Podcasts about esr1

In this episode, we unpack game-changing insights from ASCO 2025 with a spotlight on breast cancer. Joining us is Dr. Adam Brufsky, a trailblazing oncologist and professor at the University of Pittsburgh, with 30 years of experience, whose expertise has helped shape the direction of treatment. Trials discussed include the SERENA-6 trial, which examines camizestrant plus CDK4/6 inhibitors in HR-positive, ESR1 mutation breast cancer; the DESTINY-Breast09 trial, highlighting trastuzumab deruxtecan in combination with pertuzumab; and the INAVO120 trial, revealing inavolisib's triplet therapy response in PIK3CA-mutated, HR-positive, HER2-negative disease. Join us for a deep dive into these game-changing findings and their impact on patient care.Studies discussed in the episode:SERENA-6DESTINY BREAST 09INAVO 120For more episodes, resources and blog posts, visit www.inquisitiveonc.comPlease find us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comArt courtesy of Taryn SilverMusic courtesy of AlisiaBeats: https://pixabay.com/users/alisiabeats-39461785/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice.Oncology for the Inquisitive Mind is recorded with the support of education grants from our foundation partners Pfizer, Gilead Pharmaceuticals and Merck Pharmaceuticals. Our partners have access to the episode at the same time you do and have no editorial control over the content. Hosted on Acast. See acast.com/privacy for more information.

In our second plenary episode, we're spotlighting two pivotal phase 3 trials: SERENA-6, which explores ctDNA-guided treatment with camizestrant to delay progression in HR-positive, HER2-negative advanced breast cancer with ESR1 mutations, and NIVOPOSTOP, a landmark study showing improved disease-free survival with adjuvant nivolumab in high-risk, resected head and neck squamous cell carcinoma. Join us as we unpack these practice-changing findings with expert insight and a couple of dad jokes along the way.Studies discussed in the episode:SERENA-6NIVOPOSTOPFor more episodes, resources and blog posts, visit www.inquisitiveonc.comPlease find us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comArt courtesy of Taryn SilverMusic courtesy of AlisiaBeats: https://pixabay.com/users/alisiabeats-39461785/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice.Oncology for the Inquisitive Mind is recorded with the support of education grants from our foundation partners Pfizer, Gilead Pharmaceuticals and Merck Pharmaceuticals. Our partners have access to the episode at the same time you do and have no editorial control over the content. Hosted on Acast. See acast.com/privacy for more information.

The 2025 American Society of Clinical Oncology (ASCO) Annual Meeting featured five days of presentations and educational sessions on all types of cancer. Dr. Eleonora Teplinsky, a board-certified medical oncologist at the Valley-Mount Sinai Comprehensive Cancer Center in Paramus, NJ, summarizes the top breast cancer research. Listen to the episode to hear Dr. Teplinsky discuss: The SERENA-6 trial, which found that if metastatic hormone receptor-positive, HER2-negative breast cancer develops ESR1 mutations during first hormonal therapy treatment, switching to camizestrant from an aromatase inhibitor before the cancer grows improves outcomes. Results from the DESTINY-Breast09 trial showing that the combination of Enhertu (chemical name: fam-trastuzumab-deruxtecan-nxki) and Perjeta (chemical name: pertuzumab) is a better first treatment for metastatic HER2-positive breast cancer than the current standard of THP chemo.  The ASCENT-04/KEYNOTE-D19 trial, which found that people with metastatic, PD-L1-positive, triple-negative breast cancer fared better with the combo of Trodelvy (chemical name: sacituzumab govitecan-hziy) and Keytruda (chemical name: pembrolizumab) as a first treatment compared to people who received chemotherapy and Keytruda.

Dr. John Sweetenham shares highlights from Day 2 of the 2025 ASCO Annual Meeting, including new data on the treatment of ER+/HER2-negative breast cancer and potentially practice-changing results for patients with cutaneous squamous cell carcinoma at high risk of recurrence.  Transcript Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, your host of the ASCO Daily News Podcast, welcoming you to our special coverage of the 2025 ASCO Annual Meeting. Today, I'll be bringing you my takeaways on selected abstracts from Day 2 of the Meeting. My disclosures are available in the transcript of this episode.  Today's selection features important, new data on the treatment of ER-positive, HER2-negative breast cancer, the use of tumor treating fields in combination with chemotherapy for locally advanced pancreatic cancer, and potentially practice-changing results for patients with cutaneous squamous cell carcinoma at high-risk of recurrence.  Our first selected abstract is LBA1000. This important phase 3 study was presented by Dr. Erika Hamilton from the Sarah Cannon Research Institute in Nashville and evaluated the use of a novel agent, vepdegestrant, in patients with ER-positive/HER2-negative breast cancer, which had progressed after first-line endocrine therapy. Vepdegestrant is a selective oral PROTAC estrogen receptor degrader, which targets wild-type and mutant estrogen receptor through a novel mechanism of action which directly harnesses the ubiquitin-proteasome system to degrade ER. It has potential advantages over fulvestrant, a selective ER degrader which has to be administered intramuscularly and has limited benefit in patients who progress after endocrine therapy plus a CDK4/6 inhibitor.  Building on the encouraging results from the initial phase 1/2 study of vepdegestrant, Dr. Hamilton reported results from the VERITAC-2 global phase 3 trial, comparing this agent with fulvestrant. The patients in the study had already received treatment with hormone therapy and a CDK inhibitor and were randomly assigned to receive treatment with either vepdegestrant (313 patients) or fulvestrant (311 patients). The vepdegestrant was taken orally each day, while the fulvestrant was given intramuscularly on days 1 and 15 of the first cycle of treatment and day 1 of each subsequent treatment cycle. Patients were stratified by the presence of wild-type ER or ESR1 mutation. A total of 43.3% of patients had ESR1 mutations; 136 of those were in the vepdegestrant group and 134 in the fulvestrant group.   For patients with ESR1 mutations, vepdegestrant significantly increased progression-free survival compared with fulvestrant. For patients who received vepdegestrant, the median PFS was 5 months versus 2.1 months for those who received fulvestrant. The clinical benefit rate was 42.1% in the vepdegestrant group vs. 20.2% in the fulvestrant group. The overall response rate was 18.6% in the vepdegestrant group compared with only 4% in the fulvestrant group.  The PFS and response benefits of vepdegestrant were largely restricted to the population with ESR1 mutations. Overall survival data are currently immature. The safety profile was favorable, with fewer than 5% of patients having dose reductions or discontinuation due to toxicity. The most frequent toxicities were fatigue, nausea, and elevated transaminases.  The authors concluded that oral vepdegestrant demonstrates statistically significant and clinically meaningful improvement in progression-free survival compared with fulvestrant in this group of patients with ESR1-mutated ER+/HER2- advanced breast cancer who have progressed after endocrine therapy and a CDK inhibitor. Patients with recurrent disease in this context are now routinely tested for ESR1 mutations, and this agent is for sure a potential treatment option for them.  The next study on today's episode, LBA4005, reports on the use of tumor treatment fields for patients with locally advanced pancreatic cancer. Tumor treatment fields are electric fields which disrupt cell division and may also induce an enhanced immune response, using a non-invasive portable device attached to the skin, and are already approved for the treatment of some cancers, including GBM and non-small cell lung cancer. A previous phase 2 trial, PANOVA-2, confirmed the feasibility and safety of using this approach in combination with gemcitabine plus or minus nabpaclitaxel in pancreatic cancer. In today's presentation, Dr. Vincent Picozzi from the Virginia Mason Medical Center in Seattle presented the results of the PANOVA-3 trial, a phase 3 study comparing gemcitabine and nabpaclitaxel with the same chemotherapy plus tumor treatment fields in patients with locally advanced pancreatic adenocarcinoma.  Five hundred and seventy-one eligible patients were enrolled in the study with a total of 405 (198 in the treatment field group and 207 in the standard arm) comprising the modified intent- to-treat population. The duration of chemotherapy treatment was comparable in both study arms, and patients receiving treatment fields had a median exposure of almost 27 weeks.  Statistically significant improvements were observed for several study endpoints, including overall survival (a median of 16.2 versus 14.2 months), distant PFS (at 13.9 versus 11.5 months) and pain-free survival (at 15.2 versus 9.1 months), all in favor of the treatment fields arm. Although quality of life data were not reported in detail, the authors noted a significant improvement in global health status in the treatment fields arm. Safety data showed a higher level of skin adverse events in the treatment fields arm but were otherwise as expected for the GnP combination.  These are quite remarkable results which add to the growing evidence base for tumor treatment fields and are particularly compelling in this patient group given the substantial improvement in pain-free survival. It will be especially interesting to see the mature analysis of the quality-of-life endpoints in a subsequent report.  The final selection today is Abstract 6001, which describes the C-POST trial, a phase 3 trial of adjuvant cemiplimab versus placebo in patients with high-risk cutaneous squamous cell carcinoma of the skin. This study was presented by Dr. Danny Rischin from the Peter MacCallum Cancer Centre in Melbourne, Australia.   Although surgical resection with or without adjuvant radiation is curative in 90% of patients with cutaneous squamous cell carcinoma, high-risk features, including nodal disease, skin and subcutaneous metastases, perineural invasion and bone involvement, predict for an inferior prognosis.  Cemiplimab, a PD-1 targeting antibody is standard therapy for patients with locally advanced or metastatic disease who are not candidates for curative surgical resection or radiation therapy, with an overall response rate of almost 50%.  The C-POST study evaluated the use of cemiplimab as adjuvant therapy following surgery and radiation in high-risk patients, compared with placebo. Treatment was administered at 3-week intervals for 12 weeks, and then 6-week intervals for a further 36 weeks, with a primary endpoint of disease-free survival. Four hundred and fifteen patients were randomized in the study, 209 to cemiplimab and 206 to placebo. With median follow-up at 24 months, Dr. Rischin reported a highly significant improvement in disease-free survival for the cemiplimab arm, 49.4 months for placebo versus not reached for cemiplimab, with improvements also observed in the rates of locoregional recurrence and distant recurrence at 80% and 60% reductions, respectively. No new safety signals were observed.  This study is potentially practice-changing and provides strong evidence that cemiplimab should be considered the new standard of care in this clinical context.  Thanks for listening today and join me again tomorrow to hear more top takeaways from ASCO25. If you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts.  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, 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. Find out more about today's speaker:   Dr. John Sweetenham   Follow ASCO on social media:    @ASCO on Twitter   @ASCO on Bluesky   ASCO on Facebook   ASCO on LinkedIn    Disclosures:   Dr. John Sweetenham:   No relationships to disclose  

Editor's Note: This interview was recorded shortly before the 2025 American Society of Clinical Oncology Annual Meeting. Big questions associated with ESR1 mutations in patients with hormone receptor–positive breast cancer may soon have answers. New data are “going to take the whole breast oncology field from one place and put it in a different place. It's going to be an inflection point in our history of treating breast cancer,” says Jason Aboudi Mouabbi, MD, assistant professor in the Department of Breast Medical at the University of Texas MD Anderson Cancer Center in Houston. Speaking with Robert A. Figlin, MD, the interim director of Cedars-Sinai Cancer in Los Angeles and Steven Spielberg Family Chair in Hematology-Oncology, Dr. Mouabbi outlined current challenges in identifying and responding to the development of ESR1 mutations. Dr. Figlin and Dr. Mouabbi also discussed how eagerly anticipated findings may transform practice and important aspects of mutational testing to consider. Dr. Mouabbi reported consulting fees from GE Healthcare, Genentech, AstraZeneca, Gilead, Novartis, Fresenius Kabi, BostonGene, and Cardinal Health. Dr. Figlin reported various financial relationships.

Featuring an interview with Dr Rinath M Jesselsohn, including the following topics: Evaluating first-line treatment of metastatic ER-positive, HER2-positive breast cancer: heredERA Breast Cancer study (0:00) Kuemmel S et al. heredERA Breast Cancer: A phase III, randomized, open-label study evaluating the efficacy and safety of giredestrant plus the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with previously untreated HER2-positive, estrogen receptor-positive locally advanced or metastatic breast cancer. BMC Cancer 2024;24(1):641. Abstract  Treatment outcomes with CDK4/6 inhibitors and with elacestrant in real-world studies (4:13) Lloyd MR et al. CDK4/6 inhibitor efficacy in ESR1-mutant metastatic breast cancer. NEJM Evid 2024;3(5). Abstract  Lloyd M et al. Impact of prior treatment, ESR1 mutational (ESR1m) landscape, and co-occurring PI3K pathway status on real-world (RW) elacestrant outcomes in patients (pts) with hormone receptor-positive (HR+)/HER2-negative advanced breast cancer (aBC). San Antonio Breast Cancer Symposium 2024;Abstract PS7-05.  Evaluating the CNS activity of imlunestrant, an oral selective estrogen receptor degrader (SERD) (8:06) VandeKopple M et al. Preclinical characterization of imlunestrant, an oral brain-penetrant selective estrogen receptor degrader with activity in a brain metastasis (BM) model. ESMO Breast 2023;Abstract 41P.  Selective review of trials of oral SERDs in the adjuvant setting (11:27) A study of imlunestrant versus standard endocrine therapy in participants with early breast cancer (EMBER-4). NCT05514054 CME information and select publications

Ahead of the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, CancerNetwork® spoke with a variety of oncology experts about the late-breaking abstracts, plenary sessions, and other key presentations that may shift the paradigm across different cancer care fields. They highlighted anticipated clinical trial results that may transform the standard of care for gynecologic malignancies, lung cancer, and other disease types. Rachel N. Grisham, MD, section head of Ovarian Cancer and director of Gynecologic Medical Oncology at MSK Westchester of Memorial Sloan Kettering Cancer Center, shared her anticipation of findings from the phase 3 ROSELLA trial (NCT05257408) assessing relacorilant plus nab-paclitaxel in patients with platinum-resistant ovarian cancer. She stated she was excited to see if the data may represent a new opportunity for this patient population. Next, MinhTri Nguyen, MD, a medical oncologist and hematologist at Stanford Health Care, highlighted a few breast cancer presentations to look out for. These topics included a plenary session on data from the phase 3 SERENA-6 study (NCT04964934) evaluating camizestrant in combination with CDK4/6 inhibitors for those with hormone receptor–positive, HER2-negative advanced breast cancer harboring emergent ESR1 mutations. Additionally, Eric K. Singhi, MD, assistant professor in the Department of General Oncology in the Division of Cancer Medicine, and assistant professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, spoke about a range of potentially practice-changing results in the lung cancer field. For example, he described a session focused on primary results of the phase 3 IMforte trial (NCT05091567) assessing lurbinectedin (Zepzelca) plus atezolizumab (Tecentriq) for those with extensive-stage small cell lung cancer (ES-SCLC). According to Singhi, data from IMforte may shift the paradigm of maintenance therapy for this SCLC population. In the world of head and neck cancer, Douglas R. Adkins, MD, associate professor of Internal Medicine, Division of Oncology, Section of Medical Oncology at Washington University School of Medicine in St. Louis, Missouri, highlighted the session on the phase 3 NIVOPOSTOP GORTEC 2018-01 trial (NCT03576417). Investigators of this study evaluated nivolumab (Opdivo) in combination with chemoradiotherapy for those with resected head and neck squamous cell carcinoma. Adkins noted his excitement to see how these data may impact the standard of care, particularly for patients in Europe, where investigators conducted the study. As part of an Oncology Decoded discussion, Benjamin Garmezy, MD, the associate director of genitourinary research and executive cochair of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI) and medical oncologist at SCRI Oncology Partners specializing in genitourinary cancers, discussed key abstracts in bladder cancer. One specific presentation included additional findings from the phase 3 NIAGARA trial (NCT03732677), which may show how circulating tumor DNA can influence treatment decision-making regarding perioperative durvalumab (Imfinzi) for patients with muscle-invasive bladder cancer.

Featuring an interview with Dr Rinath M Jesselsohn, including the following topics: Imlunestrant with or without abemaciclib in advanced breast cancer: Results of the Phase III EMBER-3 trial (0:00) Jhaveri KL et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med 2025;392(12):1189-202. Abstract  Jhaveri KL et al. Imlunestrant, an oral selective estrogen receptor degrader (SERD), as monotherapy & combined with abemaciclib, for patients with ER+, HER2- advanced breast cancer (ABC), pretreated with endocrine therapy (ET): Results of the Phase 3 EMBER-3 trial. San Antonio Breast Cancer Symposium 2024;Abstract GS1-01. Comprehensive genomic profiling of ESR1, PIK3CA, AKT1 and PTEN in HR-positive, HER2-negative metastatic breast cancer: Prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice (7:00) Bhave MA et al. Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: Prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice. Breast Cancer Res Treat 2024;207(3):599-609. Abstract Camizestrant, a next-generation oral selective estrogen receptor degrader (SERD), versus fulvestrant for postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): A multi-dose, open-label, randomized, Phase II trial (10:25) Oliveira M et al. Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): A multi-dose, open-label, randomised, phase 2 trial. Lancet Oncol 2024;25(11):1424-39. Abstract Latest on SERDs: An education session at San Antonio Breast Cancer Symposium 2024 (13:57) Jeselsohn RM. Latest on selective estrogen receptor degraders (SERDs). San Antonio Breast Cancer Symposium 2024;Education Session 5. CME information and select publications

This featured podcast includes a data review and candid conversation with 4 experts on challenges in the current treatment paradigm for hormone receptor–positive/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC) due to endocrine resistance. This session occurred during a satellite symposium held in conjunction with the 42nd Annual Miami Breast Cancer Conference® in March 2025.  ESR1 mutations are a critical mechanism of resistance, spurring the development of next-generation endocrine agents targeting these mutations. These agents including oral selective estrogen receptor degraders (SERDs) and agents with novel mechanisms, including proteolysis-targeting chimeras (PROTACs), which may offer potential improvements over current treatments. This program will review mechanisms of resistance to current endocrine regimens, strategies to overcome this resistance including comparative mechanisms of novel endocrine agents, emerging data from ongoing clinical trials, and expert perspectives on where these new agents may fit into current algorithms.

The approach to ESR1 and PIK3CA mutations in patients with hormone receptor–positive metastatic breast cancer continues to evolve. What role does circulating tumor DNA (ctDNA) play in treatment decisions? How should oncologists best approach patients with PIK3CA mutations who subsequently develop ESR1 mutations? VK Gadi, MD, PhD, professor and director of medical oncology and deputy director of the University of Illinois Cancer Center in Chicago, discusses with Robert A. Figlin, MD, the interim director of Cedars-Sinai Cancer in Los Angeles and Steven Spielberg Family Chair in Hematology-Oncology, how recent data are informing care for patients with comutations. “We now have at least one ESR1-targeting drug out there, and more to come,” Dr. Gadi explains. “Elacestrant is the drug I'm of course referencing, and that is used essentially like a single agent and works well for those patients. Even when they have, for example, PIK3CA mutations present.” He and Dr. Figlin consider when to act on ctDNA findings and potential future strategies. Dr. Gadi reported no relevant financial relationships. Dr. Figlin reported various financial relationships.

