Consensus or Controversy? Documenting and Discussing Investigators’ Approaches to the Use of Oral SERDs and Agents Targeting the PI3K/AKT/mTOR Pathway in Breast Cancer — Symposium Proceedings

Faculty

TARGET AUDIENCE
This activity is intended for medical and radiation oncologists, hematologists, hematology-oncology fellows, general and breast surgeons and other healthcare providers involved in the treatment of breast cancer.

LEARNING OBJECTIVES

• Appreciate the incidence and clinical implications of ESR1 mutations in endocrine-resistant metastatic breast cancer (mBC), and determine optimal strategies to effectively identify patients harboring these abnormalities.
• Understand the biological rationale for, mechanism of action of and pharmacologic similarities and differences among available and investigational oral selective estrogen receptor degraders (SERDs).
• Interrogate published research documenting the efficacy of oral SERD monotherapy for hormone receptor (HR)-positive, HER2-negative, ESR1-mutated mBC progressing on standard endocrine therapy in combination with a CDK4/6 inhibitor in order to optimally integrate these agents into the care of appropriately selected patients.
• Review available research data evaluating serial ESR1 testing using circulating tumor DNA to inform early therapeutic switching for patients with HR-positive mBC receiving CDK4/6 inhibitor-based first-line therapy, and consider the potential role of this novel strategy.
• Evaluate available clinical trial data with oral SERDs in combination with other systemic therapies (eg, CDK4/6 inhibitors, mTOR inhibitors), and consider the potential role of these regimens.
• Recognize the frequency of PIK3CA/AKT1/PTEN alterations in patients with HR-positive mBC, and employ evidence-based approaches to target these aberrations for appropriate candidates with newly diagnosed and relapsed/refractory disease.
• Understand the biological rationale for the development of agents targeting multiple components of the PI3K/AKT/mTOR pathway, and recognize available and emerging data employing this strategy for patients with HR-positive, PIK3CA wild-type and PIK3CA-mutant mBC.
• Appreciate side effects associated with available and investigational oral SERDs and agents targeting the PI3K/AKT/mTOR pathway, and use this information to develop supportive care plans for patients receiving these treatments.
• Assess ongoing clinical research studies evaluating novel applications of oral SERDs and PI3K/AKT/mTOR inhibitor-based approaches, and counsel patients regarding the potential benefits of trial participation.

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Research To Practice designates this enduring material for a maximum of 2.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Successful completion of this CME activity, which includes participation in the evaluation component and a post-test, enables the participant to earn up to 2.25 Medical Knowledge MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

Please note, this program has been specifically designed for the following ABIM specialty: medical oncology.

AMERICAN BOARD OF SURGERY (ABS) — CONTINUOUS CERTIFICATION (CC)
Successful completion of this CME activity, which includes participation in the evaluation component and a post-test, enables the learner to earn credit toward the CME and Self-Assessment requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABS credit.

Please note, this program has been specifically designed for the following ABS practice area: complex general surgical oncology.

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HOW TO USE THIS CME ACTIVITY
To receive credit for this activity, the participant should review the CME information, watch the video, complete the post-test with a score of 80% or better, and fill out the evaluation.

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FACULTY — The following faculty reported relevant financial relationships with ineligible entities:

