Podcasts about Mylan

Quatorzième épisode de Lucarne Américaine, on fait le tour de l'actualité aux Amériques avec l'actualité continentale (CONCAChampions, Libertadores et Sudamericana) et un nouveau scandale aux paris sportifs au Brésil avant un dossier consacré à la tragédie qui a touché le Chili en milieu de semaine dernière. Présenté par Nicolas Cougot   Pour élire le #golazolo ⤵️ https://x.com/LucarneOpposee/status/1911904479558988030   Lucarne Américaine, tous les lundis à 22h sur LOTV

This Day in Legal History: Patent Act of 1790On April 10, 1790, the United States passed its first patent law, the Patent Act of 1790, laying the groundwork for a legal framework that would protect inventors and promote innovation. This early legislation granted inventors the exclusive right to their discoveries for a period of 14 years, provided the invention was deemed "useful and important." It was signed into law by President George Washington and represented one of the earliest legal efforts by the new republic to encourage economic growth through technological advancement. The law established a board composed of the Secretary of State, the Secretary of War, and the Attorney General, who were tasked with reviewing patent applications and deciding whether to approve them.Notably, the law gave the federal government broad discretion over what could be patented and required that a patent be granted only if the invention was new and useful. The first U.S. patent under this act was issued on July 31, 1790, to Samuel Hopkins for a process of making potash, a key industrial chemical. Although modest in scope, the law was revolutionary in its recognition of intellectual property as a public good worth safeguarding. It helped move the United States toward a more structured innovation economy, setting a precedent that influenced global norms on patent protection.The 1790 law was replaced just three years later by the Patent Act of 1793, which shifted the review process to a more administrative function, but the foundational principle—that inventors should have exclusive rights to their creations—remained intact. This early commitment to fostering invention through legal means helped spur the rapid technological growth that would define American industry in the 19th century and beyond. The act exemplified how the law could be used to incentivize creativity and economic development at a national scale.Bristol Myers Squibb successfully got a proposed class action lawsuit dismissed that had accused it of using fraudulent tactics to maintain a monopoly over its cancer drug, Pomalyst. The suit, led by Blue Cross Blue Shield of Louisiana, claimed that Bristol Myers and its subsidiary Celgene illegally secured patents and filed sham lawsuits to delay the entry of generic versions of Pomalyst, which is used to treat multiple myeloma. However, U.S. District Judge Edgardo Ramos ruled that the plaintiffs failed to prove that any of the six patents were obtained through fraud. He also found no evidence that the nine lawsuits Celgene filed between 2017 and 2020 against generic manufacturers like Teva and Mylan were baseless or intended to secure fraudulent settlements.The plaintiffs alleged that they had been overpaying for the drug since October 2020, the point at which generics could have entered the market if not for the alleged conduct. Pomalyst brought in $3.55 billion in sales in 2024, accounting for more than 7% of Bristol Myers' revenue. Celgene originally developed the drug, and Bristol Myers acquired the company in 2019. The case was heard in the U.S. District Court for the Southern District of New York.Bristol Myers wins dismissal of lawsuit alleging Pomalyst monopoly | ReutersThe Trump administration has frozen over $1 billion in federal funding for Cornell University and $790 million for Northwestern University amid investigations into alleged civil rights violations. The freeze affects grants and contracts from several federal agencies, including health, education, agriculture, and defense. This move is part of a broader crackdown targeting universities over pro-Palestinian campus protests, diversity programs, and transgender policies. The administration previously warned 60 universities, including Cornell and Northwestern, about potential enforcement if they failed to address what it labeled as antisemitism.Cornell confirmed it received “stop work” orders from the defense department affecting research projects but said it hasn't been formally notified of the total funding freeze. Northwestern similarly acknowledged awareness of media reports but stated it hadn't received official notice. The university emphasized the freeze could endanger critical research, including projects on cybersecurity, pacemakers, and Alzheimer's treatment.This action follows similar measures taken against Harvard, Princeton, Columbia, and the University of Pennsylvania. Columbia, which lost $400 million in funding, later agreed to administrative changes in exchange for potential reinstatement. Federal agents have also begun detaining and deporting some foreign student protesters, revoking visas in the process. Critics, including human rights groups, have voiced concerns over free speech, academic freedom, Islamophobia, and anti-Arab discrimination amid the escalating response to pro-Palestinian activism on campuses.US freezes funding for Cornell, Northwestern University in latest crackdownPresident Trump has issued a new executive order aimed at blocking state-level climate policies that seek to reduce fossil fuel use and limit carbon emissions. The directive instructs the U.S. attorney general to identify and challenge state laws related to climate change, environmental justice, ESG (environmental, social, and governance) standards, and carbon regulation. The move aligns with Trump's broader agenda to boost domestic fossil fuel production and roll back Democratic-led environmental initiatives.The order specifically targets policies in states like New York, Vermont, and California, including financial penalties on fossil fuel companies, California's cap-and-trade system, and climate-related lawsuits brought by state governments. Trump described these measures as ideologically driven and harmful to national energy and economic security.Governors Kathy Hochul (NY) and Michelle Lujan Grisham (NM), co-chairs of the U.S. Climate Alliance, condemned the order, asserting states' rights to enact environmental protections. They reaffirmed their commitment to clean energy and climate resilience. The American Petroleum Institute supported Trump's move, framing it as a defense against unconstitutional state actions that burden oil and gas companies.Trump issues order to block state climate change policies | Reuters This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.minimumcomp.com/subscribe

Mylan Pharmaceuticals Inc. v. Bausch Health Ireland Ltd.

SEASON: 5 EPISODE: 5Episode Overview:Crisis can strike at any moment. Are you or your business crisis capable? My guest today will share with us strategies and tactics to become crisis capable, how we can build our capacity to survive, and succeed in every environment. She will also be sharing her key messages on how to approach negotiations as relationship-building opportunities, how to think through scenarios and formulate a plan in advance, how to notice details that others may overlook, how to leverage your EQ to remain calm and navigate difficult conversations, and how to lean into your intuition and follow any hunch.Fabiana is a passionate advocate for negotiation, and she is committed to helping others to develop the skills they need to succeed in any situation.Please join me for my interesting conversation with Fabiana-Lacerca-Allen.Guest Bio: Fabiana Lacerca-Allen is the Senior Vice President of Compliance at Aimmune Therapeutics, a Nestle Health Science corporation, a biopharmaceutical company developing treatments for potentially life-threatening food allergies.Practicing law and compliance for more than 30 years, Lacerca-Allen's passion as a compliance leader stems from values instilled in her at an early age and have helped to shape her career path as a global thought leader in law and compliance. In addition to leading the compliance team at Aimmune, Lacerca-Allen serves as a member of the Board of Directors and an audit Committee member at Shield Therapeutics plc.Lacerca has a track record of building and implementing successful compliance programs across Fortune 100 organizations, particularly within pharmaceutical, biotech and medical device industries. Her expertise includes negotiating and implementing corporate integrity agreements, deferred prosecution agreements and consent decrees for U.S. corporations with extensive global operations.Prior to her roles at Aimmune , Lacerca-Allen was the Senior Vice President and Chief Compliance Officer at Elan where she had global responsibilities in strategic initiatives and implementation of compliance programs. And prior to this, she held roles as a Board Member at ArthroCare, Senior Vice President and Chief Compliance Officer at Mylan, Director of Compliance at Bristol Myers & Squibb and Senior Counsel at Microsoft.Resource Links:Website: https://fabianalacercaallen.com/Product Link: https://www.amazon.com/Crisis-Capable-Building-Capacity-Environment-ebook/dp/B0D9BY131HInsight Gold Timestamps:03:02 We're all going to die, so don't worry about it. Worry about what you're going to live for04:24 You overheard a conversation with your father 06:04 He said, That's why you should only get information when you can do something about it07:54 Most people follow action09:45 Somebody asked me, How do you choose people to work with?11:43 I think intuition is important, as a marker to pay more attention14:05 D on't collect regrets17:29 There's no situation that's not a win win, that's sustainable19:58 Your bottom line is, you have to be willing to walk out of anything, period23:18 One typical mistake I found23:50 We have more in common than not25:21 What are the three things that people that don't like you will tell me about you? 28:25 I say, Act with integrity and accept the results30:16 The book is called Crisis Capable, Building Your...

Comment les rhumatologues peuvent-ils gérer la prescription d'un vaccin en tenant compte des traitements immunosuppresseurs ? Quel est le délai recommandé pour vacciner un patient ayant récemment contracté une infection, et pourquoi ? Quels sont les conseils pour motiver les patients qui hésitent ou ont des inquiétudes face aux vaccins ? Comment adapter les recommandations vaccinales en fonction des spécificités des patients en rhumatologie ? Le Professeur Jacques Morel, rhumatologue au CHU de Montpellier et responsable du centre de référence des maladies auto-immunes, nous éclaire à ce sujet. Notre invité déclare avoir des liens d'intérêt avec : Bristol Myers Squibb, Celltrion, Lilly, Novartis, Pfizer, Sanofi, Merck Sharp and Dohme, Abbvie, Fresenius Kabi, Mylan, Boehringer Ingelheim, Galapagos, Glaxo Smith Kline, Roche, Union Chimique Belge, Janssen, Medac, Sandoz, Nordic Pharma. L'équipe : Comité scientifique :  Pr Jérémie Sellam, Pr Thao Pham, Dr Catherine Beauvais, Dr Véronique Gaud Listrat, Dr Nicolas Poursac, Dr Céline Vidal, Dr Margaux Moret. Animation : Marguerite de Rodellec Production : MedShake Studio Soutien institutionnel : Pfizer

Regeneron Pharmaceuticals, Inc. v. Mylan Pharmaceuticals Inc.

Regeneron Pharmaceuticals, Inc. v. Mylan Pharmaceuticals Inc.

Janssen Pharmaceuticals, Inc. v. Mylan Laboratories Ltd.

Quelles sont les raisons principales pour lesquelles les rhumatologues doivent s'intéresser à la vaccination ? Quels sont les nouveaux vaccins susceptibles d'avoir un impact sur les patients suivis en rhumatologie ? Quelles avancées récentes marquent l'actualité dans le domaine des vaccinations ?  Le Professeur Jacques Morel, rhumatologue au CHU de Montpellier et responsable du centre de référence des maladies auto-immunes, nous éclaire à ce sujet. Notre invité déclare avoir des liens d'intérêt avec : Bristol Myers Squibb, Celltrion, Lilly, Novartis, Pfizer, Sanofi, Merck Sharp and Dohme, Abbvie, Fresenius Kabi, Mylan, Boehringer Ingelheim, Galapagos, Glaxo Smith Kline, Roche, Union Chimique Belge, Janssen, Medac, Sandoz, Nordic Pharma. L'équipe : Comité scientifique :  Pr Jérémie Sellam, Pr Thao Pham, Dr Catherine Beauvais, Dr Véronique Gaud Listrat, Dr Nicolas Poursac, Dr Céline Vidal, Dr Margaux Moret. Animation : Marguerite de Rodellec Production : MedShake Studio Soutien institutionnel : Pfizer

Broadcast from KSQD, Santa Cruz on 1-23-2025: Dr. Dawn announces a recall of Mylan's generic levothyroxine due to quality testing failures, affecting lots expiring in 2025 that don't meet FDA's 5% threshold for stated content. She provides comprehensive guidance on health impacts from the Moss Landing California battery fire, discussing cancer risks, heavy metal exposure, and detoxification methods including testing options and protective measures. The show explores promising research on bisphosphonate treatment for osteoporosis prevention, discussing a study showing one or two doses of Reclast could prevent fractures in post-menopausal women with normal bone density. Dr. Dawn examines innovative research on transplanting foot sole cells to improve prosthetic comfort for amputees, explaining how fibroblast transplantation could create more durable skin surfaces. She discusses alternative treatments for gallstones, particularly focusing on using ursodiol combined with lithotripsy as a potential surgery alternative for high-risk patients. The show addresses listener questions about knee injections for osteoarthritis, explaining cortisone's benefits and discussing vitamin supplementation including vitamins D3 and K2 for bone health. Dr. Dawn provides detailed information to a caller about ischial bursitis treatment, discussing injection techniques and cushioning options for managing tailbone area pain.

Regeneron Pharmaceuticals, Inc. v. Mylan Pharmaceuticals Inc.

In this episode, Mylan and Rick from Decolonized Buffalo have a conversation on the presence and pressure of "the holidays" and delving into the colonial and systemic roots of Christmas and its impact on Indigenous communities. They discuss the social pressure of this season, challenges of family dynamics, commercialization of the holidays, and the stress of navigating colonizer traditions while raising children in a settler society. The conversation touches on history, family dynamics, food culture, Indigenous cuisines, and the financial burdens tied to holiday expectations. They also emphasize the importance of centering Indigenous voices in media, promoting safety during the holiday season, and fostering meaningful connections over materialism.

Regeneron Pharmaceuticals, Inc. v. Mylan Pharmaceuticals Inc.

Regeneron Pharmaceuticals, Inc. v. Mylan Pharmaceuticals Inc.

More than 6000 women have signed a petition calling for Pharmac to keep funding their preferred HRT patches after they were blind sided by the agency's decision to change to a brand many say does not work for them. Following a shortage of estrogen patches, Pharmac has decided to switch the hormone therapy patches it funds from Estradot to Mylan by the end of next year. Pharmac Chief Executive Sarah Fitt spoke to Lisa Owen. 

Estrogen patches have been in short supply and this week Pharmac revealed it's changing suppliers for funded HRT patches exclusively to Mylan, from the end of next year. Meaning alternatives like Estradot patches, that many women find more effective, will no longer be subsidised. Westmere Pharmacist Samantha Tibshraeny spoke to Lisa Owen.

Increased restrictions for HRT menopause treatment, as Pharmac finds ways shore up supply of oestradiol patches. It's changing its main funded brand to Estradiol TDP Mylan from supplier Viatris from next July. In order to ensure supply, it'll be the only funded brand available by December 2025. Menodoctor Clinical Director, Linda Dear, says those who can't use the Mylan brand will have other options. "Most women who get on with other, non-Mylan brands will get on with gel fine - but it means they'll have to start probably thinking about that transition." LISTEN ABOVESee omnystudio.com/listener for privacy information.

In February 1998, 20-year-old Steven Mylan left Ontario to visit the United States to purchase a hair loss medication. A few days later, his car was found in Arizona, but there was no sign of Steven. (Case 1)On July 21st, 1997, Harold "Bill" Roland vanished from his lake house on Lake Sam Rayburn in Texas. Over the following months, his belongings were found and they indicated foul play was involved in Bill's disappearance. (Case 2)Email: keytothecase@gmail.comInstagramSources:https://www.newspapers.com/image/516612074/?match=1&terms=Steven%20Mylan https://www.newspapers.com/image/517352365/?match=1&terms=Steven%20Mylan https://charleyproject.org/case/steven-vincent-mylanhttps://ucfiles.com/CA/104200195.phphttps://www.washingtonpost.com/archive/politics/1996/02/13/fda-approves-nonprescription-rogaine/75c3bf83-d4c4-46af-afac-5e66dfb14807/https://www.newspapers.com/image/590410389/?match=1&terms=%22Harold%20William%20Roland%22 https://www.newspapers.com/image/590408788/?match=1&terms=%22Harold%20William%20Roland%22 https://www.dailysentinel.com/news/local/mystery-behind-lufkin-man-s-disappearance-still-unsolved/article_2845720e-2fc6-11e3-825f-0019bb2963f4.html https://lufkindailynews.com/news/local/man-s-disappearance-still-a-mystery-20-years-later/article_eef21c14-6dba-11e7-a916-1bd9ea49721c.html https://www.cbs19.tv/article/news/local/dps-asking-public-for-information-on-lufkin-man-who-disappeared-more-than-20-years-ago/501-614956721 https://www.youtube.com/watch?v=C8sfb_lIqCI https://www.ketk.com/news/special-reports/vanished/vanished-harold-william-roland/ https://www.dps.texas.gov/apps/coldCase/Home/Details/135https://web.archive.org/web/20220813054216/https://www.texasranger.org/wp-content/uploads/2017/07/Oral-History-Morris-Don.pdf

Dans cet épisode, nous recevons Florian Lecerf, fondateur de 135 Média, et Mylan Aké, chef de projet digital, pour explorer l'univers du rap sur les réseaux sociaux. Comment les artistes et les marques adaptent-ils leurs stratégies social media dans un monde où la viralité prime ? Découvrez les clés d'une stratégie social media efficace pour les rappeurs, l'influence des réseaux sur l'évolution du genre, et les insights de l'agence 135 Média sur le futur de cette alliance.Un épisode inspirant pour quiconque s'intéresse à l'influence croissante du digital sur la musique.Bonne écoute

Andréa et Pierre sont ensemble depuis 9 ans. Basés à Bordeaux, ils sont mariés depuis 2 ans et ont deux enfants, Mylan 5 ans et Nina 1 an.Andréa a 30 ans, elle est gestionnaire de contrat en assurance et Pierre a 28 ans, il est gérant d'un organisme de formation en Santé et Sécurité au travail (2PSI). Hébergé par Acast. Visitez acast.com/privacy pour plus d'informations.

