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ER⁺/HER2⁻ Metastatic Breast Cancer: Latest Advances

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Description

Acknowledgment: This activity is supported by an educational grant from Pfizer Inc. and Arvinas. This online education program has been designed for healthcare professionals globally.

In this virtual 60-minute live webinar recording, leading breast cancer experts Dr. Mark Pegram, MD and Dr. Seth Wander, MD, PhD explore advanced sequencing and shared decision-making strategies in ER⁺/HER2⁻ metastatic breast cancer. Together, they will:

Differentiate emerging endocrine therapies (SERDs, oral SERDs, PROTAC degraders) and their mechanisms of action, clarifying how they fit into resistance biology and sequencing decisions.
Apply biomarker-informed, patient-centred strategies using ESR1, PIK3CA, HER2-low, and other markers to guide treatment selection through real-world case vignettes.
Integrate evolving guideline recommendations and trial evidence to map post-CDK4/6 pathways, supporting personalized care after progression.

This activity is available for CME/CE credit from the 18th of October 2025 to the 16th of October 2026.

Original date of broadcast: October 16th 2025.

Accreditation: EBAC

Session Highlights

Mechanisms of action: Compare SERMs, SERDs, and PROTAC degraders, with practical insights for therapy selection in endocrine-resistant ER⁺/HER2⁻ mBC.
Biomarker-driven personalization: Translate ESR1, PIK3CA, and HER2-low results into evidence-based treatment decisions.
Sequencing beyond CDK4/6 inhibitors: Review case-based strategies and trial data to inform next-line therapy selection.

Target Audience - Who should watch?

Medical Oncologists
Hematologist-Oncologists
Nurse Practitioners
Physician Assistants
Oncology Nurses
Oncology Fellows
Pharmacists
Pathologists & Molecular Tumor Board participants
Other HCPs involved in metastatic breast cancer care

Faculty

Dr. Mark Pegram, MD – is the Suzy Yuan-Huey Hung Endowed Professor of Medical Oncology at Stanford University School of Medicine and Associate Director of Clinical Research at the Stanford Comprehensive Cancer Institute. He also serves as Associate Dean for Clinical Research Quality and Medical Director of the Stanford Clinical Translational Research Unit, specializing in early-phase clinical trials.

Dr. Seth Wander, MD, PhD – is a medical oncologist at Massachusetts General Hospital and assistant professor at Harvard Medical School, specializing in breast cancer and cancer genomics. His research focuses on understanding resistance to targeted therapies in metastatic breast cancer through genomic and molecular sequencing.

Jessica Fioretti (patient) and Phil McElnay (CEO, MedAll and Interview Moderator)

Continuing Education Information

This activity is provided by MedAll Inc.

Target Audience

HCPs involved in treatment of ER+/HER2- mBC; Medical Oncologists, Hematologist-Oncologists, Advanced Practice Providers (Nurse Practitioners and Physician Associates) in Oncology.

Pathologists involved in biomarker testing and molecular profiling, Molecular Tumor Board Participants, Oncology Pharmacists, Oncology Nurses, Other multidisciplinary team members involved in therapy selection and sequencing.

Statement of Need/Program Overview

Estrogen receptor-positive (ER+), HER2-negative (HER2-) metastatic breast cancer (mBC) is the most common subtype, but progression on endocrine therapies is inevitable due to complex resistance mechanisms like ESR1 mutations. The therapeutic landscape has rapidly evolved with novel agents, including oral Selective Estrogen Receptor Degraders (SERDs), PROteolysis TArgeting Chimeras (PROTACs), and PI3K inhibitors, which increases treatment complexity. Clinicians face challenges in differentiating these new mechanisms of action, applying critical biomarker testing for ESR1, PIK3CA, and HER2-low status, and navigating treatment sequencing after progression on CDK4/6 inhibitors in the absence of a universally accepted algorithm. This creates an urgent clinical need for targeted education to help healthcare providers integrate emerging trial data and biomarker-informed strategies into their practice, ultimately personalizing care and improving patient outcomes.

