ESR1 Mutations Linked To Metastatic ER-Positive Breast Cancer Survival

Estrogen receptor α (ESR1) variants may impact survival of patients being treated for metastatic, oestrogen receptor-positive metastatic breast cancer

medwireNews: Mutations in the estrogen receptor α (ESR1) gene may influence the outcome of postmenopausal patients with oestrogen receptor (ER)-positive metastatic breast cancer treated with aromatase inhibitors, research suggests.

Analysis of cell-free DNA in plasma samples taken from 541 participants of the BOLERO-2 phase III clinical trial comparing exemestane 25 mg/day plus everolimus 10 mg/day or exemestane 25 mg/day plus placebo detected the ESR1 D538G mutation in 21.1% and the Y537S mutation in 13.3%, with 5.5% of patients carrying both variants.

Overall survival was significantly shorter in the patients with any ESR1 mutation than in patients who were wild-type for ESR1, at 20.73 versus 32.10 months, and this was also true for carriers of the D538G or Y537S mutations at 25.99 and 19.98 months, respectively.

Furthermore, overall survival was just 15.5 months for patients carrying both ESR1 mutations, report Sarat Chandarlapaty, from Memorial Sloan Kettering Cancer Center in New York, USA, and co-workers.

The team also found that among patients who received exemestane plus placebo, those with the D538G mutation had significantly shorter progression-free survival (PFS) than their wild-type counterparts (median 2.69 vs 3.94 months, hazard ratio [HR]=1.71) but no such difference was found for carriers of Y537S, who had a median PFS of 4.14 months.

Both wild-type carriers and patients with the D538G mutation derived a significant PFS benefit from the addition to everolimus to exemestane, with PFS of 8.48 months and 5.78 months, respectively.

The researchers observe that there were too few Y537S carriers in the exemestane plus everolimus arm of the trial to definitively determine the impact of the mutation but say it is “hypothesis-generating” to note that there was no apparent PFS benefit for combined over monotherapy in patients with the Y537S gene alone or in combination with D538G mutation, with median PFS times of 4.17 and 5.42 months, respectively.

“The D538G and Y537S ESR1 mutations promote constitutive biochemical activation of the receptor, which is a well-known driver of breast cancer growth”, the team explains in JAMA Oncology.

Describing the high prevalence of ESR1 mutations in patients with ER-positive metastatic breast cancer as a “key finding”, they conclude that further research is warranted into the impact between ESR1 mutations and targeted therapies.

“Overall, as a large suite of drugs (CDK4/6 inhibitors, HDAC inhibitors, PI3K inhibitors, new ER antagonists) are being developed for ER-positive [metastatic breast cancer], assessment of ESR1 mutation status may prove to be a valuable predictive biomarker and ought to be incorporated in these studies”, the authors say.

Reference

Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer. A secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol 2016; Advance online publication 11 August. doi:10.1001/jamaoncol.2016.1279

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