Welcome to the daily304 – your window into Wonderful, Almost Heaven, West Virginia.   Today is Tuesday, Sept. 10, 2024. A Morgantown company is blazing new ground in AI drug development…Huntington's Corduroy Brown goes on safari for the band's new video…and MHIRJ Aviation's leaders discuss the company's future in #YesWV (hint…it involves more jobs!)…on today's daily304.   #1 – From DOMINION POST – GATC West Virginia is breaking new ground in using artificial intelligence to craft new molecules to cure diseases, and in drastically reducing the staggering costs of developing and bringing drugs to market. GATC WV was one of the first tenants in WVU Innovation Corp.'s new headquarters — what was the Mylan plant.  In March, the state Economic Development Authority and the Jobs Investment Trust approved a $5 million investment into GATC WV to bring jobs here and advance its work. The company has received its first $2 million and will receive an additional $1 million for each 10 people it hires, according to GATC Health Chief Operating Officer Ty Lam. “We're bringing talent back into the state and keeping talent in the state,” Lam said. Read more: https://www.dominionpost.com/2024/08/03/morgantown-company-gatc-west-virginia-blazing-trails-in-ai-drug-development-and-financing/   #2 – From WOUB.ORG – Be warned: watching the music video for Corduroy Brown's latest single, Doin' My Best, might conjure the urge to dust off your old pith helmet and go wandering. In the video, Alan “Corduroy” Brown and musical collaborators Chris Barker (bassist/Alan's best friend) and Jacob Barr (drummer) explore the Appalachian wilderness of Kenova, West Virginia. And, well, it looks like a lot of fun. The video premiered on Aug. 20 and you can watch it using this link. Check out the Huntington-based band via Instagram, YouTube, Apple Music and Spotify. Read more: https://woub.org/2024/08/20/corduroy-brown-debuts-music-video-for-new-single-tonight/   #3 – From INNOVATORS & ENTREPRENEURS – Ross Mitchell, Vice-President of MHIRJ Aviation Global, and Michael Genin, Director of Operations for MHIRJ Aviation in Bridgeport, West Virginia, talk about soaring to new high heights in #YesWV. MHIRJ is the leader in aviation maintenance for the CRJ Series, the world's most successful regional jet. With more than 550 employees in West Virginia and state-of-the-art hangars in Bridgeport, MHIRJ supports the top three airlines in the US and top regional airlines in the world. The company is in the process of hiring 400 technicians and is looking to fill over 100 job vacancies over the next year. Check out the interview on Innovators and Entrepreneurs, a bi-weekly segment of the daily304 that features discussions and wisdom from West Virginians who have built their companies and launched new ideas here in the Mountain State. Read more: https://www.youtube.com/watch?si=8vN8ag1ltoIKhao0&v=fs0uSJ5IgIA&feature=youtu.be   Find these stories and more at wv.gov/daily304. The daily304 curated news and information is brought to you by the West Virginia Department of Commerce: Sharing the wealth, beauty and opportunity in West Virginia with the world. Follow the daily304 on Facebook, Twitter and Instagram @daily304. Or find us online at wv.gov and just click the daily304 logo.  That's all for now. Take care. Be safe. Get outside and enjoy all the opportunity West Virginia has to offer.  

Hi, I'm John Sorensen, President of Evangelism Explosion International, and you're listening to Share Life Today. What happens when you make sharing the Gospel a part of your daily life? Well, God starts to send people to you to hear the Good News. This happened in Don's life when he and his wife went to the park with their grandchildren. Don's grandson wanted to play basketball, but he didn't have anything to shoot with. He ended up trying to use a tetherball (but without much success). A man named Mylan saw his plight and brought over a basketball. As the grandchild played, Mylan and Don struck up a conversation. Don was able to start asking about spiritual things; and when he asked Mylan what he would say if God were to ask, "why should I let you into My heaven?" Mylan didn't know what he'd say. So Don shared the Gospel with him, and Mylan gave his heart to Christ that day. And then he recorded a video about his decision and shared it on his social media! For resources on sharing your faith, visit our website at www.sharelife.today.

une émission Minute papillon faite avec Dahlia, Mylan, Kiana, Rafaël, Isaac, Naama, Asmaa, Evan, Nour et Nadir, de la classe de CM1 de Livane Moderne de l'école Elsa Triolet à Nanterre - dans le cadre du projet des petits reporters culturels de la ville, financé par la Cité éducative de Nanterre, en partenariat avec le théâtre Nanterre Amandiers réalisation au studio du collège Evariste Galois : Fatima Jamil et Murielle Jeannot montage et animation des ateliers de préparation, coordination du projet : Emmanuelle Soler

Dr. Joseph Maroon is a World-Renowned NeurosurgeonHe's also my mentor, friend, and the primary reason I became a neurosurgeon.Today, an incredible talk with one of the giants of my profession about legacy, hardship, mindset, faith, and more. You should read Dr. Maroon's excellent book, Square One:A Simple Guide To A Balanced Life.  Official Bio:Joe is clinical professor and vice-chairman of the Department of Neurological Surgery and the Heindl Scholar in Neuroscience at the University of Pittsburgh Medical Center. He received his education at Georgetown and Oxford Universities, the University of Vermont, and Indiana University in Bloomington, where he is a distinguished alumnus. He has authored over 280 peer-reviewed scientific papers and six previous books, including Fish Oil: The Natural Anti-Inflammatory and The Longevity Factor: How Resveratrol and Red Wine Activate Genes for a Longer and Healthier Life. Joe is a sports medicine expert and has served as the team neurosurgeon for the Pittsburgh Steelers for over 20 years. He is also a member of the NFL Head, Neck and Spine Committee, and is the medical director for World Wrestling Entertainment. In the early 1990s, Joe co-developed the ImPACT concussion test, the only FDA-approved, worldwide standard tool to assess concussions. He is the senior vice president of the American Academy of Anti-Aging Medicine; chairs the scientific advisory board of both Mylan and Stemedica; and is the scientific consultant for GNC. Joe is an inductee in both the National Fitness and the Lou Holtz Halls of Fame and remains a dedicated athlete, having completed eight Ironman triathlons-including five world championships in Kona, Hawaii-as well as over 70 other elite marathon and triathlon events. To learn more about Dr. Maroon, visit www.josephmaroon.comLeave a voicemail with your question or comment!Five Ways You Can Support this show:Pray for us!Subscribe, like, and share it with your friends! (We even have a YouTube channel!)Leave reviews and comments wherever you listen to podcasts!You can become a paid partner of the podcast and get special bonus episodes and lots more content by clicking here. Visit one of our affiliate partners and consider using their products (we use them every day):Improve your gut health, immune system, and protect your brain with Pique!Other Helpful Links:Click here to access the Hope Is the First Dose playlist of hopeful, healing songs!Be sure to check out my new book, Hope Is the First Dose!Here's a free 5-day Bible study on YouVersion/BibleApp based on my new book!Sign up for my weekly Self-Brain Surgery Newsletter here!All recent episodes with transcripts are available here! (00:01) - Introduction to Dr. Joe Maroon (08:24) - Visionary Microsurgery Techniques (12:25) - Reconnecting with Dr. Maroon (16:14) - Honoring the Opportunity to Train (21:46) - Importance of Faith and Gratitude (25:58) - Transformation Through Running and Triathlons (29:59) - The Power of Preparation (33:25) - The Influence of Early Connections (37:49) - Understanding the Frontal Lobes (40:46) - Benefiting from Past Innovations (42:18) - Building on the Legacy of Pioneers (46:32) - Navigating Major Adversity (49:09) - Mindful Awareness and Stress Management (53:31) - Gratitude and Mindset Shifts (56:47) - Changing Your Mind, Changing Your Life

Ted Karkus CEO & Chairman Of The Board Of ProPhase Labs $PRPH   Ticker: PRPH   Website: https://www.prophaselabs.com/ Bio: Ted Karkus Chairman & CEO of ProPhase Labs Ted Karkus, CEO and Chairman of ProPhase Labs, drives the company's diverse and synergistic businesses with his successful track record in biomedical and health companies. He transformed ID Biomedical's strategy and valuation from $25 million to $1.4 billion sale to GlaxoSmithKline. As CEO of ProPhase Labs, he restructured the go-to-market strategy for the flagship product Cold-EEZE, turned around and significantly grew revenues, ultimately selling it for $50 million to Mylan. ProPhase Labs is a fast-growing biotech, genomics and diagnostics company due to its commitment to growth, innovation, and execution excellence outlined in Ted's high growth roadmap. He pivoted into industry leading CLIA labs, and then further diversified by acquiring genomics leader Nebula Genomics. Constantly innovating, Ted then created ProPhase BioPharma to deliver antivirals, cancer tests and therapeutic cancer compounds. The new acquisitions and legacy businesses work to drive synergistic growth with multi-billion-dollar potential. He holds a BS in Psychology from Tufts University with Magna Cum Laude Honors and an MBA in Finance from Columbia University School of Business with Beta Gamma Sigma Honors. --- Support this podcast: https://podcasters.spotify.com/pod/show/smartmoneycircle/support

In this episode Mylan sit and discusses building homes through a Post-Idle No More project called One House Many Nations (OHMN), who is in partner ship with Nutana Collegiate at Saskatoon where students in the city will build a home for indigenous youth living on a reserve. Alan Sukut is the educator in charge of the program and homes being built the students, check it out as we discuss the Nutana Industry and Career Education (NICE) program Show Notes: https://www.ohmn.ca/ https://www.spsd.sk.ca/school/nutana/Pages/default.aspx

Mylan sits down with Rachel Snow to discuss the importance of treaty history and nationhood in the americas, as well as the current agricultural settlements taking place in this neoliberal era and how they do not fit within an indigenous paradigm . Next Event: Beyond Cows and Plows The Big Picture: Understanding the Treaty Right to Agriculture March 21st Saskatoon, Saskatchewan, Rusty Mcdonald Library 4:30-8:30pm Name of Authors: Sarah Carter: Lost Harvests Taiaike Alfred: Wasase, Peace, Power Righteousness, and Its all about the Land James Daschuk: Clearing the Plains Art Manual: Unsettling Canada, and the Reconciliation Manifesto

Tony Gillingham is a seasoned real estate investor with over 35 years of experience in the industry. He started his journey in 1986 when he obtained his real estate license and began buying duplexes and single-family homes. Over the years, Tony built a portfolio of properties, including a 14-unit townhouse complex in Mylan, Ohio. He is also the owner of a trailer park and several duplexes and single-family homes. Tony joined Josh Cantwell's mastermind program in 2021, which has helped him expand his real estate knowledge and achieve even greater success in the industry. Episode Summary: In this episode, Tony Gillingham shares his real estate journey and how he found success in the industry. He discusses his early experiences buying duplexes and single-family homes, as well as his transition to larger multifamily properties. Tony explains how he came across Josh Cantwell and joined his mastermind program, which has been instrumental in his growth as a real estate investor. He highlights the importance of mentorship and the support he has received from Josh and the program's community. Tony also talks about his current projects, including a 38-unit townhouse complex and a trailer park, and shares his plans for the future. Key Takeaways: Tony Gillingham started his real estate journey in 1986 by buying duplexes and single-family homes. He transitioned to larger multifamily properties after attending a meeting where Josh Cantwell was a keynote speaker. Joining Josh Cantwell's mastermind program has provided Tony with valuable mentorship and a supportive community of like-minded investors. Tony emphasizes the importance of having a can-do attitude and believing in oneself when pursuing real estate investments. He recommends reading "Rich Dad, Poor Dad" by Robert Kiyosaki and listening to podcasts like Jake and Gino and BiggerPockets for additional real estate education. Notable Quotes: "You try to figure this out on your own, you make one mistake, and your whole life savings is gone. Anyways, since being there, I bought a 38-unit townhouse complex right here in my hometown of Huron, Ohio, and I am in the process of turning that right now." - Tony Gillingham "He teaches you everything, and it's raw. I mean, he will give you information you will not get anywhere else. He'll hold you to it. He wants accountability because you are him, not just Josh all. It's the whole group." - Tony Gillingham Subscribe to our Podcast: https://itunes.apple.com/us/podcast/strategic-real-estate-investor/id570750792?mt=2 Like our page on facebook: https://www.facebook.com/srecnow Visit our blog: http://www.strategicrealestatecoach.com ************************************ STRATEGIC REAL ESTATE COACH is dedicated to giving real estate investors and agents the best, most up to date resources, training, tools, techniques, tips, videos, news, interviews and insider information on today's best strategies and techniques for real estate investing in today's troubled market. This includes marketing for motivated seller leads, wholesaling, rehabs, rentals, foreclosures, pre-foreclosures, REO's, short sales, raising funding and financing, asset protection, internet marketing, real estate investing for beginners, and much much more, including teaching how to make money in real estate and how to become a real estate investor.

