Resistance Mutations: Next in ER+ Metastatic Breast Cancer?

Kate Johnson

December 10, 2015

SAN ANTONIO, Texas — Estrogen receptor (ER) mutations can be easily detected in the plasma of patients with metastatic breast cancer and may hold the key to targeted treatments for women with endocrine-resistant disease, according to new analysis of patients in the BOLERO-2 trial.

"Patients who had mutations had a shorter median survival than those who did not…and patients with different mutations might have different responses to therapies," Sarat Chandarlapaty, MD, PhD, a breast medical oncologist from Memorial Sloan Kettering Cancer Center in New York reported at the San Antonio Breast Cancer Symposium.

BOLERO-2 enrolled postmenopausal women with metastatic, endocrine-resistant, ER-positive breast cancer and changed the standard of care in this setting, as reported by Medscape Medical News.

Dr Chandarlapaty's team analyzed plasma samples taken from 541 patients at the time of enrolment and found a high rate of two of the most common ER mutations: D538G and Y537S.

Overall, 28.8% of the samples had these mutations: 15.3% had D538G only, 7.8% had Y537S only, and 5.5% had both.

"This is a common alteration in patients with metastatic breast cancer," he said. "We don't think the aromatase inhibitors cause these mutations directly, we think it's more an indirect effect…. The idea is the low estrogen environment that the aromatase inhibitors create can be a nidus for selecting these mutations."

Dr Sarat Chandarlapaty

Examining patient survival with their mutation status, the researchers also found that median progression-free survival was significantly lower for patients with either mutation compared with those without a mutation (20.7 vs 32.1 months, hazard ratio [HR], 1.4).

Overall, the BOLERO-2 trial showed that the addition of everolimus to exemestane doubled progression-free survival (HR, 0.4), but the new analysis showed that treatment response was dependent on mutation status.

"Most patients benefited from adding the everolimus…and that was also true for patients with the D538G mutation (HR, 0.34). But unexpectedly, the group that had the Y537S mutation did not show this benefit (HR, 0.98)," he reported.

However, there were only 21 patients with the Y537S mutation who received both everolimus and exemestane, he cautioned. "It's not something we would say don't give today based on this result, but it does tell us the biology and that we need to look at these mutations going forward and ask how do they impact therapies."

"We don't have much actionability for this information," agreed Carlos Arteaga, MD, codirector of the San Antonio Breast Cancer Symposium.

"Follow-up studies will be needed to determine whether detecting ER mutations in patients indicates a change in treatment is warranted," added Arul M. Chinnaiyan, MD, PhD, Director of the University of Michigan's Center for Translational Pathology, who published a recent review on the topic (Breast Cancer Research 2014, 16:494).

But, the study "is impressive as it is one of the largest assessments of ER mutations in patients with metastatic breast cancer treated with aromatase inhibitors," he told Medscape Medical News. "One limitation is that they only monitored 2 specific ER mutations, which may represent a little over half of the ER mutations that have been described by our group, and others."

And Lidia Schapira MD, from the Dana-Farber/Harvard Cancer Center, told Medscape Medical News, "It is precisely this kind of research that will lead us to be able to provide personalized advice for treatments in the future to patients with metastatic disease, and we can imagine the possible benefits that will ensue when we will be able to select a treatment with a clearer understanding of the expected clinical benefit."

The study was funded by Novartis.

Dr Chandarlapaty disclosed consulting fees from Chugai, Foresite, and Oncothyreon.

San Antonio Breast Cancer Symposium (SABCS) 2015: Abstract S2-07. Presented December 9, 2015.


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