Plasma ESR 1 Mutations and the Treatment of Estrogen Receptor – Positive Advanced Breast Cancer
Purpose ESR1mutations 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. Materials and Methods In a prospective-retrospective analysis,weassessedESR1mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus ExemestaneWith 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. Results In SoFEA, ESR1mutations 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 withESR1mutationshad improvedprogression-freesurvival (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 patientswithwildtype ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3,ESR1mutationswere found in theplasmaof 25.3%of patients (91of 360), ofwhom28.6% (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 ESR1mutant (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). Conclusion 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. J Clin Oncol 34:2961-2968. © 2016 by American Society of Clinical Oncology