Can people diagnosed with metastatic hormone receptor-positive breast cancer avoid chemotherapy and take a CDK4/6 inhibitor instead? Do people diagnosed with DCIS need to have surgery? Will there soon be another oral selective estrogen degrader available? Breastcancer.org medical advisor Dr. Kevin Fox explains the details of the studies and what they mean for you. Listen to the episode to hear Dr. Fox discuss these studies: Young-PEARL: Ibrance plus Aromasin, along with ovarian suppression, offers better progression-free survival than Xeloda for pre-menopausal women with metastatic hormone receptor-positive, HER2-negative breast cancer who had previously received tamoxifen. PATINA: Adding Ibrance to standard-of-care first treatments for metastatic hormone receptor-positive, HER2-positive breast cancer increased progression-free survival by more than a year. EMBER-3:Imlunestrant led to longer progression-free survival than standard therapy if the cancer had an ESR1 mutation among people with estrogen receptor-positive, HER2-negative advanced-stage breast cancer. Adding Verzenio to imlunestrant improved progression-free survival compared to imlunestrant alone, whether the cancer had an ESR1-mutation or not. COMET: Can people with low-risk DCIS just be monitored instead of having surgery with or without radiation? 

“Second-line [estrogen receptor (ER)]-positive breast cancer has just become very complicated,” says Erika P. Hamilton, MD, the director of breast cancer and gynecologic cancer research at Sarah Cannon Research Institute in Nashville. She discusses the role of ESR1 mutations in selecting appropriate treatments and combination regimens for patients with ER-positive breast cancer who have disease progression with Robert A. Figlin, MD, the interim director of Cedars-Sinai Cancer in Los Angeles, and Steven Spielberg Family Chair in Hematology-Oncology. From when and how best to assess for ESR1 mutations to which trials inform current treatment options in clinic, Dr. Hamilton walks through the complex decision-making process. She also shares which trial readouts she is looking forward to seeing and how social media is influencing patient choices. Dr. Hamilton reported various financial relationships. Dr. Figlin reported various financial relationships.

Featuring an interview with Dr Sara A Hurvitz, including the following topics: Role of endocrine therapy in the management of HER2-positive breast cancer; implications of the Phase III PATINA study (0:00) Case: A woman in her mid 60s with node-negative, HR-positive, HER2-negative localized breast cancer and a Recurrence Score® of 28 (8:38) Available data guiding the selection of an adjuvant CDK4/6 inhibitor (12:49) Selection of a CDK4/6 inhibitor in the metastatic setting (23:16) Available therapies for patients with HR-positive metastatic breast cancer (mBC) and PIK3CA mutations; implications of the Phase III INAVO120 study (29:17) Case: A woman in her early 60s with HR-positive, HER2-negative mBC with short duration of benefit from a first-line CDK4/6 inhibitor and an aromatase inhibitor (AI) and coexisting PIK3CA and ESR1 mutations (37:11) Available data with approved and investigational oral SERDs (selective estrogen receptor degraders) (43:23) Case: A woman in her early 70s with HR-positive, HER2-negative mBC and an ESR1 mutation detected on disease progression after durable responses to first-line endocrine therapy and second-line CDK4/6 inhibitor with an AI (51:38) Selection of therapy for patients with HR-positive mBC and coexisting targetable genetic mutations (53:11) Case: A woman in her late 50s with HR-positive, HER2-negative mBC and an ESR1 mutation detected on disease progression after first-line CDK4/6 inhibitor with an AI (1:00:17) CME information and select publications

Featuring an interview with Dr Komal Jhaveri, including the following topics: Imlunestrant, an oral selective estrogen receptor degrader (SERD), with and without abemaciclib for ER-positive, HER2-negative advanced or metastatic breast cancer (0:00) Jhaveri KL et al. Imlunestrant, an oral selective estrogen receptor degrader (SERD), as monotherapy & combined with abemaciclib, for patients with ER+, HER2- advanced breast cancer (ABC), pretreated with endocrine therapy (ET): Results of the phase 3 EMBER-3 trial. San Antonio Breast Cancer Symposium 2024;Abstract GS1-01. Jhaveri KL et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med 2024;[Online ahead of print]. Abstract Rugo HS et al. Elacestrant abemaciclib (abema) combination in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced or metastatic breast cancer (mBC). San Antonio Breast Cancer Symposium 2024; Abstract PS7-07. Elacestrant for ER-positive, HER2-negative metastatic breast cancer with ESR1-mutated tumors: Subgroup analyses from the Phase III EMERALD trial by duration of prior endocrine therapy with a CDK4/6 inhibitor and in clinical subgroups (7:40) Bardia A et al. Elacestrant in ER+, HER2- MBC with ESR1-mutated tumors: Subgroup analyses from the phase III EMERALD trial by prior duration of endocrine therapy plus CDK4/6 inhibitor and in clinical subgroups. Clin Cancer Res 2024;30(19):4299-309. Abstract Pharmacokinetics and safety of imlunestrant in patients with hepatic impairment (11:25) Wang XA et al. Evaluation of pharmacokinetics and safety of imlunestrant in participants with hepatic impairment. San Antonio Breast Cancer Symposium 2024;Abstract P4-10-07. Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer (13:15) Lloyd MR et al. Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer. Nat Rev Clin Oncol 2024;21(10):743-61. Abstract CME information and select publications

In this episode, Jame Abraham, MD, FACP; William J. Gradishar, MD, FACP, FASCO; and Laura Spring, MD, review key insights and frequently asked questions related to the CDK4/6 inhibitors used to treat patients with early and metastatic hormone receptor (HR)–positive/HER2-negative breast cancer from a live program held in January 2025. Key clinical pearls include:Adjuvant treatment selection recommendations for patients with HR-positive/HER2-negative early breast cancer based on disease and patient characteristics as well as the latest data and guidelines presented by Dr. GradisharTherapeutic strategies for patients diagnosed with HR-positive/HER2-negative metastatic breast cancer (MBC) presented by Dr. AbrahamAddressing challenges related to CDK4/6 inhibitor adherence and adverse event mitigation presented by Dr. SpringPresenters:Jame Abraham, MD, FACPEnterprise Chair and Professor of MedicineDepartment of Hematology and Medical OncologyCleveland ClinicCleveland, OhioWilliam J. Gradishar, MD, FACP, FASCOBetsy Bramsen Professor of Breast OncologyRobert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicago, IllinoisLaura Spring, MDBreast Medical OncologistMass General Hospital Cancer CenterHarvard Medical SchoolBoston, MassachusettsLink to full program including downloadable slides and on-demand webcasts: https://bit.ly/4b5GFqqTo claim credit for listening to this episode, please visit the podcast online at the link above.

Featuring slide presentations and related discussion from Dr Joyce O'Shaughnessy, Dr Mark Pegram and Prof Peter Schmid, including the following topics: Strategies to Identify Patients with HER2-Low and HER2-Ultralow Breast Cancer (0:00) Case: A woman in her mid 50s initially presenting with ER-positive, HER2 IHC 1+ locally advanced breast cancer who experiences progression to HER2 0 metastatic disease (20:53) Case: A woman in her early 60s with ER-positive, HER2 IHC 1+ metastatic breast cancer (mBC) who experiences disease progression 8 months after starting first-line CDK4/6 and aromatase inhibitor (29:14) Expanding the Spectrum of Targeted Therapy (38:52) Case: A woman in her early 60s with HR-positive, HER2 IHC 1+ mBC who receives fifth-line T-DXd resulting in stable disease (1:04:13) Case: A woman in her early 50s with progressive HR-positive, HER2 IHC 0 mBC and an ESR1 mutation who has ultralow HER2 expression on rebiopsy of new liver lesions (1:12:35) Identification and Management of Adverse Events with T-DXd (1:20:27) Case: A woman in her late 40s with HR-positive, HER2 IHC 2+ mBC who experienced persistent low-grade nausea with T-DXd that resolved with olanzapine (1:34:02) Case: A woman in her early 60s with ER-positive, HER2 2+ mBC who received T-DXd resulting in fatigue and asymptomatic interstitial lung disease (1:48:58) CME information and select publications  

Featuring an interview with Dr Seth Wander, including the following topics: Therapy selection after CDK4/6 inhibitor failure: A review of current and investigational treatment for HR-positive, HER2-negative breast cancer Astore S et al. A therapeutic algorithm guiding subsequent therapy selection after CDK4/6 inhibitors' failure: A review of current and investigational treatment for HR+/Her2- breast cancer. Crit Rev Oncol Hematol 2024;204:104535. Abstract (0:00) A preoperative window-of-opportunity study of the oral SERD imlunestrant for newly diagnosed ER-positive, HER2-negative localized breast cancer Neven P et al. A preoperative window-of-opportunity study of oral SERD, imlunestrant, in newly diagnosed ER-positive, HER2-negative early breast cancer: Results from the EMBER-2 Study. Clin Cancer Res 2024;30(23):5304-13. Abstract (3:30) An assessment of an exosome-based ESR1-monitoring RT-qPCR kit that detects acquired resistance variants in liquid biopsy samples Statt S et al. An exosome-based ESR1 monitoring RT-qPCR kit that rapidly and accurately detects acquired resistance variants at ≤ 0.1% frequency in liquid biopsy samples. ESMO 2024;Abstract 420P. (7:08) CME information and select publications

Featuring an interview with Dr Seth Wander, including the following topics: The clinical utility of ESR1 mutations in HR-positive, HER2-negative advanced breast cancer Grinshpun A et al. The clinical utility of ESR1 mutations in hormone receptor-positive, HER2-negative advanced breast cancer. Hematol Oncol Clin North Am 2023;37(1):169-81. Abstract (0:00) Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and in combination with targeted therapy for ER-positive, HER2-negative advanced breast cancer Jhaveri KL et al. Imlunestrant, an oral selective estrogen receptor degrader, as monotherapy and in combination with targeted therapy in estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Phase Ia/Ib EMBER study. J Clin Oncol 2024;[Online ahead of print]. Abstract (6:01) EORTC-2129-BCG: Elacestrant for ER-positive/HER2-negative breast cancer patients with ctDNA relapse Ignatiadis M et al. EORTC-2129-BCG: Elacestrant for treating ER+/HER2- breast cancer patients with ctDNA relapse (TREAT ctDNA). ESMO 2024;Abstract 338TiP. (8:20) CME information and select publications  

Welcome back to Oncology for the Inquisitive Mind, where we head back to late 2024 and cover some pivotal trials and ideas from the San Antonio Breast Cancer Conference 2024.This episode broadly covers hormone receptor-positive breast cancer and looks at another CDK comparison (real-world data). While the idea is not new, the potential implications from well-gathered "phase 4" data is a curious discussion point. Other topics include the ESR1 mutation and Imlunestrant, Patritumab Deruxtecan in hormone receptor-positive disease and the role of CTDNA in tumour burden and recurrence in early breast cancerStudies discussed in the episode:SOLTI-VALENTINEEMBER 3ctDNA in EBCCDK ComparisonFor more episodes, resources and blog posts, visit www.inquisitiveonc.comPlease find us on Twitter @InquisitiveOnc!If you want us to look at a specific trial or subject, email us at inquisitiveonc@gmail.comArt courtesy of Taryn SilverMusic courtesy of AlisiaBeats: https://pixabay.com/users/alisiabeats-39461785/Disclaimer: This podcast is for educational purposes only. If you are unwell, seek medical advice.Oncology for the Inquisitive Mind is recorded with the support of education grants from our foundation partners Pfizer, Gilead Pharmaceuticals and Merck Pharmaceuticals. Our partners have no editorial rights or early previews, and they have access to the episode at the same time you do. Hosted on Acast. See acast.com/privacy for more information.

In this episode, listen to Virginia Kaklamani, MD, DSc; Erica L. Mayer, MD, MPH; and Laura M. Spring, MD, share their clinical insights and takeaways from a live symposium, including from key abstracts presented at the 2024 San Antonio Breast Cancer Symposium:Estrogen Receptor Mutations in Patients With HR-Positive/HER2-Negative Advanced Breast CancerCurrent Guideline Recommendations for When to Pursue ESR1 Mutation Testing Mutations in Patients With HR-Positive/HER2-Negative Advanced Breast CancerChoice and Sequencing of Next Line of Systemic Therapy for ESR1-Mutated Advanced Breast Cancer Based on Tumor Molecular AlterationsOverview of Class-Related and Unique Adverse Events With Approved and Emerging Oral SERDSExpert Recommendations for the Management of Oral SERDs-Related Adverse EventsProgram faculty:Virginia Kaklamani, MD, DScProfessor of MedicineRuth McLean Bowman Bowers Chair in Breast Cancer Research and TreatmentA.B. Alexander Distinguished Chair in Oncology LeaderBreast Oncology ProgramUT Health San AntonioMD Anderson Cancer CenterSan Antonio, TexasErica L. Mayer, MD, MPHDirector of Breast Cancer Clinical ResearchDana-Farber Cancer InstituteAssociate Professor in MedicineHarvard Medical SchoolBoston, MassachusettsLaura M. Spring, MDBreast Medical OncologistMass General Hospital Cancer CenterHarvard Medical SchoolBoston, Massachusetts Resources:To download the slides associated with this podcast discussion, please visit the program page.

In this JCO Article Insights episode, Giselle de Souza Carvalho provides a summary on  "Navigating Treatment Pathways in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer: Optimizing Second-Line Endocrine and Targeted Therapies" by Bhardwarj, et al and "US Food and Drug Administration Approval Summary: Capivasertib With Fulvestrant for Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Locally Advanced or Metastatic Breast Cancer With PIK3CA/AKT1/PTEN Alterations" by Dilawari et al published in the Journal of Clinical Oncology.  TRANSCRIPT Giselle Carvalho: Hello and welcome to JCO Article Insights episode for the December issue of the Journal of Clinical Oncology. I'm your host Giselle Carvalho, Medical Oncologist in Brazil focusing on breast cancer and melanoma skin cancers and one of the ASCO Editorial Fellows at JCO this year. Today, I will be discussing two articles. The first one is “Navigating Treatment Pathways in Metastatic Hormone Receptor–Positive, HER2-Negative Breast Cancer: Optimizing Second-Line Endocrine and Targeted Therapies,” and the second one is the “US FDA Approval Summary on Capivasertib with Fulvestrant  for HR-positive HER2-negative Locally Advanced or Metastatic Breast Cancer with PIK3CA/AKT1/PTEN Alteration.”  As we know, 65% to 70% of all breast cancers are HR-positive HER2-negative and this is also the most common subtype of metastatic breast cancer. The current standard of care for frontline therapy of patients with luminal metastatic disease is a CDK4/6 inhibitor in combination with endocrine therapy. However, as new endocrine and targeted therapies gain approval, choosing the best systemic therapy upon disease progression after frontline therapy is a topic of ongoing debate. Nearly 40 to 50% of HR-positive breast cancers have actionable genomic alterations and molecular testing should be a routine recommendation for patients with metastatic HR-positive HER2-negative disease. This can be performed repeating tissue biopsy at the time of progression or from archival tissue. Treatment options after progression on CDK4/6 inhibitors include alpelisib in combination with fulvestrant in patients with PIK3CA mutant tumors as seen in the SOLAR-1 trial, or capivasertib with fulvestrant in patients with a tumor mutation in (PI3K)–AKT–PTEN pathway as seen in the CAPItello-291 study, which will be discussed further.  In approximately 30% of patients, progression on frontline endocrine plus CDK4/6 inhibitor treatment is caused by endocrine resistance, frequently involving activating mutations in ESR1. For those tumors, elacestrant, an oral SERD is an option as demonstrated in the EMERALD trial. For patients with a BRCA mutation, PARP inhibitors represent another option. If no mutations are detected, everolimus, an mTOR inhibitor, can be used based on the BOLERO-2 results. The phase 2 MAINTAIN and PACE trials, along with the phase 3 postMONARCH trial support changing the endocrine therapy backbone with or without switching the CDK4/6 inhibitor. In less resourced areas, fulvestrant monotherapy is still an option to delay cytotoxic chemotherapy, though its efficacy is limited when used as a single agent. Finally, after progression on at least one line of chemotherapy, antibody drug conjugates including sacituzumab govitecan or trastuzumab deruxtecan may be an option.  Now focusing on the PI3K AKT PTEN signaling pathway, activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN occur in approximately half of luminal breast cancers. In June 2023, the CAPItello-291 trial was published and treatment with fulvestrant plus capivasertib, a PTEN AKT inhibitor, demonstrated a 3.6 month PFS benefit compared to fulvestrant alone, regardless of the presence of AKT pathway alterations. However, for those with tumors without AKT pathway alteration, an exploratory analysis showed that although there was a numerical improvement in PFS, it did not meet statistical significance, indicating that the biomarker positive population primarily drove the positive results noted in the overall population. Therefore, capivasertib plus fulvestrant was approved by the US FDA in November 2023 exclusively for patients with PI3K/AKT1/PTEN tumor alterations after progression on an aromatized inhibitor with or without a CDK4/6 inhibitor. The approved schedule of capivasertib is slightly different from that of other agents used in breast cancer. It is 400 milligrams taken orally twice a day for four days per week every week in a 28-day cycle in combination with fulvestrant. Diarrhea, rash and hyperglycemia were the most commonly reported grade three or four adverse events in the interventional group. I would like to highlight that even though the CAPItello trial excluded patients with glycosylated hemoglobin levels higher than 8% or those diagnosed with diabetes who required insulin, hyperglycemia occurred in 19% of biomarker positive patients treated with capivasertib, with nearly 2% of this population experiencing grade 3 or 4 hyperglycemia and some patients experiencing life threatening outcomes such as diabetic ketoacidosis.  By way of comparison, hyperglycemia of any grade was three times higher with alpelisib therapy in the SOLAR-1 trial, occurring in 64% of the patients and grade three or higher hyperglycemia was seen in 37% of the patients. Diarrhea was the most common treatment related adverse event experienced by 77% of the biomarker positive population. Prompt use of the antidiarrheal drugs when needed, such as loperamide must be encouraged as untreated diarrhea can lead to dehydration and renal injury. Cutaneous rash occurred in 56% of the biomarker positive population in the interventional group and 15% experienced a grade 3 or 4 rash. Nearly half of the patients with cutaneous adverse reactions required treatment and this was the leading reason for dose reduction of capivasertib.  In the biomarker positive population, the improvement in medium PFS were 4.3 months by investigator assessment. Overall survival data from the CAPItello-291 trial is still immature, but quality of life data was recently published in September this year and was assessed by the 30 item QLQ C30 questionnaire and the QLQ BR23, the breast module. According to Oliveira et al, global health status and quality of life were maintained for a longer period with capivasertib fulvestrant than with placebo fulvestrant except for symptoms of diarrhea which were significantly worse in the capivasertib group. The median time of deterioration of global health status and quality of life was twice as long in the capivasertib group being almost 25 months versus 12 months in the placebo fulvestrant group. These data reinforced the use of capivasertib in combination with fulvestrant for the treatment of HR-positive HER2-negative advanced breast cancer patients with PIK3CA/AKT1/PTEN tumor alterations who have progressed after an aromatase inhibitor-based therapy with or without a CDK4/6 inhibitor.  Thank you for listening to JCO Article Insights. This is Giselle Carvalho. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. See you next time.   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.  