Drs. Hope Rugo and Sara Tolaney discuss the promise of antibody-drug conjugates (ADCs) in the treatment of breast cancer, highlighting key trials that shed light on matching the right ADC to the right patient in the right setting. They also explore how combinations and sequencing of ADCs can augment their efficacy, the mechanisms of resistance, and the future potential of biomarkers to predict patient response. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco's Comprehensive Cancer Center. Antibody-drug conjugates, or ADCs, are rapidly changing the treatment landscape for patients with breast cancer. ADCs consist of antibodies that target tumor-specific antigens on the cell surface, chemical linkers, and cytotoxic payloads that can act powerfully to kill cancer cells. On today's episode, we'll be discussing advances in research to match the right ADC to the right patients and in the right setting. We'll also talk about the next steps, assessing how combinations and sequencing of ADCs can augment their efficacy, improve options for patients, and identify biomarkers in the future to predict how patients will respond so that we can match the right treatment to the right patient and their tumor. We need to gain a better understanding of the mechanisms of resistance that occur upfront as well as under the pressure of treatment.  Joining me for this important discussion is Dr. Sara Tolaney. Dr. Tolaney is an associate professor of medicine at Harvard Medical School, associate director of the Susan Smith Center for Women's Cancer, and chief of the Division of Breast Oncology at the Dana-Farber Cancer Institute in Boston.  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. Tolaney, we're delighted to have you on the podcast today. Thanks for being here. Dr. Sara Tolaney: Thank you so much for having me. I'm looking forward to the discussion. Dr. Hope Rugo: Great! So, we'll move forward, and because we're friends and colleagues, I'm going to refer to you as Sara, and I'm Hope, since we'll dispense with formalities in our discussion.  A lot of the talks that we give about ADCs start out with “a revolution in breast cancer therapy.” And indeed, this is a really exciting time with ADCs as treatment for breast cancer, and we're rapidly moving these agents into earlier disease settings. Can you tell us a little bit about the possibilities and challenges of using ADCs for the treatment of breast cancer today? Dr. Sara Tolaney: It's interesting that you say antibody-drug conjugates as revolutionizing outcomes of breast cancer, which I think is true. But on the flip side, I think it's also bringing up a lot of questions about how to use them, when to use them, and how to manage side effects. So there are a lot of good strengths for these antibody-drug conjugates, but a lot of unknowns that we're still trying to figure out. We had an older antibody-drug conjugate T-DM1 that we were all very familiar with that for years had been a treatment that we used very commonly in metastatic disease and now even use in early breast cancer, and I think has changed outcomes for patients. But over time, we've been able to develop newer antibody-drug conjugates as the technology has really evolved so that these agents now are able to deliver a lot of chemotherapy into a cancer cell. We're seeing very high drug-to-antibody ratios, and we're also seeing that these drugs can function via bystander effect, whereas T-DM1, for example, was not able to do that. But our newer ADCs, like sacituzumab govitecan or trastuzumab deruxtecan, are agents that do allow chemotherapy to get into that cancer cell, but also to get into neighboring cells.  And I think the technology evolution in being able to build these so-called next-generation ADCs has allowed for really unprecedented efficacy that we've not seen before. And it's also allowed us to develop these drugs in a way that's been different. Originally, we were developing T-DM1 to turn off HER2 signaling and to deliver chemotherapy into a HER2 cell. At least that's what we thought originally. And now we're really evolving so that we can just find a tiny bit of protein on a cancer cell and use it as a target, really in a subtype-agnostic way. And I think it's just a different way of thinking about how to use these agents to really deliver a lot of chemotherapy into cancer cells and have very robust efficacy. Dr. Hope Rugo: Yes, it is fascinating that some of the suppositions that we made with the first ADC don't seem to really hold true as well. And maybe they hold true in varying levels for the different ADCs. For example, this bystander effect is thought to allow us to target cells that have very low expression of the receptor that can be internalized even lower than our ability to detect these receptors by immunohistochemistry. And maybe we'll talk about that in a little bit.   But first, you mentioned already sacituzumab and trastuzumab deruxtecan, the ADCs that are currently approved for breast cancer. But can you tell us a little more about those ADCs and the key trials that have led to approval of these targeted agents? Dr. Sara Tolaney: Yes, I think when we first saw the data that came out with T-DXd and DESTINY-Breast01, I think my jaw dropped because I had never seen a waterfall plot like that. This was a single-arm study that looked at T-DXd in patients with very heavily pretreated metastatic HER2-positive breast cancer and saw very high response rates of over 60% and a clinical benefit rate of almost 98%, meaning that almost every single patient who got the drug and had a median of six prior lines of therapy had reduction in tumor size. And that's unreal. I think it was revolutionary in the sense that we had never seen that kind of activity in such a pretreated population. The agent was studied in other registration trials, DESTINY-Breast03, which looked at T-DXd and compared it head to head with T-DM1 in a predominantly second-line metastatic HER2-positive population, and here, again, unprecedented results. I've never seen a p value like that or a hazard ratio of, again unreal, of a little under 0.3 and seeing a 28-month PFS with T-DXd relative to just a little under 7 months PFS with T-DM1. We have never seen patients with metastatic HER2-positive breast cancer have a PFS that long. Even in CLEOPATRA, it's a little under 19 months in the first-line setting, where people were predominantly naïve to HER2-directed therapies. This, again, is really changing outcomes for patients.   But then, I think, when we go to the next step, we studied T-DXd in patients with HER2-positive breast cancer and it had again these unprecedented results. But there was some early data suggesting that it could even work in tumors that weren't truly HER2-positive but what we call HER2-low, meaning that they weren't HER2/3+, they weren't HER2-0 but they were 1+ to 2+ and not FISH amplified. And so even with a little bit of protein there, they were seeing activity in the early phase studies and so it led to DESTINY-Breast04, which compared T-DXd to chemotherapy of physician's choice in people who had had one or two prior lines of chemotherapy in the metastatic setting. It was predominantly geared to look at outcomes in hormone receptor-positive breast cancer. But there was a small group of 58 patients with triple-negative disease that were also included in that trial. And here again, a very unprecedented outcome seeing a response rate of about 50%, which, again, we never see in pretreated hormone receptor-positive disease. And a PFS of 10 months, and again, these are people who already had one or two prior lines of chemotherapy. So it's, again, really changing outcomes. And so now I think it leads us to a lot of other questions that we are addressing in trials - can this drug work even if the tumor has maybe no HER2 expression, what about HER2-0, what about HER2-ultra low, meaning a little bit of staining but not quite 1+. And so these are questions that I think we will need to address and there are studies that will help us address that. On the flip side, we saw sacituzumab govitecan get developed in breast cancer. Initially, we saw very impressive results from a single arm study of sacituzumab in metastatic triple-negative disease where we saw response rates of a little over 30%. These are patients who were very heavily pretreated with metastatic triple negative breast cancer where, unfortunately, response rates end up being in a 5% range so it was a home run in that setting. So that led to the ASCENT trial, which compared sacituzumab govitecan to treatment of physician's choice therapy and that study really enrolled people who were, in essence, second line and beyond in the metastatic triple-negative setting and showed almost triple progression free survival, in essence, doubled overall survival. So again, very robust efficacy leading to confirming its approval. And then we saw data from TROPiCS-02, which looked at sacituzumab in metastatic hormone receptor-positive disease and also showed improvements in both progression free and overall survival. And this was in pre-treated populations of 2 to 4 prior lines of chemotherapy. These agents, again, have established robust efficacy, and so now the idea is can we move these drugs earlier in development into earlier line settings and can we even move these agents into the early disease setting and potentially cure more patients? So hopefully, we'll figure out ways to make that happen. Dr. Hope Rugo: Yeah, that was a great summary of this exciting data. And I think we really got an idea of what waterfall plots could tell us from DESTINY-Breast01 where you could count the number of patients whose cancers grew with therapy on one hand. It's been a huge advance. I think it's where we get this “revolution” even in patients with a median of 4 lines of prior chemo, and, in the ASCENT trial, we were able to see this improvement and survival in the hardest-treated subset of metastatic breast cancer triple negative disease. And then the remarkable data in HER2-positive and HER2-low breast cancer hormone receptor positive disease. We're really covering all of the subset of breast cancers.   When we introduce new therapies though, and of course, our interest is moving them earlier as lines of therapy in the metastatic setting, we really have to think about the adverse events and how those are going to affect their patients, and balancing the risk benefit ratio. Obviously when the benefit is so huge, we're more thinking about how do we proactively manage these side effects, educate our patients, use prophylaxis when possible. Can you share with us some of your insights on management strategies for toxicities?  Dr. Sara Tolaney: You bring up a very good point, and I will say the ADCs were designed with the idea being that we could deliver a ton of chemotherapy into a cancer cell. So obviously, my hope had been that we weren't going to see a lot of chemotherapy-like side effects because the goal was to try to spare normal cells of these side effects. But unfortunately, we do see that these agents do have real toxicities, and I think that is an important message. So, for example, with sacituzumab, for people who have hair going into it, they will lose their hair during the course of treatment, and so that's important to make patients aware of. It can lower blood counts, and about 50% of patients who are on sacituzumab will end up needing growth factor support while they're on treatment. So, that is again something that needs to be monitored and managed. But usually, we're pretty good at managing neutropenia, and with the growth factor support, I find that it actually works really well.  Another thing with sacituzumab is the potential risk of diarrhea, but most of the diarrhea is low-grade diarrhea. It's rare that you get someone who has high-grade diarrhea with sacituzumab. Usually, I find it works to just instruct patients to use loperamide as needed. And again, usually that works well. And certainly when needed, dose modification can also help with these side effects and so it is important to keep in mind that this is another option. With T-DXd, one thing that we do have to keep in mind as an unusual side effect is the potential risk of interstitial lung disease. We see that in about 10% to 15% of patients getting T-DXd. That is something that we do have to be very mindful of. For the most part it is low-grade ILD. But there are rare occasions where there have been deaths from ILD. And we're seeing with some of the newer trials, the death rate is usually under 1%, but it is a real potential risk. And so it is really important to counsel patients when getting T-DXd about this potential side effect, that way they are good about communicating with you if they get any new symptoms, such as shortness of breath or dry cough, to get you aware of it and can work it up and get imaging certainly if that occurs.  And then I think the management for ILD is a little unique and a little different truthfully than the way we manage pneumonitis from other drugs. Normally, when I am treating patients who develop pneumonitis, even if it is mildly symptomatic, we often will hold treatment, give steroids, and rechallenge them when it gets better. But with T-DXd, if anyone develops symptomatic pneumonitis, you actually have to permanently discontinue the T-DXd per the guidelines because we just don't know the safety of being able to rechallenge that patient once that pneumonitis resolves. For grade 1 ILD, meaning someone who has, for example, ground glass changes seen on imaging but doesn't have any symptoms, you have to hold the drug and wait until those imaging findings resolve and then you can restart. I usually do treat grade 1 ILD patients with steroids with the hope being that maybe it will allow for the pneumonitis to resolve more quickly, although in truth I don't know if that's the case. I have just taken that approach because I don't like leaving patients off the drug for too long if not needed. Again, I typically treat them with steroids, reimage in three to four weeks, and see if I'm able to restart. If they resolve within 28 days, you can restart at the same dose. If it takes longer to resolve, you need to dose modify.  And then I think the other big thing with T-DXd is to know that it is categorized as a highly emetogenic agent. Most of us are using three-drug prophylaxis, which I think works really well. It is also important to realize that there can be some delayed nausea, which is a little unusual with some of our other agents. And so to warn patients about that and I find that use of olanzapine or ondansetron for the delayed nausea tends to work pretty well.  Hope, do you have any pearls for us? Obviously, you are very experienced in using these agents; are there any things you would recommend for the management of ADCs?  Dr. Hope Rugo: Yes, it's such a great question and an important area because, particularly as we are using these agents earlier, we really need to have strategies for both how long to continue as well as manage the toxicities. I agree with the nausea, olanzapine has been really a great addition, and using a triplet as initial premedication makes a big difference for T-DXd and other deruxtecan ADCs that are in the pipeline. And then I think that the ILD issue, we're really learning more about the risk factors as well as retreatment. And hopefully, we'll have more data this year at ESMO Breast and maybe ASCO on retreatment for grade 1. We certainly now do not have any data on the safety of retreatment for grade 2, so that is really not accepted now. For sacituzumab, I think the interesting area is the metabolism and the impact. So with neutropenia, as we move the drug earlier, it's easier and easier to manage, we see less severe neutropenia. We can give growth factors, which we are all good at in oncology. But I think the question about managing diarrhea and who is at risk still exists. Understanding pharmacogenomics and UGT1A1 is an interesting area where patients who have diarrhea could be tested to see if they are poor metabolizers which affects a little under 10% of the overall population. Because in that group, you could give less drug and get the same benefit with less toxicity. So I think this is all very interesting. It is important for providers and patients to be educated so that we can manage this appropriately. And I think you gave an excellent overview.   We have new agents in the pipeline also and maybe we'll talk about those next, and then we'll talk a little bit about sequencing and resistance, as well as the unmet need for brain metastases. So lots of areas to talk about. There are a number of TROP-2 ADCs that are in the pipeline, and one that has presented phase III data, datopotamab deruxtecan. But other studies are being developed with new TROP-2 ADCs as well. But then there are a huge number of ADCs there with new targets, for example, immune effector targets, and new payloads, even immunotherapy and two different payloads or bispecific antibodies. And then there is interest in combining ADCs with immunotherapy and PARP inhibitors. We saw data in bladder cancer, I think it was bladder cancer, with combined 2 different ADCs at ESMO in 2023. So a lot of new approaches. How are we going to manage this moving forward? And where do you think we are going to position some of these next sort of "me-too" drugs?  Dr. Sara Tolaney: It's an excellent question, and you're right, the field is exploding with new antibody- drug conjugates. So, it's going to leave us with this conundrum of what to do. And you brought up the really interesting example of the fact that we have an approved TROP-2 ADC, we have as sacituzumab govitecan, and for example, we've recently seen some really exciting data come out from TROPION-Breast01 looking at another TROP-2 ADC, datopotamab deruxtecan or Dato-DXd where that ADC performed better than chemotherapy in a head-to-head trial in terms of progression-free survival in a hormone receptor-positive population. Then there's another TROP-2 ADC, moving forward in development moving to phase III that Merck is developing MK-2870. All three of these ADCs are targeting TROP-2 and have a TOPO 1 payload. So, it leaves you with the question of how do you think about that? Is there going to be a role for using serial TROP-2 ADCs? Could one work after the other, even when they have very similar payloads? How are we going to incorporate them? How do you pick one over the other? So, it is going to be tricky for us as we get more and more of these agents. I think we're all excited about seeing ADCs that may have different targets and different payloads, where maybe we will see that sequential utilization will have robust efficacy if we swap things out. Again, we don't have data here yet, but I think there are other agents in development. For example, you could think of like, disitamab vedotin targets HER2 and has an MMAE payload. So, could it be that someone progresses on T-DXd for HER2-low, but then could go on to disitamab vedotin? How will that work? So, we have a lot to learn, but it's really nice to have so many options.  Dr. Hope Rugo: Yeah, it'll be interesting to see whether or not we select the ADC based on a rational understanding of the tumor and the patient, or whether it's simply what's easier to give and has the right toxicity for that patient.  So, that sort of brings us to our next topic, which is how are we going to sequence these agents? How are we going to understand the mechanisms of ADC resistance? At San Antonio in 2023, we saw a presentation where there was a top-alteration, and the patient had a really long response to a top-directed ADC, or an agent that carried a topoisomerase inhibitor. And that really struck me that we're going to see these alterations. There was a fresh autopsy study that suggested that the alterations may be different in different organ sites of disease. How are we going to figure this out? Dr. Sara Tolaney: Yeah, I also was really puzzled to see those data from San Antonio where we've sort of simplified ADC resistance in our heads to say, well, maybe someone becomes resistant because they lose target expression, or maybe someone becomes resistant because they've developed resistance to the payload, kind of like the way we think of someone developing resistance to getting chemotherapy. But obviously, it's probably far more complex than that. With these ADCs, they need to be able to internalize the ADC and could there be mechanisms of resistance related to the internalization process? So, I think there are lots of potential areas where resistance could be occurring. I think, we don't understand it very well. We've seen patients, for example, who have responded. This is just anecdotal, but we have data, for example looking at, Dato-DXd in the phase 1 triple-negative study where there were some patients who responded despite having progressed on sacituzumab. Well, why is that? You would think if it's target resistance or payload resistance, it would be the same target and a very similar payload. So, why would those drugs work one after the other? And that's why I think we just don't understand this well enough at this point in time.   So, it's clearly an area where more research is needed because it does have significant implications on how we think about using these drugs sequentially. We will need to understand these resistance mechanisms because there do seem to be some rare patients who benefit from these sequencing strategies and then others who don't. So, it would be nice to be able to figure this out and hopefully in the future, we'll be able to test patients and know what drugs to give them. But I think we're far off from that, unfortunately, right now. Dr. Hope Rugo: Yeah, it does seem to be a relatively elusive approach, and I think, in part, it's due to the heterogeneity of cancer. And maybe, as we're better and better at analyzing tumor cells in the blood, which are a rare group, and ctDNA, which, of course, we do now to look for mutations, maybe that'll be an approach that we'll be able to take. And also, of course, moving the drugs earlier into the disease setting with less heterogeneity and mechanisms of resistance might help as well.  I was fascinated by the fact that although the PFS to the first ADC seems to be overall much greater than the PFS to the second ADC, when you sequence them, there are a few patients who have a longer PFS with the second, even if these are just sacituzumab T-DXd sequencing in various directions. So, it's clearly very complex. And right now, I think we're just sequencing and we don't really know how to do it. We just choose what we think is best for that patient first and go on to the next one later, which is interesting. And one of the choices might be treating brain metastases, which of course remains a huge unmet need. And if we could find effective treatment for brain metastases, maybe we could also prevent them in some patients more. What do we know about the central nervous system (CNS) penetration of ADCs and the clinical results? Dr. Sara Tolaney: At first, we were not optimistic that these drugs would have activity in the brain because we thought that these were very large agents that probably couldn't penetrate into the blood-brain barrier. But in fact, I think we were all very excited to see that there is actually data suggesting that these drugs can actually have robust efficacy in the CNS in patients who have active brain metastases. And so what we've seen so far is data with trastuzumab deruxtecan or T-DXd, there have been some trials that have been done, including studies like DEBRA and TUXEDO, which have looked at T-DXd in patients who have active brain metastases and are showing very robust response rates within the CNS. So, we're seeing intracranial response rates on the order of 40% to 50%. And clinically, this is what we're seeing as well. These are smaller studies and there's a larger trial, DESTINY-Breast12, which will hopefully validate the robust efficacy in the CNS with T-DXd. So, again, it's really nice to see this.  To your point, though, one area that I'm curious about, as you were alluding to, is will these drugs be able to prevent CNS disease? And I think that is a very different question because here the blood-brain barrier is not intact when patients have progressive brain metastases, and so these ADCs are causing robust activity. But if you look, for example, and I'll be curious to see what happens, DESTINY-Breast05 is looking at T-DXd in the post preoperative setting for patients who have residual disease and comparing it to T-DM1. And unfortunately, we saw that T-DM1 was not able to prevent brain metastases when looking at data from KATHERINE, where in fact, rates of CNS as the first site of recurrence were similar with T-DM1 and trastuzumab. So, now we'll be interested to see, will it be any different with T-DXd? Will T-DXd be able to have any role in prevention? I think we haven't seen anything like that with ADCs to date, so that would be a paradigm shift in our way of thinking.  Right now, there are strategies being taken from a prevention standpoint of trying to add a tyrosine kinase inhibitor in that early-stage setting, such as what is being done in the COMPASS-RD trying to add tucatinib to T-DM1 to see if that would do it. But again, we really need to understand, again, how these drugs work, particularly when the blood-brain barrier may not be intact. But again, very exciting data with T-DXd in an ongoing trial, actually through SWOG looking at sacituzumab for patients with CNS disease. And we've seen some preliminary data with sacituzumab showing that it actually does penetrate into the brain when they've looked at drug levels in the tumor in the brain, comparing it to plasma, it actually looks similar. So, we know it's getting in there and we'll have more robust efficacy data, hopefully coming soon. Dr. Hope Rugo: Yeah, that was a great summary of that data. It's been exciting also to see some responses in patients with leptomeningeal disease as well, where we've really been struggling with anything that works for more than a few weeks or months at the most. So I'm holding out great hope that we're going to see a big difference because even though TDM-1 had some efficacy, it was nothing like what we're seeing with T-DXd. So we'll see. And the same with sacituzumab with triple negative disease, where sometimes brain metastases can be an isolated site of recurrence, even in patients who have a pathologic complete response. So it has been a big challenge.  So I think that what we've learned from you is a lot about the mechanisms and the data about these new ADCs, the tremendous hope that these are bringing to our patients, but also the really exciting new approaches with new payloads, new targets of drugs that are in development, as well as potentially some different ADCs that have the same target and similar mechanisms of action of this payload. Really fascinating to hear about this, the future work on sequencing, on mechanisms of resistance, and on brain metastases. We have, of course, 2 prospective trials that we'll be looking at sequencing, one with T-DXd and Dato-DXd, and one registry trial with T-DXd and sacituzumab govitecan in the US. So that's also going to, I think, provide us with some important information.  We could talk for a long time about this, but I just wonder if you have any closing comments to sum up your thoughts.  Dr. Sara Tolaney: I think you did a great job leading us through thinking about ADCs, and I think it'll be really interesting to see what happens in the future. While again, these agents have become a standard for us for patients with metastatic disease, I'm going to be curious to see how everything evolves and to see if we'll be able to substitute chemotherapy with ADCs in early disease settings and change outcomes. Will we be able to have novel combinations? Will we be able to sequence these drugs one after another? Will we actually have biomarker predictors to help us sort out which drug to give when? So, still a lot to learn, but clearly a very exciting field right now. Dr. Hope Rugo: Indeed. Sara, thank you for sharing your valuable insights with us today on the ASCO Daily News Podcast on your great work to develop novel therapies for breast cancer. It's always a pleasure to talk to you, and even greater to work with you on the future progress of treatment for breast cancer. Dr. Sara Tolaney: Thank you so much, Hope. Again, really nice to always discuss these data with you. I always learn a lot, so thank you. Dr. Hope Rugo: Thank you. And thank you to our listeners for joining us today. You'll find a link to all of 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. Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of a product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers:   Dr. Hope Rugo  @hoperugo  Dr. Sara Tolaney @stolaney1     Follow ASCO on social media:   @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Hope Rugo:  Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, Daiichi Sankyo Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Talho Oncology, Veru, GlaxoSmithKline, Hoffmann-LaRoche AG/Genentech, Inc, Stemline Therapeutics Travel, Accommodations, Expenses: Merck, AstraZeneca   Dr. Sara Tolaney: Consulting or Advisory Role: Novartis, Pfizer, Merck, AstraZeneca, Genentech, Eisai, Sanofi, Bristol-Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Immunomedics/Gilead, BeyondSpring Pharmaceuticals, OncXerna Therapeutics, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Umoja Biopharma, Menarini/Stemline, Aadi Bio, Artio Biopharmaceuticals, Incyte Corp, Zetagen, Bayer, Infinity Therapeutics, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR Therapeutics, Hengrui Pharmaceutical (USA), Sumitovant Biopharma Research Funding (Inst.): Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol-Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Seattle Genetics, OncoPep, Gilead Travel, Accommodations, Expenses: Eli Lilly, Sanofi, Gilead Sciences