Educational Objectives

After completing this activity, the participant should be better able to:

Differentiate emerging endocrine therapies in ER⁺/HER2⁻ mBC based on mechanism of action (MoA) and clinical role
Personalize treatment in ER⁺/HER2⁻ mBC using biomarker test results and evidence-based decision-making
Optimize post-CDK4/6 sequencing in ER⁺/HER2⁻ mBC based on clinical and molecular resistance patterns

Program Agenda (for live event)

15mins - Prof Mark Pegrum - Differentiate emerging endocrine therapies (SERDs, oral SERDs, PROTAC degraders) and their mechanisms of action, clarifying how they fit into resistance biology and sequencing decisions.
15mins - Prof Mark Pegrum - Apply biomarker-informed, patient-centred strategies using ESR1, PIK3CA, HER2-low, and other markers to guide treatment selection through real-world case vignettes.
15mins - Prof Seth Wander - Integrate evolving guideline recommendations and trial evidence to map post-CDK4/6 pathways, supporting personalized care after progression.
15 mins - Jessica Fioretti - Patient Advocate Interview - bringing the patient voice into education and decision making
Questions and Answers

Instructions to Receive Credit

In order to receive credit for this activity, participants must attend the full session webinar, pass a post-test with 70% or better, and complete the program evaluation.

System Requirement

PC

1.4 GHz Intel Pentium 4 or faster processor (or equivalent)

Windows 10, 8.1 (32-bit/64-bit), Windows 7 (32-bit/64-bit)

512 MB of RAM (1 GB recommended)

Microsoft Internet Explorer 11 or later, Windows Edge browser, Mozilla Firefox, and Google Chrome

For HTML Client – Google Chrome (v70.0 & above), Mozilla Firefox (v65.0 & above), and Edge (v42.0 & above)

MAC

1.83 GHz Intel Core Duo or faster processor

512 MB of RAM (1 GB recommended)

MAC OS X 10.12, 10.13 and 10.14

Mozilla Firefox, Apple Safari, Google Chrome

For HTML Client – Google Chrome (v70.0 & above), Apple Safari (v12.0 & above), and Mozilla Firefox (v65.0 & above)

Fee Information& Refund/Cancellation Policy

There is no fee for this educational activity.

Disclosures of Relevant Financial Relationships

MedAll adheres to the policies and guidelines set forth to providers by EBAC and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scientifically rigorous. All persons in a position to control the content of an accredited continuing education program provided by MedAll are required to disclose all financial relationships with any ineligible company. All financial relationships reported are identified as relevant and mitigated by MedAll in accordance with the standards for accredited CE in advance of delivery of the activity to learners. The content of this activity was vetted by MedAll to assure objectivity and that the activity is free of commercial bias.

All relevant financial relationships have been mitigated.

The faculty have the following relevant financial relationships with ineligible companies:

Dr. Mark Pegram has disclosed financial relationships within the past 24 months with the following ineligible companies. He has received consulting fees from Astra-Zeneca, Roche/Genentech, Daiichi Sankyo, SeaGen/Pfizer, Novartis, Puma Biotechnology and Stemline Therapeutics.

Dr. Seth Wander has disclosed financial relationships within the past 24 months with the following ineligible companies. He has received consulting fees from Foundation Medicine, Veracyte, Hologic, Eli Lilly, Biovica, Pfizer/Arvinas, Puma Biotechnology, Novartis, AstraZeneca, Genentech, Regor Therapeutics, Stemline/Menarini, and Gilead. He has received contracted research support from Genentech, Eli Lilly, Pfizer/Arvinas, Nuvation Bio, Regor Therapeutics, Sermonix, Puma Biotechnology, Stemline/Menarini, and Phoenix Molecular Designs. In addition, he has received honoraria from Eli Lilly, Guardant Health, and 2ndMD.

Jessica Fioretti (patient) and Phil McElnay (CEO, MedAll and Interview Moderator): Nothing to disclose

The planners and managers at MedAll Inc. have no relevant financial relationships with ineligible companies.

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. MedAll Inc. does not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

EBAC Compliance and Credit Conversion

This program is accredited by the European Board for Accreditation of Continuing Education for Health Professionals (EBAC®) for 1.00 hours of effective education time.

In compliance with EBAC guidelines, all speakers and chairpersons participating in this programme have disclosed or indicated potential conflicts of interest that might cause a bias in the presentations. The Organizing Committee/Course Director is responsible for ensuring that all potential conflicts of interest relevant to the event are declared to the audience prior to the CE activities.

EBAC® holds an agreement on mutual recognition of substantive equivalency with the US Accreditation Council for CME (ACCME) and the Royal College of Physicians and Surgeons of Canada, respectively.