Dr Hurvitz — Advisory Committees: Akari Therapeutics, BeOne, Boundless Bio, BriaCell, BridgeBio, Bristol Myers Squibb, Daiichi Sankyo Inc, Gilead Sciences Inc, Jazz Pharmaceuticals Inc, Lilly, Luminate, Mersana Therapeutics Inc, Novartis, Prelude Therapeutics, Roche Laboratories Inc; Consulting Agreements: ALX Oncology, Bayer HealthCare Pharmaceuticals, BeOne, Blueprint Medicines, Ellipses Pharma, EMBioSys, Genentech, a member of the Roche Group, Jazz Pharmaceuticals Inc, Myricx Bio; Contracted Research: AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, Menarini Group, Novartis, Stemline Therapeutics Inc; Data and Safety Monitoring Boards/Committees: Atossa Therapeutics (paid to institution), Roche Laboratories Inc (paid to UW); Nonrelevant Financial Relationships: Alliance for Clinical Trials in Oncology Foundation, InClin, Quantum Leap Healthcare Collaborative, ROMTech (stocks for orthopedic device for postop pts; not cancer related). Dr Mayer — Consulting Agreements: Aktis Oncology, AstraZeneca Pharmaceuticals LP, Genentech, a member of the Roche Group, Lilly, Novartis. Dr O’Shaughnessy — Advisory Committees and Consulting Agreements: Aadi Bioscience, Agendia Inc, Amgen Inc, Aptitude Health, AstraZeneca Pharmaceuticals LP, BioNTech SE, Bristol Myers Squibb, Daiichi Sankyo Inc, Duality Biologics, Eisai Inc, Ellipses Pharma, Exact Sciences Corporation, G1 Therapeutics Inc, Genentech, a member of the Roche Group, Gilead Sciences Inc, Guardant Health, HiberCell, Jazz Pharmaceuticals Inc, Johnson & Johnson, Lilly, Menarini Group, Merck, Mersana Therapeutics Inc, Natera Inc, Novartis, Pfizer Inc, Pierre Fabre, Puma Biotechnology Inc, RayzeBio, Roche Laboratories Inc, Sanofi, Seagen Inc, Stemline Therapeutics Inc, Summit Therapeutics, Tempus, TerSera Therapeutics LLC. Dr Turner — Consultant/Advisory: AstraZeneca Pharmaceuticals LP, Exact Sciences Corporation, Genentech, a member of the Roche Group, GSK, Guardant Health, Inivata, Lilly, Novartis, Pfizer Inc, Repare Therapeutics; Research Funding: AstraZeneca Pharmaceuticals LP, Genentech, a member of the Roche Group, Guardant Health, Inivata, Invitae, Labcorp, MSD, Natera Inc, Personalis, Pfizer Inc.

CONTRIBUTING CLINICAL INVESTIGATOR
Virginia Kaklamani, MD, DSc — Consulting Agreements: AstraZeneca Pharmaceuticals LP, Daiichi Sankyo Inc, Genentech, a member of the Roche Group, Gilead Sciences Inc, Lilly, Menarini Group, Novartis, Pfizer Inc; Speakers Bureaus: AstraZeneca Pharmaceuticals LP, Gilead Sciences Inc.

MODERATOR
Dr Tolaney — Consulting Agreements: Aadi Bioscience, Ambrx, Artios Pharma Limited, Arvinas, AstraZeneca Pharmaceuticals LP, Aktis Oncology, Avenzo Therapeutics, Bayer HealthCare Pharmaceuticals, BeOne, Bicycle Therapeutics, BioNTech SE, Blueprint Medicines, Boehringer Ingelheim Pharmaceuticals Inc, Boundless Bio, Bristol Myers Squibb, Celcuity, Circle Pharma, Cullinan Therapeutics, Daiichi Sankyo Inc, Denali Therapeutics, eFFECTOR Therapeutics Inc, Eisai Inc, Genentech, a member of the Roche Group, Gilead Sciences Inc, Hengrui Therapeutics Inc, Jazz Pharmaceuticals Inc, Johnson & Johnson, Launch Therapeutics, Lilly, Menarini Group, Merck, Mersana Therapeutics Inc, Natera Inc, Novartis, Olema Oncology, Pfizer Inc, Reveal Genomics, Samsung Bioepis, Seagen Inc, Stemline Therapeutics Inc, Sumitovant Biopharma, Summit Therapeutics, SystImmune Inc, Tango Therapeutics, Tempus, Zuellig Pharma; Contracted Research: AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb, Daiichi Sankyo Inc, Exelixis Inc, Genentech, a member of the Roche Group, Gilead Sciences Inc, Jazz Pharmaceuticals Inc, Lilly, Menarini Group, Merck, NanoString Technologies, Novartis, OncoPep, Pfizer Inc, Seagen Inc, Stemline Therapeutics Inc; Travel: Arvinas, AstraZeneca Pharmaceuticals LP, Gilead Sciences Inc, Jazz Pharmaceuticals Inc, Lilly, Pfizer Inc, Roche Laboratories Inc.

