University Hospital's Seidman Cancer Center. Let me begin by presenting the first patient scenario. Case 1: A 72-year-old male was referred to urology for evaluation of hematuria. A rectal exam revealed an enlarged prostate without any nodules. A CT urogram was performed that revealed an enlarged prostate with bladder trabeculations. A cystoscopy revealed no stones or tumors in the bladder, but the prostatic urethra appeared to be abnormal looking. Transurethral resection of the prostate was performed. The pathology revealed Gleason score 4+5=9 prostate cancer, involving 90% of the submitted tissue. PSA was performed one week later and was elevated at 50. Patient declined the option of radical prostatectomy and was referred to radiation and medical oncology. So I guess the question at this point is, Dr. Garcia, in 2023, how do you stage patients with high-risk localized prostate cancer and how would you approach this case? Dr. Jorge Garcia: That's a great question and a great case, by the way, sort of what you and I in our practice will call ‘bread and butter'. Patients like this type of case that you just presented come from different places to our practice. So either they come through urology or oftentimes they may come through radiation oncology. And certainly, it depends where you practice in the United States, at ‘X', US, they may come through medical oncology. So I think that the first question that I have is in whatever role I'm playing in this case, where the patient has seen a urologist or a rad onc or me first, I think it's important for us in medical oncology, at least in the prostate cancer space, to talk about how do we think of their case and put those comments into context for the patient. It's very simple for you to tell a patient you can probably have surgery, radiation therapy, but at the end of the day, how do you counsel that patient as to the implications of the features of his disease is going to be really important. I use very simple examples that I relate to my patients, but really this patient is a patient that has very high-risk prostate cancer based upon the NCCN guidelines and how we actually stratify patients into what we call low-risk, intermediate-, and high-risk, and between those very low and very high risk. So his PSA is high, very high, I would argue. His Gleason score, now, what we call group grading is high. He has high-volume disease. So the first question that I would have is, what are the choices for treatment for a patient like this? But even before you and I may talk about treatment options, we really want to understand the volume of their disease and whether or not they have localized prostate cancer with high-risk features or whether or not they have locally advanced or hopefully not metastatic disease. So back in the days prior to the FDA approval for PSMA PET imaging, we probably will have a Technetium-99 whole-body bone scan, and/or we probably will actually use CT scanning. Most people in the past, we used to do just a CT of the abdomen and pelvic region. As you know, with the movement of oral agents in the advanced setting, I think most of us will do a chest CT, abdomen and pelvic region, and certainly we also probably will have a Technetium-99 bone scan. Now, with the utility and the use of PET imaging, I think most people like him will probably undergo PET PSMA, where you use F-18 PSMA or Gallium-68 PSMA. I think the importance depends on how you look at the approval of these two technologies. I think that PET PSMA imaging is here to stay. It's probably what most of us will use. And based upon that, we will define yet the truest stage of this patient. So right now, what we know is he has high-risk features. Hopefully, their disease is localized. We'll probably put the patient through an imaging technology. If you don't have access to a PET, then obviously CT and a bone scan will do. But if you do, the PET will actually help us define if the patient has disease outside of the prostate region, in the pelvic area, or even if they have distant metastases. Dr. Kriti Mittal: I would agree with that approach, Dr. Garcia. I think in the United States, we've been late adopters of PSMA scans. I think this patient with high-risk localized disease, if insurance allows at our institution, would get a PSMA for staging. There are still some patients where insurance companies, despite peer-to-peer evaluations, are not approving PSMAs. And in those situations, the patient would benefit from conventional CTs and a bone scan. So let's say this patient had a PSMA and was found not to have any regional or distant metastases. He decided against surgery, and he is seeing you as his medical oncologist together with radiation. What would your recommendations be? Dr. Jorge Garcia: I think the bigger question is, do