Radicle Narrative is Rebroadcasting Episode 138 of Southpaw. Here are the details, "On this episode of Southpaw, Sam is joined by activists Emma Taylor and Mylan Tootoosis for an anti-colonial discussion on de-escalation and community care. "The Cunning of the Adult Supremacist": https:// www.colbytootoosis.com/writings/adult-supremacy Radicle Narrative: https://linktr.ee/radiclenarrative Listen to Fighter's Brew: https://www.patreon.com/posts/76751767 Sign up for Liberation Martial Arts Online: https://www.patreon.com/posts/ liberation-arts-72505630 We can't continue to produce important episodes like this one without your solidarity. There is no Southpaw network without your financial support. In return, not only do you help produce our shows but you also get access to more great content. It's mutual aid. Find our Patreon, swag, and other ways to support us at: https://www.southpawpod.com You can find Southpaw on Facebook, Twitter, and Instagram: @SouthpawPod You can find Radicle Narrative on Instagram and Facebook: @RadicleNarrative www.RadicleNarrative.com Music by Boss of Three: https://www.facebook.com/BossofThree/

Did you know that, on average, the peak age for body confidence is 60? It's surprising but true! The good news is we don't have to fear changes in our body as we age, and there is SO much we can do to support ourselves as we transition through perimenopause, menopause and beyond—which is what we dive into in today's episode!In this episode you'll learn: * Early signs of perimenopause* How to use food as medicine in the transition * Why you might be gaining weight in this stage* How hormones impact brain health* How to get your libido back* And more…Dr. Harper has an understanding of the symptoms and concerns that women face as she herself is one of six sisters and has a grown up daughter. Her areas of expertise include Perimenopause and Menopause, Polycystic Ovarian Syndrome, Premenstrual Stress disorder, Healthy Aging and Weight Management. She believes in the early management of symptoms to stay youthful and healthy.She has given educational lectures to GPs on: Menopause, Mood and Sex; Menopause Myths and HRT- Putting the Risks of HRT into Perspective; Mood Disorder during the Menopause Transition; Breast cancer and HRT. She has acted as an Advisor on best practice for women going through the menopause transition in the workplace to companies—such as Coutts bank and Mylan pharmaceuticals, Channel 4 and filmed a webinar for PricewaterhouseCoopers.This episode is brought to you by beeya: * Learn more about beeya's seed cycling bundle at https://beeyawellness.com/free to find out how to tackle hormonal imbalances. * Get $10 off your order by using promo code BEHINDHEREMPIREFollow Yasmin:* Instagram: https://www.instagram.com/yasminknouri/* Website: https://www.behindherempire.com/Follow Dr. Shahzadi:* Website: https://theharperclinic.com/* Instagram: https://www.instagram.com/drshahzadiharper/ Hosted on Acast. See acast.com/privacy for more information.

Do your current moral values require you to stop eating meat? Will going vegan actually prevent animal cruelty? Is the vegan movement a force for good?

On this day in legal history, October 12, 1977, the US Supreme Court heard arguments in the landmark case of Allan Bakke, which centered around the contentious issue of "reverse discrimination." Bakke, a white student, had been denied admission to the University of California Davis Medical School, with the school reserving a specific number of seats for minority applicants. Bakke argued that this affirmative action policy amounted to racial discrimination against him. The case was seen as a significant challenge to affirmative action programs aimed at redressing past racial injustices.During the oral arguments, the justices grappled with the complex question of whether race-based admissions policies violated the equal protection clause of the Fourteenth Amendment. The case ultimately led to a divided decision. In 1978, the Supreme Court ruled in favor of Bakke, stating that while affirmative action was permissible, the use of racial quotas in admissions was unconstitutional. This decision had far-reaching implications for affirmative action policies in higher education and set a precedent for future legal battles on the issue.A divided en banc US appeals court has granted California's emergency stay of a lower court ruling that barred the state from enforcing its law limiting the capacity of gun magazines to 10 bullets or less. The US Court of Appeals for the Ninth Circuit voted 7-4, allowing most of the trial judge's order to be stayed, with the exception of magazines lawfully acquired and possessed before the judge's order granting a permanent injunction. The court stated that Attorney General Rob Bonta was likely to succeed on the merits, citing the 2021 US Supreme Court decision in New York State Rifle & Pistol Ass'n, Inc. v. Bruen, which limited the restrictions states can place on where gun owners can take their firearms. This majority decision noted that, since the Bruen decision, ten other federal district courts have considered Second Amendment challenges to large-capacity magazine restrictions, and only one court, the Southern District of Illinois, granted a preliminary injunction.The majority found that California demonstrated that it would face significant harm if the stay was denied, as it could lead to an influx of large-capacity magazines, posing potential threats to public safety. The ruling stated that other interested parties would not be substantially harmed by the stay, and it does not impede the public's ability to purchase and possess various firearms and magazines containing 10 rounds or fewer. This recent decision, while not deciding the case's merits, has temporarily stayed the injunction, allowing California to enforce its large-capacity magazine limit while the case proceeds. California High Capacity Gun Magazine Ban Mostly Unblocked (1)Anti-affirmative action activist Edward Blum's American Alliance for Equal Rights has dropped a lawsuit against Perkins Coie, a U.S. law firm, over its diversity fellowship program. The decision came after Perkins Coie revised its application criteria, allowing all law students to apply, not just those from "historically underrepresented" groups. Blum's group had initially sued two firms in August, alleging that their diversity fellowship programs unlawfully excluded individuals, including white students, based on their race. The move to open these programs to all students preempted further legal action, though Blum highlighted the existence of similar "racially discriminatory programs" at other law firms, encouraging them to do the same. Last year, major U.S. law firms had just 11.4% partners from people of color, according to the National Association for Law Placement.Affirmative action opponent drops case over law firm's diversity fellowship | ReutersPfizer has agreed to a $50 million settlement to resolve claims by drug wholesalers that they overpaid for EpiPen allergy treatment devices due to alleged anticompetitive practices by the drugmaker. The wholesalers argued that Pfizer, which manufactured the EpiPen for Mylan, engaged in anticompetitive behavior that allowed them to maintain a monopoly over the market for EpiPens, leading to inflated prices. This class action settlement, filed in a Kansas City, Kansas federal court, must still be approved by the judge.The legal action against Pfizer and Mylan followed public outrage in 2016 when Mylan raised the price of EpiPens from $100 to $600. The lawsuits claimed that the companies engaged in anticompetitive practices to stifle competition and maintain high profits, including paying Teva Pharmaceutical Industries to delay the launch of a generic version of the EpiPen. In 2021, U.S. District Judge Daniel Crabtree dismissed the claims against Pfizer on the grounds that it was Mylan, not Pfizer, that directly sold the EpiPen. In 2021 and 2022, groups of consumers reached settlements of $345 million and $264 million with Pfizer and Mylan, respectively, over related claims.Pfizer to pay $50 mln to settle drug wholesalers' EpiPen antitrust claims | Reuters Get full access to Minimum Competence - Daily Legal News Podcast at www.minimumcomp.com/subscribe

Welcome back to BM - your favorite podcast! This week we start out with our smoothest intro in a minute and get right into some new drops that Luke has pulled for maximum ridiculousness. Last week, the entire show was on vacation exploring the great state of Michigan (feel the powder). Edward and Katie did a lighthouse tour up the beautiful western coast of the state starting in Grand Haven to Whitehall, Pentwater, Ludington and Manistee and stayed at the Weathervane Inn in Montague. There were cookies and balconies and no underpants and hot tubs. Katie found lots of rocks on the ground (what up magoons) especially in Ludington and ate great food at Mylan's Waterfront Grille in Whitehall. Luke and Jenn took a trip to Beaver Island to visit with some dear friends. The island is 32 mile ferry ride from Charlevoix, MI and takes a bit over two hours. The whole island is made out of dust and there's nothing to do there except get drunk and drive around. It's very beautiful and very quiet and there is great food at the Dalwhinnie Restaurant. Both of these trips are highly recommended by the show! This week, Edward felt the need to get back to our roots and play an old school board game instead of the highly creative bullcrap we've been pumping out as of late. The game is called Zero and it's a reverse version of Family Feud made by a-holes (because Luke didn't win). We learn that we're all pretty stupid at geography and musicals and 1970's TV shows. We also learn about The Beatles, The 10 Commandments, But whatever - it's a fun game! Email the show at bubbmush@gmail.com and follow us on Instagram & TikTok @bubbmush - if you have any friends that like stupid podcasts be sure to tell them you like our show. They might like it too! Thanks viewers :)

Before covering Ohio State's 17-14 win over Notre Dame last week, Stephen Means and Andrew Gillis stopped to watch five-star wide receiver commit Mylan Graham. So on this Friday episode of Buckeye Talk, the two discuss what they saw or didn't see. Then they wrap things up with a conversation about the future of OSU's wide receiver room which could lose its top four players after the 2023 season leaving room for anyone to claim a starting spot next season. That includes the three commits in the 2024 class the latest highly-rate recruits Brian Hartline has landed. Thanks for listening to Buckeye Talk. Learn more about your ad choices. Visit megaphone.fm/adchoices