RESEARCH TO PRACTICE CME PLANNING COMMITTEE MEMBERS, STAFF AND REVIEWERS — Planners, scientific staff and independent reviewers for Research To Practice have no relevant financial relationships to disclose.

This educational activity contains discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. Research To Practice does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP, Celcuity, Genentech, a member of the Roche Group, Lilly, and Stemline Therapeutics Inc.

Release date: July 2026
Expiration date: July 2027

After completing the post-test, learners may download and review the answers here in order to identify further areas of study.

Dr Turner 

Herrera-Abreu MT et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res 2016;76(8):2301-13. Abstract 

Jhaveri KL et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med 2025;392(12):1189-202. Abstract 

Turner N et al. Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): Phase 3, double-blind ctDNA-guided SERENA-6 trial. ASCO 2025;Abstract LBA4. 

Turner N et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med 2024;391(17):1584-1596. Abstract 

Dr O’Shaughnessy 

Bardia A et al. Elacestrant in ER+, HER2- metastatic breast cancer 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 

Bardia A et al. EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting. San Antonio Breast Cancer Symposium 2022;Abstract GS3-01. 

Bidard FC et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from the randomized phase III EMERALD trial. J Clin Oncol 2022 Oct 1;40(28):3246-3256. Abstract 

Brett JO et al. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res 2021;23(1):85. Abstract 

Campone M et al. Vepdegestrant, a PROTAC estrogen receptor degrader, in advanced breast cancer. N Engl J Med 2025;393(6):556-68. Abstract 

Hamilton EP et al. Subgroup analyses of VERITAC-2: A phase 3 trial of vepdegestrant, a PROTAC estrogen receptor (ER) degrader, versus fulvestrant in ER-positive/ human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC). San Antonio Breast Cancer Symposium 2025;Abstract PD10-03. 

Hamilton EP et al. Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomized, phase 3 VERITAC-2 study. ASCO 2025;Abstract LBA1000. 

Jhaveri KL et al. Imlunestrant with or without abemaciclib in advanced breast cancer: Updated efficacy results from the phase III EMBER-3 trial. Ann Oncol 2026;37(4):532-43. Abstract 

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 with or without abemaciclib in advanced breast cancer (ABC): Updated efficacy results from the phase 3 EMBER-3 trial. San Antonio Breast Cancer Symposium 2025;Abstract GS3-08. 

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. 

Lloyd M et al. Clinical and genomic factors associated with elacestrant outcomes in ESR1-mutant metastatic breast cancer. Clin Cancer Res 2026;32(1):169-78. Abstract 

Rugo HS et al. Real-world outcomes of elacestrant in ER+, HER2-, ESR1-mutant metastatic breast cancer. Clin Cancer Res 2026;32(1):179-87. Abstract 

Dr Mayer 

Bidard F et al. Updated results and an exploratory analysis of ESR1m circulating tumor DNA (ctDNA) dynamics from SERENA-6, a phase 3 trial of camizestrant (CAMI) + CDK4/6 inhibitor (CDK4/6i) for emergent ESR1 mutations (ESR1m) during first-line (1L) endocrine-based therapy and ahead of disease progression in patients (pts) with HR+/HER2- advanced breast cancer (ABC). San Antonio Breast Cancer Symposium 2025;Abstract RF7-03. 