we have any data to suggest or to demonstrate that if in the absence of metastatic disease with conventional imaging or with emerging technologies such as PSMA PET, there is no evidence of distant disease, which I think you probably agree with me, that would be sort of unlikely with a patient with these features not to have some form of PSMA uptake somewhere in their body. But let's assume that indeed then the PSMA PET was negative, so we're really talking about high-risk localized prostate cancer. So I don't think we can tell a patient that radical prostatectomy would not be a standard of care. We never had a randomized trial comparing surgery against radiation therapy. This patient has already made that decision and surgery is not an option for him. If he, indeed, had elected radiotherapy, the three bigger questions that I ask myself are where are you going to aim the beam of that radiation therapy? What technology, dose, and fractionation are you going to use? And lastly, what sort of systemic therapy do you need, if any, for that matter? Where we do have some data maybe less controversial today in 2023 compared to the past? But I think the question is, do we do radiation to the prostate only or do we expand the field of that radiation to include the pelvic nodes? Secondly, do we use IMRT? Do you use proton beam or not? Again, that's a big question that I think that opens up significant discussions. But more important, in my opinion, is the term of hypofractionation. I think the field of radiation oncology has shifted away from the old standard, five, seven weeks of radiation therapy to more hypofractionation, which in simple terms means a higher dose over a short period of time. And there was a concern in the past that when you give more radiation on a short period of time, toxicities or side effects would increase. And I think that there is plenty of data right now, very elegant data, demonstrated that hypofractionation is not worse with regards to side effects. I think most of us will be doing or supporting hypofractionation. And perhaps even to stretch that, the question now is of SBRT. Can we offer SBRT to a selected group of patients with high-risk prostate cancer? And again, those are discussions that we will naturally, I assume, in your practice, in your group, you probably also have along with radiation oncology. Now, the bigger question, which in my mind is really not debatable today in the United States, is the need for systemic therapy. And I think we all will go back to the old data from the European EORTC data looking at the duration of androgen deprivation therapy. And I think most of us would suggest that at the very least, 24 months of androgen deprivation therapy is the standard of care for men with high-risk prostate cancer who elect to have local definitive radiation therapy as their modality of treatment. I think that whether or not it's 24 or 36, I think that the Canadian data looking at 18 months didn't hit the mark. But I think the radiation oncology community in the prostate cancer space probably has agreed that 24 months clinically is the right sort of the sweetest spot. What I think is a bit different right now is whether or not these patients need treatment intensification. And we have now very elegant data from the British group and also from the French group, suggesting, in fact, that patients with very high-risk prostate cancer who don't have evidence of objective metastasis may, in fact, benefit from ADT plus one of the novel hormonal agents, in this case, the use of an adrenal biosynthesis inhibitor such as abiraterone acetate. So I think in my practice, what I would counsel this patient is to probably embark on radiotherapy as local definitive therapy and also to consider 24 months of androgen deprivation therapy. But I would, based upon his Gleason score of group grading, his high-volume disease in the prostate gland, and his PSA, to probably consider the use of the addition of abiraterone in that context. Dr. Kriti Mittal: That is in fact how this patient was offered treatment. The patient decided to proceed with radiation therapy with two years of androgen deprivation. And based on data from the multi-arm STAMPEDE platform, the patient met two of the following three high-risk features Gleason score >8, PSA >40, and clinical >T3 disease. He was offered two years of abiraterone therapy. Unfortunately, the patient chose to decline upfront intensification of therapy. In addition, given the diagnosis of high-risk localized prostate cancer, the patient was also referred to genetic counseling based on the current Philadelphia Consensus Conference guidelines. Germline testing should be considered in patients with high-risk localized node-positive or metastatic prostate cancer, regardless of their family