Public Release: 

Blood samples analysis finds ESR1 gene mutations prevalent, associated with worse overall survival

The different mutations may predict different responses to everolimus

American Association for Cancer Research

SAN ANTONIO -- Among patients with estrogen receptor (ER)-positive, metastatic breast cancer, those who had a D538G and/or a Y537S mutation in the estrogen receptor 1 (ESR1) gene, as detected in cell-free DNA obtained from patient blood samples, had significantly worse median overall survival, according to data presented at the 2015 San Antonio Breast Cancer Symposium, held Dec. 8-12.

"Even though patients with ER-positive, metastatic breast cancer are all generally given treatments targeting the estrogen receptor, there is a real diversity in how their tumors respond to these drugs, and, therefore, a real diversity in patient outcomes," said Sarat Chandarlapaty, MD, PhD, a breast medical oncologist at Memorial Sloan Kettering Cancer Center in New York. "Our goal was to determine if changes in the estrogen receptor itself might explain these differences. Specifically, we wanted to know: Are mutations in the estrogen receptor common in patients with advanced breast cancer? And do they have an effect on outcomes?

"Using a simple blood test, we found that the D538G and Y537S mutations in the estrogen receptor are more common in patients with advanced, ER-positive breast cancer than previously appreciated and that patients with these mutations don't respond as well to currently used therapies and die from their disease sooner than patients who do not have these mutations," added Chandarlapaty. "The data also suggest that there appear to be differences in how these two mutations affect response to everolimus, but there is more work needed to confirm this. Finding out which cancers respond best to which treatments is key to directing clinical and research efforts and will help breast cancer care become more precise and effective in the future."

Previously published results from the phase III BOLERO-2 clinical trial showed that adding everolimus to the standard hormonal therapy exemestane improved outcomes for postmenopausal women with ER-positive, locally advanced or metastatic breast cancer that has progressed after treatment with an aromatase inhibitor, and led to the U.S. Food and Drug Administration approving everolimus for this use in July 2012.

In this analysis, Chandarlapaty and colleagues evaluated blood samples from 541 of the 724 patients enrolled in BOLERO-2. They detected the D538G ESR1 mutation in samples from 83 patients, the Y537S ESR1 mutation in samples from 42 patients, and both mutations in samples from 30 patients.

Median overall survival was 32.1 months for patients with neither a D538G nor a Y537S ESR1 mutation, 26 months for those with only a D538G mutation, 20 months for those with only a Y537S mutation, and 15.2 months for those with both mutations. Exploratory analyses showed that adding everolimus to exemestane more than doubled progression-free survival for patients with neither ESR1 mutation and for those with a D538G mutation. However, the treatment combination did not appear to increase progression-free survival for patients with a Y537S mutation.

Chandarlapaty stated, "These data show clearly that the D538G and Y537S ESR1 mutations are prevalent among patients with advanced, ER-positive breast cancer that has progressed after treatment with an aromatase inhibitor and that they are associated with worse outcomes. However, the number of patients with the Y537S ESR1 mutation was small so further studies are needed before we can consider bypassing everolimus treatment for this patient population."

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This study was supported by Novartis and the Memorial Sloan Kettering Cancer Center's Center for Metastasis Research. Chandarlapaty receives consulting fees from Chugai, Foresite Capital, and Oncotheyreon, and conducts contracted research for Novartis.

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The mission of the 2015 San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR's scientific prestige in basic, translational, and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit http://www.sabcs.org.

Abstract: S2-07

Title: cfDNA analysis from BOLERO-2 plasma samples identifies a high rate of ESR1 mutations: Exploratory analysis for prognostic and predictive correlation of mutations reveals different efficacy outcomes of endocrine therapy-based regimens

Authors: Sarat Chandarlapaty1, Patricia Sung1, David Chen2, Wei He2, Aliaksandra Samoila1, Daoqi You1, Trusha Bhatt1, Parul Patel2, Maurizio Voi2, Michael Gnant3, Gabriel Hortobagyi4, Jose Baselga1 and Mary Ellen Moynahan1. 1Memorial Sloan Kettering Cancer Center, New York, NY; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ; 3Medical University of Vienna, Vienna, Austria and 4The University of Texas MD Anderson Cancer Center, Houston, TX.