Send us a textIn this episode, we are thrilled to welcome back Tiffany Troso-Sandoval MD, a distinguished medical oncologist with a quarter-century of experience in women's cancers. Dr. Troso shares her insights from a recent breast cancer symposium, illuminating groundbreaking patient care and treatment strategy advancements. As she shares her journey from the clinic to her broader role in cancer advocacy through her company, Winning The Cancer Journey, Dr. Troso unveils some of her plans aimed at educating and empowering both patients and caregivers.We explore the complex world of metastatic breast cancer treatment, emphasizing estrogen receptor-positive cases. We review the different types of anti-estrogen therapies including how and why they work.  We discuss the role of CDK4/6 inhibitors used with aromatase inhibitors, breaking down how these treatments target estrogen pathways to curb cancer growth. We navigate the intricacies of ESR1 mutations and explore how selective estrogen receptor degraders (SERDs) are crucial in overcoming treatment resistance. From chemotherapy timing to empowering caregivers, we delve into the multifaceted nature of breast cancer treatment decisions. Dr. Troso shares her transition from hands-on patient care to creating impactful online resources, highlighting the ongoing nature of the cancer journey for both patients and caregivers.  drtiffanytroso@winningthecancerjourney.comDr. Troso on Facebook Winning The Cancer Journey on FacebookDr. Troso on Instagram Winning The Cancer Journey on TikTok San Antonio Breast Cancer Symposium GuideCNN interview:  https://www.youtube.com/watch?v=MU38D89YlQ0 Are you loving the Test Those Breasts! Podcast? You can show your support by donating to the Test Those Breasts Nonprofit @ https://testthosebreasts.org/donate/ Where to find Jamie:Instagram LinkedIn TikTok Test Those Breasts Facebook Group LinkTree Jamie Vaughn in the News! Thanks for listening! I would appreciate your rating and review where you listen to podcasts!I am not a doctor and not all information in this podcast comes from qualified healthcare providers, therefore may not constitute medical advice. For personalized medical advice, you should reach out to one of the qualified healthcare providers interviewed on this podcast and/or seek medical advice from your own providers .

Featuring an interview with Dr Seth Wander, including the following topics: Design of SERENA-6, a Phase III switching trial of camizestrant for ESR1-mutant breast cancer during first-line treatment Turner N et al. Design of SERENA-6, a phase III switching trial of camizestrant in ESR1-mutant breast cancer during first-line treatment. Future Oncol 2023;19(8):559-73. Abstract (0:00) EMERALD trial analysis of patient-reported outcomes with oral elacestrant compared to standard of care endocrine therapy for ER-positive, HER2-negative advanced or metastatic breast cancer Cortes J et al. EMERALD trial analysis of patient-reported outcomes (PROs) in patients with ER+/HER2− advanced or metastatic breast cancer (mBC) comparing oral elacestrant vs standard of care (SoC) endocrine therapy. ESMO Breast 2023;Abstract 188O. (5:50) Imlunestrant, an oral selective estrogen receptor degrader, in combination with HER2-directed therapy, with or without abemaciclib, for ER-positive, HER2-positive advanced breast cancer Bhave MA et al. Imlunestrant, an oral selective estrogen receptor degrader (SERD), in combination with human epidermal growth factor receptor 2 (HER2) directed therapy, with or without abemaciclib, in estrogen receptor (ER) positive, HER2 positive advanced breast cancer (aBC): EMBER phase 1a/1b study. ASCO 2024;Abstract 1027. (9:43) CME information and select publications

Sagar D. Sardesai, MBBS, discusses the phase 3 ELAINE-3 trial evaluating lasofoxifene plus abemaciclib in ESR1-mutant, ER+/HER2- metastatic breast cancer.

Host: Jennifer Caudle, DO Guest: Virginia Kaklamani, MD Guest: Anne O'Dea, MD When caring for patients with ER-positive/HER2-negative metastatic breast cancer, there's uncertainty on the optimal second-line sequencing of treatments after disease progression on first-line CDK4/6 inhibition and endocrine therapy. But the findings from the EMERALD trial, which led to the approval of ORSERDU® (elacestrant) for patients with ER-positive/HER2-negative ESR1-mutated metastatic breast cancer after disease progression on endocrine therapy,1 contribute to our understanding of second-line treatment options. Dive into the results from the EMERALD trial and subgroup analysis with Drs. Virginia Kaklamani and Anne O'Dea. Dr. Kaklamani is a Professor of Medicine in the Division of Hematology and Medical Oncology at the UT Health Sciences Center in San Antonio, and Dr. O'Dea is a breast medical oncologist at the University of Kansas Cancer Center.

Host: Jennifer Caudle, DO Guest: Virginia Kaklamani, MD Guest: Anne O'Dea, MD When caring for patients with ER-positive/HER2-negative metastatic breast cancer, there's uncertainty on the optimal second-line sequencing of treatments after disease progression on first-line CDK4/6 inhibition and endocrine therapy. But the findings from the EMERALD trial, which led to the approval of ORSERDU® (elacestrant) for patients with ER-positive/HER2-negative ESR1-mutated metastatic breast cancer after disease progression on endocrine therapy,1 contribute to our understanding of second-line treatment options. Dive into the results from the EMERALD trial and subgroup analysis with Drs. Virginia Kaklamani and Anne O'Dea. Dr. Kaklamani is a Professor of Medicine in the Division of Hematology and Medical Oncology at the UT Health Sciences Center in San Antonio, and Dr. O'Dea is a breast medical oncologist at the University of Kansas Cancer Center.

In this episode of Targeted Talks, Seth Wander, MD, PhD, medical oncologist at Massachusetts General Hospital and assistant professor at Harvard Medical School, discusses the clinical importance of ESR1 mutations in hormone receptor-positive metastatic breast cancer and how these mutations influence treatment approaches.

Host: Charles Turck, PharmD, BCPS, BCCCP Guest: Erika Hamilton, MD The ELECTRA trial is seeking to evaluate the combination of elacestrant with abemaciclib in patients with ER+/HER2- metastatic breast cancer regardless of metastatic site and ESR1 status to see if this could be an all-oral treatment option before using fulvestrant-based combinations or chemotherapy-based regimens. And now, the preliminary results are here. Joining Dr. Charles Turck to share what we've learned so far from the ELECTRA trial is study investigator Dr. Erika Hamilton.

Host: Jennifer Caudle, DO Guest: Joyce O'Shaughnessy, MD The results from the phase III EMERALD trial led to the approval of ORSERDU® (elacestrant) as the first oral selective estrogen receptor degrader for ER-positive/HER2-negative metastatic breast cancer patients with ESR1 mutations after disease progression following at least one line of endocrine therapy.1 But given the results from prior analyses, clinicians wanted to better understand the data for elacestrant in subgroups of patients with key clinical or biomarker characteristics, and so a post hoc analysis of elacestrant in these subgroups who typically have a poorer prognosis was conducted. Explore the EMERALD trial and the key outcomes from this subgroup analysis with Dr. Jennifer Caudle and medical oncologist Dr. Joyce O'Shaughnessy.

Host: Jennifer Caudle, DO Guest: Joyce O'Shaughnessy, MD The results from the phase III EMERALD trial led to the approval of ORSERDU® (elacestrant) as the first oral selective estrogen receptor degrader for ER-positive/HER2-negative metastatic breast cancer patients with ESR1 mutations after disease progression following at least one line of endocrine therapy.1 But given the results from prior analyses, clinicians wanted to better understand the data for elacestrant in subgroups of patients with key clinical or biomarker characteristics, and so a post hoc analysis of elacestrant in these subgroups who typically have a poorer prognosis was conducted. Explore the EMERALD trial and the key outcomes from this subgroup analysis with Dr. Jennifer Caudle and medical oncologist Dr. Joyce O'Shaughnessy.

Host: Jennifer Caudle, DO Guest: Joyce O'Shaughnessy, MD The results from the phase III EMERALD trial led to the approval of ORSERDU® (elacestrant) as the first oral selective estrogen receptor degrader for ER-positive/HER2-negative metastatic breast cancer patients with ESR1 mutations after disease progression following at least one line of endocrine therapy.1 But given the results from prior analyses, clinicians wanted to better understand the data for elacestrant in subgroups of patients with key clinical or biomarker characteristics, and so a post hoc analysis of elacestrant in these subgroups who typically have a poorer prognosis was conducted. Explore the EMERALD trial and the key outcomes from this subgroup analysis with Dr. Jennifer Caudle and medical oncologist Dr. Joyce O'Shaughnessy.

Featuring perspectives from Dr Seth Wander, including the following topics: Case: A woman in her mid-50s with ER-positive, PR-negative, HER2 IHC 1+ metastatic breast cancer (mBC), Recurrence Score® (RS) = 35 (0:00) Mechanisms of resistance to antiestrogen therapy in HR-positive mBC (2:33) Optimal approaches to biomarker assessment (15:37) Case (continued): A woman in her mid-50s with ER-positive, PR-negative, HER2 IHC 1+ mBC, RS = 35 (18:27) Case: A woman in her early 60s with de novo HR-positive, HER2-negative mBC with an ESR1 mutation after disease progression on first-line ribociclib/letrozole (20:22) EMERALD — Phase III data guiding the use of elacestrant (21:39) Emerging oral selective estrogen receptor degraders — camizestrant and imlunestrant (29:32) Case (continued): A woman in her early 60s with de novo HR-positive, HER2-negative mBC with an ESR1 mutation after disease progression on first-line ribociclib/letrozole (45:44) Case: A woman in her early 60s with HR-positive, HER2-negative mBC and a PIK3CA mutation who develops a new ESR1 mutation after disease progression on CDK4/6i and aromatase inhibitor (47:22) CAPItello-291 — Phase III data guiding the use of capivasertib (48:52) Case (continued): A woman in her early 60s with HR-positive, HER2-negative mBC and a PIK3CA mutation who develops a new ESR1 mutation after disease progression on CDK4/6i and aromatase inhibitor (52:41) Additional promising antiestrogens — vepdegestrant and lasofoxifene (58:41) CME information and select publications  

Dr. Angela DeMichele, Dr. Lynn Henry, and Dr. Harold Burstein present the latest breast cancer rapid recommendation update impacting two ASCO guidelines. This update focuses on the new option, capivasertib plus fulvestrant, for patients with hormone receptor-positive, HER2-negative metastatic breast cancer with activating PIK3CA or AKT1 mutations or inactivating alterations in PTEN based on data from the recent CAPItello-291 trial. They discuss the updated recommendations on lines of endocrine treatment and selecting between the options for patients with activating PIK3CA mutations. Additionally, we discuss implications for clinicians and patients, and what ongoing research is occurring in the field. Read the latest update, “Endocrine and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer – Capivasertib-Fulvestrant: ASCO Rapid Guideline Update“ at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00248 Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.   My name is Brittany Harvey, and today I am interviewing Dr. Harold Burstein from Dana-Farber Cancer Institute, Dr. Angela DeMichele from the University of Pennsylvania, and Dr. Lynn Henry from the University of Michigan, co-chairs on “Endocrine and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Capivasertib–Fulvestrant: ASCO Rapid Guideline Update.” Thank you for being here, Dr. Burstein, Dr. DeMichele, and Dr. Henry. Dr. Harold Burstein: We're happy to be here.  Brittany Harvey: And before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this episode today, are available online with the publication of the guideline update in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to kick us off, Dr. Burstein, could you first describe what prompted this rapid update, which provides updated recommendations for two ASCO guidelines: the biomarkers for systemic therapy in metastatic breast cancer guideline, and the endocrine treatment and targeted therapy for hormone receptor-positive, HER2-negative metastatic breast cancer guideline? Dr. Harold Burstein: Thanks, Brittany. Well, this team has been working, as you mentioned, actually, on two guidelines, which are clearly evolving in parallel and kind of converging, actually, when you look at data, as we'll be talking about in the next few minutes. The particular catalyst here was a large randomized clinical trial which looked at a new targeted therapy in the space of estrogen receptor-positive, HER2-negative breast cancer. That drug is capivasertib. And the trial was the so-called CAPItello study. In that trial, patients who were receiving second-line therapy with fulvestrant were randomized to that treatment alone, or that plus capivasertib. So the data from that study were the first strong signal that we needed to update the guideline because they were important clinical data.   The other strong signal was that the drug was tested in a cohort of patients who had a specific set of mutations in their cancers. And that included PIK3CA mutations, a class of mutations for which we already had a targeted drug. But it also included some new potential targets, including mutations in the AKT gene itself, capivasertib is an AKT inhibitor, as well as loss of PTEN protein functionality, which potentially sensitizes tumors to the targeted action of this drug as well. So while we had a couple of guidelines catching up on the endocrine therapy space, which is increasingly looking like a targeted therapy space, it was clear that this major study, which had clinical and diagnostic implications, would sort of push them together and served as the impetus for updating both guidelines at the same time. Brittany Harvey: Understood. I appreciate that background information.   So then, Dr. DeMichele, based on this updated data that Dr. Burstein just described, what is the updated recommendation from the guideline panel regarding lines of endocrine treatment? Dr. Angela DeMichele: Well, I think this is where the biomarker evolution that Dr. Burstein just referred to really comes in because now we have the opportunity to perform genomic testing in patients who have ER-positive, HER2-negative metastatic breast cancer, on either the tumor or commonly from the blood. And we can now start to tailor treatment to the specific genomic abnormalities that that patient's tumor contains. So now our guideline really marries both the genomic abnormality with the therapeutic option. First-line treatment remains endocrine therapy plus a CDK 4/6 inhibitor. But things then really start to diverge once we enter second and third-line therapy because at that point, we now have the option to test for several genomic markers: ESR1 mutations, PIK3CA mutations, AKT1 mutations, and PTEN inactivation. And based on whether the tumor has one or any of those mutations, we can then select the therapy based on that.  So in the case of capivasertib, as you just heard, that is a therapy for patients whose tumors have PIK3CA mutations or activating mutations in AKT1 or loss of PTEN. But other patients who don't have one of those mutations may, in the second line, go on to another drug. For example, if they have an ESR1 mutation, they then may be eligible to take elacestrant. Patients who have no targetable mutations still have a targeted option in that they can use everolimus. And in all of these settings, the endocrine therapy partner for this line of therapy is typically fulvestrant. So now we're really starting to tailor therapy in the second- and third-line based on genomic changes. Brittany Harvey: Excellent. That information is helpful for choosing optimal therapy tailored to the individual patients, as you just described.  So then, Dr. Henry, what guidance does the expert panel provide regarding choosing a PIK3CA targeted option? Dr. Lynn Henry: Thank you. So for patients whose tumors are found to have an activating mutation in PIK3CA, we now have two drug options: either alpelisib or capivasertib in combination with fulvestrant. And the problem is, these drugs have not been compared head-to-head. We can't say that one is clearly better than the other, either in terms of efficacy or in terms of side effect profile. What we do have is information from two separate trials in which they were each tested against placebo. The efficacy appears to be fairly similar based on the data that we have. It does appear that the side effect profiles may be slightly different. And so, when you have a patient sitting in front of you and you're trying to decide how best to treat her, you really have to think about, what symptoms does my patient already have? What is she more or less likely to tolerate? So what we do know is that it appears that the rates of grade 3 diarrhea and rash were slightly higher with capivasertib. It looks like hyperglycemia was higher with alpelisib, as was treatment discontinuation. So really you have to make an individualized decision when you have a patient sitting in front of you about which drug you'd like to try. Of course, if someone doesn't tolerate one drug, you can always switch to the other one.  Brittany Harvey: I appreciate that analysis and to provide guidance without a head-to-head trial and to specifically provide options based on an individual patient's profile.   So then, Dr. DeMichele, what should clinicians know as they implement these new recommendations?  Dr. Angela DeMichele: Well, first of all, I think most clinicians now are becoming more familiar with the procedures required for doing genomic testing. But this is something that now has become the standard of care. And so, it is incumbent upon all of us who treat these patients to understand what the options for genomic testing are for that patient, which companies offer this testing, how to send a sample, and how to interpret the report that comes back. So, I think this has really added a level of complexity to the therapy for patients. I also think that one can't simply apply an algorithm to a patient. We have to really treat the whole patient and we have to take into consideration, as Dr. Henry said, the toxicities of these agents and the cost which is also a major issue. So I think that while it is more complex, really that doctor-patient relationship is so important in communicating what these genomic tests mean for a patient and for their options, and also important for the clinician to really understand what the different therapeutic agents might mean for a patient, and really try to pick the agent that's best for that patient. Using genomic testing is just one of several different features that they'll consider. Brittany Harvey: Absolutely. It's key to obtain the data needed to select appropriate patients and to recognize the complexity.   So then, Dr. Henry, in your view, how will this update impact patients with metastatic breast cancer? Dr. Lynn Henry: Yes, so as we've discussed, I think this is really exciting. Over the last few years, we have had quite a number of new medications that have become available for patients and have been FDA-approved. And so this is yet the latest in a series. For those patients whose tumors have a PIK3CA mutation, as we discussed, there are now two options. So you have a choice depending on which one is better covered by insurance, by which one you may tolerate better. But I think the other thing is now, although it's a smaller subset of patients, there are patients out there whose tumors have mutations in AKT1 or alterations in PTEN, and so there's an entirely new endocrine therapy-based option available for them that wasn't available before. So I think that thinking about the new data that are out there, the new drugs that are out there, really is exciting because there are new options available and hopefully there are more to come as well.    Brittany Harvey: Absolutely. It's great to have these new options.  So, finally, Dr. Burstein, Dr. Henry just mentioned what's to come. Could you touch on what some of the outstanding questions are regarding endocrine therapy for patients with metastatic breast cancer?  Dr. Harold Burstein: A couple of things to say. First, ER-positive metastatic breast cancer is the most common kind of metastatic breast cancer, roughly three quarters of metastatic cases of breast cancer will be hormone receptor-positive cancers. So this is a very big public health issue around the world, actually, breast cancer being the number one most commonly diagnosed cancer of women around the world. So minor or major improvements in treatment for advanced ER-positive breast cancer really have a tremendous impact.  The second thing is it's been remarkable to see the progress in the past decade. We've gone from simply targeting the hormonal access itself with medicines like tamoxifen or aromatase inhibitors or an injectable selective estrogen receptor degrader like fulvestrant to incorporating targeted therapies at the same time. And this whole class of drugs called CDK4/6 inhibitors has emerged which we use in either first- or in second-line therapy. Those drugs have transformed our standard of care, improved survival for patients with advanced ER-positive disease, now with median survival nearly 50% longer than what we had seen in the past.  And if you've heard, we have a wealth of opportunities. We can target PIK3CA, we can target ESR1 mutations. Other drugs emerging in the space include PROTACs which is another way of degrading the estrogen receptor. And so there's going to be more progress in the years to come.   So one of the biggest challenges has been to try and understand, is there really an optimal way to use these drugs, or can we be smarter about the particular sequence of all these particular things that are happening.  So one example of this was a recent study that is on a drug, not as yet FDA-approved, called inavolisib, which is a PIK3CA targeted drug used in first line in combination with a CDK4/6 inhibitor and endocrine therapy. And that study, for a high-risk group of women with ER-positive metastatic disease, actually showed a dramatic improvement in overall survival, asking the question if combining some of these targeted therapies together might yet further improve outcomes.  And as you've heard from the diagnostic space, one of the other interesting things is that tumors evolve over time. And so acquisition of the estrogen receptor mutations, ESR1 mutations, which are typically not found early in the course of advanced breast cancer but otherwise later, now have targeted treatments. So there's a whole bunch of stuff going on all at the same time, including multiple ways of targeting things, serial testing to look for acquisition of ESR1 mutations and new pathways to explore. It's an embarrassment of riches in some respects because it has meant it's actually really hard to write a guideline as you've heard, which says, “Do this first, do this second, and do this third.” I suppose that's a good problem to have under the circumstances, but it's going to require really thoughtful clinical trials and careful analysis to help guide specific lines of treatment recommendations like that.  Brittany Harvey: Excellent. We'll look forward to these exciting, continuing developments for patients with metastatic breast cancer. And I want to thank you all so much for your work to develop this rapid recommendation update for these two guidelines. And thank you for taking the time on this podcast today. Dr. Harold Burstein: Thanks. Dr. Lynn Henry: Thank you so much.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Featuring an interview with Dr Komal Jhaveri, including the following topics: Case: A woman in her mid 50s with ER-positive, HER2-low (IHC 1+) metastatic breast cancer with an ESR1 mutation (0:00) Case: A woman in her late 40s with ER-positive, HER2-low ESR1 wild-type metastatic breast cancer who received imlunestrant on a clinical trial (7:25) Case: A woman in her early 60s with a history of localized breast cancer who received imlunestrant and abemaciclib on a trial for newly diagnosed metastatic breast cancer after disease progression on endocrine therapy (12:03) Beyond the Guidelines: A survey of clinical investigator perspectives on the current and future role of oral SERDs (selective estrogen receptor degraders) for ER-positive metastatic breast cancer (17:35) CME information and select publications