history. In addition, patients with intermediate-risk prostate cancer who have cribriform histology should also consider germline genetic testing. Access to genetic counseling remains a challenge at several sites across the US, including ours. There is a growing need to educate urologists and medical oncologists to make them feel comfortable administering pretest counseling themselves and potentially ordering the test while waiting for the results and then referring patients who are found to have abnormalities for a formal genetics evaluation. In fact, the Philadelphia Consensus Conference Guideline offers a very elegant framework to help implement this workflow paradigm in clinical practice. And at our site, one of our fellows is actually using this as a research project so that patients don't have to wait months to be seen by genetics. This will have implications, as we will see later in this podcast, not only for this individual patient as we talk about the role of PARP inhibitors but also has implications for cascade testing and preventative cancer screening in the next of kin. Dr. Jorge Garcia: Dr. Mittal, I think that we cannot stress enough the importance of genetic testing for these patients. Oftentimes I think one of the challenges that our patients are facing is how they come into the system. If you come through urology, especially in the community side, what I have heard is that there are challenges trying to get to that genetic counsel. Not so much because you cannot do the test, but rather the interpretation of the testing and the downstream effect as you're describing the consequences of having a positive test and how you're going to counsel that patient. If you disregard the potential of you having an active agent based upon your genomic alteration, is the downstream of how your family may be impacted by a finding such as the DNA repair deficiency or something of that nature. So for us at major academic institutions because the flow how those patients come through us, and certainly the bigger utilization of multi-disciplinary clinics where we actually have more proximity with radiation oncology urology, and we actually maybe finesse those cases through the three teams more often than not, at least discuss them, then I think that's less likely to occur. But I think the bigger question is the timing of when we do testing and how we do it. So there are two ways -- and I'd love to hear how you do it at your institution -- because there are two ways that I can think one can do that. The low-hanging fruit is you have tissue material from the biopsy specimen. So what you do, you actually use any of the commercial platforms to do genomic or next-generation sequencing or you can do in-house sequencing if your facility has an in-house lab that can do testing. And that only gets you to what we call ‘somatic testing', which is really epigenetic changes over time that are only found in abnormal cells. It may not tell you the entire story of that patient because you may be missing the potential of identifying a germline finding. So when you do that, did you do germline testing at the same time that you do somatic testing or did you start with one and then you send to genetic counseling and then they define who gets germline testing? Dr. Kriti Mittal: So at our site, we start with germline genetic testing. We use either blood testing or a cheek swab assay and we send the full 84-gene multigene panel. Dr. Jorge Garcia: Yeah, and I think for our audience, Dr. Mittal, that's great. I don't think you and I will be too draconian deciding which platform one uses. It's just that we want to make sure that at least you test those patients. And I think the importance of this is if you look at the New England Journal paper from many years ago, from the Pritchard data looking at the incidence of DNA repair deficiency in men with prostate cancer in North America, that was about what, around 10% or so, take it or leave it. So if you were to look only for germline testing, you only will, in theory, capture around 10% of patients. But if you add somatic changes that are also impacting the DNA pathway, then you may add around 23%, 25% of patients. So we really are talking that if we only do one type of testing, we may be missing a significant proportion of patients who still may be candidates, maybe not for family counseling if you had a somatic change, rather than germline testing, the positivity, but if you do have somatic, then you can add into that equation the potential for that patient to embark on PARP inhibitors down the road as you stated earlier. It may not change how we think of the patient today, or the treatment for that matter. But you may allow to counsel that patient differently and may allow to sequence your treatments in a different way