<i>ESR1</i> Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor-Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials.

Abstract

<i>ESR1</i> mutations are acquired frequently in hormone receptor-positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline <i>ESR1</i> circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane. The phase III EFECT and SoFEA trials randomized patients with hormone receptor-positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for <i>ESR1</i> mutations by digital PCR. The primary objectives were to assess the impact of <i>ESR1</i> mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies. <i>ESR1</i> mutations were detected in 30% (151/383) baseline samples. In patients with <i>ESR1</i> mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0-2.6] on exemestane and 3.9 months (95% CI, 3.0-6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39-0.89; <i>P</i> = 0.01). In patients without <i>ESR1</i> mutations detected, PFS was 4.8 months (95% CI, 3.7-6.2) on exemestane and 4.1 months (95% CI, 3.6-5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81-1.37; <i>P</i> = 0.69). There was an interaction between <i>ESR1</i> mutation and treatment (<i>P</i> = 0.02). Patients with <i>ESR1</i> mutation detected had 1-year OS of 62% (95% CI, 45%-75%) on exemestane and 80% (95% CI, 68%-87%) on fulvestrant (<i>P</i> = 0.04; restricted mean survival analysis). Patients without <i>ESR1</i> mutations detected had 1-year OS of 79% (95% CI, 71%-85%) on exemestane and 81% (95% CI, 74%-87%) on fulvestrant (<i>P</i> = 0.69). Detection of <i>ESR1</i> mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant.