ESR1 Mutations Predict Worse Outcome in HR-positive Metastatic Breast Cancer Treated with Aromatase Inhibitors

ESR1 Mutations Predict Worse Outcome in HR-positive Metastatic Breast Cancer Treated with Aromatase Inhibitors
ESR1 Mutations Predict Worse Outcome in HR-positive Metastatic Breast Cancer Treated with Aromatase Inhibitors

CHICAGO — The presence of circulating ESR1 somatic mutations at disease progression in patients with hormone receptor (HR)-positive metastatic breast cancer treated with first-line aromatase inhibitors (AIs) represent a strong and independent poor prognostic value for overall survival but no predictive value, a study presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting has found.1

The ESR1 circulating mutations are commonly detectable 3 to 6 months before progression and are an important variability after end of AI exposure, Florian Clatot, MD, PhD, Centre Henri Becquerel, University of Normandy, Rouen, France, and colleagues reported.

Recently, the investigators found that detection of such mutations is related to AI resistance. For this study, they evaluated the predictive and prognostic values of circulating ESR1 mutations detected at disease progression.

The retrospective analysis included all consecutive patients treated from January 2008 through December 2010. Using plasma samples, rates of ESR1 circulating mutations — D538G, Y537S/N/C — were assessed using droplet digital PCR. Univariate and multivariate analyses were used to assess the effect of mutational status on overall survival, progression-free survival, and clinical response to subsequent treatments.

A total of 144 patients with hormone receptor positive metastatic breast cancer had circulating mutation analysis at progression; however, 3 patients died, leaving 141 for the survival analysis. Median follow-up from initiation of aromatase inhibitor treatment was 40 months (range, 4 to 94 months).

“At progression, 44 patients (30.6%) presented at least one ESR1 circulating mutation,” Dr. Clatot said. Of the total of 63 mutations, 19% of patients had a single mutation; 9%, a double mutation; and 2%, a triple mutation. The mutation type was D538G in 38%, Y537S in 33%, Y537N in 25%, and Y537C in 3%).

At a follow-up of 40 months (range, 4 to 94 months), there were 108 deaths. Median overall survival after progression was 15 months (range, 2 to 44 months) for patients with the mutations compared with 24 months (range, 2 to 70 months) for patients without mutations (hazard ratio [HR], 1.9; P = .006).

For all patients, independent prognostic factors for overall survival were performance status greater than 1 (HR, 3.0; P < .0001), circulating ESR1 mutation (HR, 1.9; P = .002), and high level of cfDNA (HR, 1.8; P = .006). They found that mutational status was also independently related to a worse progression-free survival (HR, 1.7; P = .008).

Treatment after progression on AI included 1 patient who was switched to another AI, 3 who had everolimus added, 19 who received chemotherapy, and 16 who received tamoxifen/fulvestrant. Five received “other/no treatment” and none received the addition of an HER2-inhibitor.



1. Augusto L, Sarafan-Vasseur N, Perdrix A, et al. Prognostic and predictive value of circulating ESR1 mutations in metastatic breast cancer patients (mBC) progressing under aromatase inhibitor (AI) treatment. Oral presentation at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL.

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