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SABCS 2015: ESR1 Gene Mutations Are Associated With Worse Overall Survival in Metastatic ER-Positive Breast Cancer

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Key Points

  • D538G and Y537S mutations in the estrogen receptor 1 gene are common among patients with advanced estrogen receptor–positive breast cancer.
  • Patients with these mutations had a significantly worse median overall survival than women who did not have these mutations: 15.2 months for women with both D538 and Y537 mutations vs 32.1 months for patients without these mutations.
  • D538G and Y537S mutations appear to have differential effects on exemestane and everolimus sensitivity, highlighting new areas for research in estrogen receptor biology.

A study by Chandarlapaty et al investigating whether mutations in the estrogen receptor are common in patients with advanced breast cancer and how they affect patient outcomes has found that the D538G and Y537S mutations in the estrogen receptor 1 (ESR1) gene are prevalent in patients with advanced estrogen receptor–positive breast cancer that has progressed after treatment with an aromatase inhibitor.

In addition, these patients had a significantly worse median overall survival than women who did not have these mutations: 15.2 months for women with both D538 and Y537 mutations vs 32.1 months for patients without these mutations. The study (Abstract S2-07) was presented at the 2015 San Antonio Breast Cancer Symposium held December 8–12.

Study Methodology

The researchers evaluated blood samples from patients enrolled in the BOLERO-2 clinical trial. Cell-free DNA (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 mutations. Cox-proportional hazards model was used to assess progression-free survival in patient subgroups defined by each ESR1 mutation, and the prognostic effect of each ESR1 mutation on overall survival.

Key Findings

Of the 541 evaluable patients (74% of the 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 yielded only four instances of D538G (1.3%) and one instance of Y537S (0.3%).

In the overall population, both mutations were poor prognostic factors associated with shorter overall survival: 32.1 months for patients with neither a D538G or 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.

Progression-free survival results were different for the two mutations. The D538G mutation, but not the Y537S mutation, was associated with a shorter progression-free survival with exemestane compared to the wild type, (hazard ratios, D538G = 1.44 [95% confidence intervals [CIs] = 1.04–1.99] and Y537S: 0.92 [95% CIs = 0.44–1.93]). The D538G mutant group derived a benefit similar to that seen in the wild-type group with the addition of everolimus (Afinitor) to exemestane, whereas the Y537S group did not.

Using Plasma Analysis to Detect Gene Mutations

During a press briefing announcing his study results, Sarat Chandarlapaty, MD, PhD, a breast medical oncologist at Memorial Sloan Kettering Cancer Center in New York, and the first author of the study, reiterated several conclusions from his findings.

“First, we can detect mutations in the estrogen receptor pretty readily using plasma analysis. These were plasma samples that were collected not with the intent of looking specifically for estrogen-receptor mutations, but they were collected as standard plasma, and we were able to use them. Second, mutation was quite frequent in this population; at least 30% have mutations in the estrogen receptor,” he said.

“Third, by using plasma, we think we are doing better at detecting mutations than if we go to the old archival tumor materials,” he continued. “Fourth, patients who had mutations had a shorter median survival than those who did not. And, fifth, the patients with different mutations might end up having different responses to therapies in the future, and that is an important area for future research.”

Carlos L. Arteaga, MD, moderator of the press briefing, Co-director of the San Antonio Breast Cancer Symposium, and Director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center in Nashville, emphasized that using this type of plasma analysis was not a test for detecting breast cancer. “It is a test that picks up on mutations; [it is] not something that tells whether or not a person has cancer,” he said.

Funding for this study was provided by Novartis and the Memorial Sloan Kettering Cancer Center’s Center for Metastasis Research. Dr. Chandarlapaty receives consulting fees from Chugai Pharmaceutical, Foresite Capital, and Oncotheyreon, and conducts research for Novartis.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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