based upon the findings that you have. So I could not stress the importance of the NCCN guidelines and the importance of doing genetic testing for pretty much the vast majority of our patients with prostate cancer. Dr. Kriti Mittal: Going back to our patient, three years after completion of his therapy, the patient was noted to have a rising PSA. On surveillance testing, his PSA rose from 0.05 a few months prior to 12.2 at the time of his medical oncology appointment. He was also noted to have worsening low back pain. A PSMA scan was performed that was noteworthy for innumerable intensely PSMA avid osseous lesions throughout his axial and appendicular skeleton. The largest lesion involved the right acetabulum and the right ischium. Multiple additional sizable lesions were seen throughout the pelvis and spine without any evidence of pathologic fractures. So the question is, what do we do next? Dr. Jorge Garcia: The first question that I would have is, the patient completed ADT, right? So the patient did not have treatment intensification, but at the very least he got at least systemic therapy based upon the EORTC data. And therefore, one would predict that his outcome will have been improved compared to those patients who receive either no ADT or less time on ADT. But what I'm interested in understanding is his nadir PSA matters to me while he was on radiation and ADT. I would like to know if his nadir PSA was undetectable, that's one thing. If he was unable to achieve an undetectable PSA nadir, that would be a different thought process for me. And secondly, before I can comment, I would like to know if you have access to his testosterone level. Because notably, what happens to patients like this maybe is that you will drive down testosterone while you get ADT, PSAs become undetectable. Any of us could assume that the undetectability is the result of the radiation therapy. But the true benefit of the combination of radiation and ADT in that context really comes to be seen when the patient has got off the ADT, has recovered testosterone, and only when your testosterone has normalized or is not castrated, then we'll know what happens with your serologic changes. If you rise your PSA while you recover testosterone, that is one makeup of patient. But if you rise your PSA while you have a testosterone at the castrated level, that would be a different makeup of a patient. So do we have a sense as to when the patient recovered testosterone and whether or not if his PSA rose after recovery? Dr. Kriti Mittal: At the time his PSA rose to 12, his testosterone was 275. Dr. Jorge Garcia: Okay, perfect. You and I would call this patient castration-naive or castration-sensitive. I know that it's semantics. A lot of people struggle with the castration-naive and castration-sensitive state. What that means really to me, castration-naive is not necessarily that you have not seen ADT before. It's just that your cancer progression is dependent on the primary fuel that is feeding prostate cancer, in this case, testosterone or dihydrotestosterone, which is the active metabolite of testosterone. So in this case, recognizing the patient had a testosterone recovery and his biochemical recurrence, which is the rising of his PSA occur when you have recovery of testosterone, makes this patient castration-sensitive. Now the PET scan demonstrates now progression of his disease. So clearly he has a serologic progression, he has radiographic progression. I assume that the patient may have no symptoms, right, from his disease? Dr. Kriti Mittal: This patient had some low back pain at the time of this visit. So I think we can conclude he has clinical progression as well. Dr. Jorge Garcia: Okay, so he had the triple progression, serologic, clinical, and radiographic progression. The first order of business for me would be to understand the volume of his disease and whether we use the US CHAARTED definition of high volume or low volume, or whether we use the French definition for high volume from Latitude, or whether we use STAMPEDE variation for definition, it does appear to me that this patient does have high-volume disease. Why? If you follow the French, it's a Gleason score of >8, more than three bone metastases, and the presence of visceral disease, and you need to have two out of the three. If you follow CHAARTED definition, we did not use Gleason scoring, the US definition. We only use either the presence of visceral metastases or the presence of more than four bone lesions, two of which had to be outside the appendicular skeleton. So if we were to follow either/or, this patient would be high-volume in nature. So the standard of care for someone with metastatic disease, regardless of volume, is treatment intensification, is you suppress testosterone with androgen deprivation