Drs. Hope Rugo and Nancy Davidson discuss the next generation of endocrine therapy in hormone receptor-positive breast cancer – SERDs, SERMs, CERANs, and PROTACs – and challenges relating to the optimal sequence of therapeutic options. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. Hormone receptor-positive (HR+) breast cancer is the most common subset of this disease and breast cancer is the most common cancer diagnosed in women worldwide. Endocrine therapy (ET) is the cornerstone of management in hormone receptor-positive breast cancer and may involve suppressing estrogen production with aromatase inhibitors in the cancer cell itself, or directly blocking the estrogen receptor pathway through selective estrogen receptor modulators, such as tamoxifen, or the injectable selective estrogen receptor degrader, fulvestrant. However, despite the availability of these therapies, the largest unmet need lies in treatment of HR-positive HER-negative disease lies after progression on endocrine therapy. On today's episode, we'll be discussing the emerging generation of endocrine therapies in breast cancer, some of which were designed to overcome common mechanisms of endocrine resistance, and the challenges relating to the optimal sequence of therapeutic options. Today, I'm delighted to welcome the world-renowned breast cancer researcher, Dr. Nancy Davidson, to the podcast. She's a professor and the executive vice president for clinical affairs at the Fred Hutchinson Cancer Center and professor of medicine at the University of Washington as well as past president of ASCO and AACR. You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod. Nancy, it's great to have you on the podcast today. Thanks so much for being here. Dr. Nancy Davidson: Thank you so much, Hope, for the opportunity. Dr. Hope Rugo:  You've done incredible work in the area of treating HR+ disease, but also in understanding some of the agents and pathways that are most important to our understanding of how we treat and really think about developing new drugs for HR+ breast cancer. The first generation of anti-estrogen drugs really included selective estrogen receptor modulators, but now we have a new generation of these anti-estrogen drugs. And there's also orally administered selective estrogen receptor degraders, so-called SERDs, that we hope someday will be an alternative with already one approved for the injectable SERD, fulvestrant. But there's a whole additional class of drugs, complete estrogen receptor antagonists, referred to as CERANs, and proteolysis targeting chimerics, PROTACs. These agents are all at various stages of development in both early and metastatic settings and really represent, I think, a confusing array of different treatments that are being studied, some of which of course are approved. Nancy, it would be great if you could tell us some about these exciting new agents, starting with our approved drugs and moving on to the agents that we're studying in clinical trials. Dr. Nancy Davidson: Hope, this is a terrific example of how basic science has really begun to inform clinical practice. For us as breast cancer practitioners, it was really easy for a long time because we only had tamoxifen. And then things like the aromatase inhibitors as a means of decreasing the estrogen ligand came into practice, as did fulvestrant, as you mentioned, a selective estrogen receptor degrader. Thanks though to a lot of understanding about estrogen receptor biology, and specifically, the discovery about a decade ago of estrogen receptor mutations, something that we didn't think exist ed for a long time, but which we now know exists in maybe a third to a half of breast cancers after exposure to aromatase inhibitors, that's led to really an explosion, this alphabet soup of possibilities that you talked about. SERMs, selective estrogen receptor modulators, tamoxifen is the classic one—something that acts as an agonist and as an antagonist, depending on the tissue. The SERDs, the selective estrogen receptor degraders, lead to estrogen receptor destruction. Fulvestrant is the classic example of this right now. But we're very excited that a second one has been FDA approved. That's elacestrant that was approved earlier this year, and it has specifically been developed to try to target those estrogen receptor mutant breast cancers because those are the ones that are particularly resistant. So that's the first of this new generation of SERDs that's coming on the market, has come on the market. As you say, a key advantage there is that it's oral, unlike  fulvestrant, which requires 2 monthly injections and is very, very inconvenient and uncomfortable for patients. Other SERDs are coming along. I think another one that is well along in clinical development is giredestrant, which is in the same family and being tested in clinical trials of the classic varieties. It's been tested in a window trial, looking at its ability to down-regulate Ki67. It's being tested against standard of care in first-line metastatic breast cancer. And there are some studies that are going to begin looking at it in the adjuvant setting as well. There are other members of this particular family, but I think that elacestrant is the one that we have at our fingertips right now, and giredestrant is one that's certainly coming along in clinical trials, and we should look forward to those results. For those who are interested in the giredestrant, the trials in question right now that are going on are persevERA, which is in stage 4 breast cancer, and lidERA, which is in the adjuvant setting. Now that's one new category, or it's an old category with a new twist. A second is these agents that are called complete estrogen receptor antagonists, CERANs, as you talked about them. The key here is that what they do is, the estrogen receptor has a couple of domains, and in particular, it has 2 different activation domains, AFT1 and AFT2. And these CERANs are complete estrogen receptor antagonists, so they block both of those domains. And the hope would be that they might end up being more effective than the other agents that we have available to us right now. So those are also in clinical trial at the present time, and we're waiting to see whether or not there's going be any value in that particular area that's going to able to go forward for us.   Another area that I think we want to talk about is the PROTACs, as you mentioned. These are proteolysis targeting chimeric entities. So, this is a kind of a complicated situation where you have a kind of bivalent situation where you have something that binds both to the estrogen receptor and then also to E3 ubiquinase. So, it leads to degradation again of the agents; that's another area for us to be watching. And then finally the SERCAs. So those are the selective estrogen receptor covalent antagonists, and what they do is they bind very specifically to a cysteine 530 that exists in the estrogen receptor but not in other steroid receptors. So that's where the selective part of this comes along. Now these are all in various stages of clinical investigation. Some of them are pretty early at this point, but I think the ones that are well established are elacestrant, giredestrant is coming along as we just talked about. Camizestrant is also coming along through the SERENA series of trials, and imlunestrant is also coming on through the EMBER series of trials. Hope, I would also be remiss if I didn't go back to an old drug that's a new drug, and that's lasofoxifene, which is also in the SERM family. Those who have been in our field for a while will remember that lasofoxifene was actually originally kind of tested in the prevention setting, where it seemed to have some activity. It came back into our interest because it has really strong activity against estrogen receptor mutant breast cancer models in the laboratory. And as a consequence of that, it's coming back into the clinic through a series of trials that are called the ELAINE trials, where we're looking to see whether or not it might also be better than fulvestrant. It too is an oral agent, so that's a real plus for us, and the first set of ELAINE trials would suggest that there's some nice activity without a lot of toxicity. So, lots going on in this field. You know, I think for all of these things, obviously, we're also working very hard to think about the toxicities. All of these, as I recall, are oral agents. So that gets rid of  1 huge toxicity, which is you don't have the need for some sort of injection. But they all do have some side effects. Frequently, [the toxicities] are like GI side effects or fatigue. In a couple of cases, there might be some concern about cardiac arrhythmias, but I think GI turns out to be one of the most important things that we have seen in some of these trials. Generally, it's very well tolerated, though. I think another important question, which I'm sure is in your head and is in mine, is that how are we going to integrate these into what we already have? And so, I think a lot of the work right now is looking at patients who have already received an aromatase inhibitor plus a CDK4/6 inhibitor and are now going on to one of these new agents. But you might wonder, if they turn out to be effective and well-tolerated, whether they too should be perhaps combined with CDK4/6 inhibitors in place of the aromatase inhibitors or the fulvestrant that we use now. So, I think that we can imagine that those clinical trials are either in progress in some cases or will be coming on as we try to think about how to integrate these new approaches into our existing standard of care, which is already quite complicated, right? We've gone far from tamoxifen, which was good for everybody, to now a really complex algorithm about how we think about hormone therapy, both in early breast cancer and in metastatic breast cancer.  Dr. Hope Rugo: Well, that was a fabulous discussion about the new agents and our existing agents and both the exciting aspects, as well as the challenges. One question that comes up, I think a lot, and this is of course a huge question in many ways, but for ER-positive metastatic breast cancer, where these drugs are first being tested, maybe we'll talk about that first. There's one trial at SERENA-6, looking at camizestrant in patients who have developed evidence of an ESR1 mutation in circulating tumor DNA, who are on first-line therapy with an AI and a CDK4/6 inhibitor. What do you think about that study and where do you think that progress might go? Of course, that's based on data from another trial, which wasn't definitive, but suggested, had sort of a suggestion, you know, without studying the sequencing in detail that maybe you would have improved progression-free survival with that approach. Dr. Nancy Davidson: Yeah, by which you mean the idea of monitoring pre-ESR1 mutations and circulating DNA and then making therapy changes based on that? Is that what you're talking about? Dr. Hope Rugo:  The PADA-1 trial, yes, and that led to this huge SERENA-6 trial, which of course is now accruing. Dr. Nancy Davidson: So, you know, we would love that, right? I think that obviously breast cancer for many years has been interested in trying to have circulating markers that we could use to help to guide our therapy in a more meaningful way than we have in the past. And I think that the trial that you've talked about is certainly one that's trying to make that see whether that's a possibility for us based on information like the PADA trial. I'm hopeful it's going to work out. I would say, let's see what that looks like, whether it's going to be useful or not. It seems to me in some cases, some of these trials have not been quite what we hoped for, but I don't think we necessarily had the molecular techniques or the sensitivity, nor did we necessarily have other things to move to because, you know, those two approaches require both a really good test, but also the ability to use the test to define a new therapy that's going to lead to improved patient outcomes. And I think that these are ingredients that we now have available to us at our fingertips more than we did, say, a decade or 2 decades ago. Exciting approach. Dr. Hope Rugo:  I do think there's a lot of challenges inherent in this process, monitoring blood on a regular basis and following up and then randomizing based on results. But I think [SERENA-6] is an incredibly important trial, as you have mentioned, to try and think about moving past using circulating tumor cells, which didn't work, to just change blindly to the next therapy, but more have a rational reason to change to a drug that may be more effective before the disease itself progresses. And just for our listeners, the unique aspect of trials like this in SERENA-6 is that you change therapy before you have evidence of disease progression, but only this molecular evidence of a mutation that is associated with resistance to the therapy you're on. So, it's a really important question. We'll see what happens, as you mentioned, sometimes we're not clever enough to really get around the fact that there are multiple mutations driving resistance in this setting, so we'll see how straightforward this is. The question also comes up, and I think that's a question with many of these trials now, is they're randomizing patients after a progression on an AI and CDK4/6 inhibitor to receive the novel endocrine therapy or fulvestrant. One of, I think, the concerns of treating oncologists is that then you're sort of eliminating the possibility of a targeted agent in that setting. And of course, we have new targeted agents we're studying as well, AKT inhibitors and new inhibitors of the PI3 kinase pathway. So, the newer trials are now combining, as you mentioned. There's a lot of concerns about drug-drug interactions here and how you might really combine them. And then there are triplet studies looking at CDK4/6 inhibitors, oral SERDs primarily, and pi3-kinase and CDK4/6 inhibitors. What's your thought on these and will they really help to move the needle forward? Dr. Nancy Davidson: I think that's a really interesting question, Hope, is whether or not we're going to find that combination therapies from the get-go are the way to go, or whether we're going to end up having to use maybe more serial therapies. Because not only is it a question about whether or not you can tackle all of these different resistance mechanisms simultaneously, but I think the other question is, as you say, are there negative drug-drug interactions, and are there toxicities that are intolerable? Although these are targeted in all cases and they're relatively benign in terms of side effects from the breast cancer perspective, they're not devoid of toxicity. And so, I think that's going to be another issue for us – whether they're well tolerated during the time that patients are taking them. I guess the other thing I always think about, Hope,  is that it's hard to know about value of cancer care, but you know, we are talking about agents that are not inexpensive. You know, when you think about the financial toxicity, in addition to the side effect toxicity that you and I just talked about, trying to think about what that value is going to look like is going to be very important for us. Also, as somebody who worked for a long time in the lab and in the clinic, you know, there are an infinite number of combinations that you and I could think about that are rational. And so, the question is, how are we going to pick the ones that are the most rational, if you will, the ones that seem to be the most promising, and take them forward into clinical trials? Because patients are our most precious resource. And so, we want to make sure that we are bringing forward only those things that really seem to have a very strong foundation and the opportunity to improve outcomes over time. Tough, tough question for us to try to think about, as you've talked about. The other thing is that, you know, these trials are not only for postmenopausal women, who are the majority of patients, but we also want to target them to premenopausal women. So, in those women, we're also looking at using an LHRH agonist on top of this, right, because many of these things are really at least so far designed for the postmenopausal state. So stay tuned. Lots of work going on. I think one of the interesting things will be making the leap from using these in metastatic disease at time of progression to taking them forward into the early breast cancer space. And several of the agents are now beginning to do that because of very strong preclinical and clinical data to date. Dr. Hope Rugo: So, we have new agents that we're studying in the metastatic setting, and we've seen a trend to move fairly rapidly from phase 1B trials directly into phase 3 trials, because as you pointed out so clearly, there are a number of drugs in this setting, and we don't really know not only which agent is better, but even what class of agents is better. So, as we move more quickly from phase 1B to phase 3, the question comes up about how we're going to study these agents optimally in the early-stage setting. They, I think we all thought that maybe changing based on ctDNA evidence of a mutation might be an approach, but that's complicated. A big question for you is whether or not you think that's ready for prime time as it's being marketed as such. And then the second question is really, are we better changing our whole approach upfront in high-risk disease or should we wait until after patients are exposed to their endocrine therapy and then switch as we go along; the EMBER-4 trial is looking at that switching approach? Dr. Nancy Davidson: Yeah, I think that this is obviously the billion-dollar question for many companies and for many of us as investigators. I don't know that I have a crystal ball into what the best approach might be. We know that already some of these have been abandoned. For example, amcenestrant. So, I don't even have to learn how to say it because it has been abandoned. It did go to phase 3, as you pointed out, in the advanced setting, looking at it with palbo vs letrozole plus palbo, and it didn't really show a whole lot that the company wanted to pursue.  So, I think that sometimes these things are going to be abandoned based on the metastatic setting, which is a large trial, and that's a trial where obviously it might be a little easier to the circulating markers, as you talked about, than maybe in the early-stage breast cancer setting.  I think that probably these early-stage trials are going to end up being big; they're going to have be clean. I'm guessing that most companies and most investigators will want to target them towards high-risk individuals, as you talked about, for 2 reasons. One is that ethically, I think we feel more comfortable with that. These are individuals where standard therapies are maybe not serving them as well as we would like and where we have information to think that we can at least have equipoise about a new approach. And the second is that from a trial design point of view, the event rate is likely to be higher, and therefore you might get answers earlier and with a smaller clinical trial. So that's where I suspect we're going to go. But it's a challenging question, and I think that many investigators and many companies are really trying to struggle with that right now because we do have so many options. And we're not quite sure how to, first, develop these new drugs, but then really importantly, put them in the context of our existing drugs. And as you say, we're also simultaneously trying to develop superior molecular or circulating markers to guide us. So, there's so many variables that are going on right now in this field that, from my point of view, itmakes it really exciting, but it also makes it pretty complicated, both for investigators and for pharma as we try to think about how to position these going forward. But what a great problem to have, Hope, because remember when you and I started in breast cancer, pretty much all you needed to know was tamoxifen. And I think you and I also probably started at the tail end of the time when we were using androgens and progestins and agents that now have basically completely fallen out of favor. Dr. Hope Rugo: Estrogen Dr. Nancy Davidson: Estrogen, yeah, and your side effect profiles were not as good. So, it's a good problem to have. It's a nice situation when science can inform our clinical investigation, our clinical practice. Dr. Hope Rugo: Yes, I think it'll be fascinating to see where we end up at the end, but of course, the complexities of this include the fact that sometimes just the clinical trial design leads to a less than positive result because of the way the trial itself has been designed, which I think is the nice part about moving these earlier into treatment of high-risk disease, but also brings up the question of all sorts of areas we're not really a place to discuss today, like how the statistical design is made, et cetera, that can sometimes result in poor evaluation of excellent agents. One of the questions that comes up, and you brought this up earlier, which I think is really important, is that we are in the era of combining our endocrine agents with targeted agents, and, oral agents, in a fascinating way, really bring up drug-drug interactions in a way that the injectable fulvestrant hasn't, and aromatase inhibitors were kind of quiet on the impacting metabolism, unlike tamoxifen. But we are seeing some drug-drug interactions and certainly the discussions about using these agents may include the question about whether or not you're having more diarrhea or nausea or fatigue or one drug causes photopsia, flashing lights, things like that. Keratitis is becoming a new toxicity to follow.  How are we going to figure out how to sequence these drugs and are they only going to work better all of them as a class in patients with ESR1 mutations in their tumors? Dr. Nancy Davidson: I think we don't know the answer to the second question yet. That's something that really needs to be sorted out. Even if they do, that's still a really important subset of patients, assuming that we continue to start with the aromatase inhibitors, right? That's where those things really seem to emerge right now. I don't know how we're going to figure those things out. I guess that I'm hoping that maybe a couple of agents in these classes will become kind of the lead agents. And so, we'll be able to do this work with a handful of things as opposed to a whole array of things. But we'll see. I think that even within classes, obviously, these agents are going be slightly different, probably. And so it may be that one member of a class may be slightly better from a, maybe not from an efficacy point of view, but from a toxicity point of view. And we'll just have to see how it goes. I don't think I have any magic answers about that. Dr. Hope Rugo: Yes, it'll be interesting to see whether or not the agents work in sequence too. You know, could you use a PROTAC after an oral SERD, for example, or a CERAN? That'll be fascinating to see. Dr. Nancy Davidson:  I'm hoping that preclinical modeling may help with that a little bit, though of course we all know that there are plenty of things that do well in preclinical models, GEMS and rodent models and PDXs, and sometimes those things translate nicely into clinical practice, but sometimes they don't. Dr. Hope Rugo: You mentioned, Nancy, that when we started out, that it was a fairly simple decision about what endocrine therapies, and we ran out very quickly. We're seeing some of those old classes come up with new agents. And you mentioned lasofoxifene, the oral SERM that seems to have some benefits and works in the later-line setting and also can be combined with a CDK4/6 inhibitor; [and also] has data with abemaciclib. There's also a new androgen receptor agonist, enobosarm, that's being tested as well. Do you think that these older mechanisms have a future as well? Dr. Nancy Davidson: I do. I think that because we'll be able to understand the biology better than we did in the past. A lot of our hormone therapy was pretty empiric several decades ago. But I think with better understanding of mechanisms and better understanding of what the patterns of resistance might be for a particular tumor, that we might be able to think about those things. You're right that there's a whole parallel universe right now in androgen receptor targeted therapies that we're not talking about today, both in perhaps in hormone-responsive breast cancers, but also in triple-negative breast cancers in a certain subset. And so that's an area where we probably need to be watching what our prostate cancer colleagues are doing as they develop these agents and thinking about where they might mechanistically make sense to apply in the breast cancer field. It won't be the first time that we've received insights from them because remember, prostate cancer people knew about androgen receptor mutations a really long time before we figured out that they existed in estrogen receptor as well. So, there's a nice cross talk, I think, between the prostate cancer field and the breast cancer field in that regard. Dr. Hope Rugo:  That's an excellent point. And we learn a lot from our colleagues studying other malignancies, and prostate cancer has been a big area there for us and hopefully will help us with studying these agents because there's different toxicity profiles, of course, as well. And then you mentioned the approval of elacestrant, the first oral SERD to have regulatory approval, and it's approved in patients who have ESR1 mutations in their tumors. We're also studying it in the ELEVATE trial in combination with all of the different targeted agents, the CDK4/6 inhibitors, mTOR inhibitor, everolimus, and the PI3 kinase inhibitor, alpelisib, to really try and understand how these can be optimally combined. Would you check for ESR1 mutations at diagnosis of metastatic disease, or would you do this more after progression or start of progression of disease on an aromatase inhibitor? Dr. Nancy Davidson: I tend to be a conservative, Hope, and so unless there's a clinical trial that might be able to be considered, I would tend to check it only after progression on the aromatase inhibitor. But I think some people are earlier adopters, and I suppose it's possible that they might want to know from the get-go. Having said that, I do think elacestrant has an approval after aromatase inhibitor, as I recall. So, presumably the patient would have to have that exposure before you would be able to act on the ESR1 mutation by administering the oral SERD. This is also a new area that may well change with time, right? You know, as we develop different agents, as the agents have different requirements or different indications, and as we perhaps have better tests, it may be things that we don't do routinely now will become very routine in the future. And perhaps in series like you talked about in a serial fashion. Dr. Hope Rugo: Absolutely. I think that's a really important comment about how we're going to think about treating hormone receptor positive disease and potentially, you know, we have new chemo options, of course, not part of our talk discussion today and antibody drug conjugates. So, the future is certainly challenging in terms of understanding this appropriate sequencing. We need data, but it's exciting to have these options. As you pointed out, this is this is a great problem to have, you know, too many drugs with efficacy to try and understand how to use these in the most appropriate way. And as you also pointed out, the use in young women is particularly important. Whether or not you need to suppress the ovaries with all of these new agents is going to be important to understand as well as a next step. I don't know if you have specific thoughts on that area as well. I mean, that may reduce toxicity for younger women. Dr. Nancy Davidson: I guess our approach right now has been to suppress them, but I agree with you; you wonder if you look at some of the mechanisms of action, whether that's really a requirement biologically and medically, or whether it's something that's kind of a leftover from the approval process. You know, that for the drug approval, these women were suppressed. I think we need to work that out because that's another area where certainly women could have ovaries removed. That's pretty straightforward, although it requires a surgical procedure. But otherwise use of LHRH agonists continues to be injections, right? And so, if we're trying to minimize convenience or maximize convenience and minimize toxicity for women with any stage of breast cancer, anything we can do, it seems to me to eliminate an injection is going to be a good thing. So important for us to be able to work that out as well, even though numerically it's a smaller number of women, it's obviously a very important number. population of women. Dr. Hope Rugo: Last question for you. One question that comes up and sent to me and panels all the time is, if you have done your next generation sequencing and you see an ESR1 mutation and a P13CA mutation, what do you prioritize in terms of your choice of treatment, because we have the choice of either using elacestrant or a fulvestrant in combination with an agent targeting the PI3 kinase pathway? Dr. Nancy Davidson: I don't know that there's a right answer to that medically right now. So, when I talk about it with patients, I suggest to them that it's probably not one or the other. It's kind of the question of which one to use first. So, we talk a little bit about side effect profiles. We talk a little bit about patient preference and neither of these drugs is devoid of problems, but sometimes patients have pretty strong feelings about which set of side effects seems the least unattractive to them or the possibility of having those side effects. And I know that if one isn't well tolerated, you can swap over to the other. Dr. Hope Rugo: Absolutely. I think that's a very important way to think about next therapies in our era of not really knowing what's right. And this idea of shared decision-making is so incredibly important. Nancy, thank you so much for sharing your insights and knowledge with us today. I could talk to you for hours about this. Dr. Nancy Davidson: Hope, thank you so much for the opportunity. It is an exciting area and I really enjoyed talking with you about what we know and the many things that we don't yet know, but we're working on. Dr. Hope Rugo: Indeed, it's certainly an exciting time. Thank you to our listeners for joining us today. And thanks to the ASCO Daily News Podcast for highlighting this important area. You'll find a link to all of 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. Thanks so much.   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. Hope Rugo  @hoperugo  Dr. Nancy Davidson     Follow ASCO on social media:     @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:     Dr. Hope Rugo:  Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, Daiichi Sankyo Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Talho Oncology, Veru, GlaxoSmithKline, Hoffmann-LaRoche AG/Genentech, Inc Travel, Accommodations, Expenses: Merck, AstraZeneca   Dr. Nancy Davidson: No Relationships to Disclose    

What is knowledge? Does a justified true belief count as knowledge? And is our knowledge lucky?

On this episode Mylan sits down with Raymond Fox Jr, from Sweet Grass Indian Reserve and grew up in North Battleford, Saskatchewan. Besides being a goalkeeper for the USask Men's Soccer team, Raymond is deeply committed to his community and passionate about fostering the next generation of indigenous athletes. As he pursues his education degree at the Indian Teachers Education Program (ITEP) at the University of Saskatchewan, Raymond also finds time to actively promote community sport camps and program for indigenous youth. Through his involvement, he aims to inspire and mentor young indigenous athletes, empowering them to pursue their dreams in sports and beyond. Raymond's dedication to nurturing talent and encouraging a sense of belonging in the sporting world has made him a notable figuring both on and off the field. Listen in as we discuss his experiences with soccer, training regime, and his take on working with indigenous communities .