Featuring a slide presentation and related discussion from Dr Komal Jhaveri, including the following topics: Role of ESR1 mutations in sensitivity and resistance to endocrine therapy in patients with ER-positive metastatic breast cancer (0:00) Efficacy and safety of oral SERDs in patients with ER-positive metastatic breast cancer (13:26) Similarities and differences among available and investigational oral SERDs for ER-positive metastatic breast cancer (24:21) CME information and select publications

New therapeutic options are now available for HR+ MBC.  Dr. Virginia Kaklamani will discuss endocrine therapy resistance, liquid biopsy/blood test, mutations, and treatment sequencing of targeted therapy. You will learn about oral selective estrogen receptor degraders (SERDS), clinical trials, and more. 

Host: Charles Turck, PharmD, BCPS, BCCCP Guest: Pavani Chalasani, MD, MPH Acquired ESR1 mutations cannot be detected on archival tissue and require liquid biopsy. Fortunately, this approach circumvents the challenges of acquiring serial tissue while allowing for the real-time monitoring of ESR1 status in patients with metastatic breast cancer. Learn more about the rationale behind liquid biopsies and best practices for utilizing them in clinical practice with Dr. Charles Turck and Dr. Pavani Chalasani, Division Director of Hematology-Oncology at the GW Cancer Center in Washington, DC.

Host: Charles Turck, PharmD, BCPS, BCCCP Guest: Stephanie Graff, MD Guest: Pavani Chalasani, MD, MPH When treating patients with metastatic breast cancer, it's important to repeatedly conduct liquid biopsies to look for acquired ESR1 mutations when patients progress after endocrine therapy, even if initial testing was done. That's why Dr. Charles Turck is breaking down best practices for utilizing liquid biopsies to detect ESR1 mutations with Drs. Stephanie Graff and Pavani Chalasani. Dr. Graff is the Director of Breast Oncology at the Lifespan Cancer Institute in Providence, Rhode Island, and Dr. Chalasani is the Division Director of Hematology-Oncology at the GW Cancer Center in Washington, DC.

Host: Pavani Chalasani, MD, MPH Guest: Marcela Mazo Canola, MD Recent studies have examined the implications of ESR1 mutations in metastatic breast cancer and found that ESR1 mutations predict poor response to subsequent endocrine therapy. These acquired mutations also correlate with aggressive disease and, by extension, worse prognosis. Dive further into these findings from various studies and how they might impact the way we treat patients with metastatic breast cancer with Dr. Pavani Chalasani and Dr. Marcela Mazo Canola, Assistant Professor at UT Health San Antonio's Mays Cancer Center.

Guest: Mariya Rozenblit, MD ESR1 mutations are frequently acquired during aromatase inhibitor treatment for HR+/HER2- metastatic breast cancer, making liquid biopsy monitoring vital to identify endocrine resistance. Learn more about this acquired mutation and how it can impact treatment with Dr. Mariya Rozenblit, Assistant Professor of Medicine in the Section of Medical Oncology at the Yale School of Medicine.

Guest: Megan Kruse, MD While intrinsic mutations, like PIK3CA, are present at the outset and can be identified upfront in patients with HR+/HER2- metastatic breast cancer, acquired mutations, like ESR1, cannot be detected on baseline tumor profiling. That's why longitudinal monitoring with liquid biopsies over the course of treatment is required. Learn more about these key differences in testing for acquired versus intrinsic mutations with Dr. Megan Kruse, a breast medical oncologist at the Cleveland Clinic.

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    

A new research perspective was published in Oncotarget's Volume 14 on July 1, 2023, entitled, “Deciphering the mechanisms of action of progesterone in breast cancer.” A practice-changing, randomized, controlled clinical study established that preoperative hydroxyprogesterone administration improves disease-free and overall survival in patients with node-positive breast cancer. In this new perspective, researchers Gaurav Chakravorty, Suhail Ahmad, Mukul S. Godbole, Sudeep Gupta, Rajendra A. Badwe, and Amit Dutt from Tata Memorial Centre, Homi Bhabha National Institute and MIT World Peace University summarized evidence from their studies that preoperative hydroxyprogesterone administration may improve disease-free and overall survival in patients with node-positive breast cancer by modulating cellular stress response and negative regulation of inflammation. “This research perspective is aimed to highlight the multipronged roles of progesterone in breast cancer that underlie the associated clinical response. We also present our opinion on the role of progesterone in overcoming endocrine resistance in the patients, especially by countering the genomic effects of overexpression and mutation of ESR1 and its targets.” Non-coding RNAs, particularly DSCAM-AS1, play a regulatory role in this process, along with the upregulation of the kinase gene SGK1 and activation of the SGK1/AP-1/NDRG1 axis. Progesterone-induced modification of the progesterone receptor and estrogen receptor genomic binding pattern is also involved in orchestrating estrogen signaling in breast cancer, preventing cell migration and invasion, and improving patient outcomes. The team continues on to highlight the role of progesterone in endocrine therapy resistance, which could lead to novel treatment options for patients with hormone receptor-positive breast cancer and for those who develop resistance to traditional endocrine therapies. “Overall, while preoperative hydroxyprogesterone administration appears to be a promising strategy for improving the prognosis of patients with node-positive breast cancer, the investigation of the mechanism of actions of progesterone in breast cancer remains an important area of research that holds great promise for improving patient outcomes.” DOI - https://doi.org/10.18632/oncotarget.28455 Correspondence to - Amit Dutt - adutt@actrec.gov.in Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28455 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - breast cancer, progesterone, DSCAM-AS1, endocrine therapy About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

How should community oncologists best approach ESR1 mutations in breast cancer, given the latest findings? Recent data presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting and elsewhere have shed light on issues related to ESR1 testing and treatment selection. Bob Figlin, MD, the Steven Spielberg Family Chair in hematology oncology at Cedars-Sinai Cancer in Los Angeles, speaks with Hope Rugo, MD, professor of medicine in the division of hematology and oncology, department of medicine, and director of breast oncology and clinical trials education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, about how to put new findings into practice. Dr. Rugo provides key recommendations, as she explains that “It's really important that we don't just throw drugs together in clinical practice.”

Dr. Angie DeMichele and Dr. Lynn Henry present the latest rapid recommendation impacting two ASCO guidelines. This update focuses on testing for ESR1 mutations in patients with hormone receptor-positive, HER2-negative metastatic breast cancer, and presents treatment recommendations for patients with a detectable ESR1 mutation. Dr. DeMichele and Dr. Henry review the recent data from the EMERALD trial, discuss it's implications for practice, and ongoing developments they're monitoring for more effective therapeutic options. Read the latest update, "Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the update and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.2300638  Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Angie DeMichele from University of Pennsylvania, and Dr. Lynn Henry from the University of Michigan, authors on ‘Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update'.  Thank you for being here, Dr. DeMichele and Dr. Henry. Dr. Angie DeMichele: It's a pleasure.  Dr. Lynn Henry: Thank you.  Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this podcast episode today, are available online with a publication of the rapid recommendation update in the Journal of Clinical Oncology, which is linked in the show notes.  So then, getting into the content of this rapid recommendation first, Dr. Henry, what prompted this rapid update, which provides updated recommendations for two ASCO guidelines? First, the ‘Biomarkers for Systemic Therapy and Metastatic Breast Cancer Guideline', last published in 2022, and the ‘Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer Guideline', which was last updated in 2021. Dr. Lynn Henry: Thank you, Brittany. There's been a lot of exciting news for the treatment of metastatic breast cancer in the last few years. This particular update reflects the results of the phase III EMERALD trial. This trial compared the new oral selective estrogen receptor degrader, elacestrant, to standard-of-care endocrine therapy with either fulvestrant or an aromatase inhibitor in patients with hormone receptor-positive, HER2-negative metastatic breast cancer that had previously progressed during treatment with a CDK4/6 inhibitor in combination with endocrine therapy. Compared to standard-of-care, in this trial, they showed improved progression-free survival in both the overall study population as well as specifically in the patients who had a detectable ESR1 mutation in their circulating tumor DNA. These findings were published in the Journal of Clinical Oncology in 2022, and the drug was subsequently approved by the US Food and Drug Administration in January 2023. Therefore, we felt that it was important to update the guidelines to reflect the results of this trial and the new drug approval.  Brittany Harvey: Excellent. Thank you for describing the results of that trial and the new approval.  So then, based on this data, Dr. DeMichele, what is the updated recommendation from the guideline expert panel for testing for ESR1 mutations?  Dr. Angie DeMichele: So, the guideline panel has now recommended that ESR1 mutation testing occur for any patient who develops a recurrence or progression on endocrine therapy. And this is specifically in reference to the development of ESR1 mutations that can occur after a patient has been exposed to aromatase inhibitors. The guideline itself recommends that this testing be done on either tumor or blood, but blood is preferable because there is increased sensitivity using ctDNA testing over tumor testing. So this was an important component of the change in the recommendation because it's linked to the approval of elacestrant as a therapy. Patients are only eligible to receive elacestrant if they harbor an ESR1 mutation. Brittany Harvey: Understood. I appreciate that explanation.   So then, Dr. Henry, following that recommendation for testing, what is the new recommendation for treatment for patients with a detectable ESR1 mutation? Dr. Lynn Henry: Yes. So patients who have a detectable ESR1 mutation and who have previously received treatment with endocrine therapy in combination with the CDK4/6 inhibitor for advanced breast cancer now have multiple treatment options. The newest option is this new drug, elacestrant, which is given 345 milligrams orally daily. There are still the other options that we already knew about, which include a different endocrine therapy alone, such as fulvestrant or an aromatase inhibitor, or possibly an endocrine therapy in combination with a targeted agent, such as alpelisib or everolimus. And those decisions really need to be based on what other mutations are present in the patient's cancer.  Importantly, at this time, there are no safety or efficacy data to support using elacestrant in combination with targeted agents. Therefore, to date, it has only been approved to be used as monotherapy. But really, this is an exciting new potential option for treatment for patients whose tumors have a detectable ESR1 mutation. Brittany Harvey: Yes, this is an exciting option, and I appreciate you describing how this fits in with the existing treatment paradigm for these patients.   So then, Dr. DeMichele, as these new recommendations are implemented, what should clinicians know? Dr. Angie DeMichele: I think this is a really important new step in breast cancer in testing for ESR1 mutations. We've not previously had a medication that required the existence of an ESR1 mutation for patients to be eligible for therapy. So obtaining ESR1 mutation testing may be new for some clinicians. As I stated earlier, this can be done either on a tumor biopsy or on blood testing using the Guardant360 ctDNA test, which is the test that was used in the clinical trial. And it was stated that the ctDNA test is more sensitive than the tumor test. But what's really important here is that the testing occur at the time that the clinician is considering switching therapies, because it's important to find that ESR1 mutation prior to starting the next therapy. ESR1 mutations don't typically exist in a tumor at the time it's diagnosed. They only emerge over time after patients have been exposed to different endocrine therapies, particularly aromatase inhibitors. It's also possible that at the time of a recurrence after aromatase inhibitor therapy or progression on an aromatase inhibitor, there will not be any detectable ESR1 mutation. However, with subsequent therapy, an ESR1 mutation can occur. So a patient may need serial testing over time to determine whether an ESR1 mutation has developed.  Brittany Harvey: Understood. Those are important clinical implications.  So then, Dr. Henry, Dr. DeMichele just described some of the testing implications for patients. But in your view, how does this rapid update impact patients with hormone receptor-positive, HER2-negative metastatic breast cancer? Dr. Lynn Henry: So as Dr. DeMichele mentioned, this update specifically highlights approval of a new drug, oral SERD elacestrant. This is an exciting new option for treatment of patients whose tumors have an ESR1 mutation. So previous data have demonstrated that cancers with ESR1 mutations do not respond as well to previously available standard-of-care treatments such as aromatase inhibitors. It's nice to have a drug that may be a better option than some of the previously existing treatments for hormone receptor-positive, HER2-negative metastatic breast cancer. Brittany Harvey: Definitely. That's great to hear.  So then, finally, Dr. DeMichele, are there ongoing research developments that the panel is monitoring for future updates to these guidelines? Dr. Angie DeMichele: We certainly are monitoring additional research developments, Brittany. Specifically, there are numerous other selective estrogen receptor degraders that are being tested, and these also may ultimately require ESR1 mutation testing and detection for therapies. So we'll be monitoring the results of those clinical trials. We'll also be watching for additional trials that help us understand how to best utilize elacestrant and whether it can be combined with other therapies. And then, finally, I think we have to think about how to place this in the context of other types of molecular changes that we may detect in metastatic breast cancer, such as PIK3CA mutations and others. And as we move forward, I anticipate that we will have additional therapies that are specifically targeted to molecular changes in the tumor. And I think this is a really exciting development because this is a major step forward toward precision medicine, where we're really tailoring the therapy to the specific biology of the patient's tumor and actually responding to the ways in which the tumor is evolving over time and in response to treatment. So as tumors become increasingly resistant to therapies, we can actually take advantage of those resistance mechanisms to develop therapies that will be more effective. Brittany Harvey: Yes, we'll look forward to those new therapies and research developments and then updated guidelines in the future.  So I want to thank you both so much for your work on this rapid recommendation update and for your time today, Dr. DeMichele and Dr. Henry.  Dr. Angie DeMichele: Thank you.  Dr. Lynn Henry: Thank you very much.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guidelines, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this Podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr Bidard discusses the FDA approval of elacestrant in patients with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, key efficacy and safety data from the EMERALD trial, and the importance of testing for ESR1 mutations in patients with ER-positive, HER2-negative disease.

Listen to a soundcast of the January 27, 2023, FDA approvals of Jaypirca (pirtobrutinib) for relapsed or refractory mantle cell lymphoma, and Orserdu (elacestrant) for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer.