therapy. And in this case, I'd love to hear how you do it in Massachusetts, but here, for the most part, I would actually use a GnRH agonist-based approach, any of the agents that we have. Having said that, I think there is a role to do GnRH antagonist-based therapy. In this case, degarelix, or the oral GnRH antagonist, relugolix, is easier to get patients on a three-month injection or six-month injection with GnRH agonist than what it is on a monthly basis. But I think it's also fair for our audience to realize that there is data suggesting that perhaps degarelix can render testosterone at a lower level, meaning that you can castrate even further or have very low levels of testosterone contrary to GnRH agonist-based approaches. And also for patients maybe like this patient that you're describing, you can minimize the flare that possibly you could get with a GnRH agonist by transiently raising the DHT before the hypothalamic-pituitary axis would shut it down. So either/or would be fine with me. Relugolix, as you know, the attraction of relugolix for us right now, based upon the HERO data, is that you may have possibly less cardiovascular side effects. My rationale not to use a lot of relugolix when I need treatment intensification is quite simple. I'm not aware, I don't know if you can mitigate or minimize that potential cardiovascular benefit by adding abiraterone or adding one of the ARIs, because ARIs and abiraterone by themselves also have cardiovascular side effects. But either/or would be fine with me. The goal of the game is to suppress your male hormone. But very important is that regardless of volume, high or low, every patient with metastatic disease requires treatment intensification. You can do an adrenal biosynthesis inhibitor such as abiraterone acetate. You can pick an androgen receptor inhibitor such as apalutamide or enzalutamide if that's the case. The subtleties in how people feel comfortable using these agents, I think, none of us – as you know, Dr. Mittal - can comment that one oral agent is better than the other one. Independently, each of these three oral agents have randomized level 1, phase III data demonstrating survival improvement when you do treatment intensification with each respective agent. But we don't have, obviously, head-to-head data looking at this. What I think is different right now, as you know, is the data with the ARASENS data, which was a randomized phase III trial, an international effort looking at triple therapy, and that is male hormone suppression plus docetaxel-based chemotherapy against testosterone suppression plus docetaxel-based chemotherapy plus the novel androgen receptor inhibitor known as darolutamide. This trial demonstrated an outcome survival improvement when you do triple therapy for those high-volume patients. And therefore, what I can tell you in my personal opinion and when I define a patient of mine who is in need of chemotherapy, then the standard of care in my practice will be triple therapy. So if I know you are a candidate for chemotherapy, however, I make that decision that I want you to get on docetaxel upfront. If you have high-volume features, then the standard of care would not be ADT and chemo alone, it would be ADT, chemo, and darolutamide. What I don't know, and what we don't know, as you know, is whether or not triple therapy for a high-volume patient is better, the same, equivalent, or less than giving someone ADT plus a novel hormonal agent. That is the data that we don't have. There are some meta-analyses looking at the data, but I can tell you that at the very least, if you prefer chemo, it should be triple therapy. If you prefer an oral agent, it certainly should be either apalutamide, abiraterone acetate, and/or enzalutamide. But either/or, patients do need treatment intensification, and what is perplexing to me, and I know for you as well, is that a significant proportion of our patients in North America are still not getting treatment intensification, which is really sub-optimal and sub-standard for our practice. Dr. Kriti Mittal: Thank you, Dr. Garcia, for a terrific discussion on the application of recent advances in prostate cancer to clinical practice. In an upcoming podcast, we will continue that discussion exploring management of de novo metastatic prostate cancer. The ASCO Education Podcast is where we explore topics ranging from implementing new cancer treatments and improving patient care to oncologists' well-being and professional development. If you have an idea for a topic or a guest you'd like to see on the ASCO Education Podcast, please email us at education@asco.org. To stay up to date with the latest episodes and explore other educational content, please visit education.asco.org. 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.
