Plasma <i>ESR1</i> Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

TLDR

ESR1 mutations are selected by prior aromatase inhibitor therapy in advanced breast cancer. The study evaluated how ESR1 mutations influence sensitivity to standard endocrine therapies in two phase III randomized trials for estrogen receptor‑positive advanced breast cancer. Plasma ESR1 mutations were detected by multiplex digital PCR in archived baseline samples from the SoFEA and PALOMA3 trials, revealing 39.1% and 25.3% mutation rates, respectively, with a substantial proportion of polyclonal mutations. Patients with ESR1 mutations had better progression‑free survival on fulvestrant versus exemestane, while wild‑type patients showed no difference, and in both mutant and wild‑type groups fulvestrant plus palbociclib improved PFS over fulvestrant alone, indicating that mutation testing can guide endocrine therapy choice, though further confirmation is required.

Abstract

ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor-positive advanced breast cancer.In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction.In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001).ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.