Featuring perspectives from Dr Komal Jhaveri, including the following topics: •      Case: A premenopausal woman in her early 40s with a 5.8-cm, ER/PR-positive, HER2-negative infiltrating lobular carcinoma and microscopic sentinel node involvement — Arielle Heeke, MD (11:58) •      Case: A premenopausal woman in her early 40s with a 3.1-cm ER/PR-positive, HER2-negative localized invasive ductal carcinoma (IDC) and a Recurrence Score® of 18 — Alan B Astrow, MD (14:51) •      Case: A woman in her late 50s with ER/PR-positive, HER2-negative, microsatellite stable, BRCA1/2 wild-type, metastatic IDC with PALB2 mutation who receives palbociclib/letrozole and zoledronic acid — Shaachi Gupta, MD, MPH (19:37) •      Case: A postmenopausal woman in her early 60s with de novo ER/PR-positive, HER2-low (IHC 1+) metastatic IDC after disease progression on abemaciclib/letrozole and alpelisib/fulvestrant — Zanetta S Lamar, MD (29:32) •      Case: A premenopausal woman in her mid 30s with ER/PR-positive, HER2-negative IDC receiving neoadjuvant chemotherapy and goserelin, now with sexual dysfunction — Laila Agrawal, MD (34:48) •      Case: A woman in her mid 60s with ER/PR-positive, HER2-low bone-only metastatic IDC on endocrine therapy alone since 2001, now experiencing asymptomatic disease progression (ESR1 variant, AKT1 mutation on liquid biopsy) — Philip L Brooks, MD (45:55) CME information and select publications

You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, Cancer.Net Associate Editor Dr. Norah Lynn Henry covers new research in breast cancer treatment, prevention, and survivorship presented at the 2022 San Antonio Breast Cancer Symposium, held December 6-10. Dr. Henry is a Professor and Interim Chief of the University of Michigan's Division of Hematology/Oncology in the Department of Internal Medicine and is the Breast Oncology Disease Lead at the Rogel Cancer Center in Ann Arbor, Michigan. View Dr. Henry's disclosures at Cancer.Net. Dr. Henry: Hi, I'm Dr. Lynn Henry, a breast cancer oncologist from the University of Michigan Rogel Cancer Center. Welcome to this quick summary of updates from the 2022 San Antonio Breast Cancer Symposium. I have no conflicts of interest for any of the trials that I will talk about today. First, I'm going to give a very brief overview of the types of breast cancer, and then talk about some research that was presented on both metastatic and early-stage breast cancer. As a reminder, there are multiple kinds of breast cancer. Some breast cancers are called hormone receptor-positive or estrogen receptor-positive and are stimulated to grow by the hormone estrogen. We treat those cancers with anti-estrogen treatments, which block estrogen or lower estrogen levels. We often combine anti-estrogen treatments with other medications to try to make them work even better against the cancer. Other breast cancers are called HER2-positive. These are often more aggressive cancers, but because they have extra copies of HER2, they often respond to treatments that block HER2. Finally, there are breast cancers that don't have hormone receptors or HER2 receptors. These are called triple-negative breast cancer and are also often fairly aggressive cancers. One of the most exciting takeaways from the San Antonio meeting was the promise of new medications on the horizon to treat hormone receptor-positive, HER2-negative metastatic breast cancer. A commonly used treatment for metastatic breast cancer that is hormone receptor-positive and HER2-negative is fulvestrant, which is a type of medicine called “SERD,” or selective estrogen receptor degrader. At the meeting, we heard new data about 2 new SERD medications: elacestrant that was tested in the EMERALD trial and camizestrant that was tested in the SERENA trial, both of which are oral pills instead of injection medications and both of which may work particularly well against tumors that have mutations in the estrogen receptor called ESR1. In addition, we heard about capivasertib, which is an AKT inhibitor that was shown to work well when combined with fulvestrant and had less toxicity than some of the similar drugs that had previously been tested. For treatment of HER2-positive metastatic breast cancer, there are now a lot of medications that have been FDA approved, so some of the questions that clinical trials are now examining are related to what order we should use the medications in when we are treating patients. We heard about 2 studies of the medication trastuzumab deruxtecan, which I'm going to refer to as Enhertu. This drug is a combination of the anti-HER2 antibody trastuzumab plus a chemotherapy drug, and the antibody targets the drug to a cancer like a guided missile. Enhertu is currently routinely used to treat patients with metastatic HER2-positive breast cancer. We heard updated data that showed that when Enhertu was compared head-to-head against trastuzumab emtansine, also known as Kadcyla, patients who were treated with Enhertu were able to stay on the medication for a lot longer compared to patients who were treated with Kadcyla. We also heard that for patients who had already been treated with Kadcyla but it was no longer working, it is reasonable to switch to treatment with Enhertu at that point, because it is still likely to be effective. These studies may help oncologists decide what order to use these newer medications when treating patients with HER2-positive breast cancer. To switch gears a little bit, I'll now talk about another study I found interesting. This one is in the setting of people who are at high risk of developing breast cancer, but who haven't actually been diagnosed with cancer yet. In general, people are recommended to take either tamoxifen or an aromatase inhibitor medication, which is the same as treatment for patients who have been diagnosed with hormone receptor-positive breast cancer. But in this case, it's trying to prevent them from ever getting breast cancer in the first place. However, many people don't take the medications because they are concerned about side effects. A study was therefore performed in Italy that compared the 5-milligram dose of tamoxifen, which is only one-quarter of the full dose, with placebo for 3 years. After 7 years of follow-up, this low dose of tamoxifen, which is being referred to as “babytam,” was shown to reduce the risk of developing breast cancer by about half, which is similar to the effects seen with the full dose of the medication. Plus, there were fewer side effects. This lower dose is likely to be used regularly for prevention of breast cancer based on these findings, although this lower dose of tamoxifen has not yet been tested to see if it is as effective as the full dose of medication for preventing breast cancer recurrence, so it is not routinely recommended for patients who have a diagnosis of breast cancer to receive this lower dose. Finally, I will touch briefly on exciting results from the POSITIVE trial, which is a trial conducted around the world that examined whether it is safe for young women with hormone receptor-positive breast cancer to stop taking anti-hormone therapy to become pregnant. The women on this trial stopped taking endocrine therapy after taking it for about 18 to 30 months, and then spent up to 2 years trying to become pregnant. About three-quarters of the patients had at least 1 pregnancy during that time, and importantly, there was no increased risk of breast cancer recurrence seen in these patients. Once patients were done with their pregnancy, it was recommended that they restart taking endocrine therapy again. There were a lot of other research findings presented that were related to treatment for both early-stage and metastatic breast cancer at this meeting. Importantly, we got glimpses of the many new drugs on the horizon for treatment of breast cancer, including the 3 that I mentioned already. And we eagerly await the results of large, randomized trials so that the drugs that work can be used to care for patients with breast cancer. But for now, that's it for this quick summary of important research from the 2022 San Antonio Breast Cancer Symposium. Stay tuned to Cancer.Net for future updates from upcoming breast cancer conferences. Thank you. ASCO: Thank you, Dr. Henry. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

For patients with ER+/HER2- advanced breast cancer, current treatment guidelines recommend the use of endocrine therapy plus a CDK 4/6 inhibitor as a first-line treatment. And while the guidelines recommend sequential endocrine therapy for disease progressions, this progression can lead to ESR1 mutations and resistance to endocrine therapy. Could a novel oral selective estrogen receptor have more efficacy in preventing ESR1 mutations associated with endocrine resistance? That's the exact question the EMERALD trial sought to answer, and what this study found in its subgroup analyses is the focus of this Audio Abstract.

Endocrine therapy is the recommended treatment for ER+/HER2- advanced breast cancer, but progression to advanced disease can lead to ESR1 mutations, which can then lead to endocrine therapy resistance. But could treatment with an oral selective estrogen receptor degrader (SERD) improve outcomes for our patients? Join us as we take a deep dive into the EMERALD trial, which explored that exact question, in this Audio Abstract.

Featuring perspectives from Drs Aditya Bardia, Matthew Goetz, Virginia Kaklamani, Kevin Kalinsky and Hope Rugo, including the following topics: Current Role of Genomic Assays for Hormone Receptor (HR)-Positive Localized Breast Cancer  Introduction (0:00) Case: A premenopausal woman in her early 40s with 9-mm, Grade III, ER/PR-positive, HER2-negative, node-negative infiltrating ductal carcinoma (IDC) – 21-gene Recurrence Score® 22 — Alan B Astrow, MD (3:39) Case: A premenopausal woman in her mid 30s with 3.6-cm, ER/PR-positive, HER2-low (IHC 1+), sentinel node-positive (4/4) multifocal IDC after bilateral mastectomies, adjuvant AC-T and ovarian function suppression (OFS)/aromatase inhibitor, Ki67 50% — Laila Agrawal, MD (9:40) Dr Goetz presentation (19:43) Optimizing the Management of Localized ER-Positive Breast Cancer  Case: A woman in her early 40s with 5.5-cm, ER/PR-positive, HER2-negative, node-positive (20/21) IDC after bilateral mastectomies, bilateral salpingo-oophorectomy, adjuvant AC-T and initiation of letrozole/abemaciclib, Ki-67 3% — Susmitha Apuri, MD (32:22) Case: A woman in her mid 50s with de novo ER-positive, PR-negative, HER2-negative ulcerated breast cancer with pulmonary and extensive spinal metastases — Jennifer L Dallas, MD (40:45)  Dr Kaklamani presentation (45:32) Selection and Sequencing of Therapy for Patients with ER-Positive Metastatic Breast Cancer (mBC)  Case: A woman in her early 50s with ER/PR-positive, HER2-low mBC with a PI3KCA mutation who experiences a dramatic response to rechallenge with fulvestrant and a CDK4/6i (abemaciclib); now with progression and cytopenias — Kapisthalam (KS) Kumar, MD (59:07) Dr Kalinsky presentation (1:09:53) Recent Appreciation of HER2 Low as a Unique Subset of HR-Positive Breast Cancer  Case: A premenopausal woman in her late 30s with ER/PR-positive, HER2-low (IHC 1+) IDC after adjuvant tamoxifen and OFS x 5 years, now with bone and liver metastases — Dr Agrawal (1:19:45) Dr Bardia presentation (1:24:29) Novel Strategies Under Investigation for Patients with HR-Positive mBC  Case: A woman in her early 90s with ER/PR-positive, HER2-low (IHC 1+) mBC and progressive disease on multiple lines of endocrine and chemotherapy receives T-DXd — Dr Astrow (1:38:44) Case: A woman in her mid 40s with ER/PR-positive, HER2-low (IHC 2+) mBC who has received fulvestrant/abemaciclib, now receiving exemestane/everolimus – ESR1 and PIK3CA mutations — Dr Dallas (1:44:15) Dr Rugo presentation (1:49:58) CME information and select publications

Doctors are looking for new treatment options for people diagnosed with metastatic hormone receptor-positive, HER2-negative breast cancer that has grown during treatment with hormonal therapy and a CDK4/6 inhibitor. Dr. Virginia Kaklamani is part of the team investigating elacestrant, an oral medicine, to see if offers more benefits than Faslodex (chemical name: fulvestrant), which is the current standard of care. Listen to the podcast to hear Dr. Kaklamani explain: the type of medicine elacestrant is and how it works why it's important that elacestrant showed benefits for breast cancers with an ESR1 mutation when we might hear if elacestrant is approved by the U.S. Food and Drug Administration (FDA)

Listen to a blog summary of a trending research paper published by Aging (Aging-US), entitled, "ESR1 dysfunction triggers neuroinflammation as a critical upstream causative factor of the Alzheimer's disease process.” _________________________________________________ The United States government currently has a mind-blowing annual budget of $3.5 billion designated for Alzheimer's disease (AD) and dementia research funding. Therapeutics pushed forward thus far have been largely based on the amyloid-beta (Aβ) cascade hypothesis of AD. Surprisingly, despite decades and billions, these interventions have yielded little to no benefits for AD patients. This lack of efficacy has encouraged some researchers to rethink AD pathology and focus on discovering key triggers and mechanisms of neuroinflammation. “There has been a lengthy and ongoing scientific debate around the causative factors of AD, and the relative importance of both senile Aβ plaques and tau tangles has been largely informed by postmortem investigations of the AD brain. For several decades, the amyloid hypothesis has dominated the field, which has brought forth many high-profile therapeutic attempts that have produced side effects but no real benefits [5].” Women compose two-thirds of the United States Alzheimer's population. Is this gender-specific risk a result of living longer or is it due to other causes, perhaps related to hormonal differences or gender-associated differential gene expression? Previous studies have found that estrogen may protect neurons from the damaging effects of amyloid-beta plaques and tau tangles. However, in women, estrogen levels tend to decline with age, which could be one reason why aging women are more susceptible to AD. In a new study, researchers Junying Liu, Shouli Yuan, Xinhui Niu, Robbie Kelleher, and Helen Sheridan from Trinity College Dublin, Peking University and Jilin University examined the potential relationship between the estrogen receptor-α gene (ESR1) and neuroinflammation. Their research paper was published on November 1, 2022, in Aging's Volume 14, Issue 21, and entitled, “ESR1 dysfunction triggers neuroinflammation as a critical upstream causative factor of the Alzheimer's disease process.” “AD is characterized by three major questions: Why is age the primary risk factor? Why are women more sensitive to the onset of this form of dementia? And why are neurons in areas of the brain that are essential for memory selectively targeted?” Full blog - https://aging-us.org/2022/11/is-estrogen-dysregulation-behind-alzheimers-pathology/ DOI - https://doi.org/10.18632/aging.204359 Corresponding authors - Junying Liu - juliu@tcd.ie Video - https://www.youtube.com/watch?v=NPWv39SJOpQ Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204359 Keywords - ESR1, Alzheimer's disease, CEBPB/ATF4, APOE, pyroptosis About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.20.517219v1?rss=1 Authors: Schaefer, J., Chadchan, S., George, A., Roan, N., Bhattacharya, M., Kommagaini, R., Babwah, A. Abstract: Defective endometrial stromal cell decidualization is a major cause of recurrent implantation failure (RIF), a condition with a prevalence of ~15%. To treat RIF, a stronger understanding of the endometrial factors that regulate decidualization is required. Here we studied the role of the kisspeptin receptor (KISS1R) in regulating human endometrial stromal cell (HESC) decidualization. Our data revealed KISS1R inhibits HESC decidualization in vitro in a manner associated with a striking reduction in ESR1 protein levels. To determine whether KISSR inhibition of decidualization results from reduced ESR1 levels we expressed the dominant negative ESR1-46 isoform in decidualizing HESCs. We found that expression of ESR1-46 in decidualizing HESCs ablated the expression of ESR1-66 and ESR1-54 isomers, and blocked decidualization. Interestingly, when ESR1-64 was co-expressed with ESR1-46, ESR1-66 and ESR1-54 expression was restored and decidualization was rescued. Taken together, these results suggest that KISS1R inhibits HESC decidualization by downregulating ESR1 levels. Based on our findings, we suggest that by inhibiting HESC decidualization, KISS1R regulates the depth of embryo invasion of the stroma, a requirement for a successful pregnancy. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.17.516965v1?rss=1 Authors: Calvigioni, D., Fuzik, J., Le Merre, P., Slashcheva, M., Jung, F., Ortiz, C., Lentini, A., Csillag, V., Graziano, M., Nikolakopoulou, I., Weglage, M., Lazaridis, I., Kim, H., Lenzi, L., Park, H., Reinius, B., Carlen, M., Meletis, K. Abstract: Excitatory projections from the lateral hypothalamic area (LHA) to the lateral habenula (LHb) drive aversive responses. We used Patch-seq guided multimodal classification to define the structural and functional heterogeneity of the LHA- LHb pathway. Our classification identified six glutamatergic neuron types with unique electrophysiological properties, molecular profiles, and projection patterns. We found that genetically-defined LHA-LHb neurons signal distinct aspects of emotional or naturalistic behaviors: Esr1+ LHA-LHb neurons induce aversion, whereas Npy+ LHA-LHb neurons control rearing behavior. Repeated optogenetic drive of Esr1+ LHA-LHb neurons induces a behaviorally persistent aversive state, and large-scale recordings showed a region-specific neural representation of the aversive state in the prelimbic region of the prefrontal cortex. We further found that exposure to unpredictable mild shocks induced a sex- specific sensitivity to develop a stress state in female mice, which was associated with a specific shift in the intrinsic properties of bursting-type Esr1+ LHA-LHb neurons. In summary, we describe the diversity of LHA-LHb neuron types, and provide evidence for the role of Esr1+ neurons in aversion and sexually dimorphic stress sensitivity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Go online to PeerView.com/DFJ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Breast cancer is a heterogeneous disease comprising different subtypes, with estrogen receptor positive (ER+) being the most common subtype. Endocrine therapy (ET) is the primary treatment in ER+ breast cancer, which includes different strategies that directly or indirectly modify estrogen production. CDK4 and 6 inhibition as well as PI3K inhibition have improved outcomes in these patients, but most still develop endocrine resistance. ESR1 gene mutations, somatic alterations, microenvironmental factors, and epigenetic changes have all been implicated as underlying mechanisms promoting resistance. Novel ER-targeting agents such as oral selective estrogen receptor degraders (SERDs) are showing therapeutic promise in the face of ET resistance. In addition, other agents are being evaluated in ER+ disease, including selective estrogen receptor modifiers (SERMs), SERM/SERD hybrids, selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimeras (PROTACs), and others.This PeerView educational activity, based on a recent live symposium, highlights and analyzes the latest evidence and advances in the treatment of ER+/HER2- breast cancer, focusing on the expanding evidence base supporting the use of novel ER-targeted agents such as oral SERDs as a new standard of care in pretreated ER+/HER2- breast cancer. Practical guidance is also provided on how to apply the latest evidence to practice, optimize the use of these agents, and individualize treatment plans that take into account key data, patient- and tumor-related factors, and the specific needs and preferences of each patient. Upon completion of this activity, participants should be better able to: Describe the rationale, mechanisms of action, and latest efficacy and safety data of approved and emerging treatment options for patients with ER+/HER2- breast cancer, including novel oral SERDs and other ER-targeting therapies, and their evolving role in clinical practice; Develop individualized treatment plans for patients with previously treated ER+/HER2- breast cancer that take into account the latest treatment options and all the relevant treatment-, tumor-, and patient-related factors; Integrate a team-based, collaborative, coordinated, and patient-centered approach to select appropriate candidates for SERDs and other new therapies for ER+/HER2- breast cancer, provide essential patient education, and ensure optimal delivery of therapy

Go online to PeerView.com/DFJ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Breast cancer is a heterogeneous disease comprising different subtypes, with estrogen receptor positive (ER+) being the most common subtype. Endocrine therapy (ET) is the primary treatment in ER+ breast cancer, which includes different strategies that directly or indirectly modify estrogen production. CDK4 and 6 inhibition as well as PI3K inhibition have improved outcomes in these patients, but most still develop endocrine resistance. ESR1 gene mutations, somatic alterations, microenvironmental factors, and epigenetic changes have all been implicated as underlying mechanisms promoting resistance. Novel ER-targeting agents such as oral selective estrogen receptor degraders (SERDs) are showing therapeutic promise in the face of ET resistance. In addition, other agents are being evaluated in ER+ disease, including selective estrogen receptor modifiers (SERMs), SERM/SERD hybrids, selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimeras (PROTACs), and others.This PeerView educational activity, based on a recent live symposium, highlights and analyzes the latest evidence and advances in the treatment of ER+/HER2- breast cancer, focusing on the expanding evidence base supporting the use of novel ER-targeted agents such as oral SERDs as a new standard of care in pretreated ER+/HER2- breast cancer. Practical guidance is also provided on how to apply the latest evidence to practice, optimize the use of these agents, and individualize treatment plans that take into account key data, patient- and tumor-related factors, and the specific needs and preferences of each patient. Upon completion of this activity, participants should be better able to: Describe the rationale, mechanisms of action, and latest efficacy and safety data of approved and emerging treatment options for patients with ER+/HER2- breast cancer, including novel oral SERDs and other ER-targeting therapies, and their evolving role in clinical practice; Develop individualized treatment plans for patients with previously treated ER+/HER2- breast cancer that take into account the latest treatment options and all the relevant treatment-, tumor-, and patient-related factors; Integrate a team-based, collaborative, coordinated, and patient-centered approach to select appropriate candidates for SERDs and other new therapies for ER+/HER2- breast cancer, provide essential patient education, and ensure optimal delivery of therapy