Through an agreement between the European Board for Accreditation of Continuing Education for Health Professionals (EBAC®) and the American Medical Association, physicians may convert EBAC® External CME credits to _AMA PRA Category 1 Credits_™. Information on the process to convert EBAC® credit to AMA credit can be found on the AMA website https://edhub.ama-assn.org/pages/applications. Other healthcare professionals may obtain from the AMA a certificate of participation in an activity eligible for conversion of credit to _AMA PRA Category 1 Credit_™.

EBAC® is a member of the International Academy for CPD Accreditation (IACPDA) and a partner member of the International Association of Medical Regulatory Authorities (IAMRA).

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Computer generated transcript

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The following transcript was generated automatically from the content and has not been checked or corrected manually.

My name is Mark Pegram. I'm a professor of medical oncology at the Stanford University School of Medicine in Palo Alto, California. I'm pleased to present this presentation entitled Differentiation of Emerging Endocrine therapies in Estrogen receptor-positive HER2 negative metastatic Breast Cancer based on mechanism of action and clinical role. Please keep in mind my disclosures of financial relationships within the past 24 months and take these into consideration as you listen to my remarks today. The learning objectives for this presentation are to differentiate emerging endocrine therapies and estrogen receptor-positive HER2 negative metastatic breast cancer based on mechanism of action and clinical role, to describe the mechanisms of novel endocrine therapies including proteolysis targeting estrogen receptor degraders, so-called protax. Contrast these therapies with traditional selective estrogen receptor-degrading agents and selective estrogen receptor modulating agents based upon efficacy and mechanism. And finally, evaluate how mechanistic differences influence therapy selection and endocrine resistant hormone receptor-positive HER2 negative metastatic breast cancer. As you can see from the summary slide timeline, the FDA has been quite busy over the past decade or so in this space with multiple new drug approvals, including the CDK46 inhibitors in the first line combined with uh aromatase inhibitors, uh, immunotherapy for um, uh, uh, uh, triple negative breast cancer. Uh, more targeted therapies targeting Etre and RET. Also trastuzumabroxan, uh, for HER2 low and ultra-low metastatic breast cancers that are hormone receptor positive, uh, data datapodumabdroican, uh, involliib plus fulvestrin palbociclib, Capivasertib, Eliestrin, stuzumab, gobotecan. And finally, um, just last week, there was a new FDA approval of immunnester shown in the lower right by the dotted red box that was approved on September 25th with the indication statement from the FDA and estrogen receptor antagonist indicated for treatment of adults with ER positive HER2 negative ESR1 mutated advanced or metastatic breast cancers with disease progression following at least one line of endocrine therapy. Uh, the companion diagnostic for that agent is the Garden 360 CTDNA assay. Doctor Gratischer at this year's ASCO presented a very nice, uh, summary of endocrine agents in development. As you can see, there's, uh, many oral certs that have been in development over the past years, including some not even shown on the slide that I actually worked on, including G1T4A, for example. Um, and in addition to the oral serts, there are also the protax and the CERNs and the circus. CERA stands for complete estrogen receptor antagonist. It's kind of, uh, I would describe it as midway between a SERD and a SERM. It can both block ER binding to estradiol completely, and it also leads to at least some degradation. Meanwhile, CICA stands for selective estrogen receptor covalent antagonist by targeting A unique cystine residue, C530 within the ligand binding domain of the estrogen receptor. And uh that also blocks ER action as a transcription factor. Estrogen receptor gene mutations were first described by Suzanne Fuqua at San Antonio uh back in the early to mid 90s and published in Cancer Research in 1997. And what she described was one patient with advanced disease out of 30 samples tested that had a Y537N. ESR1 gene mutation. She postulated a model that describes this mutant as being constitutively activated as a transcription factor, even in the absence of estradiol. This also uh had a phenotype of being drug resistant uh against uh drugs like tamoxifen and aromatase inhibition, for example. Now, uh, the SED drugs, uh, particularly the oral bioavailable SEDs, uh, an example is shown on the right, and I've chosen Camiestrin simply because we have both X-ray crystal structure available for this drug, as, as well as Western blood analysis and cell-proliferation essays, uh, published in a paper by Scott. But I could have chosen any one of the oral surges to describe this mechanism of action, so there's no specialty about Cammizestrin in this case. You can see by the Western blood analysis at the bottom center of the slide, that compared to fulvestrant, there's