Drs. Hope Rugo and Kristin Rojas discuss advances in the management of menopausal symptoms, fertility preservation, and bone health for women on endocrine therapy for breast cancer. TRANSCRIPT Dr. Hope Rugo: Hello. I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. And I'm also an associate editor of the ASCO Educational Book.   In patients with hormone receptor positive breast cancer, the most common subset of the most common cancer in women worldwide, adjuvant endocrine therapy significantly reduces the risk of recurrence and death. However, prolonged estrogen suppression associated with the use of endocrine therapy can cause life-altering menopausal symptoms, bone loss, and fertility concerns. These issues impact the use of endocrine therapy and potentially breast cancer outcome.    Today, we'll be discussing mitigation strategies to manage the side effects of endocrine therapy, which we hope will improve our patient's quality of life and adherence to treatment with Dr. Kristin Rojas, who addressed these issues in a recently published article in the 2023 ASCO Educational Book. Dr. Rojas is an assistant professor of surgery and a breast surgical oncologist and gynecologic surgeon at the University of Miami Sylvester Comprehensive Cancer Center.    Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod.    Dr. Rojas, thank you for being on the podcast today.   Dr. Kristin Rojas: Thanks, Dr. Rugo, thank you so much for having me. Thank you to ASCO as well. It's truly an honor to be here with you today.  Dr. Hope Rugo: Your excellent article provides an updated overview of the existing approaches and a little forward thinking for improving the quality of life of breast cancer patients who are receiving estrogen deprivation therapy, a really broad term we use for all the hormone therapy we use in ovarian function suppression in the treatment of breast cancer. And then you had a very nice session education session at the ASCO Annual Meeting discussing these issues. Can you briefly discuss the educational session, your speakers and topics, and then we'll get more into the details of this important topic?   Dr. Kristin Rojas: At our educational session at ASCO this year, I chaired the session and presented on managing the sexual side effects and menopausal symptoms of estrogen suppression. And I had two wonderful colleagues with me: Dr. Matteo Lambertini, who shared guidelines regarding bone-targeted agents and managing bone health during endocrine suppression. And then we also had Dr. Terri Woodard, who is a reproductive endocrinologist from MD Anderson, who spoke on managing fertility concerns, which is a very important topic right now.   Dr. Hope Rugo: Yeah, that's great. And it was such a fabulous session. Our listeners can view it online at asco.org if you missed this session. But let's talk a little bit about what was in your article and what was discussed. First, I think the physical and psychological effects of cancer care we know are critical components of survivorship care. Can you tell me a little bit more about that and how we need to understand that as oncologists?  Dr. Kristin Rojas: So, as you know, as treatment continues to improve, our cancer outcomes are improving and the population of survivors continues to grow. So, I think that for many breast cancer patients, or having the diagnosis of breast cancer, becomes more of a chronic illness and less a life-threatening issue for some. I think that the conversation is now changing from “Will you live?” to “How will you live?” And I was thrilled to see that other big organizations, along with ASCO, are prioritizing managing these important symptoms in survivorship. Because I think that, as most patients will be on some form of estrogen suppression, managing the toxicity of these therapies, as you pointed out, probably does influence treatment adherence, which directly translates to an oncologic improvement. So, it's not just managing these soft symptoms, it actually will have a direct influence on probably overall survival along with disease-free survival.  Dr. Hope Rugo: Yeah, I think that's incredibly important and it's not just about doing the exam and finding out symptoms that might signify recurrence, it's really trying to address the effects of the treatment patients have gotten of chemo and their ongoing treatment with endocrine therapy that's so incredibly important. And now, of course, in medical oncology, we're adding on more agents which add to symptoms. That'll be the topic of next year's ASCO educational session. What do you do with the CDK4/6 inhibitors and managing those. But in more than 80% of women who are on the antiestrogen or various, I'm going to call hormone therapies, for early-stage breast cancer, vasomotor symptoms are a big issue. They're typically more severe in younger patients because of course they have estrogen and we take it away. So, how do we mitigate this problem in patients that can result in poor sleep and impact many aspects of one's psychosocial status? And these issues, not sleeping, of course, you make everything worse.  Dr. Kristin Rojas: Yeah, that's a really important point. And you're right, this is a really common symptom experienced by the majority of patients on endocrine suppression. And not only those patients, but patients with triple negative disease who are put into menopause from chemotherapy, etc., along with women with cancer of other disease sites. And so, as the director of our program at the Sylvester Comprehensive Cancer Center, the program is called MUSIC, which stands for Menopause Urogenital Sexual Health and Intimacy Clinic.    This is a very common symptom that patients often report. And one of the important things about this that I've realized is that hot flashes or vasomotor symptoms can actually have a pretty varied presentation. So, it's not just intense sweating. Sometimes these patients can present with palpitations, panic attacks, and they don't even realize that they're hot flashes. This is an effect of estrogen suppression and it's a central mechanism. So, it's probably related to hypothalamic dysregulation regarding how our body senses temperature changes, but it results in widespread flushing and sweating and those other aspects I told you about.   So, we've known for a long time that there are some behavioral modifications that can help with vasomotor symptoms or hot flashes. But now, we actually do have some pretty effective pharmacologic therapies for these patients as well, for whom behavioral modifications aren't completely helping the issue. Or, as you said, when patients are being woken up all night long with these hot flashes, it totally disrupts how their day goes and disrupts coping with their disease and all the other aspects of their treatment.   So, there's some effective treatments that we have. One of those being cognitive behavioral therapy has been shown to be helpful. The data on acupuncture is mixed, but I'm hopeful about this. And then the pharmacologic therapies we have. Traditionally or historically, clonidine, which is an alpha agonist, has been used along with gabapentin. But I think when choosing a medication to prescribe to a patient for hot flashes, you have to take into account the side effect profile. Clonidine does have some issues with blood pressure rebound, and gabapentin is really only effective in large doses, which can be very sedating for patients.    In the MUSIC Sexual Health After Cancer program, we typically stick to low dose SSRIs or SNRIs. I usually go with venlafaxine at a really low dose of 37.5 milligrams, and I can titrate up. I have patients take it at night in case they feel a little foggy when they first start it. But more recently, we've started using oxybutynin, which is an anticholinergic medication originally FDA approved for overactive bladder. I use the XL formulation, or you can do 2.5 or 5 milligrams BID. And this, in a study a few years ago, was shown to significantly reduce hot flashes and improve quality of life in a placebo-controlled trial.   So, important aspects of side effects of these medications with SSRIs or SNRIs working in the MUSIC Sexual Health After Cancer Program, sexual health concerns are often an issue, so those drugs can be libido zappers sometimes. But, the biggest side effect I've come across with oxybutynin for patients is dry mouth, and usually that resolves after a little while. So, we've had a lot of success in managing patients' hot flashes with these medications.  Dr. Hope Rugo: That's great and incredibly helpful. And I will say that as we're talking about these issues on this podcast, this is really important for all of our staff and our clinics because most of us don't have a fabulous clinic like the one you've started. But we are managing this with our staff, our APPs, and other areas that our patients are seeing. If everybody has this education, it will really help in the management of symptoms. And I just want to point out that venlafaxine was the first drug to be studied in this area really successful, but that we can use a whole host of different antidepressants. If people have side effects from one another, one may work really well, and generally low doses work well. The oxybutynin was such a very cool study. I think that's a great additional option.    In addition to hot flashes, we also see genitourinary syndrome of menopause, and that's part of what you deal with every day in your clinic, GSM. And this can be not just vaginal dryness, which is bad enough, but also increased infections, painful sex, recurrent bladder infections and also reduced libido, which is a really big issue, we just don't talk about very much. What's the most effective and safe treatment for GSM? And we use a lot of low dose vaginal estrogen and a variety of delivery mechanisms. What are the risk and benefits when patients really need something more?   Dr. Kristin Rojas: GSM, or genitourinary syndrome of menopause, is this newer umbrella term for what we used to call vaginal atrophy. And you're right, it encompasses not only dryness, but all the other changes that can happen to the vulvovaginal mucosa along with anatomic changes to the pelvic floor. This is critically important, I think, that we address these issues or these potential side effects at the time of endocrine therapy prescription because what we have found in our program is that while hot flashes might get better, these symptoms do not get better. And left untreated, they get worse.   And one of the surprising findings that we have presented earlier at another conference this year was that almost half of our patients, when they had their pelvic exam in the program, were also found to have vaginal stenosis. So narrowing and shortening of the vagina, making penetrative sex actually impossible. So it's really not just dryness, but a host of these other symptoms that go along with that. I like to break this down in a really simple way because I know that a lot of providers may be intimidated when patients might bring this up. But I think about it this way. Number 1, eliminate irritants. Number 2, moisturize. Number 3, lubricate. And 4, address the pelvic floor.   Oftentimes when patients present in the MUSIC program, they've been putting a lot of over the counter topical therapies on the vulva and the vagina using intravaginal washes. One of the biggest offenders of some of these symptoms is artificial fragrance, which we can actually develop an allergic reaction to, which manifests as burning and stinging. So these patients may also report burning and stinging in addition to dryness. These offenders can be in all kinds of products. So not only feminine washes, which I don't recommend in our program, but things like bath bombs, bubble bath, toilet paper. And so we kind of go through an inventory of everything that's touching the delicate tissues of the vulva and the vagina and try to back off those products.   The second thing is moisturization. It's important to talk to patients about the difference between moisturization, which I say is for maintenance, and lubricants, which are for PRN use sexual activity. But I tell patients, "lubricants for love." That's how I differentiate the use of these two different types of products because they have different properties. Usually after eliminating irritants, our first step is to start with a non-hormonal moisturizer because there's some really good high-tech non-hormonal moisturizers out there, specifically those containing hyaluronic acid, which pulls moisture from the environment and holds it on the skin. And by using this first—this is my personal opinion—but I think by improving the mucosa a little bit and kind of improving the dryness, maybe even the elasticity a little bit, I think that when patients do have persistent symptoms after using regularly these non-hormonal moisturizers at least three times a week, that adding in a low dose vaginal hormone at that time, instead of putting it on completely atrophic mucosa, you're putting it on kind of like a pretreated mucosa, which I think might decrease systemic absorption.   I'm so glad you brought up vaginal estrogen. I could give an entire talk just on that, so I'd be happy to do that next year for ASCO if anybody wants. But it is very controversial. Historically, there have not been studies showing an increased risk of recurrence with the use of local estrogen therapy, so estrogen in the vulva and the vagina. However, there was a recent study that came out this year that was a large analysis of breast cancer patients receiving different types of hormone therapy. And in a subset analysis of the group who got local vaginal estrogen, just in those patients on aromatase inhibitors, there was a slightly, but statistically significant–according to their analysis–increase in the risk of recurrence. I think there's some issues with this analysis because it was a large study and there's a lot of recall bias and measuring this in patients is really challenging. But I think it's still important to mention because a lot of patients are going to read about those things, these types of studies.   The way I approach it is to start with the lowest dose and I start with infrequent dosing. If patients have persistent symptoms, I start them with once a week or twice a week, which is different from the original pharmacokinetic studies of higher dose estrogens, which showed a bump in their serum estradiol when they used it every night for two weeks. So I actually do the opposite and taper them up. I'll do once a week to twice a week. And usually, patient symptoms are resolved at that point.   But I do want to point out, that's a great option for patients on tamoxifen because mechanistically, as you know, it probably doesn't matter if they have a little bump in their serum estrogen. But for the patients on aromatase inhibitors, we actually have a new kid on the block, a vaginal androgen called prasterone or DHEA. I dose this in the same way, titrate it up. But this can be really helpful for patients on aromatase inhibitors because the ALLIANCE trial showed that for those patients on AIs that their systemic estrogen levels do not increase. And so that's kind of how I manage that discussion. I do think it takes some multidisciplinary collaboration, so I always involve my medical oncology colleagues on this.    Lastly, lubricants. So, everyone seems to be really into using water-based lubricants, but I try to tell patients, unless you're depending on condoms for STD or contraception protection, silicone-based lubricants that are like preservative-free and don't have a lot of those gimmicks or additives, are great—they stay slippery for longer—and there's some really great brands out there. And then for patients who still have persistent pain with sex, we address the pelvic floor, which is either through the use of dilators, referring them to pelvic floor physical therapy, or other sexual devices that we use in the MUSIC program.  Dr. Hope Rugo: This is really helpful, and I think that for many of us in practice, we really want to get the specifics of what you use. I think this prasterone, the idea of DHEA is really very interesting and something that personally I haven't used, but we did use in the distant past before there was an FDA-approved version.   So I guess I have several questions just to ask about the details. So one is, when you prescribe this, do you find it's generally covered by insurance? And when you say low dose, do you mean just try it once a week? And then do you use the estrogen tablets, the brand names are often Yuvafem or Vagifem, we often use those twice a week. How often do you use them and do you use the estrogen ring also? What are the absolute specifics of what you're recommending to these women? And do you feel like sometimes in patients who are developing these symptoms that early use can help avoid the more severe symptoms and therefore reduce the exposure?   And lastly, just to say, that paper which was so interesting about the slightly increased risk of recurrence, I felt was so flawed in terms of what people were using and if they were taking their hormone therapy and risk of recurrence, the risk of the cancer itself, that I really felt like I couldn't make anything out of it in terms of the risk to patients. But I'm really interested in your specific recommendations.  Dr. Kristin Rojas: Thanks for asking about specifics. And I'm happy to give our treatment algorithms here, which we also discussed in our session and we listed in our EdBook manuscript. We do pelvic exams in the MUSIC program and I often find that there's very specific points in the vestibule or the opening of the vagina that are tender and have pain, specifically, what's known as the posterior fourchette, which is the kind of connection between the right and the left side towards the posterior aspect. So, I usually start with a 1% estradiol cream and have patients tap it to the outside and then bring in a dilator and have patients use not only a silicone lubricant, but put some of the estradiol cream on the dilator. And so that brings the product up to the top of the vagina for patients that have some of those anatomic changes that I discussed.   So this is 1 option, and we really don't have a lot of issues with insurance authorization for the cream, just every once in a while. We can also use a 4 microgram or a 10 microgram dose of estradiol, which is a tablet, which are newer options. This is in contrast to the old pharmacokinetic studies that use 25 micrograms. So this is much, much lower. I do run into some prior authorization issues with those because there tend to be newer versions of this. But as you mentioned, the estradiol ring, which I do think is a great option and when you calculate it out, releases a very low dose of estradiol every day. And it's good for patients who want a more low maintenance regimen. The only challenge I've had with that is it's a large rigid ring. And for patients who already have those anatomic changes, it can be really hard to place that in the vagina.   And so, just like you said, early prevention and treatment of these issues can prevent not only anatomic changes, but even potentially the need for exposure for larger doses of hormones. For all of those options, I tend to do it once or twice a week and then can move up. But we sometimes get kind of creative in how we use these options in terms of placing them on the dilator, placing them externally. For patients that have recurrent urinary tract infections, I also have them kind of tap some of the estradiol cream around the urethra as well to improve the urethral and potentially bladder microbiome and decrease risk of recurrent UTIs.  Dr. Hope Rugo: That's really interesting, and I think those specifics are incredibly helpful. We also will check, although I have to say there's no data to support it, the serum estradiol levels in patients who are using more than our minimal amount. We have plenty of studies that have shown that there really isn't systemic estrogen if people are using very low doses. But we will check sometimes, just sometimes people use these topical creams where they get premenopausal levels of estrogen, which of course we don't want. So, this is an incredibly helpful and useful discussion.    One of the other things that happens for these patients and our younger patients, which breast cancer is still increasing in small numbers in younger patients every year, and many of these patients have hormone receptor positive disease. And it just breaks your heart to see a 38-year-old who is planning to get pregnant next month with their new partner who develops a hormone receptor positive breast cancer. and we want to give people all the options they possibly can. We are strong proponents for harvesting eggs and either freezing eggs or embryos before you start treatment. And we figure we always have 2 weeks for breast cancer. We also use ovarian function suppression during chemo just for whatever help it might have.   But then after patients have finished their treatment and they're on hormone therapy, it's a really big issue for women about when they can have a child because we don't want to wait until they're 45. So, you had noted in your article that some women could take a break from endocrine therapy after 18 to 24 months to try and conceive. Can you tell me a little more about that?  Dr. Kristin Rojas: Sure. Well, this aspect of our discussion was very well presented by my colleague, Dr. Terri Woodard from MD Anderson, a reproductive endocrinologist, and she also put together the aspect of this for our manuscript. She talks about how fertility counseling and referral is probably underutilized, but definitely indicated for most of these patients who are of pregnancy age or premenopausal status. And observational data for a long time didn't show that pregnancy after treatment worsened oncologic outcomes. However, patients as well as many providers had reservations.   So, it's been very helpful that we now have a prospective, large, international trial known as the POSITIVE trial, the early results of which came out earlier this year, which showed that women, after 18 to 24 months, could interrupt endocrine therapy and did not have a worsened short-term oncologic outcome. And those are women with early-stage breast cancer. However, there is a concern that many patients do take longer to get pregnant in that age group or after treatment, potentially if they've received chemo. There is a concern about the duration of time that they're not on endocrine therapy afterwards, which might be further clarified in later analyses. So that's my takeaway from that study, which did show us that very helpful, reassuring information. But I think we're still waiting for the long-term data and it's definitely still a very important patient-centered discussion.   Dr. Hope Rugo: This is a really excellent point, and I think that one of the things of a trial like this, which is sort of a registry study, is that we're always going to speak with our feet to some degree. So, if patients have very, very high risk of recurrence and highly proliferative disease, we might not want them to stop at 18 months because their risks are so high early. So, it has to be a risk versus benefit discussion for individual patients, of course. But I think this data was incredibly reassuring.   It was interesting there were some patients who hadn't restarted their endocrine therapy. In the paper in the New England Journal, it told us that some of those patients were still trying to conceive. But one of the things that's going to be really important for these patients is to really make a big effort on the part of our clinical practices to get patients to restart their hormone therapy. It's very hard to do that, as you can imagine, in that setting.    Another area here is monitoring bone health. And I know that's not part of the MUSIC clinic per se because you're really focusing on GSM and other areas that we've just discussed, which are so incredibly important. And it's funny, bone health is silent, right? So, although some patients don't want to take aromatase inhibitors because they're worried about losing further bone density, they don't feel it. So that's, of course, a different kind of a toxicity. But we know that by suppressing ovarian function in young women, we cause a lot of bone loss, and in older women, already in menopause, that this continuous loss of bone increases the risk of fractures, which can be a huge impact on quality of life and even survival in some cases. So, we're really interested in trying to prevent bone demineralization and reducing the risk of fractures. I believe that Matteo Lambertini from Italy discussed this in your paper and that there's a lot of discussion about use of denosumab and zoledronate. I wonder if you could just comment a little bit on that in our last couple of minutes.  Dr. Kristin Rojas: Well, as you said, my colleague Dr. Lambertini put this aspect of our paper together, but he did put together a very nice summary of bisphosphonates and denosumab and separated their use by premenopausal and postmenopausal patients because the data surrounding those patient populations is slightly different or nuanced. But as you mentioned, it is important to monitor these patients' bone density. We have our standard recommendations such as a calcium-enriched diet, resistance and weight-bearing exercise, and vitamin D for patients, for those patients with a vitamin D deficiency or at risk of bone density loss. And so these pharmacologic agents can also help decrease bone mineral density loss and potentially decrease or likely decrease bone recurrences, which, as we know, influences survival. I think he provides a very nice summary of that, as you mentioned.  Dr. Hope Rugo: I think that's so incredibly important. And thank you for really emphasizing the weight-bearing exercise and checking vitamin D and making sure patients are taking vitamin D and at least some calcium. And then, of course, our institution, we work closely with our endocrinologists specializing in bone as well, when issues come up about risk of osteonecrosis of the jaw, and we require dental clearance for everybody starting medication just to make sure that we've reduced risk to the patient. And then when we're trying to think about stopping denosumab and should we bridge with zoledronate to reduce the risk of fracture, we also talk to our bone doc. So it's really important.   And in our last just 1 minute, I know you were thinking of saying something about measuring estrogen in the blood in patients who are using vaginal estrogens. Do you do that?   Dr. Kristin Rojas: Yeah, great question. I'm glad you brought that up. We actually don't routinely do this in the MUSIC program, but it is an important aspect to think about today, because I don't know about where you are, but here in South Florida we have a lot of patients who are receiving therapies outside of the FDA-approved space and these are typically marketed as bioidentical hormones, which is a marketing term. Oftentimes, they'll get either transdermal formulations or pelleted hormone therapy that can result in really high superphysiologic testosterone or estrogen levels. And so we typically, for those patients, do try to get them off those non FDA-approved therapies because the safety of those is unknown.   Dr. Hope Rugo: That's really interesting and so helpful. Yes, I know this whole idea of bioidentical hormones drives me crazy, but I think that's great that you brought that up, actually. We do measure it. Who knows? I think if you're really worried, measuring “Yeah, everybody's hot flashes went away,” it's probably worthwhile checking.   This was such a fabulous conversation. I learned so much. We really appreciate your contribution to the educational manuscript, to the educational program, and your fabulous insights with us today. Thank you so much for participating on the ASCO Daily News Podcast. I think everyone will find this very helpful.   Dr. Kristin Rojas: Thank you so much for having me.   Dr. Hope Rugo: And thank you to you, our listeners, for joining us today. You'll find a link to Dr. Rojas and her colleagues' article in the transcript of this episode and in the 2023 ASCO Educational Book, which features practice-changing oncology research and a wide range of compelling studies on quality and equitable cancer care.    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. Thanks again.    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. Hope Rugo  @hoperugo  Dr. Kristin Rojas  @kristinrojasmd    Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. Hope Rugo:  Honoraria: Puma Biotechnology, Mylan, Samsung Bioepis, Chugai Pharma, Blueprint MedicinesConsulting or Advisory Role: Napo PharmaceuticalsResearch Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Odonate Therapeutics, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Ayala Pharmaceuticals, Astellas Pharma, Seattle Genetics, Macrogenics, Boehringer Ingelheim, Polyphor  Dr. Kristin Rojas:   Honoraria: Pacira Pharmaceuticals  Consulting or Advisory Role: Roche Diagnostics, Merck  Research Funding (Inst): Bristol Myers Squibb Foundation       