Go online to PeerView.com/DFJ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Breast cancer is a heterogeneous disease comprising different subtypes, with estrogen receptor positive (ER+) being the most common subtype. Endocrine therapy (ET) is the primary treatment in ER+ breast cancer, which includes different strategies that directly or indirectly modify estrogen production. CDK4 and 6 inhibition as well as PI3K inhibition have improved outcomes in these patients, but most still develop endocrine resistance. ESR1 gene mutations, somatic alterations, microenvironmental factors, and epigenetic changes have all been implicated as underlying mechanisms promoting resistance. Novel ER-targeting agents such as oral selective estrogen receptor degraders (SERDs) are showing therapeutic promise in the face of ET resistance. In addition, other agents are being evaluated in ER+ disease, including selective estrogen receptor modifiers (SERMs), SERM/SERD hybrids, selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimeras (PROTACs), and others.This PeerView educational activity, based on a recent live symposium, highlights and analyzes the latest evidence and advances in the treatment of ER+/HER2- breast cancer, focusing on the expanding evidence base supporting the use of novel ER-targeted agents such as oral SERDs as a new standard of care in pretreated ER+/HER2- breast cancer. Practical guidance is also provided on how to apply the latest evidence to practice, optimize the use of these agents, and individualize treatment plans that take into account key data, patient- and tumor-related factors, and the specific needs and preferences of each patient. Upon completion of this activity, participants should be better able to: Describe the rationale, mechanisms of action, and latest efficacy and safety data of approved and emerging treatment options for patients with ER+/HER2- breast cancer, including novel oral SERDs and other ER-targeting therapies, and their evolving role in clinical practice; Develop individualized treatment plans for patients with previously treated ER+/HER2- breast cancer that take into account the latest treatment options and all the relevant treatment-, tumor-, and patient-related factors; Integrate a team-based, collaborative, coordinated, and patient-centered approach to select appropriate candidates for SERDs and other new therapies for ER+/HER2- breast cancer, provide essential patient education, and ensure optimal delivery of therapy

Go online to PeerView.com/DFJ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Breast cancer is a heterogeneous disease comprising different subtypes, with estrogen receptor positive (ER+) being the most common subtype. Endocrine therapy (ET) is the primary treatment in ER+ breast cancer, which includes different strategies that directly or indirectly modify estrogen production. CDK4 and 6 inhibition as well as PI3K inhibition have improved outcomes in these patients, but most still develop endocrine resistance. ESR1 gene mutations, somatic alterations, microenvironmental factors, and epigenetic changes have all been implicated as underlying mechanisms promoting resistance. Novel ER-targeting agents such as oral selective estrogen receptor degraders (SERDs) are showing therapeutic promise in the face of ET resistance. In addition, other agents are being evaluated in ER+ disease, including selective estrogen receptor modifiers (SERMs), SERM/SERD hybrids, selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimeras (PROTACs), and others.This PeerView educational activity, based on a recent live symposium, highlights and analyzes the latest evidence and advances in the treatment of ER+/HER2- breast cancer, focusing on the expanding evidence base supporting the use of novel ER-targeted agents such as oral SERDs as a new standard of care in pretreated ER+/HER2- breast cancer. Practical guidance is also provided on how to apply the latest evidence to practice, optimize the use of these agents, and individualize treatment plans that take into account key data, patient- and tumor-related factors, and the specific needs and preferences of each patient. Upon completion of this activity, participants should be better able to: Describe the rationale, mechanisms of action, and latest efficacy and safety data of approved and emerging treatment options for patients with ER+/HER2- breast cancer, including novel oral SERDs and other ER-targeting therapies, and their evolving role in clinical practice; Develop individualized treatment plans for patients with previously treated ER+/HER2- breast cancer that take into account the latest treatment options and all the relevant treatment-, tumor-, and patient-related factors; Integrate a team-based, collaborative, coordinated, and patient-centered approach to select appropriate candidates for SERDs and other new therapies for ER+/HER2- breast cancer, provide essential patient education, and ensure optimal delivery of therapy

Go online to PeerView.com/DFJ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Breast cancer is a heterogeneous disease comprising different subtypes, with estrogen receptor positive (ER+) being the most common subtype. Endocrine therapy (ET) is the primary treatment in ER+ breast cancer, which includes different strategies that directly or indirectly modify estrogen production. CDK4 and 6 inhibition as well as PI3K inhibition have improved outcomes in these patients, but most still develop endocrine resistance. ESR1 gene mutations, somatic alterations, microenvironmental factors, and epigenetic changes have all been implicated as underlying mechanisms promoting resistance. Novel ER-targeting agents such as oral selective estrogen receptor degraders (SERDs) are showing therapeutic promise in the face of ET resistance. In addition, other agents are being evaluated in ER+ disease, including selective estrogen receptor modifiers (SERMs), SERM/SERD hybrids, selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimeras (PROTACs), and others.This PeerView educational activity, based on a recent live symposium, highlights and analyzes the latest evidence and advances in the treatment of ER+/HER2- breast cancer, focusing on the expanding evidence base supporting the use of novel ER-targeted agents such as oral SERDs as a new standard of care in pretreated ER+/HER2- breast cancer. Practical guidance is also provided on how to apply the latest evidence to practice, optimize the use of these agents, and individualize treatment plans that take into account key data, patient- and tumor-related factors, and the specific needs and preferences of each patient. Upon completion of this activity, participants should be better able to: Describe the rationale, mechanisms of action, and latest efficacy and safety data of approved and emerging treatment options for patients with ER+/HER2- breast cancer, including novel oral SERDs and other ER-targeting therapies, and their evolving role in clinical practice; Develop individualized treatment plans for patients with previously treated ER+/HER2- breast cancer that take into account the latest treatment options and all the relevant treatment-, tumor-, and patient-related factors; Integrate a team-based, collaborative, coordinated, and patient-centered approach to select appropriate candidates for SERDs and other new therapies for ER+/HER2- breast cancer, provide essential patient education, and ensure optimal delivery of therapy

Go online to PeerView.com/DFJ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Breast cancer is a heterogeneous disease comprising different subtypes, with estrogen receptor positive (ER+) being the most common subtype. Endocrine therapy (ET) is the primary treatment in ER+ breast cancer, which includes different strategies that directly or indirectly modify estrogen production. CDK4 and 6 inhibition as well as PI3K inhibition have improved outcomes in these patients, but most still develop endocrine resistance. ESR1 gene mutations, somatic alterations, microenvironmental factors, and epigenetic changes have all been implicated as underlying mechanisms promoting resistance. Novel ER-targeting agents such as oral selective estrogen receptor degraders (SERDs) are showing therapeutic promise in the face of ET resistance. In addition, other agents are being evaluated in ER+ disease, including selective estrogen receptor modifiers (SERMs), SERM/SERD hybrids, selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimeras (PROTACs), and others.This PeerView educational activity, based on a recent live symposium, highlights and analyzes the latest evidence and advances in the treatment of ER+/HER2- breast cancer, focusing on the expanding evidence base supporting the use of novel ER-targeted agents such as oral SERDs as a new standard of care in pretreated ER+/HER2- breast cancer. Practical guidance is also provided on how to apply the latest evidence to practice, optimize the use of these agents, and individualize treatment plans that take into account key data, patient- and tumor-related factors, and the specific needs and preferences of each patient. Upon completion of this activity, participants should be better able to: Describe the rationale, mechanisms of action, and latest efficacy and safety data of approved and emerging treatment options for patients with ER+/HER2- breast cancer, including novel oral SERDs and other ER-targeting therapies, and their evolving role in clinical practice; Develop individualized treatment plans for patients with previously treated ER+/HER2- breast cancer that take into account the latest treatment options and all the relevant treatment-, tumor-, and patient-related factors; Integrate a team-based, collaborative, coordinated, and patient-centered approach to select appropriate candidates for SERDs and other new therapies for ER+/HER2- breast cancer, provide essential patient education, and ensure optimal delivery of therapy

A new FGFR inhibitor, futibatinib, is approved. Is ESR1 mutation monitoring the next thing in HR+ metastatic breast cancer? The PADA-1 trial offers insight. What the heck is GPRC5D (rhymes with CAR-T)? PADA-1: https://doi.org/10.1016/S1470-2045(22)00555-1 GPRC5D CAR-T in Myeloma: https://www.nejm.org/doi/full/10.1056/NEJMoa2209900

An interview with Dr. Lynn Henry from the University of Michigan in Ann Arbor, MI, lead author on "Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update." Dr. Henry reviews new biomarkers for the purposes of making treatment decisions for triple-negative breast cancer, and hormone receptor-positive, HER2-negative breast cancer, as well as tumor agnostic tumor biomarkers. Specific biomarkers addressed in this conversation include PIK3CA, ESR1, BRCA 1/2, PALB2, HRD, PD-L1, dMMR/MSI-H, TMB, NTRK, ctDNA, and CTCs. Read the full guideline at www.asco.org/breast-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lynn Henry from the University of Michigan in Ann Arbor, Michigan, lead author on 'Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update'. Thank you for being here, Dr. Henry. Dr. Lynn Henry: Thank you very much for inviting me to participate. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Henry, do you have any relevant disclosures that are related to this guideline topic? Dr. Lynn Henry: No, I do not. Brittany Harvey: Great! Thank you. Then let's talk about the scope of this guideline. So, what prompted this update to the guideline on the use of biomarkers to guide decisions on systemic therapy for patients with metastatic breast cancer, which was last updated in 2015? And what is the scope of this guideline update? Dr. Lynn Henry: Yes, so a lot has happened in the past six or seven years that influence how we treat metastatic breast cancer. And there are many new drugs that have been approved by the FDA during that time. When we reviewed the prior guideline and the new treatment landscape, we realized that while much of what was included in the old guideline was still relevant, there were quite a number of new biomarkers related to new drugs that needed to be included. The newly recommended biomarkers are primarily applicable to making decisions about treatment of estrogen receptor, progesterone receptor, and HER2-negative breast cancer, also called triple-negative breast cancer, as well as for treatment of hormone receptor-positive HER2-negative breast cancer. And finally, there are now some tumor biomarkers that can be tested for that are tumor agnostic, and these were included as well. Brittany Harvey: Great! So, then let's discuss the updated guideline recommendations based off these new biomarkers for our listeners. The guideline reviews testing for several different biomarkers. So, I would like to review each of the biomarkers that the panel assessed. Let's start with what is the role of PIK3CA mutation testing? Dr. Lynn Henry: Yeah! So, PIK3CA activating mutations are commonly found in tumors that are hormone receptor-positive and HER2-negative. Based on the results of the SOLAR-1 trial, patients whose tumors have an activating PIK3CA mutation had improved progression-free survival when treated with the PI3 kinase inhibitor alpelisib plus fulvestrant compared to fulvestrant alone. This improvement was not seen in patients whose cancers didn't have a mutation. So, therefore, this provided the evidence for the clinical utility of evaluating tumors for the somatic PIK3CA mutations. Testing of either a tumor specimen or plasma to look for PIK3CA mutations can be performed. However, it's important that if the plasma is tested, and no PIK3CA mutations are identified in the circulating tumor DNA, then our tumor specimen should really be tested if possible, because of the possibility of a false negative finding in the plasma. Also, since these mutations can be acquired over time, a more recent specimen should be tested if possible, as opposed to testing the primary tumor. Finally, in the SOLAR-1 trial, a patient's tumor had to have one of the 11 pre-specified PIK3CA mutations in exon 7, 9, or 20. And therefore, when mutations are identified using next-generation sequencing, it is important to confirm that the identified mutation is one of those 11 activating mutations and not a different one that may not convey benefit from treatment with a PI3 kinase inhibitor. Brittany Harvey: Great! I appreciate you're reviewing that recommendation, as well as the clinical utility of it and the evidence behind it. So, then following those recommendations, what is the role of testing for ESR1 mutations? Dr. Lynn Henry: At this time, there are insufficient data to support routine testing of metastatic hormone receptor-positive HER2-negative tumors for ESR1 mutations. However, the panel did note that there's a retrospective analysis of two different phases three trials that demonstrated that fulvestrant improved progression-free survival compared to the aromatase inhibitor exemestane in patients who had previously progressed on a non-steroidal AI and whose tumors had an ESR1 mutation. Importantly, there are ongoing clinical trials addressing this issue, including the PADA-1 trial, which is evaluating the effect of the switch of fulvestrant from aromatase inhibitor therapy, versus remaining on that therapy when ESR1 mutations are detected in the blood. However, although preliminary findings were presented at a recent large breast cancer meeting, and were suggestive of a possible progression-free survival benefit from switching therapy, data have not yet been published, and therefore they were not included in this guideline. Brittany Harvey: Great! So, we'll look forward to those updated data to potentially review that recommendation in the future. So, following those recommendations, what is the role of testing for germline BRCA 1 or 2 and PALB2 pathogenic mutations? Dr. Lynn Henry: So, the answer for germline BRCA1 and BRCA2 mutations is relatively straightforward. Patients with metastatic HER2-negative breast cancer can be either hormone receptor-positive or negative, and who are candidates for treatment with a PARP inhibitor should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine whether they should receive treatment with a PARP inhibitor. This recommendation is based on the results of two large randomized clinical trials comparing PARP inhibitor therapy to physician's choice chemotherapy, although notably, the chemotherapy options did not include taxanes, anthracyclines, or platinums. In contrast, there remains insufficient evidence to support a recommendation either for or against testing for germline PALB2 pathogenic variant for the purpose of determining eligibility for treatment with a PARP inhibitor. The panel did note, however, that there are small single-arm studies that show that there is high response rate to PARP inhibitors in patients with metastatic breast cancer and coding DNA repair defects, such as either germline PALB2 pathogenic variants or somatic BRCA1 or 2 mutations. It was also noted that it is likely that patients who harbored mutations in these genes will actually be identified through routine testing with panel testing for germline variants. Brittany Harvey: Okay, understood. So, then following those recommendations, what is the role of testing tumors for homologous recombination deficiency? Dr. Lynn Henry: So, although there are emerging data from other solid tumors to support the use of homologous recombination deficiency, or HRD testing to guide therapy, current data do not support the assessment of HRD in the management of metastatic breast cancer. Therefore, we did not recommend routine testing of tumors for HRD at this time. Brittany Harvey: It's important to note where we both have evidence and where we don't have evidence. So, then what is the role of testing for expression of PD-L1 in metastatic breast cancer? Dr. Lynn Henry: So, the panel recommends that patients who are candidates for treatment with immunotherapy, with either a PD1 or PD-L1 inhibitor, should undergo testing for expression of PD-L1 in the tumor and immune cells with an FDA-approved test. At present in the United States, pembrolizumab is the only approved immunotherapy for the treatment of metastatic breast cancer, and it is given in combination with chemotherapy. The FDA-approved test for this drug is the 22C3 assay which evaluates PD-L1 staining in the tumor and surrounding stroma to calculate a combined positive score or CPS, with positive considered to be a score of 10 or greater. Of note, in other countries, there are different anti PD1 and PD-L1 antibodies that are approved for treatment, and each has been approved with its own companion diagnostic. So, it is important to make sure that you're using the right biomarker test, depending on which drug you are planning to use. Brittany Harvey: Great! I appreciate you reviewing the test in addition to the role of the biomarker. So, then, following those recommendations, what is the role of testing for deficient mismatch repair microsatellite instability-high? Dr. Lynn Henry: Similar to PD-L1 testing, it is recommended that patients with metastatic breast cancer who are candidates for a treatment regimen that includes an immune checkpoint inhibitor should undergo testing for deficient mismatch repair or microsatellite instability-high to determine eligibility for treatment with one of the drugs that is currently FDA approved, either dostarlimab or pembrolizumab. In contrast to the PD-L1 data, however, there are no randomized studies that have been conducted specifically in patients with breast cancer addressing this question. The testing recommendation was therefore included in these guidelines because of the tumor agnostic FDA approval of these drugs. In terms of which biomarker methodology to use, it was noted that, while the original studies assessed the deficient mismatch repair and MSI high using immunochemistry, and PCR respectively. The FDA has subsequently approved the next-generation sequencing platform to use in selecting candidates for these treatments. And so, therefore, there are a number of different tests that can be used. Brittany Harvey: Thank you for reviewing those recommendations as well. So, then following, what is the role of testing for tumor mutational burden? Dr. Henry Lynn: So, tumor mutational burden describes the quantity of somatic mutations in the tumor. Similar to the biomarkers we were previously discussing, there are minimal data specifically in metastatic breast cancer to support the assessment of tumor mutational burden for making treatment decisions. However, the testing recommendation was again included in the guidelines because of the tumor agnostic FDA approval of the drug pembrolizumab in the setting of high TMB. And also there is one single arm phase two trial that looked at this specifically. Importantly, the panel noted that there are a variety of factors that influence assessment of TMB. These include sample type, pre-analytical factors so how the sample was handled, the size of the panel and mutations that are tested, depths of the sequencing, type of the mutations that are included on the panel, and cut point variables. So, in particular, assessment of TMB in cell-free DNA assays such as circulating tumor DNA is an area of evolving evidence. There are therefore very important caveats to be aware of when selecting a TMB assay and assessing the results, many of which are outlined in the guideline manuscript itself, and different assays can yield different results for the same tissue specimen. It is therefore very important to use the approved companion assay and the approved cut point when making decisions regarding a specific treatment. Brittany Harvey: Absolutely. I appreciate your reviewing those details. So, then what is the role of testing for neurotrophic tyrosine receptor kinase? Dr. Lynn Henry: So, I'm going to abbreviate that to NTRK. So, NTRK fusions are rare in metastatic breast cancer. One study said 0.39% of all breast cancers have NTRK fusions. So, as with the above biomarkers, the NTRK testing recommendation is based on the results of phase 1 and phase 2 studies that were identified by the panel evaluating the efficacy and safety of these inhibitors for the treatment of advanced solid tumors with NTRK gene fusions, noting that there are only minimal data available that are specific to metastatic breast cancer. Brittany Harvey: Understood. Some of these are very rare in metastatic breast cancer. So, then, following that recommendation, what is the role of using circulating tumor DNA? Dr. Lynn Henry: So, for circulating tumor DNA, although the ctDNA technology holds promise in metastatic disease, for its ability to potentially identify tumor-specific mutations that are shed into the blood and that may be targetable, to date, neither the measurement of changes in ctDNA as a marker of treatment responsiveness nor identification of specific mutations in the blood to direct therapy has actually been prospectively shown to improve patient outcomes compared to standard imaging-based detection of tumor progression. Therefore, at present, the guideline does not recommend routine assessment of ctDNA for monitoring response to therapy among patients with metastatic breast cancer, although many studies are underway evaluating this question. Brittany Harvey: Understood. Then the last biomarker that the panel assessed in this guideline update, what is the role of using circulating tumor cells? Dr. Lynn Henry: Similar to circulating tumor DNA, there are insufficient data to recommend routine use of circulating tumor cells to monitor response to therapy among patients with metastatic breast cancer. To date, studies that have examined the clinical utility of this marker to determine the optimal time for treatment change have not led to improvements in outcomes in metastatic breast cancer. Brittany Harvey: Great! Well, thank you for reviewing all of these recommendations. The panel certainly took on a lot of biomarkers and performed a critical review of all the evidence to make recommendations in this setting. So, in your view, Dr. Henry, what is the importance of this guideline update and what should clinicians know as they implement these updated recommendations? Dr. Lynn Henry: Yeah, that's an excellent question. So, this guideline addresses the key questions that we face, as we're making decisions about how best to treat patients with metastatic breast cancer. Importantly, the guideline highlights the current state of the science, with a focus on the available published data from randomized clinical trials. It also discusses the limitations of our current knowledge, as well as key considerations for different biomarkers. Of course, we recognize that there are new data emerging on a regular basis. And the panel therefore also highlighted where data are anticipated but not yet available, as well as key questions which we hope will be able to be addressed in the more distant future. Brittany Harvey: And then finally, how will these guideline recommendations affect patients with metastatic breast cancer? Dr. Lynn Henry: Yeah, so really, that is the bottom line, isn't it? So, ideally, this guideline will enable the dissemination of best practices in terms of biomarker selection and analysis to guide clinicians as they are making treatment decisions in conjunction with patients. Treatment of metastatic breast cancer has become more complex, with regimen selection affected by both inherited germline genetics and somatic changes in the cancer that can evolve over time. The assessment of relevant biomarkers should allow patients to receive the optimal therapies that are most likely to be effective based on the individual characteristics of their cancers. Brittany Harvey: Well, I want to thank you so much for reviewing this guideline with me today, and all of the recommendations and our gaps in evidence, for our listeners. Thank you for your work on this guideline update and thank you for your time today, Dr. Henry. Dr. Lynn Henry: Thank you so much! Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

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.

