A Decade of MSK Research Laid Groundwork for Recent Approval of a Targeted Therapy for Metastatic Breast Cancer

physician-scientist Sarat Chandarlapaty, MD, PhD and colleague working in their MSK laboratory.

MSK physician-scientist Sarat Chandarlapaty, MD, PhD, led research that revealed insights into the prevalence of specific mutations in ER-positive metastatic breast cancer, laying the groundwork for a new targeted therapy.

You may have heard that the U.S. Food and Drug Administration (FDA) approved elacestrant for postmenopausal women or adult men with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer on January 27, 2023. In addition, the FDA also approved the Guardant360 CDx assay, a companion liquid biopsy diagnostic device for identifying patients for treatment.

But did you know that the foundational work for these approvals was pioneered at MSK by physician-scientist Sarat Chandarlapaty, MD, PhD, and colleagues? Their work revealed insights into the prevalence of specific ESR1 mutations in ER-positive metastatic breast cancer, the underlying mechanisms causing resistance to anti-estrogen therapies, the feasibility of liquid biopsy for identifying ESR1 alterations, and selective alterations associated with heightened sensitivity to ER antagonists.

2013: Identifying Resistance Mechanisms

More than 70% of breast cancers express the normal estrogen receptor and initially respond to anti-estrogen therapy. However, most of these cancers develop resistance to anti-estrogen drugs over time. Dr. Chandarlapaty; research fellow Weiyi Toy, PhD; and colleagues performed genomic analysis on resistant tumors and discovered more than 20% had acquired new ESR1 mutations that caused resistance and were not present in tumors collected before hormone therapy.

Their work, published in Nature Genetics, demonstrated how these mutations activated the hormone receptor without estrogen present, suggesting selective estrogen receptor degraders (SERDs) as a potential strategy to overcome resistance. (1)

2016: Liquid Biopsy Research Points to New Testing Strategy

Physician-scientist Mary Ellen Moynahan, MD; Dr. Chandarlapaty; and colleagues analyzed circulating cell-free DNA in plasma samples from 541 individuals with metastatic breast cancer who participated in the phase 3 BOLERO-2 clinical trial (NCT00863655).

The investigators discovered about 30% of patients with ER-positive, HER2-negative advanced breast cancer harbored one of the two most common ESR1 mutations (Y537S and D538G) associated with more aggressive disease and shorter overall survival. Their research confirmed the feasibility of using liquid biopsies to identify mutations and spurred research into therapies targeting them. Their findings were published in JAMA Oncology(2)

2017: Identifying a Next-Generation ER Antagonist

Dr. Chandarlapaty, Dr. Toy, and colleagues characterized the diversity of ESR1 mutations using cell cultures, models derived from patient samples, and animal studies, and by sequencing metastatic breast tumor samples with MSK-IMPACT® (which stands for Integrated Mutation Profiling of Actionable Cancer Targets).

They discovered a variety of activating ESR1 mutations in more than 900 patient samples, including selective alterations associated with notably reduced sensitivity to ER antagonists in vivo. Their findings, published in Cancer Discovery, highlighted the potential for next-generation SERDs to overcome resistance and become a viable treatment strategy. (3)

Advancing Cancer Research

Multidisciplinary physicians and scientists at MSK are dedicated to advancing cancer research and improving patient outcomes. The present studies included experts from MSK’s Human Oncology and Pathogenesis Program, Breast Service (Department of Surgery), Breast Medicine Service (Department of Medicine), Department of Pathology and Laboratory Medicine, and Antitumor Assessment Core Facility, as well as colleagues from other leading centers.

Please refer to the papers above for study-specific funding support and disclosures. Refer to the MSK website for current disclosures for Dr. Chandarlapaty.

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  1. Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45(12):1439-1445.
  2. Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial. JAMA Oncol. 2016;2(10):1310-1315.
  3. Toy W, Weir H, Razavi P, et al. Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists. Cancer Discov. 2017;7(3):277-287.