On this episode of Southpaw, Sam is joined by activists Emma Taylor and Mylan Tootoosis for an anti-colonial discussion on de-escalation and community care. "The Cunning of the Adult Supremacist": https://www.colbytootoosis.com/writings/adult-supremacy Radicle Narrative: https://linktr.ee/radiclenarrative Listen to Fighter's Brew: ⁠⁠⁠⁠⁠https://www.patreon.com/posts/76751767⁠⁠⁠⁠⁠ Sign up for Liberation Martial Arts Online: ⁠⁠⁠⁠⁠https://www.patreon.com/posts/liberation-arts-72505630⁠⁠⁠⁠⁠ We can't continue to produce important episodes like this one without your solidarity. There is no Southpaw network without your financial support. In return, not only do you help produce our shows but you also get access to more great content. It's mutual aid. Find our Patreon, swag, and other ways to support us at: ⁠⁠⁠⁠⁠https://www.southpawpod.com⁠⁠⁠⁠⁠ You can find Southpaw on Facebook, Twitter, and Instagram: @SouthpawPod

Actelion Pharmaceuticals Ltd v. Mylan Pharmaceuticals Inc.

On this episode we are Sharing "Episode 131: This is for Settler Comrades to listen to" of the Decolonized Buffalo Podcast where our host Mylan was featured as a panelist. Episode Details: Host: Derek (“PlantsFanon” on social media) Guests: - Mylan (Radicle Narrative Podcast) - Yahmo - Victor - Rick (Decolonized Buffalo Podcast) Since there has been a lot of reactionary takes against decolonization, and the work of Dr. Horne, we decided to give our analysis on the situation, and give some advice to settler/non-Indigenous comrades. Music: By Dale Memnook on Soundcloud The Rabbit Stomp

Join the Oak Cliff Cultural Center for a conversation with Artists Mylan Nguyen, Taro Waggoner, and Brent Ozaeta. In our twelfth episode, we talk with the group about their work, influences, and experiences as a collaborative team. OCCC is a division of the City of Dallas Office of Arts and Culture. The views and opinions expressed here are of the individuals only and do not necessarily reflect views or positions of the City of Dallas, the Office of Arts and Culture, or the Oak Cliff Cultural Center. Intro + Outro royalty free music prod. by Danya Vodovoz of VMP

On this episode Mylan sits down with Rick from The Decolonized Buffalo Podcast. We discuss Marxist Theory, Decolonization and Settler Colonialism. Shownotes: Other episodes and show notes are available here, https://linktr.ee/decolonizedbuffalo If you want to join our Patreon, click the link, https://linktr.ee/radiclenarrative Music by: William Bird from Peguis First Nation, Treaty One Territory. (Manitoba, Canada)

Ohio State just added a second 5-star wide receiver to its 2024 recruiting class. Mylan Graham, a deep-threat prospect with elite speed, just committed to the Buckeyes on Tuesday night. He is the second out-of-state offensive skill player to commit to OSU this week. Kevin Noon of BuckeyeHuddle.com joins host Tom Orr to discuss where Graham might fit in the Buckeyes' offense, and whether another big offensive commitment could be on the way later this week.

I give you my instant reaction to the Tuesday night commitment of 2024 Indiana wide receiver Mylan Graham. Love Ohio State Football? Subscribe!!! https://www.youtube.com/@TheBuckeyeCast?sub_confirmation=1 ⭐️ Join us every Sunday night at 8 PM on YouTube Live!!!

The boys welcome back Richard Mylan and talk about the huge response the 1st podcast got, Richard talks about how he wants to challenge people's response to addiction, the boys talk about social media algorithms and sneaking into movies. Richard describes his process of writing his new play “Sorter”, the origins of Methadone, the drug purchase process, how a Play is put together, writing raps and Donna has been on a TV show plus much much more….@ambitioniscritcal1997 on Instagram @TheAiCPodcast on Twitter

Episode 113: 1 on 1 with Radicle Narrative Podcast Guest: Mylan Tootoosis On this Episode I speak to Mylan about a variation of topics, rom Indigenous media, to parenting, revitalization of Indigenous languages, community & politics. Radicle Narrative Linktree: https://linktr.ee/radiclenarrative Rick is a citizen of the Comanche Nation, and has a master's in Indigenous People's law, from the University of Oklahoma.

Few people truly appreciate the complexity, effort, and vision required to establish and maintain global leadership in any industry, let alone luxury beauty products. The Estée Lauder Companies Inc. is the global leader in prestige beauty and a Fortune 500 company with over 25 brands spanning across 150 countries.This week, we take a look inside the playbook of the company's CIO, Michael Smith, who is spearheading innovation through technology in exciting new ways. Prior to joining The Estée Lauder Companies, Michael spent 22 years in IT leadership roles at Nike and 4 years leading technology and digital innovation at Mylan. Michael also sits in board advisory positions at multiple companies. He is the founder and Chair of The TechPACT, a coalition of tech leaders and CIOs that is leading the charge for diversity, inclusion, and equity in the technology industry. He also founded Tech Day of Pink to unite technologists and IT professionals worldwide around breast cancer awareness, education, and fundraising. Join us as we discuss: Michael's leadership philosophy of joy, and how it helps him bring out the best in people The value of “patient persistence” and “confident calm” in a constantly changing environment How Estée Lauder is using technology to anticipate customer needs and deliver innovative, superior products How The TechPACT is working for increased representation and equity in the technology space More information about Michael and today's topics: LinkedIn Profile: https://www.linkedin.com/in/mwshome/ Company Website: https://www.linkedin.com/company/the-estee-lauder-companies-inc/ Other Relevant Links: https://techpact.org/ https://www.techdayofpink.com/

