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

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 trial, a case-cohort-like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models.

Results: Analysis of mutations and CNGs 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 mutations (42%) and CNGs of (15%), (10%), (8%), and (8%). mutations and CNGs were associated with lower ( = 0.03) and higher ( = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with , and CNGs ( = 0.01, < 0.001, and = 0.03, respectively). CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48-6.92; = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61-7.75; = 0.002) and in multivariable models adjusted for clinicopathologic factors.

Conclusions: Postmenopausal women with hormone receptor-positive early breast cancer harboring CNG had an increased risk of late recurrence despite extended therapy. CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.