Rick Greene, MD, discusses with Julie Culver, MS, LCGC, CCRP, the implementation of genetic testing for all patients with breast cancer and how this can be incorporated into oncology care. Ms. Culver is author of “Integration of Universal Germline Genetic Testing for All New Breast Cancer Patients.” Julie Culver is the Director of Genetic Counseling at the USC Norris Cancer Hospital and is a Clinical Instructor of Medicine at the USC Keck School of Medicine, Los Angeles, CA. http://doi.org/10.1245/S10434-022-12595-W
We are excited to partner with GoPath Diagnostics for today's podcast and have Dr. Paul Yonover join us on the show to bring listeners up to speed on the newly-available comprehensive germline test called ProstateNow that addresses all patient needs specific to prostate cancer. Dr. Paul Yonover is a board-certified urologist who completed his residency programs in surgery and urology at Loyola University Medical Center. Dr. Yonover has done extensive research in urology and has published in numerous clinical journals. He is the Chief Analytics Officer and Director of Clinical Research for Uro Partners in Chicago, Illinois. In addition, he is currently a Clinical Assistant Professor of Urology at the University of Illinois Chicago College of Medicine and a Chief of Urology at Advocate Illinois Masonic Hospital and Amita Presence St. Joseph Hospital. Tune in to find out what the ProstateNow test is, how it works, who can benefit from it, and how urologists are incorporating it into their clinical practices! Disclaimer: The Prostate Health Podcast is for informational purposes only. Nothing in this podcast should be construed as medical advice. By listening to the podcast, no physician-patient relationship has been formed. For more information and counseling, you must contact your personal physician or urologist with questions about your unique situation. Show highlights: Dr. Yonover explains how he approaches germline testing related to prostate cancer in his practice. Dr. Yonover explains the importance of identifying the rare pathogenic mutations that are risk factors for disease. Why is family history a risk factor for prostate cancer? What should patients be advised to do if they have a pathogenic mutation? Dr. Yonover explains what rare pathogenic mutations are. Some of the historic barriers urologists and oncologists have had in integrating prostate cancer genetic testing into their practices. How did Dr. Yonover's practice overcome the barriers and incorporate germline testing? Dr. Yonover dives into what the ProstateNow test is and how it works. Dr. Yonover shares some important things to bear in mind regarding germline testing. Links: Follow Dr. Pohlman on Twitter and Instagram - @gpohlmanmd Get your free What To Expect Guide (or find the link on our podcast website) Join our Facebook group Follow Dr. Pohlman on Twitter and Instagram Go to the Prostate Health Academy to sign up. You can access Dr. Pohlman's free mini webinar, where he discusses his top three tips to promote men's prostate health, longevity, and quality of life here. GoPath Diagnostics UroPartners
In this bonus episode Associate Editor, Dr. Mario Cazzola discusses the review series on Germline predisposition to hematologic malignancies with authors, Dr. Lucy Godley, Dr. Anna Brown, and Dr. Dennis Hickstein.
In this episode of BackTable Urology, Dr. Aditya Bagrodia, Dr. Ari Hakimi (Memorial Sloan Kettering Cancer Center), and Dr. Nirmish Singla (Johns Hopkins University), discuss the value and indications for germline testing in renal cell carcinoma (RCC). --- SHOW NOTES First, the doctors explain basic information about germline mutations and kidney cancer. Although historical data has shown that 5% of kidney cancers are inherited, recent efforts to increase testing through commercial testing and large scale efforts at cancer centers have proven that 8-10% of kidney cancers are inherited. Von Hippel Lindau (VHL) syndrome is the most prototypical kidney cancer predisposition syndrome, but there are other less common ones as well. Extrarenal manifestations of VHL syndrome include pancreatic tumors, pancreatic cysts, pheochromocytomas, retinoblastomas, and CNS hemangioblastomas. These tumors have a variable penetrance, but African Americans and women are more likely to have hereditary RCC. The doctors recommend asking newly diagnosed RCC patients about a broad spectrum of their family history that includes cancer and non-malignant conditions, such as uterine leiomyomata. Dr. Hakimi notes that some patients will confuse germline testing with somatic tumor testing, so urologists will have to explain to patients that the VHL mutation was found in their tumor, not in their blood or saliva. Extended physical exams to look for syndromic conditions can also be performed. A thorough cutaneous exam to look for fibrofolliculomas, leiomyomas, facial angiofibromas, and cafe-au-lait spots can help indicate the presence of a familial syndrome. According to guidelines, all patients diagnosed with RCC under 46 years of age should be recommended to have germline testing. Dr. Bagrodia mentions that having experienced genetic counselors and setting up thorough dot phrases to send to patients explaining their results is helpful for him. Dr. Singla adds that medical geneticists have the ability to counsel the patients more extensively on the risks and benefits of giving consent to go forward with genetic testing. They can also provide psychosocial support and education for the patients. The doctors then move on to discuss how germline mutations may lead to different treatment modalities. Precision surgery, or utilizing pretest probability information about a tumor to guide surgical approach, may be possible with germline testing. Additionally, testing may help surgeons to decide whether to perform a retroperitoneal lymph node dissection (RPLND). Next, the doctors discuss belzutifan, which is an oral drug used to treat VHL familial syndrome tumors. Finally, they discuss the use of tumor sequencing for research purposes and share what they are most excited for in the field of RCC research.
