Estrogen Receptor Mutations Linked to Lower Survival in HR+/HER2- Breast Cancer

Jason M. Broderick @jasoncology
Published: Friday, Dec 11, 2015

Dr. Sarat Chandarlapaty

Sarat Chandarlapaty, MD, PhD

Estrogen receptor mutations are prevalent and associated with poorer survival in patients with pretreated HR+/HER2- metastatic breast cancer, according to an analysis of plasma samples from the BOLERO-2 trial.

The findings, which were presented at the 2015 San Antonio Breast Cancer Symposium, suggest that these mutations may eventually help guide treatment selection in this setting.

“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,” lead researcher Sarat Chandarlapaty, MD, PhD, a breast medical oncologist at Memorial Sloan Kettering Cancer Center said in a statement. “Our goal was to determine if changes in the estrogen receptor itself might explain these differences.

The phase III BOLERO-2 trial enrolled 724 postmenopausal women with hormone receptor­–positive metastatic breast cancer who had progressed on a nonsteroidal aromatase inhibitor (AI), such as anastrozole or letrozole. In the study, progression-free survival (PFS) was 7.8 months with everolimus (Afinitor) plus exemestane versus 3.2 months with exemestane alone. Overall survival was 31.0 versus 26.6 months, respectively. Based on these data, the FDA approved everolimus in this setting in 2012.

Chandarlapaty et al analyzed cell free DNA (cfDNA) extracted from 541 plasma samples from patients enrolled in BOLERO-2. The samples had been stored since they were taken at the time of patient enrollment. The investigators looked for the 2 most common estrogen receptor 1 (ESR1) mutations they had found in previous analyses, D538G and Y537S.  

The cfDNA analysis showed that 156 patients (28.8%) had either a D538G or a Y537S mutation, including 83 patients (15.3%) with a D538G mutation, 42 patients (7.8%) with a Y537S mutation, and 30 patients (5.5%) with both. In comparison to the plasma test, sequencing of 302 specimens from archival tumor biopsies found only 4 D538G mutations (1.3%) and 1 Y537S mutation (0.3%).

Chandarlapaty offered possible explanations for the discrepancy between the mutation frequency in the plasma test and the tumor biopsy. The archival tumor samples were often from the primary breast cancer, whereas the plasma samples were taken at BOLERO-2 baseline, when patients had metastatic disease. Also, Chandarlapaty said that plasma testing likely captures a “summation of metastases”—not just one lesion, but many different lesions from different locations—and thus probably detects more mutations.

In the plasma analysis, both ESR1 mutations were poor prognostic factors linked to shorter overall survival. Patients harboring either of the ESR1 mutations (n = 156) had a median overall survival (OS) of 20.7 months compared with 32.1 months in wild-type patients (n = 385; HR, 1.40; 95% CI, 1.2-1.65; P = .000037). Median OS was 26.0, 20.0, and 15.2 months for patients harboring D538G (n = 83), Y537S (n = 42), and both mutations (n = 30), respectively.  

Chandarlapaty et al also examined how patients with the ESR1 mutations faired with the BOLERO-2 regimens, specifically in terms of PFS. Their analysis found that the PFS results were different for the 2 mutations, with D538G patients but not Y537S patients experiencing a benefit with everolimus.

Among patients with both mutations, median PFS was 5.42 months with everolimus versus 2.78 months with exemestane alone (HR, 0.53; 95% CI, 0.23-1.25; P = .15). In the D538G group, patients receiving everolimus plus exemestane had a median PFS of 5.8 months versus 2.7 months with exemestane alone (HR, 0.34; 95% CI, 0.2-0.57; P = .00006). However, patients with Y537S mutations had a median PFS of 4.2 months with the addition of everolimus and an almost identical 4.1-month PFS with exemestane alone (HR, 0.98; 95% CI, 0.49-1.94; P = .95).

Chandarlapaty cautioned that it is much too soon to change practice based on these Y537S data. 

“This is a small group of patients in the Y537S group…it's not something where we would now say, ‘Don't go out and give [everolimus] today based on this result.’ But it does tell us the biology and what we need to do going forward in the clinic is look at these mutations not just as a whole, but individually, and ask how do they impact therapies that we're developing going forward."


Chandarlapaty S, Sung P, Chen D, et al. 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. Presented at the 2015 San Antonio Breast Cancer Symposium; San Antonio, Texas, December 8-12, 2015. Abstract: S2-07.

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