Genomic Aberrations and Late Recurrence in Postmenopausal Women with Hormone Receptor–positive Early Breast Cancer: Results from the SOLE Trial

Abstract

Purpose: Women with hormone-receptor-positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late recurrence risk. Experimental Design: In a secondary analysis of Study of Letrozole Extension (SOLE) trial, a case-cohort-like sampling selected 598 primary breast cancer for targeted next-generation sequencing (NGS) analysis of gene mutations and copy number gains (CNG). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence free-intervals (BCFI and DRFI) were analyzed using weighted Cox models. Results: Analysis of mutations and CNG was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time: 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%) and MYC (8%). PIK3CA mutations and MYC CNG were associated with lower (p=0.03) and higher (p=0.004) tumor grade respectively; a higher Ki67 was seen in tumor with CCND1, ERBB2 and MYC CNGs (p=0.01, FGFR1 CNG was associated with an increased risk of late events in univariate analyses (17/29 patients; BCFI: HR=3.2, 95%CI: 1.48-6.92, p =0.003; DRFI: HR=3.5, 95%CI: 1.61-7.75, p=0.002) and in multivariable models adjusted for clinicopathologic factors. Conclusions: Postmenopausal women with hormone receptor-positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.