An interview with Dr. Harold Burstein from Dana Farber Cancer Institute in Boston, MA, chair on “Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Update.” This guideline updates recommendations on use of alpelisib, and the role of biomarkers and CDK4/6 inhibitors. Read the guideline at asco.org/breast-cancer-guidelines. Suggest a topic for guideline development at surveymonkey.com/r/ascoguidelinesurvey.   TRANSCRIPT [MUSIC PLAYING] SPEAKER: 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] BRITTANY HARVEY: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at podcasts.asco.org. My name is Brittany Harvey. And today I'm interviewing Dr. Harold Burstein from Dana-Farber Cancer Institute in Boston, Massachusetts, chair and lead author on endocrine treatment and targeted therapy for hormone receptor-positive HER2 negative metastatic breast cancer ASCO guideline update. Thank you for being here, Dr. Burstein. HAROLD BURSTEIN: Glad to be with you. BRITTANY HARVEY: First I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Burstein, do you have any relevant disclosures that are related to this guideline topic? HAROLD BURSTEIN: I do not. BRITTANY HARVEY: Great, thank you. Then let's delve into the content of this guideline. So first, what prompted the update of this guideline and what is the focus of this update? HAROLD BURSTEIN: So this guideline focuses on metastatic breast cancer, and in particular, estrogen receptor-positive HER2 negative metastatic breast cancer. Worldwide in 2021, actually breast cancer became the most commonly diagnosed cancer in the world, excepting superficial skin cancers. And so it is a true global health problem. And the most common type of breast cancer is estrogen receptor-positive HER2 negative breast cancer, which accounts for 70% to 75% of all cancer diagnoses in the breast cancer space, and as a consequence, also accounts for 70% to 75% of the cases of metastatic breast cancer. So it's really important from a public health point of view and a quality point of view, both in the United States and globally, to have current up-to-date guidance for the management of this most common form of breast cancer that we have. In addition, there have been several innovations in the way of targeted therapies that are coming into place for advanced ER-positive breast cancer. And increasingly, we are using genomic tests to help us understand how best to treat patients with advanced ER-positive breast cancer. So those two initiatives-- the interest in genomic testing and the use of targeted therapies-- all warranted and justified an update to the guidelines. BRITTANY HARVEY: Great. Thank you for reviewing that landscape of where we are in clinical practice for this guideline. So then I'd like to review the key recommendations that this guideline addresses. So first, should alpelisib be given to post-menopausal women and to male patients with hormone receptor-positive HER2 negative PIK3CA-mutated advanced or metastatic breast cancer? HAROLD BURSTEIN: So alpelisib, as you indicated, is a new drug. It is now FDA approved. And it is a protein kinase targeted inhibitor. And it goes after the PIK3CA-mutated tumors. And in a seminal study called the SOLAR-1 study, there was randomization to endocrine therapy alone with fulvestrant or endocrine therapy plus alpelisib for ER-positive HER2 negative breast cancer. And that study showed two important things. First was that in women whose tumors did not have a PIK3CA mutation, there was no benefit for alpelisib. However, in the women whose tumors did have a PIK3CA mutation, there was an improvement in progression-free survival with the use of this targeted drug alpelisib. So based on that, the guidelines now incorporate alpelisib into the treatment algorithm. And as a corollary, it means that all patients who have ER-positive metastatic breast cancer now need testing of the tumor to see if they have a PIK3CA mutation because that's going to guide therapy. In the guideline, we now suggest that this be a standard thing to do-- to test all tumors for PIK3CA mutation. And in those cases where there is a PIK3CA mutation to add alpelisib-based therapy with endocrine treatment typically in second or subsequent lines of therapy. BRITTANY HARVEY: Great. And thank you for reviewing the evidence base behind that recommendation. So next, what is recommended regarding the role of biomarkers in treatment selection for patients with hormone receptor-positive metastatic breast cancer? HAROLD BURSTEIN: So there are two different ways of thinking about biomarkers. One is traditional biomarkers, such as estrogen receptor, progesterone receptor, and HER2. Those are familiar to all clinicians who have been dealing with breast cancer. The second is to think about some of the newer technologies, including tumor genomic sequencing and the kind of mutational analysis we just discussed with the PIK3CA mutations. So in the breast cancer space, there are some important innovations in that latter genomic or genetic testing. One, of course, is the PIK3CA mutation testing that we now recommend for all cancers. That can be done on the primary tumor, or it can be done on cell-free or circulating tumor DNA samples from the bloodstream in most cases. The other kind of testing we do relates to ESR1 mutations. And one of the reasons that tumors become resistant to aromatase inhibitors is that they acquire mutations in the estrogen receptor itself, so-called ESR1 activating mutations. Those mutations mean that the estrogen receptor is on even in the absence of estrogen. And that accounts for probably 50% to 60% of the resistance that we see in treatment with aromatase inhibitors. So the panel really struggled with this because, on the one hand, this is not a uniformly accepted way to decide how to treat patients. On the other hand, there are a lot of data that women whose tumors have ESR1 mutations get negligible benefit from ongoing use of aromatase inhibitor therapy. So this recommendation fell into sort of our practice suggestions, which is that if you have the information on ESR1, then it probably is the case that there's very little, if any, role for ongoing aromatase inhibitor treatment. This fell short of the highest level in endorsement because, first, it's not a uniformly tested assay. And secondly, it's important to remember that these tumors can still benefit from ongoing anti-estrogen therapy with different anti-estrogens like fulvestrant. And finally, and perhaps this is the most practical issue, the way you become ESR1 mutated is usually through exposure to aromatase inhibitors. And if you've already had a patient with extensive exposure to AIs, and they need ongoing anti-estrogen therapy in the metastatic setting, it usually means you're switching treatment anyway. So that's an example of where we're sort of on the frontier of thinking about dynamic changes in the tumor as a way to select treatment for ER-positive metastatic disease. BRITTANY HARVEY: Great. That's helpful for a clinical interpretation of the recommendations and incorporating these into practice. So the final question that was addressed in this focused update was, what is the role of CDK4/6 inhibitors in the treatment of patients with hormone receptor-positive metastatic breast cancer? HAROLD BURSTEIN: So CDK4/6 inhibitors are another tyrosine kinase inhibitor class of drugs that has really emerged as an important part of first-line therapy for ER-positive metastatic disease. There have been multiple randomized trials looking at either first-line therapy with an aromatase inhibitor with or without a CDKI4/6 inhibitor, or second-line treatment typically with fulvestrant with or without a CDKI4/6 inhibitor in the metastatic setting. And the panel was able to update the guidance here based on the maturation of multiple randomized trials, as well as extensive subset analyses that have been performed by investigators associated with the individual pharmaceutical-led studies and by the FDA itself. So here are some important takeaways. The first is that in long-term follow-up, these drugs as a class are improving overall survival for women with ER-positive HER2 negative metastatic breast cancer. And for that reason, they are a very important part of the standard armamentarium for ER-positive disease. It's important to say that they also delay the onset of need for chemotherapy, and in general, are associated with a very well preserved quality of life. So this is a big win for patients with ER-positive metastatic breast cancer. We typically recommend them in the first-line setting. So if a patient has de novo metastatic disease, then they should get an endocrine therapy such as an aromatase inhibitor with a CDK4/6 inhibitor. If they've previously had adjuvant aromatase inhibitor treatment or recur while on adjuvant endocrine therapy, we often move to fulvestrant plus a CDKI4/6 inhibitor. Both settings have shown substantial benefit for this class of drugs. It's important that clinicians understand the side effects of these drugs. Neutropenia and diarrhea are common side effects associated with the various drugs. And because of the prevalence of ER-positive metastatic disease, it's really important for clinicians and all those who care for advanced breast cancer patients to know how to manage those side effects carefully. The panel discussed controversial issues, I suppose you might say, in the management. What about patients who have truly minimal metastatic disease? There aren't a lot of data on how best to think about those patients. And we all can imagine on a case-by-case basis an individual who might not need a CDK4/6 inhibitor at a given moment in time. But what was impressive when we pulled all the data was that in subset analyses, it's really hard to find a group of patients that does not benefit from the incorporation of these drugs. So that included premenopausal women who also get concurrent ovarian suppression and then endocrine therapy plus the CDK4/6 inhibitor. It included women with bone-only metastatic disease. It included women whose tumors were ER-positive but PR negative, or had other variations in ER expression. It included patients who had less rather than more metastatic cancer, including visceral disease. So in the literature, one is hard-pressed to see a subset that does not benefit meaningfully from this class of drugs. So we really wanted to reiterate in the algorithms just how important these are. They should be the standard first-line treatment for metastatic disease either paired with an AI or with fulvestrant. And so one of the other nice things that the update gave us was the opportunity to put in some fresh sort of algorithm flow sheets. I would very much encourage people to look at that. They make fantastic PowerPoint or downloadable Twitter documents if you are so inclined. But it's very clear the way the treatment should flow, which is the initial therapy is endocrine treatment plus a CDK4/6 inhibitor. While the patients are getting that, we typically test for PIK3CA mutations. In second line, if it's a PIK3CA mutated, you have the option of using alpelisib. You also might consider an older drug for PIK3CA wild type tumors called everolimus. We reiterated that recommendation in the guideline. Finally, one more thing to touch on that is emerging in the guidelines we generated and in the parallel guideline process for the ASCO guidance on chemotherapy-resistant or refractory breast cancer is the importance of genetic testing all patients who have metastatic breast cancer to look for the possibility of a BRCA1 or BRCA2 deleterious mutation, because there now is FDA approval for PARP inhibitors in the setting of metastatic disease. And one of the interesting things is that as we test more and more, we're seeing that not all the patients who are found to have a BRCA1 or 2 mutation meet the classic criteria for genetic testing-- strong family history, or say, triple-negative breast cancer. So it's really important to test, because that class of drugs, the PARP inhibitors, can be immensely helpful in women with ER-positive metastatic disease when they harbor a BRCA1 or 2 mutation. One of the things the guideline panel wrestled with and ended up putting into the sort of clinical discussion, as opposed to the strong guidance, was the 1% of patients who have PALB2 mutations. So PALB2 mutation, another hereditary predisposing factor for breast cancer. Most tumors that arise in PALB2 mutation carriers are in fact estrogen receptor positive. And a very small study, now published in the JCO, has suggested that those patients have a very high likelihood of response to PARP inhibitors. Because there were only like 15 patients in that cohort, we didn't feel that this warranted clear endorsement in the guidelines. But at the same time, everyone on the panel acknowledges that this is an active drug in that rare subset of tumors with PALB2 mutations in addition to the BRCA1 or 2 mutations. So the takeaway here is that genetic testing should be standard for all patients with advanced metastatic breast cancer to see if the patient is a candidate for a PARP inhibitor-based therapy. BRITTANY HARVEY: Definitely. Well, thank you for reviewing all of those updated recommendations and highlighting some of the ones that were still relevant to this guideline. HAROLD BURSTEIN: Work in progress. BRITTANY HARVEY: Yeah, definitely. And then finally, what is the importance of this guideline update? And how will it impact both clinical practice and what does it mean for patients? HAROLD BURSTEIN: Well, I think guidelines like this have multiple purposes. The first is to sort of describe the state of the art. And while breast cancer is a very common disease, and most clinicians who take care of a lot of cancer patients will see a lot of advanced breast cancer, I think it's still helpful to articulate the rationale for these treatment recommendations. And one of the great things about the ASCO guideline process is the thoroughness of the literature review, the thoroughness of the search to make sure we're including all important publications, and the thoughtfulness that the panel, which includes experts, patient advocates, quality of life expertise, all those things bring to bear on really thinking through what makes sense and what does not for our patients based on the best science available. So I think it is an important activity to really sort of benchmark where we're at. The second thing we've tried to do in the guideline is to introduce areas of nuanced discussion, because not every patient is the same. And I think for those who are interested and take the time to read the guideline, there really is a very nice discussion about how our panel thought about when best to use this approach and when to use a different approach. Third, there's extensive discussion of the side effects and the appropriate management of the side effects. These are drugs that do carry risks. And while by oncology standards, many of them are, quote, "well tolerated," unquote, there's no doubt that there are side effects to these drugs. And it's important for clinical teams to know how to manage them. Finally, I think by putting forward all the evidence, you make clear to investigators, to drug companies, to patients and advocates, and others who are involved in the review of new drugs what the benchmarks are and what the criteria should be for designing clinical trials and for approving new drugs. And I think we've done a nice job of framing that discussion quite handsomely in this guideline and to all of the ASCO guidelines. BRITTANY HARVEY: Great. Well, thank you so much for your work on this guideline update and for taking the time to speak with me today, Dr. Burstein. HAROLD BURSTEIN: Happy to join you and thanks very much. BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast cancer guidelines. Additionally, our annual survey for guideline topics is open for submissions. Suggest a topic for guideline development at SurveyMonkey.com /r/ascoguidelinesurvey. The link is also available in the episode notes of this podcast. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. [MUSIC PLAYING]

Proceedings from the first in a 3-part webinar series. Featuring perspectives from Drs Andrew McKenzie, Bryan P Schneider and Milan Radovich, including the following topics: Part 1: Case Discussions Introduction (00:00) Case: A man in his mid-70s with prostate cancer (AKT1 E17k mutation) — Milan Radovich, PhD and Bryan P Schneider, MD (5:39) Case: A frail woman in her early 80s with endometrial cancer (AKT mutation) — Sulfi Ibrahim, MD (7:45) Case: A man in his late 50s with salivary gland head and neck squamous cell carcinoma (NTRK3-ETV6 fusion) — Andrew McKenzie, PhD (14:53) Case: A man in his early 80s with bladder cancer (tumor mutational burden 67 mut/Mb) — Drs Radovich and Schneider (17:15) Case: A man in his late 60s with muscle-invasive bladder cancer (PIK3CA mutation, RET amplification) — Dr Ibrahim (21:57) Case: A man in his early 60s with cholangiocarcinoma (FGFR2 rearrangement) — Dr McKenzie (25:35) Part 2: FDA-Approved and Guideline-Endorsed Platforms for Genomic Testing Advantages and limitations of available assays (29:33) Part 3: Case Discussions Case: A woman in her mid-60s with glioblastoma (FGFR3-TACC3 fusion) — Drs Radovich and Schneider (39:21) Case: A man in his early 80s with cancer of unknown primary (TMPRSS2-ERG fusion) — Dr Ibrahim (41:43) Case: A woman in her mid-60s with metastatic breast cancer (PIK3CA, ESR1 mutations) — Dr McKenzie (48:03) Case: A woman in her mid-60s with pancreatic cancer (KRAS G12C mutation) — Drs Radovich and Schneider (52:52) Case: A woman in her mid-60s with metastatic adenocarcinoma of the lung (KRAS G12C mutation) — Dr McKenzie (54:45) CME information and select publications

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.21.214619v1?rss=1 Authors: Stagkourakis, S., Spigolon, G., Liu, G., Anderson, D. J. Abstract: All animals can perform certain survival behaviors without prior experience, suggesting a "hard wiring" of underlying neural circuits. Experience, however, can alter the expression of innate behaviors. Where in the brain and how such plasticity occurs remains largely unknown. Previous studies have established the phenomenon of "aggression training," in which the repeated experience of winning successive aggressive encounters across multiple days leads to increased aggressiveness. Here we show that this procedure also leads to long-term potentiation (LTP) at an excitatory synapse, derived from the Anterior Hippocampus/Posterior Medial amygdala (AHiPM), onto estrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). We demonstrate further that the optogenetic induction of such LTP in vivo facilitates, while optogenetic long-term depression (LTD) diminishes, the behavioral effect of aggression training, implying a causal role for potentiation of the AHiPM to VMHvlEsr1 projection in mediating the effect of this training. Interestingly, ~25% of inbred C57BL/6 mice fail to respond to aggression training. We show that these individual differences are correlated both with lower levels of testosterone, relative to mice that respond to such training, and with a failure to exhibit LTP in vivo after aggression training. Administration of exogenous testosterone to such non-aggressive mice restores both behavioral and physiological plasticity in vivo. Together, these findings reveal that LTP at a hypothalamic circuit node mediates a form of experience-dependent plasticity in an innate social behavior, and a potential hormone-dependent basis for individual differences in such plasticity among genetically identical mice. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.26.172965v1?rss=1 Authors: Lopez Rodriguez, D., Aylwin, C. F., Delli, V., Sevrin, E., Campanile, M., Martin, M., Franssen, D., Gerard, A., Blacher, S., Tirelli, E., Noel, A., Lomniczi, A., Parent, A.-S. Abstract: Female reproductive development and maternal behavior are two intertwined phenotypes centrally controlled by the hypothalamus. Endocrine disrupting chemicals (EDC) can alter these processes especially when animals are exposed during development. We propose the concept that developmental exposure to a low environmentally relevant dose of EDC mixture induces a transgenerational alteration of female rat pubertal timing and ovarian physiology throughout epigenetic reprograming of hypothalamic Kiss1, Esr1 and Oxt1 loci. Such exposure also caused a multigenerational reduction of maternal behavior induced by the loss in hypothalamic dopaminergic signaling. Our results identify the hypothalamic Polycomb Group of epigenetic repressors as actors of this mechanism of transgenerational reproductive disruption. Using a cross-fostering approach, we identified that while the reduction in maternal phenotype was normalized in EDC exposed pups raised by unexposed dams, no reversal of the pubertal phenotype was achieved, suggesting a germline transmission of the reproductive phenotype. Copy rights belong to original authors. Visit the link for more info

