ESR1 MUTATIONS AND RESISTANCE TO ENDOCRINE THERAPY

For patients with estrogen receptor (ER)-positive metastatic breast cancer (MBC), the clinical course can vary widely, with relapse occurring within months — or years.

Predicting which patients achieve good disease control with single-agent hormonal therapy and which patients require more drugs for a durable treatment response is a significant clinical challenge.

Now, a secondary analysis of archival tumor specimens from the BOLERO-2 clinical trial shows that two estrogen receptor α (ESR1) mutations — Y537S and D538G — are prevalent in patients with MBC who were previously treated with a nonsteroidal aromatase inhibitor (AI).

Both of these mutations are associated with more aggressive disease biology and worse outcomes, say Sarat Chandarlapaty, MD, PhD, from the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, New York, New York, and colleagues in JAMA Oncology.

The study results were first presented at the 2015 San Antonio Breast Cancer Symposium and reported by Medscape Medical News at that time.

The full data report is now available, published online August 11.

The analysis of noncell DNA from 541 patients with MBC that recurred and/or progressed during therapy with AIs revealed that 29% of patients (n = 156) had a mutation in the ER. These patients had a significantly shorter median overall survival than patients without a mutation (20.7 months vs 32.1 months).

mportantly, prevalence of these 2 ESR1 mutations varied depending on whether the AI treatments were given in the adjuvant or metastatic setting. Patients in whom first-line therapy for MBC failed had a 3-fold increase in mutation prevalence compared with those initiating first-line treatment for metastatic disease (33% vs 11%), the study showed.

"Overall, as a large suite of drugs (CDK4/6 inhibitors, HDAC inhibitors, PI3K inhibitors, new ER antagonists) are being developed for ER-positive MBC, assessment of ESR1 mutation status may prove to be a valuable predictive biomarker and ought to be incorporated in these studies.... The ease and affordability of such a test will also enable dynamic testing that will improve our understanding of the evolution of this disease and the design of strategies to improve outcomes," the authors write.

In an interview with Medscape Medical News, Dr Chandarlapaty noted that despite the "plethora of options in terms of endocrine therapies, we have little to no guidance for when to give which drug. We need insights into how to maximize the utility of these agents rather than giving them in a somewhat haphazard fashion."

More studies are needed to determine the predictive value of mutation for different therapies, particularly as many patients are routinely given combination therapy, he said. "We hope in the future to determine if ESR1 mutation predicts for shorter response to combinations with AIs than to combinations with ER antagonists."

Currently, testing for mutations in ESR1 is not available for patients outside the clinical research setting.

Demonstrating that stored plasma from a large randomized controlled trial could be used for genomic analyses was another important finding, he said. "We are hopeful that the clinical oncology research community will be able to address many similar key questions using cell-free DNA."

In an accompanying editorial, Suzanne Fuqua, PhD, from the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, Texas, and colleagues say that when it comes to predicting therapy response, these findings could be "just the tip of the iceberg."

They caution that testing for the ESR1 mutation was "incomplete" because the researchers didn't report other "relatively frequent" mutations, such as K303R and E380Q.

Multiple ESR1 mutations can coexist in a single metastatic breast lesion as well as in distant lesions, note the editorialists. They cite results from an earlier study showing that during treatment of metastatic disease, these mutations are selected by AI drugs to become the dominant clone. Subsequent AI therapy in patients with ESR1 mutations in this earlier study resulted in a substantially shorter progression-free survival (PFS), they point out.

"Clinically it will be critical to determine whether the alternate use of tamoxifen and/or fulvestrant in the metastatic setting will more effectively block the selection and evolution of ESR1mutations during therapy, and thus avoid such dominant selection pressures," they write.

The editorialists also note that patients with the D538G ESR1 mutation experienced a median PFS of 7.8 months after treatment with everolimus (Afinitor, Novartis) whereas patients with the Y537S mutation experienced a median reduction in PFS of 3.2 months after treatment.

These experts explain the ramifications of this finding: "These results suggest that knowledge of the resistance escape mechanisms coexisting with ESR1mutant expression will need to be identified to accurately guide targeted therapy of metastatic breast cancer."

Asked to comment, Mateusz Opyrchal, MD, PhD, assistant professor of oncology at Roswell Park Cancer Institute, Buffalo, New York, said this analysis adds to existing data that ESR1 mutations "are important prognostic and potentially predictive biomarkers for hormonal therapy."

He too thought it was interesting that patients with D538G but not with Y537S mutation derived benefit from the addition of everolimus to exemestane. "This could be due to the relatively small numbers of patients or the existence of other abnormalities in ESR1 or other genes which were not part of this investigation," he told Medscape Medical News. It also raises the question of whether mutations in different parts of ESR1 lead to different functional changes, he said.

Testing for mutations in ESR1 could eventually be available to all clinicians, he said, possibly helping choose the best therapy for patients. "The true value in clinical practice would best be proven in a prospective manner and hopefully, future trials will include ESR1 mutations as part of screening potential patients," Dr Opyrchal said.

For the study, researchers analyzed cell-free DNA from baseline plasma samples in 75% of participants in the BOLERO-2 double-blind phase 3 study. The study enrolled postmenopausal women with a diagnosis of MBC and prior exposure to an AI from 189 centers in 24 countries. Participants were randomly assigned to exemestane (25 mg oral daily) along with either everolimus (10 mg oral daily) or placebo.

Analysis of Y537S and D538G — the 2 most frequent ESR1 mutations — was carried out from December 16, 2014, to August 26, 2015. Samples were scored as wild-type, D538G, Y537S, or double mutant.

The analysis showed that the mutations were associated with shorter overall survival: wild-type, 32.1 months; D538G, 25.99 months; and Y537S, 19.98 months. In the 30 patients who had both D538G and Y537S mutations, the overall survival was 15.15 months.

The BOLERO-2 study and the analysis performed in this work were supported by Novartis. Dr Chandarlapaty received consulting fees from AstraZeneca. Coauthors David Chen, Wei He, Parul Patel, and Maurizio Voi are employees of Novartis. Dr Opyrchal disclosed research funding from Pfizer. No other relevant financial relationships have been disclosed.