nice degradation of the estrogen receptor protein over time, um, following exposure to this oral ser cabaz estrin. And also this correlates with a decrease in cell-proliferation. Important to note out that uh this oral ser as well as others, blocks cell proliferation of both the wild type estrogen receptor as well as the mutant estrogen receptor. Also note that oral ser mechanism of action involves ER protein binding resulting in misfolding of the estrogen receptor protein, resulting in polyubiquitination. And subsequent proteasome degradation. And this is important because we're gonna talk about that mechanism with the protax shortly as well. Since the original publication by Fuqua and all, uh, there have been over 30 different ESR1 mutations, uh, discovered. Uh, there's a summary in the middle of the slide showing some of the locations of these, uh, uh, ESR1 gene mutations. They do tend to cluster in certain hotspot regions, including the ligand binding domain, for example. In Fuqua's original paper, the incidence of ESR1 mutation and newly diagnosed early-stage breast cancer was low, less than 1%. And so for the better part of a decade, this target was largely ignored in the research community because it was thought to be so infrequent that uh no sponsor would probably take on a project designing a new whole drug class to target such a rare mutation. But years later, it turned out that in metastatic breast cancer, the incidence of ESR1 gene mutation increases dramatically. 5% by the time of first recurrence. And uh by second line, it's up to a third of patients have ESR1 gene mutations. And third line up to 40% as shown on the uh graphic on the lower right-hand side of the slide. Again, the cartoon on the left shows the mechanism of action of these mutant receptors being constitutively activated and activating ER in um these mutant cell lines which causes increase in proliferation. And indeed activates uh metastatic cascades in terms of gene expression profiles. Next, I'll show you the phase 3 Emerald clinical trial, which was the first oral cer drug to lead to an FDA approval, that is Eliestrant. The inclusion criteria included men or women with metastatic breast cancer who were hormone receptor positive and HER2 negative, who had progressed or relapsed on or after 1 to 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK 46 inhibitor. Up to one line of prior chemotherapy for advanced disease was also allowed. And the uh ECOG performance status had to be uh very good to excellent. Patients were randomized 1 to 1 to LSestrin 400 mg a day, or investigators' choice of standard endocrine therapy, fulvestrant, or any one of the three aromatase inhibitors. The, uh, two primary endpoints were PFS in all patients and PFS in the ESR1 mutant subpopulation. Key baseline characteristics were balanced between the two randomization arms, visceral metastasis, about 70% prior adjuvant therapy in over half. Prior aromatase inhibition in over 80% and prior fulvestrin in about 25 to 30%. The Enbrel trial, uh, landmark analysis of PFS in patients with detectable ESRN1 mutations met its primary endpoint with statistical confidence. This, uh, Kanmeyer plot shows the hazard ratio of 0.5 with a P value of 0.0.0005, indicating superiority of LSestrin over fulvestrant as the control in this particular illustration. Um, note the shape of this curve. Almost a third of patients drop out at the first restaging interval at 2 months. And we need to better understand the resistance mechanisms in this patient population. Apparently, it's not something so simple as which ESR1 mutation they have because that data has been available to sponsors for months or even longer. Uh, so it, it has to be something more complex that's under active investigation and biomarker campaigns. And this and other trials that are ongoing. So we need to be able to identify those patients to exclude them from future uh SERD considerations since they do not respond. But the remaining patients clearly have a much better outcome in terms of time to events analysis. Note that there are unique side, side effects associated with this particular oral CERD and particular nausea. Which can happen in about a third of patients compared to almost 20% in the control arm. Uh, vomiting as well. Consequently, anti-emetic medication, co-medication is recommended on a PRN basis when you prescribe this agent. There can also be some anorexia in a fraction of patients, uh, and that's a little bit more compared to the fulvestri control arm. In the future, there are ongoing phase 1B and 2 combination studies that are underway combining LSSran with not only the CDK 46 inhibitors, but also, uh, Eolimus, the MTOR inhibitor. And stay tuned for future updates with these combinations that may be possible to integrate. This agent with other drug combinations in future uh studies. Hopefully, it's leading to new drug approvals in the future. Next, I'd like to talk to you about the newest oral er to be approved by the FDA last week, luneestran. This is the pivotal phase 3 trial of Fulvestrant versus Munneestrant. There was also a third arm that included a bemicycllib. This did not win FDA approval, but I'll show you the data that did win single agent approval.