A Associação Americana para Pesquisa do Câncer (AACR) realizou nos dias 27 e 28 abril a primeira versão online do AACR annual meeting 2020. Para comentar os highlights em câncer de mama, o MOC preparou este episódio de podcast, com apresentação da Dra. Graziela Zibetti Dal Molin, oncologista clínica da BP – A Beneficência Portuguesa de São Paulo. O primeiro estudo em destaque (EMBRACA) teve duas atualizações apresentadas, sendo a primeira referente aos dados de sobrevida global da análise de talazoparibe versus quimioterapia no câncer de mama HER-2 negativo avançado. A análise não conseguiu demonstrar diferença em SG entre os grupos, no entanto, dados indiretos sugerem que as terapias subsequentes com inibidores de PARP provocaram impacto na SG. Na segunda atualização, comprovou-se a existência de concordância entre mutações germinativas e mutações somáticas, corroborando dados já conhecidos no câncer de ovário. Não houve impacto, porém, em sobrevida livre de progressão. São necessário refinamentos nos testes. Destacarem-se também dois estudos que avaliaram a incorporação de imunoterapia: IMPRIME, com benefício em taxa de resposta associado ao uso de pembrolizumabe em combinação com um agente inibidor de beta-glucana em pacientes com tumores metastáticos triplo negativos; e o estudo randomizado adaptativo SPY 2, que apresentou resultados do braço comparador de durvalumabe, olaparibe e paclitaxel na doença HER-2 negativa localmente avançada não selecionada, evidenciando que ainda são necessários dados mais maduros que permitam identificar as populações que podem se beneficiar da combinação de inibidores de PARP e imunoterapia. Foi apresentado também um trabalho que avaliou a mutação ESR1 em pacientes com tumor precoce de mama. Embora rara nessa população (menos de 1%), a mutação foi relacionada de maneira estatisticamente significativa com uma piora da sobrevida global e intervalo livre de recorrência, sugerindo que a alteração possa vir a ser testada rotineiramente no futuro. Por fim, houve ainda um estudo italiano sobre dieta que mimetiza o jejum com capacidade de modular fatores metabólicos que promovem a regressão do câncer de mama. A análise corrobora a importância de incorporar avaliação dietética no câncer de mama, com dados importantes para estudos futuros.

Proceedings from a satellite symposium during the 42nd annual San Antonio Breast Cancer Symposium. Featuring perspectives from Dr Harold J Burstein, Dr Matthew Goetz, Prof Stephen RD Johnston and Dr Joseph A Sparano. Introduction Program Overview: Dr Love (00:00) Use of Genomic Classifiers to Inform Therapeutic Decision-Making for Patients with ER-Positive Localized Breast Cancer (BC) Case (Dr Goetz): A premenopausal woman in her early 40s with a 1.4-cm, ER-positive, HER2-negative, node-negative IDC and a 21-gene Recurrence Score® of 9 (1:14) Case (Prof Johnston): A woman in her late 30s with a 1.8-cm, ER-positive, HER2-negative, node-negative IDC and an intermediate 21-gene Recurrence Score (9:24) Case (Dr Burstein): A woman in her late 50s with a 1.3-cm, ER-positive, HER2-negative IDC and 1 positive sentinel lymph node (11:11) Faculty Presentation: Dr Sparano (13:57) Optimizing the Use of CDK4/6 Inhibitors in the Management of ER-Positive Metastatic BC (mBC) Case (Dr Goetz): A woman in her mid-40s develops liver and bone metastases near the completion of 5 years of letrozole for ER-positive BC (34:52) Faculty Presentation: Dr Goetz (38:28) Case (Dr Sparano): A man in his late 40s presents with de novo ER-positive, HER2-negative mBC to the lung and bones and receives abemaciclib and tamoxifen (51:17) Current and Future Management of ER-Positive mBC After Disease Progression on CDK4/6 Inhibition Case (Dr Sparano): A woman in her early 40s with ER-positive, HER2-negative mBC who has experienced disease progression on multiple lines of endocrine therapy is found to have a PIK3CA mutation (56:48) Case (Dr Goetz): A woman in her mid-40s receives abemaciclib/fulvestrant for ER-positive, HER2-negative mBC but experiences disease progression after 2 years (57:32) Faculty Presentation: Dr Burstein (1:00:03) Novel Applications of CDK4/6 Inhibitors; Ongoing Clinical Trials Faculty Presentation: Prof Johnston (1:16:55) Case (Prof Johnston): A woman in her mid-30s who has experienced disease progression on multiple lines of therapy, including most recently palbociclib/fulvestrant, undergoes multiplex testing, which reveals ESR1 and PIK3CA mutations (1:30:49) CME information and select publications

Breast Cancer Update, Issue 3, 2019 — Part 1: Our interview with Dr Goetz highlights the following topics as well as cases from his practice: Case: A woman in her mid-30s with de novo ER-positive, HER2-negative metastatic breast cancer (mBC) achieves a complete clinical response to palbociclib, letrozole and ovarian suppression (00:00) Importance of providing support to patients and their families coping with a diagnosis of mBC (01:15) Therapeutic options for patients with de novo ER-positive, HER2-negative mBC (03:45) Activity and tolerability of gonadotropin-releasing hormone agonists (05:35) Selection of patients for treatment with CDK4/6 inhibitors in combination with endocrine therapy (09:07) Mechanism of action of CDK4/6 inhibitors (12:13) Role of everolimus and alpelisib in the management of ER-positive mBC (14:30) Implications of ESR1 mutations for the management of ER-positive mBC; use of selective estrogen receptor degraders (SERDs) (16:15) Activity of the selective estrogen receptor modulators endoxifen and lasofoxifene for mBC with ESR1 mutation (19:48) Tolerability profiles of the CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib; dose reduction to mitigate side effects (21:21) CNS penetration of abemaciclib; management of abemaciclib-associated diarrhea (25:26) Effects of site and extent of metastases on outcomes with CDK4/6 inhibitors (27:02) Efficacy of CDK4/6 inhibitors in combination with endocrine therapy for ER-positive mBC (29:29) Survival outcomes with CDK4/6 inhibitors and endocrine therapy for ER-positive mBC (31:28) Response to palbociclib and endocrine therapy in patients with ER-positive mBC (34:17) Selection of therapy for patients with locally advanced ER-positive, HER2-negative breast cancer (36:41) Therapeutic approach for patients who experience disease progression on a CDK4/6 inhibitor (39:33) Activity of alpelisib for ER-positive advanced breast cancer with a PIK3CA mutation (47:02) Side-effect profile of alpelisib (49:41) Case: A woman in her late 60s with high-grade, ER-positive, HER2-negative breast cancer and a 21-gene assay Recurrence Score (RS) of 52 receives adjuvant chemotherapy (52:54) Role of bone-modifying agents for patients with ER-positive breast cancer and bone metastases (58:04) Ongoing investigations of CDK4/6 inhibitors in the adjuvant setting (59:40) Effects of CDK4/6 inhibitors on immunity; potential for combination with immune checkpoint inhibitors (1:01:14) TAILORx trial: Adjuvant chemotherapy guided by a 21-gene expression assay for women with ER-positive, HER2-negative, node-negative breast cancer (1:06:19) Impact of clinical risk on prognosis and prediction of chemotherapy benefit by age and RS in the TAILORx study for patients with early breast cancer (1:07:46) Perspective on the use of gene expression assays to determine risk of recurrence and guide adjuvant decision-making (1:14:30) Cancer cell dormancy and risk of late recurrence (1:16:47) CME information and select publications  

Breast Cancer Update, Issue 3, 2019 — Part 2: Our interview with Dr Kaklamani highlights the following topics as well as cases from her practice: Efficacy and safety of the novel SERD elacestrant for ER-positive breast cancer; Phase III EMERALD trial evaluating elacestrant versus endocrine therapy (00:00) Incidence of ESR1 mutations; activity of elacestrant after disease progression on fulvestrant and a CDK4/6 inhibitor (02:14) Results from the Phase II ANETT trial of the mTORC1/2 inhibitor TAK-228 with tamoxifen as neoadjuvant therapy for ER-positive breast cancer (03:53) Novel approaches under investigation in the neoadjuvant setting (07:20) Perspective on the use of neoadjuvant therapy to optimize surgical outcomes for patients with ER-positive, HER2-negative breast cancer (09:43) Activity of CDK4/6 inhibitors for locally advanced ER-positive breast cancer (11:30) Case: A woman in her late 60s with ER-positive, HER2-negative breast cancer and 1 of 3 positive axillary lymph nodes receives a 21-gene assay RS of 18 (13:49) Role of the 21-gene expression assay in predicting chemotherapy benefit for patients with ER-positive breast cancer (15:56) Clinical and genomic risk to guide the use of adjuvant therapy for breast cancer (19:11) Case: A premenopausal woman in her late 40s with ER-positive, HER2-negative, node-negative breast cancer receives a RS of 19 (23:19) Clinical implications of the TAILORx trial comparing chemoendocrine therapy to endocrine therapy for patients with ER-positive, node-negative breast cancer and an intermediate RS (25:00) Tailoring adjuvant endocrine therapy for premenopausal women with ER-positive breast cancer (27:54) Benefit of endocrine therapy with or without chemotherapy for patients with ER-positive breast cancer and an intermediate RS; consideration of clinical and genomic risk in assessing the likelihood of disease recurrence (30:54) Case: A woman in her early 40s with ER-positive, HER2-negative breast cancer and metastases in the liver and bones attains a partial response to ribociclib in combination with endocrine therapy (35:24) Benefit with CDK4/6 inhibitors versus chemotherapy for ER-positive breast cancer with visceral metastases (37:57) Efficacy of ribociclib in premenopausal women; QT prolongation associated with ribociclib/tamoxifen (40:54) Comparison of the efficacy and toxicity profiles of abemaciclib, palbociclib and ribociclib for women with ER-positive mBC (42:24) Activity of CDK4/6 inhibitors as monotherapy; CNS penetration of CDK4/6 inhibitors (45:47) Monitoring and management of side effects associated with CDK4/6 inhibitors (48:07) Case: A woman in her mid-50s initially diagnosed with Stage II ER-positive breast cancer develops metastatic disease to the bone 8 years later and receives palbociclib and anastrozole (50:54) Perspective on the use of multiplex genomic assays to guide treatment decision-making for patients with ER-positive mBC (53:35) Results of the Phase III SOLAR-1 trial evaluating alpelisib for patients with ER-positive advanced breast cancer (55:54) Tolerability of alpelisib for patients with ER-positive breast cancer (57:54) Sequencing everolimus and alpelisib after disease progression on a CDK4/6 inhibitor (1:00:06) Case: A postmenopausal woman in her mid-30s with ER-positive mBC and BRCA2 and PIK3CA mutations receives talazoparib in the third-line setting (1:01:46) Choice of PARP inhibitor for patients with advanced breast cancer and BRCA mutations (1:04:58) Response and side-effect profiles of alpelisib (1:06:10) Selection and sequencing of therapy for patients with mBC and germline BRCA mutations (1:07:00) CME information and select publications  

Interview with Sarat Chandarlapaty, MD, PhD, author of Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial

Dr Chanderlapaty presents, at a press conference at SABCS 2015 about the latest data on oestrogen receptor-positive, metastatic breast cancer. The data shows that among patients with oestrogen receptor-positive, metastatic breast cancer, those who had a D538G and/or a Y537S mutation in the oestrogen receptor 1 gene, as detected in cell-free DNA obtained from patient blood samples, had significantly worse median overall survival.

Dr Chandarlapaty talks to ecancertv at SABCS 2015 about the results of a study looking at two genetic mutations in the estrogen receptor 1 gene (ESR1) and how this affected the outcomes of women with estrogen receptor-positive metastatic breast cancer. The Y537S and D538G mutations in ESR1 are common alterations seen in metastatic breast cancer and result in making the receptor estrogen independent and can results in resistance to estrogen deprivation therapy such as an aromatase inhibitor. Using blood samples from the BOLERO-2 study, Dr Chandarlapaty and colleagues hypothesized that cell free DNA (cfDNA) analysis of a patient’s plasma could be used to detect the presence of the mutations. The mutations were found in about 30% of women and women with these mutations had a shorter OS than women who did not have these mutations. Dr Chandarlapaty says that one major implication of these data is that it shows a blood sample could be taken to test for these mutations and provide important prognostic information.

Dr Raj talks to ecancertv at SABCS 2015 about a novel agent that targets the estrogen receptor 1 (ESR1) and that could help overcome resistance to hormonal therapy in women with metastatic breast cancer. The central role of estrogen in the progression of breast cancer has been long known and current therapies involve either anti-estrogens or aromatase inhibitors that target ESR1. Most women treated with these drugs eventually develop resistance, so there is a need for other approaches. In the interview, Dr Raj explains how the ESR1 coregulator binding inhibitor (ECBI) is able to disrupt ESR1 signalling by blocking ESR1 interactions with its critical coregulators. The molecule is in the early phases of development but has been tested on several breast cancer and therapy-resistant model cells and on primary human breast tissue.

Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10(-6)). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Das Ziel dieser Arbeit war die Kartierung eines QTL mit Effekt auf paternalen Kalbeverlauf und paternale Totgeburt auf Bos Taurus Autosom 9 (BTA09) in einer fortgeschrittenen Fleckvieh x Red-Holstein Rückkreuzungspopulation mit positioneller und funktioneller Kandidatengenanalyse. Dazu wurden Untersuchungen mit verschiedenen Kartierungsdesigns in Granddaughter und Daughter Designs durchgeführt. Intervallkartierung und Linkage / Linkage-Disequilibrium-Kartierung wurden verwendet um den QTL feinkartieren zu können. Die LDL-Kartierung wurde in Ansätzen mit MCMC-geschätzten (durchschnittlichen) und wahrscheinlichsten Haplotypen durchgeführt. Mit der Intervallkartierung konnten zwei signifikante QTL für paternalen Kalbeverlauf und paternale Totgeburt auf BTA09 lokalisiert werden: ein QTL im proximalen Bereich und ein QTL im distalen Bereich des Chromosoms. Die Ergebnisse der LDL-Kartierung weisen auf nur einen signifikanten QTL im distalen Bereich von BTA09 hin. Als mögliches funktionelles und positionelles Kandidatengen für den distalen QTL mit Effekt auf paternalen Kalbeverlauf und Totgeburt konnte IGF2R als Rezeptor des insuline-like growth factor 2 evaluiert werden. Einflüsse von IGF2R auf das fetale und embryonale Wachstum wurden beschrieben. Die Intervallkartierung auf BTA29 - das IGF2-Hormon codierende Chromosom - ließ auf keinen QTL mit Effekt auf Kalbeverlauf oder Totgeburt schließen. Auf BTA09 wurde neben den QTL für paternalen Kalbeverlauf und paternale Totgeburt mit Intervallkartierung und Approximativem Interval-Mapping zwei QTL mit Effekt auf Proteinprozent kartiert. Diese QTL sind ebenfalls im proximalen und distalen Bereich des Chromosoms lokalisiert. Die LDL-Kartierung konnte nur einen QTL mit Effekt auf Proteinprozent im distalen Bereich bestätigen. Ein mögliches funktionelles und positionelles Kandidatengen im distalen Bereich des Chromosoms stellt der Östrogenrezeptor ESR1 (ERα) dar. ESR1 nimmt nachweislich großen Einfluss in der Entwicklung des alveolären Gewebes in der bovinen Milchdrüse.

A short-term (24 h) culture system for bovine oviduct epithelial cells (BOEC) suitable for co-culture experiments with embryos was established and evaluated. BOEC were obtained on Day 3.5 of the estrous cycle and processed by mechanical means only to obtain cell aggregates. Cell yields were 10-fold higher as described in former studies employing enzymatic treatment to achieve a single cell suspension for seeding to obtain a BOEC monolayer. Light microscopic examinations showed vigorously beating cilia on the apical side of the BOEC in aggregates and a rapid and constant motion of cell aggregates due to active ciliary beat. Scanning electron microscopy and transmission electron microscopy confirmed ultrastructural characteristics of BOEC at seeding and after 24 h in culture very similar to the situation in vivo. Both secretory cells with numerous secretory granules and ciliated cells with long, well-developed kinocilia were visible. The purity of the epithelial cell culture was > 95 %, as assessed by immunocytochemical methods. For further characterization of cultured BOEC, gene expression patterns were examined after different time spans in culture. Cultured BOEC isolated from ampullae ipsilateral to the ovulation site yielded significantly higher amounts of RNA than their contralateral counterparts (2.73 ± 0.98 versus 2.31 ± 0.14 µg per 10^6 cells). However, quantitative PCR did not detect significant differences in transcript levels between ipsi- and contralateral BOEC for the majority of marker genes (ESR1, ESR2, HMGCR, OVGP1, PGR, TRA1) throughout the 24 h culture period. The analysis of combined data obtained from different sampling time points during the culture period revealed an effect only for GPX4 (B. taurus non-selenium glutathione phospholipid hydroperoxide peroxidase), a gene known to be differentially expressed in vivo. Marker gene expression of five genes remained stable after 6h of cell culture, indicating only a short adaptation period of cultured cells. The use of two different sera (estrous cow serum versus cow serum obtained on Day 3.5 of the estrous cycle) in a concentration of 2 % did not affect gene expression patterns. Western blot analysis confirmed ESR1 (estrogen receptor α) and PGR (progesterone receptor) protein expression throughout the culture period. In agreement with cyclic differences in vivo, stimulation with 10 pg/ml estradiol-17β increased PGR transcript abundance in BOEC significantly. A response to the stimulation with 10 ng/ml progesterone was shown as INOS (inducible nitric oxide synthase) gene expression increased significantly after steroid treatment. Thus, the developed culture system provides functional BOEC with an unchanged morphology and maintained functionality as compared with cells in vivo. The system is rapidly available for use in co-culture experiments with bovine embryos and provides cultured cells in sufficient quantities for holistic transcriptome and proteome studies, thereby helping to decipher early embryo-maternal communication.