Body:

Background: The Y537S and D538G mutations in ESR1 are recurrent alterations in metastatic breast cancer (MBC) that promote ligand-independent receptor activation and resistance to estrogen deprivation therapy in laboratory models. The clinical prevalence of these mutations is not well established, but has been reported to be ~10% by tumor sequencing. Cell free DNA (cfDNA) analysis typically reflects tumor-derived genetic alterations and can be used to characterize a population of patients at a common time point. We hypothesized that cfDNA could be used to detect ESR1 mutation at entry and its clinical impact in a large subset from BOLERO-2 that randomized patients with MBC to Exemestane (EXE) or EXE plus Everolimus (EVE).

Methods: Patients with ER+/HER2- MBC with prior exposure to at least 1 non-steroidal aromatase inhibitor (NSAI) were enrolled in BOLERO-2. cfDNA was extracted from 560 baseline plasma samples using QIAamp Circulating DNA kit or QIAsymphony DSP Virus/Pathogen kit. Samples were analyzed by droplet digital PCR for Y537S and D538G. Cox-proportional hazards model was used to assess progression free survival (PFS) in patient subgroups defined by each ESR1 mutation, and the prognostic effect of each ESR1 mutation on overall survival (OS).

Results: Of 541 evaluable patients (74.7% of study population), 156 (28.8%) had mutation in ESR1 in D538G (21.1%) and/or Y537S (13.3%) with 30 samples having both mutations. Sequencing of 302 archival tumor specimens (244 primary and 57 metastases) from this study only yielded 4 instances of D538G (1.3%) and 1 Y537S (0.3%). In the overall population, both mutations were poor prognostic factors associated with shorter OS (Table 1). PFS results were different for the two mutations. D538G but not Y537S mutation was associated with a shorter PFS with EXE compared to wild type (WT), (hazard ratios, D538G: 1.44 [95%CIs, 1.04-1.99] and Y537S: 0.92 [95%CIs, 0.44-1.93]). The D538G mutant group derived a similar benefit as WT from the addition of EVE to EXE, whereas the Y537S group did not (Table 2).

Table 1

Alteration N Events Median OS (95%CI) HR (95%CI)
WT 385 217 32.1 (28.1-36.4)
D538G 83 57 26.0 (19.2-32.4) 1.25 (1.02-1.54)
Y537S 42 30 20.0 (13.0-29.3) 2.31 (1.34-3.97)
Double mt 30 24 15.2 (10.9-27.4) 1.77 (1.31-2.39)

Table 2

Alteration Group N Events Median PFS (95%CI) HR (95%CI)
WT EXE 128 116 3.9 (2.8-4.2) 0.4 (0.31-0.51)
EXE/EVE 257 172 8.5 (6.9-9.9)
D538G EXE 24 22 2.7 (1.4-2.8) 0.34 (0.2-0.57)
EXE/EVE 59 45 5.8 (4.2-8.4)
Y537S EXE 21 16 4.1 (1.4-6.7) 0.98 (0.49-1.94)
EXE/EVE 21 19 4.2 (1.4-5.4)

Conclusions: cfDNA analysis identifies a high rate of the Y537S and D538G ESR1 mutations in ER+ NSAI-treated MBC. As the two mutations may only represent 50-60% of all activating ESR1 mutations, the clinical prevalence of ESR1 mutations in ER+ MBC may be much higher than previously reported. Both mutations appear to be associated with a more aggressive disease biology. Interestingly, these two activating mutations appear to have differential effects on EXE and EVE sensitivity, highlighting new areas for research in ER biology.

This research will be presented at a press conference at the 2015 San Antonio Breast Cancer Symposium, moderated by SABCS Co-director and AACR Past-president Carlos L. Arteaga, MD, director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center, Thursday, Dec. 10, 7:30 a.m. CT in Room 217D of the Henry B. Gonzalez Convention Center. Reporters who cannot attend the press conference in person can call in using the following information:

  • United States/Canada (toll-free): 866-297-6395
  • International (toll): 1-847-944-7317
  • Conference code number: 41320576

To interview Sarat Chandarlapaty, contact Julia Gunther at julia.gunther@aacr.org or 267-250-5441.

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