Martin M et al. Safety and patient (pt)-reported outcomes (PROs) from evERA breast cancer (BC): A phase III trial of giredestrant (GIRE) + everolimus (E) in pts with oestrogen receptor-positive, HER2-negative advanced BC (ER+, HER2– aBC) previously treated with a CDK4/6 inhibitor (i). ESMO Breast Cancer Congress 2026;Abstract 418O. 

Mayer E et al. Giredestrant (GIRE), an oral selective oestrogen receptor (ER) antagonist and degrader, + everolimus (E) in patients (pts) with ER-positive, HER2-negative advanced breast cancer (ER+, HER2– aBC) previously treated with a CDK4/6 inhibitor (i): Primary results of the phase III evERA BC trial. ESMO 2025;Abstract LBA16. 

Rugo HS et al. Clinical and biomarker subgroup analysis of evERA breast cancer: A phase III trial of giredestrant plus everolimus in patients with estrogen receptor-positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor. San Antonio Breast Cancer Symposium 2025;Abstract GS3-09. 

Rugo HS et al. Elacestrant in combination with everolimus or abemaciclib in patients with ER+/HER2- locally advanced or metastatic breast cancer (mBC): Phase 2 results from ELEVATE, an open-label, umbrella study. San Antonio Breast Cancer Symposium 2025;Abstract RF7-01. 

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 Cancer Congress 2023;Abstract 41P. 

Dr Hurvitz 

André F et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Final overall survival results from SOLAR-1. Ann Oncol 2021;32(2):208-17. Abstract 

Browne IM et al. Optimal targeting of PI3K-AKT and mTOR in advanced oestrogen receptor-positive breast cancer. Lancet Oncol 2024;25(4):e139-51. Abstract 

Chia SKL et al. A double-blind placebo controlled randomized phase III trial of fulvestrant and ipatasertib as treatment for advanced HER2-negative and estrogen receptor positive (ER+) breast cancer following progression on first line CDK 4/6 inhibitor and aromatase inhibitor: The CCTG/BCT MA.40/FINER study (NCT04650581). ASCO 2025;Abstract LBA1005. 

Hurvitz SA et al. VIKTORIA-1 trial of gedatolisib plus fulvestrant with or without palbociclib in hormone receptor-positive/HER2-/PIK3CA wild-type advanced breast cancer. J Clin Oncol 2026;44(12):1108-19. Abstract 

Juric D et al. First-line inavolisib/placebo + palbociclib + fulvestrant (inavo/pbo+palbo+fulv) in patients (pts) with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer who relapsed during/within 12 months (mo) of adjuvant endocrine therapy completion: INAVO120 phase III randomized trial additional analyses. ASCO 2024;Abstract 1003. 

Layman RM et al. Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from the dose expansion groups of an open-label, phase 1b study. Lancet Oncol 2024;25(4):474-87. Abstract 

Rossetti S et al. Gedatolisib shows superior potency and efficacy versus single-node PI3K/AKT/mTOR inhibitors in breast cancer models. NPJ Breast Cancer 2024;10(1):40. Abstract 

Rugo HS et al. Capivasertib plus fulvestrant as first and second-line endocrine-based therapy in PIK3CA/AKT1/PTEN-altered hormone receptor-positive advanced breast cancer: Subgroup analysis from the phase 3 CAPItello-291 trial. ESMO 2026;Abstract 526P. 

Turner NC et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med 2023;388(22):2058-70. Abstract 

Dr Tolaney 

Bardia A et al. Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment for patients with estrogen receptor-positive, HER2-negative early breast cancer: Results from the global phase III lidERA breast cancer trial. San Antonio Breast Cancer Symposium 2025;Abstract GS1-10. 

Ignatiadis M et al. EORTC-2129-BCG: Elacestrant for treating ER+/HER2- breast cancer patients with ctDNA relapse (TREAT ctDNA). ASCO 2025;Abstract TPS620.