Dr. Allison Zibelli, of the Sidney Kimmel Cancer Center – Jefferson Health, and Dr. Hope Rugo, of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, discuss the practice-changing DESTINY-Breast04 trial as well as novel therapies in metastatic HR+/HER2- breast cancer from the TROPiCS-02 and MAINTAIN studies, all of which were featured at the 2022 ASCO Annual Meeting.   TRANSCRIPT Dr. Allison Zibelli: Hello. I'm Dr. Allison Zibelli, your host for the ASCO Daily News Podcast today. I'm a vice-chair and breast medical oncologist at the Sidney Kimmel Cancer Center, Jefferson Health in Philadelphia. My guest today is Dr. Hope Rugo, a professor of medicine and the director of Breast Oncology and Clinical Trials Education at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. We'll be discussing key advances in breast cancer that were featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes, and disclosures of all guests on the podcasts can be found on our transcripts at asco.org/podcasts. Hope, it's great to talk to you today. Dr. Hope Rugo: Nice to talk to you, too. Dr. Allison Zibelli: Let's begin with perhaps the most exciting abstract at ASCO this year, which was the DESTINY-Breast04 study, that's LBA3, a randomized phase 3 study of trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-low, unresectable and/or metastatic breast cancer. What are your thoughts about this study? Dr. Hope Rugo: Well, of course, this is a hugely practice-changing study as was noted in the second-to-last slide by the discussant [Dr.] Pat LoRusso. So, antibody-drug conjugates are really the next step in delivering chemotherapy to cancer cells. The antibody-drug conjugates allow targeted delivery of a toxin to the cancer cell. I think we didn't understand how important this was going to be. These second, sort of, verging on third-generation antibody-drug conjugates use an antibody approach and to then have a new generation of linkers, which allow the drug to be released locally, but to then have drugs which pack a big bang for the buck. So, the way antibody-drug conjugates are constructed, you need to have a drug that actually can't be given as a naked drug because it's too toxic because you're giving just very small amounts of this drug that are delivered directly to the cancer cell. And the other really critical part of this is that the drug-to-antibody ratio of at least the successful and new antibody-drug conjugates (ADC) is quite high in the 7.5 to 8 toxins per antibody. Now, what that's resulted in is really interesting, is that there's a bystander effect. So, the toxin itself can leak out of the cancer cell that it's targeted and kill neighboring cells, but also because of the construct of these antibody-drug conjugates, what's likely happening is even if the cancer cell's a very low expression of the target, really low, you're able to actually get that ADC into the cancer cell to kill the cancer cell. So that may be a big part of the so-called bystander effect. So trastuzumab deruxtecan is biosimilar trastuzumab linked to a topoisomerase inhibitor deruxtecan, and what happened here was that of course, we saw remarkable data in HER2+ disease, unbelievable p-values in DESTINY-Breast03 compared to T-DM1, a first-generation ADC. But in DESTINY-Breast04, we targeted a population of patients largely with hormone receptor-positive disease who had a little expression of HER2, 1 plus or 2 plus by immunohistochemistry and no gene amplification. And this trial, which randomly assigned patients 2:1 and included just 58 patients with triple-negative disease. So in this trial, 480 had hormone receptor-positive breast cancer, a median of 1 line of prior chemotherapy. They were only allowed up to 2. They were refractory to endocrine therapy, a median of 3 lines of endocrine therapy. In the overall patients and in the hormone receptor-positive patients, there was actually a doubling in progression-free survival (PFS). It started very early, and it continued throughout, and at every landmark analysis, T-DXd was better than the treatment of physician choice that patients were randomly assigned to. It's also important when you're thinking about trials like this to think about what the treatment of physician choice was, and it was all chemotherapy regimens we would use. Paclitaxel, nab-paclitaxel, capecitabine, eribulin, or gemcitabine. And, so, I think that that doesn't bring up any questions. When they looked at the hormone receptor-positive group, they saw, if anything, even a bigger benefit overall. Now, the other endpoint of this trial was overall survival, and at this first analysis, they saw an improvement in overall survival that was quite dramatic. The absolute difference was 6.4 months, which is pretty amazing for an overall survival difference. And then they looked at this exploratory endpoint at the 58 patients who were valuable at triple-negative breast cancer, and then that group of patients, also saw an improvement in PFS of 5.6 months, an improvement in overall survival of 9.9 months, very small group, but amazing data. The forest plots are exactly what you want to see, all the dots line up to the left of 1, and overall responses improved. One of the concerns with this drug has been toxicity. The toxicity showed no new toxicity signals, which is really important. Nausea is the biggest issue that we deal with. It's mostly grade 1 and 2, but still something that's important to manage. A little bit of hair loss, not much in the way of bone marrow suppression, which is interesting. Interstitial lung disease (ILD) or pneumonitis continues to be an important issue to follow. 12% of patients had ILD of any grade. Most of it was grade 1 and 2, but 3 patients died, representing 0.8%. So, this really highlights the importance of monitoring and managing pneumonitis. Regardless of that, few patients had a reduced ejection fraction, but again, very, in general, low grade. This is really a new standard of care, and the standing ovation was really due to the fact that all we do is dedicate ourselves to trying to help patients live longer and better with their cancers, and in this trial, we have a huge win that has no qualifications. We can help patients not only control their disease longer but live longer with T-Dxd compared to standard chemotherapy. Dr. Allison Zibelli: So, Hope, I know as a practicing medical oncologist, I find that our metastatic triple-negative patients are often the biggest therapeutic challenges for us. Will they be doing larger studies with these patients that are HER2-low? Dr. Hope Rugo: It's a really good point. About 65% of patients with hormone receptor-positive disease or so-called HER2-low, centrally confirmed in the study. So, a fair number of people, about a quarter, did not have HER2-low disease when they were tested centrally. In the triple-negative population, who really are ER, PR, HER2- by standard definitions, about a third of the patients might have HER2-low disease. So, there's a lot of interest in further exploring that and looking at the patients who have ultra-HER2-low disease, so between and 1 plus a little bit of expression. That's been studied in the hormone receptor-positive population in DESTINY-Breast06. But there's a lot of interesting further defining that triple-negative population, so to speak, they're going to be triple-negative plus now and understanding what the benefit is in that population. So definitely will be looked at more now moving forward. Dr. Allison Zibelli: Thank you. So, let's move on to Abstract 1002. And the results from the phase 1, 2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate, and patients with HER3 expressing metastatic breast cancer. What are your thoughts about this study? Dr. Hope Rugo: That's a really interesting, another one of these second- to third-generation antibody-drug conjugates. It's just the antibody, instead of being the usual, sort of, HER2 or TROP2 that we're used to thinking about is directed to HER3, 1 of the HER family of proteins. This is interesting. There's actually been a lot of work trying to target HER3 with naked antibodies with disappointing results, although I have to say most of the studies really didn't push it too far. So, with this antibody drug construct, deruxtecan, which is the same as in T-DXd and another TROP2 ADC Dato-DXd is used. So, I will say they do need to change the toxin in the next generation of ADCs. But they looked at, at first did a dose-finding study which has previously been presented, and then a dose expansion in both hormone receptor-positive HER2-negative disease and triple-negative disease. All the triple-negative patients had HER3 high disease by immunohistochemistry, and the hormone-receptor-positive patients were enrolled in 2 cohorts, HER3 high and HER3 low. And the median number of prior treatment regimens that patients had received in the hormone-receptor-positive group was 6 and 2 for the triple-negative group, but there was a huge range, up to 13 lines of treatment. They only had 14 patients with HER2+ disease. So, it's a little bit hard to know what to do with that patient group, but they were heavily pretreated 5.5 prior lines of therapy. The confirmed overall response rate in the 113 patients with combined HER3 high and low was 30%, very impressive, heavily pretreated patients. For triple-negative disease all HER3 high, it was 23%. Again, very nice. And there were 14 patients with HER2+ disease that also were HER3 high. It was about 43%. So those are nice responses, but we always want to know how durable is that. The duration of response ranged from 6 to over 8 months in those 3 different groups. So, these were quite durable. It wasn't any 2- to 3-month duration of response. So very impressive. And then when they looked to see, did it matter whether you had HER3 expression that was high or low in the hormone-receptor positive group, they actually did see responses in the HER3-low group, some very good responses. Overall, there were less patients in that group, but it does suggest that maybe you would still see responses in the HER3-low group, very impressive. And then 1 really interesting correlative study they did was they looked to see what happened to the HER3 expression on the tumor cell over time, and it went down. So, you treated the HER3 expression in most of the patients just dropped off completely, which is really interesting. It didn't have any association with clinical activity, but it's sort of an interesting correlative endpoint. This is a drug that overall was pretty well tolerated. They saw a similar toxicity to T-DXd with a lot of nauseous, a little bit of alopecia, a little bit more bone marrow suppression than we're used to seeing with T-DXd. So, neutropenia was seen in about 10% of patients at the lower dose and about a quarter of the patients at the higher dose. Overall, pretty well tolerated. Now, interstitial lung disease is a toxicity with this construct, and they saw ILD of 7% but most cases were grade 1 and 2. The other interesting toxicity that's unique to this agent is thrombocytopenia. So, they saw a grade 3 or greater rate of thrombocytopenia of 27% in the lower dose group, and in the larger group that received the higher dose, 39% of grade 3 or greater thrombocytopenia, so platelets less than 100,000. Turns out that when you stop the drug, the platelets do come back, so that's a good thing. Sometimes we saw long-term thrombocytopenia with T-DM1. They didn't see bad toxicity like bleeding, but it is something that needs to be managed with this drug because we're not great at managing thrombocytopenia. In any case, it has fast-track designation for another solid tumor, not breast cancer, and we'll have to see where this fits into our dizzying array of very effective ADCs now. Dr. Allison Zibelli: The practicing medical oncologist is not used to testing for HER3 in our patients with breast cancer. How common is it? Dr. Hope Rugo: HER3 expression is quite common in hormone receptor-positive disease, a little less common in triple-negative breast cancer. So, I think that we would see expression if we were going to be treating patients with this particular approach. Dr. Allison Zibelli: All right. Let's move on to Abstract 507, which reported long-term outcomes of adjuvant denosumab in breast cancer, specifically fracture reduction and survival results from 3,425 patients in a randomized double-blind, placebo-controlled ABCSG-18 trial. What are your thoughts about this study? Dr. Hope Rugo: Well, this trial, this is an update of a study that previously has been presented and published, most recent publication was in Lancet Oncology in 2019, and these patients were randomly assigned to receive denosumab at 60 milligrams, important to note the dose, subcutaneously every 6 months versus placebo every 6 months, and they did get placebo subcutaneous injections. And this treatment continued through their endocrine therapy. They showed a dramatic reduction in fracture rate, and that has been maintained over time. We were really surprised enough to suggest that maybe Austrian people didn't go into the sun, so they got more Vitamin D deficiency, hard to know, but the hazard ratio is 0.5. It's unbelievable the number of fractures, 92 for denosumab but 176 for placebo, a P value of less than .0001. So, this is a real endpoint, treating patients who are receiving endocrine therapy that, in this case, non-steroidal aromatase inhibitor therapy that can increase bone loss, have a reduced fracture rate when they received denosumab. So that is the big take-home message, and a medium follow-up of 8 years. But the secondary endpoints included disease-free survival. They had about 20% disease-free survival events and 8% deaths, and what they saw was really interesting. So, the caveat is that 16% of patients were unblinded at the first analysis and half of them got denosumab, so it messed up their results a little bit, but the disease-free survival was significantly better in patients who received denosumab, and the hazard ratio of 0.83 and the hazard ratio does not cross 1. So that's very interesting, and even overall survival, they looked at 2 other endpoints, bone metastasis-free survival, and overall survival. They also trend towards an improvement with a hazard ratio of 0.8 for both of them. And they didn't actually see toxicity. So, patients' brittle bone fractures and osteonecrosis of the jaw (ONJ) are all concerning, but they really just did not see any risks in this patient population. I think there was 1 patient that had what they thought was a brittle bone fracture. Obviously, they watched the mouth very carefully as well. Really dramatic, and I think it's kind of disappointing that we never had any registration approach in this, and also not well-understood why the D-CARE study did not show a benefit, but I think D-CARE was designed differently. This is a better design to focus on our patients and the specific issues, and I think it's intriguing and should be considered as part of our treatment regimen for patients who are at risk for bone loss and have early-stage breast cancer on an aromatase inhibitor. Dr. Allison Zibelli: I've been using DEXA scans and offering denosumab to my patients on AIs that have osteopenia or osteoporosis. Should we be considering it in women with normal bone mass? Dr. Hope Rugo: I think not yet. Unfortunately, this trial was not immediately powered for cancer outcome, although the data are very encouraging. We don't know what the relationship is to bone loss, and providing an environment that's friendlier for cancer cells. So, do you have to have bone loss in order to have the risk that you're reducing with these agents? Certainly, that's what we've seen with zoledronate. So, I think that we don't have sufficient data to use this simply to treat cancer, but I do think that we should be considering this as an agent to give patients who have bone loss, either when you're starting an aromatase inhibitor or during the course of therapy. I think it's well tolerated, and a subcutaneous injection is not difficult. One of the questions that's come up for people is do you get bone loss that increases your risk of fracture after you stop therapy. But clearly from these updated data, these patients were off therapy. They did not have an increase of fractures and the patients treated with denosumab fared much better, I mean the hazard ratio of 0.5. Dr. Allison Zibelli: Let's move on to TROPiCS-02. That's LBA1001. This is a randomized phase 3 study of sacituzumab govitecan versus treatment of physician's choice in patients with hormone receptor-positive, HER2-negative advanced breast cancer. How do you think this study will impact practice? Dr. Hope Rugo: That's a great question. I presented this data, and I think I presented it on a Saturday, and on Sunday we saw the plenary talk of DESTINY-Breast04. These patients enrolled in TROPiCs-02 had a median number of lines of prior chemo 3 with a range of up to 8 actually, compared to a median number of lines as 1 in the DESTINY-Breast04 population. We included all hormone receptor-positive HER2 negative-advanced breast cancer, not centrally confirmed. They included just the HER2 low subset that was centrally confirmed. Everybody in our study had received prior CDK4/6 inhibitors compared to about 70% in DB04. And then 95% of patients in this trial had visceral mets. So, we did really treat a patient population who had very advanced high risk hormone receptor-positive breast cancer. As you know, we saw an improvement and progression-free survival with a hazard ratio of 0.66 meeting the endpoint. We needed a hazard ratio of 0.7, highly statistically significant P value .0003, but the median difference in PFS was only 1.5 months, and overall survival data is not yet mature. So that's brought up the question about how this drug should be used because there was a big fall off in the first 2 months where patients had rapid disease progression with heavily pretreated chemotherapy-resistant disease. We did landmark analyses and there were big separations in PFS at 6, 9, and 12 months, and 12 months, it was 21% patients free of progression and death at 1 year versus 7% for the TPC arm. So, it was a tripling of patients who were free of progression at one year. I think that's clinically relevant. This drug is associated with more neutropenia. That's the primary issue to manage, and probably half of the patients need growth factors at some point. When we looked at other endpoints response to ratio response, etc., we're better with Sacituzumab. So where does this all fit into our treatment paradigm. I think there's the HER2-low patients who will now receive T-DXd up in the, I hope, second line and not in lieu of endocrine therapy, when they're ready for chemo. But there are patients who don't have HER2-low disease and then there are patients who are going to be in the later line setting. So, I do think it still has a place in the treatment department, receptor-positive metastatic breast cancer. The results show that it was better than chemotherapy, physician choice based on our national and international guidelines, and that's better for our patients to have that option. Overall survival data obviously is looked for with great interest and that will help us put this into the right paradigm. And then I also hope that real world data will help us understand how sequential treatment with these different ADCs will benefit our patients. Dr. Allison Zibelli: This is really exciting. Do you think that we're maybe coming toward the end of conventional chemotherapy, especially for women with HER2-positive disease? Dr. Hope Rugo: I wonder if we are. I think we were interested in T-DM1 for HER2-positive disease early on. We've seen some really nice pathologic complete response data as well as adjuvant data in the attempt trial in patients who had stage I disease. Now that we have these second-, third-generation ADCs, T-DXd, I think this could potentially completely replace our chemotherapy. We still have to deal with alopecia. And I will point out ADCs are still chemotherapy. They're just a much more efficient and effective way of delivering treatment, and we need to be very careful to manage the toxicity. Dr. Allison Zibelli: Next, we're going to talk about the main pain trial that's LBA1004, which is a randomized phase 2 trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition in patients with unresectable or hormone receptor-positive HER2-negative metastatic breast cancer, in other words CDK4/6 after CDK4/6. What are your takeaways here? Dr. Hope Rugo: First, just amazing that an investigator-initiated trial could do this well and be placebo-controlled. So, kudos to the principal investigator (PI) [Dr.] Kevin Kalinsky. This trial is a small phase 2 trial. A reasonable number, 119 patients were randomly assigned and evaluable patients could have received up to 1 line of prior chemotherapy for metastatic disease. If you had received prior exemestane, you received fulvestrant, if you received prior fulvestrant, you received exemestane, and actually if you looked at the number of patients who had received fulvestrant, it was 99 versus only 20 with exemestane. So important to keep in mind. If you looked at the overall population where the primary endpoint was progression-free survival, the hazard ratio is 0.57, just median PFS of 2.8 months in patients receiving endocrine therapy and placebo and 5.3 months for patients receiving endocrine therapy and ribociclib. So was this ribociclib after ribociclib or ribociclib after something else. 86% of patients had received palbociclib as their prior CDK4/6 inhibitor, and only about 10% to 14% had received prior ribociclib. So, there's a predominance of palbociclib followed by ribociclib. The other thing that's important to keep in mind is how sick this patient population was. Very few had received prior chemotherapy in the less than 10% range, visceral metastases in about 60%. So that's helpful. Only 19% or so had received 2 or more endocrine therapies from metastases. So, most people did this as their second line treatment. The PFS, when you looked at fulvestrant or exemestane, looked like the benefit was relatively similar, but you know you got 20 patients in the exemestane arm. The hazard ratios, looking at the subgroup analyses, all looked pretty similar, and the overall response and clinical benefit rate were better with continuing the cyclin dependent kinases (CDK) inhibitor. There was interesting sub-analysis looking at mutations and how that affected things. And they looked at patients who had ESR1 mutations or had wild-type ESR1. 42% had ESR1 mutations at study entry, very similar to what we've seen. In that group of patients, remember it's only 33 where they had this analysis, they saw a lot of other mutations. So p53, PIK3CA, FGFR, CCND1—those patients did not benefit. Only 33 patients. No benefit at all, very short PFS, about 3 months. The patients who had ESR1 wild type seemed to benefit a lot, 45 patients going from about 3 months to a little over 8 months. So, this is all hypothesis-generating data. I wouldn't run out and use this as your standard of care now because it is small data. But when the patient doesn't have other good options, I certainly would consider switching the CDK and going on, add that to the next line endocrine therapy. It's important to switch the endocrine therapy. I think we really need to look at the ongoing phase 3 trials to give us better evidence basis and understand the impact of mutations and prior therapy on who might benefit from continued CDK inhibitors after progression on a CDK inhibitor. Dr. Allison Zibelli: I think this is a really exciting trial. We all have a lot of patients on palbociclib and letrozole who've been on for 4, 5 years, and would like to continue with this kind of treatment because the side effects are really manageable. So, I look forward to seeing what's coming in the future with the phase 3 trials. So, let's talk about Abstract 1015, which I thought is a great idea. It looks at the quality of life with ribociclib plus aromatase inhibitor versus abemaciclib plus AI as first-line treatment of hormone receptor-positive, HER2-negative advanced breast cancer, assessed via matching adjusted indirect comparison. Could you tell us what matching adjusted indirect comparison is and why you chose this for the study? Dr. Hope Rugo: It's an interesting question. How do you compare across trials? So, matching this kind of make analysis, we'll call it a make analysis for the purposes of this discussion, allows you to match patients and weight based on their characteristics that might affect patient reported outcomes. And that actually is a way of trying to do a fair cross-trial comparison. So basically, take the study population, you match the inclusion and exclusion criteria, and then you weigh the different criteria so that you can try and make a better association. It's the best way we know of comparing across trials. You know, a lot of people ask why we didn't have PALOMA-2 in here, and that's because they used a different patient reported outcome tool. So, you have to use the same patient reported outcome tool in order to compare. So that's why we did this analysis, and it sort of came on the heels of a survey that Fatima Cardoso presented at San Antonio in 2021, where patients identified diarrhea as a symptom they really didn't like more than everything else. And you can imagine, I think we all have that experience in practice, the unexpected nature of diarrhea and the fact that it does limit your activities and, therefore, quality of life are important. In this analysis, interestingly but not surprisingly, ribociclib favored abemaciclib in diarrhea, and there can be associated appetite loss, so ribociclib also favored abemaciclib for appetite loss. And I thought the last one was interesting—fatigue—because I wouldn't have assumed that fatigue would be different. And maybe it's associated with diarrhea. They have these funny arm symptoms that were better. We don't really know why that was, and it's hard to assess again. We're really not clear based on the differences between the drugs. So, there are limitations to the analysis, but I think that it helps us really in individual patients try and match patients' underlying symptoms with the best treatment to offer them the best quality of life as they're being treated in the metastatic setting. Dr. Allison Zibelli: I thought this study was great because it really centered the experience of the patient and the wishes of the patient. You don't see that designed into many clinical trials, the way this was. So, I thought that was a great feature of this study. Dr. Hope Rugo: I will say that all of the 3 studies that looked at CDK inhibitors, all those 3 studies included patient-reported outcomes. That's an important new approach that is really being focused on. Dr. Allison Zibelli: Do you consider the CDK4/6 inhibitors equivalent in efficacy, and could you substitute them to try to get the side effect profile that you want? Dr. Hope Rugo: Well, I think that we saw in the early stage setting that there are differences. Now, across the different trials, there are big differences in patient populations and inclusions as we saw in the PALOMA-2 results that were presented at ASCO [Annual Meeting], whether the patients had prior chemotherapy like in PALOMA-3, whether they had a short disease-free interval, the higher risk patients in PALOMA-2. The PALOMA trials were more broadly inclusive than the other 2 studies, the MONALEESA and MONARCH series of trials. So, we do have to be a little bit careful about comparing apples to oranges, but we have the early-stage results of MONARCH E showing a clinically important difference in outcome whereas the PALLAS and Penelope-B trials didn't. So that sort of puts us into a little bit of a question period. Are these all patient populations or are there differences between the agents? The PFS and the metastatic setting, all the hazard ratios line up. So, in truth, although I know the activity against cyclin-independent kinases are different between agents, we don't still really understand the clinical differences in efficacy, but I think we all are practicing using evidence-based medicine. I wouldn't, for example, substitute a different CDK4/6 inhibitor for abemaciclib in the treatment of early-stage breast cancer. We have to just learn how to manage the diarrhea and use prophylaxis and dose reduce early to manage this and make it tolerable for our patients. And in the metastatic setting, I think we need to follow evidence-based guidelines and use the best data available to decide on the right treatment approach and sequencing for our patients. Dr. Allison Zibelli: Thank you, Hope, for coming on the podcast today. This was a really interesting review of one of the most exciting ASCO [Annual Meetings] I've been to. And thanks for sharing your valuable insights with us and helping us make sense of all this really new exciting data. We really appreciate it. Dr. Hope Rugo: Thank you. And thank you so much for inviting me. Dr. Allison Zibelli: And thank you to our listeners for joining us today. You will find the links to all the abstracts 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. That really helps other listeners find us. Thank you.   Disclosures: Dr. Allison Zibelli: None disclosed. Dr. Hope Rugo: Honoraria: Puma Biotechnology, Mylan, Samsung Bioepis, Chugai Pharma, Blueprint Medicines Consulting or Advisory Role: Napo Pharmaceuticals Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Odonate Therapeutics, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Ayala Pharmaceuticals, Astellas Pharma, Seattle Genetics, Macrogenics, Boehringer Ingelheim, Polyphor 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.