In this episode of BackTable Urology, Dr. Aditya Bagrodia interviews Dr. Todd Morgan, chief of urologic oncology at the University of Michigan, about benefits and indications for germline testing in prostate cancer patients. --- SHOW NOTES First, the doctors discuss the formal definition of germline testing, which is identifying inherited DNA mutations known to be pathological. This is different from molecular testing, which detects molecular markers specific to tumor cells. The term “genomic testing” is a broad and vague term that may confuse patients. Germline testing may be beneficial to patients and their families by notifying them to undergo cancer screening earlier. 12% of metastatic prostate cancer patients and 5 to 10% of localized prostate cancer patients have a germline mutation. Next, they discuss critical criteria for germline testing besides having a high grade and high stage cancer. Dr. Morgan recommends germline testing for all prostate cancer patients with metastatic cancer. He also believes that taking a thorough family history is fundamentally important in deciding whether or not to order testing. He emphasizes the importance of collecting information about other family members with other types of cancer, their age of diagnosis, their relationship to the patient, and their mortality from cancer. Patients may not know family history well, but he has a low threshold of testing if he suspects a pattern of heritability. Then, Dr. Morgan explains how germline testing may affect decision making. For patients with localized and low risk disease, he notes that prompt treatment may be beneficial in patients with a BRCA2 mutation, but there is still not enough evidence to eliminate active surveillance as an option. For high-risk disease, he always recommends treatment over active surveillance, regardless of germline mutation. For patients who have a BRCA2 mutation but no diagnosis of prostate cancer, he counsels them in his high risk prostate clinic. These patients receive close screening measures, such as lower PSA level thresholds, identification of urine biomarkers, and MRI scans. Additionally, the doctors discuss various testing companies. They do not recommend using 23 and Me as a comprehensive screening panel because it is exceedingly limited in the germline mutations it tests. Dr. Morgan also emphasizes that as the ordering physician, he is responsible for giving the patient the result of the test. If there is a positive result on germline mutation testing, he refers the patient to genetic counselors, who are equipped to deal with conversations regarding mutations that have non-urological implications as well. Finally, they end the discussion by chatting about different research trials about germline testing.
Emily Fassi stumbled across the field of genetic counseling when she was trying to figure out what she could do with her biology degree. Today, she is the Lead Genetic Counselor for the St. Luke's Health System, specializing in hereditary cancer predisposition. Since genetic counseling came into existence as a profession, it has evolved an enormous amount, and continues to change at a rapid rate. In this episode, Emily explains what her role as a genetic counselor entails, why this work is so important, where the main limitations lie, and what she hopes the field will look like in the future. Emily's passion for the genetic counseling realm is palpable, and this episode is full of fascinating information about a relatively little-known field which will intrigue medical and non-medical professionals alike! “Our genetic testing capabilities are changing so quickly that it is literally a full-time job just to keep up with the changes in the genetic testing space.” — @EmilyFassi Key Points from this Episode Emily explains what her work as a genetic counselor entails. How the genetics and medical fields complement one another. Continuous evolution that is taking place in the field of genetics. How Emily found out about genetic counseling, and what drew her to the field. Levels of detail that genetic counselors are able to provide their patients with, in comparison to physicians. Emily's experience working in the pediatric and rare disease counseling realm, and how this contrasts to the oncology genetic counseling realm she is now working in. The process of deciding which genetics tests to do on a patient. Germline versus somatic mutations, and the increasing frequency of paired testing. Limitations of the guidelines around who should have genetic testing. Comparing polygenic and monogenic testing, and why Emily is excited about the former. Changes that Emily hopes to see take place in the genetic counseling field in the future. Some of the factors that lead to preventable cancers not being picked up early enough.
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