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

Abstract

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. 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. 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 <i>PIK3CA</i> mutations (42%) and CNGs of <i>CCND1</i> (15%), <i>ERBB2</i> (10%), <i>FGFR1</i> (8%), and <i>MYC</i> (8%). <i>PIK3CA</i> mutations and <i>MYC</i> CNGs were associated with lower (<i>P</i> = 0.03) and higher (<i>P</i> = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with <i>CCND1, ERBB2</i>, and <i>MYC</i> CNGs (<i>P</i> = 0.01, <i>P</i> < 0.001, and <i>P</i> = 0.03, respectively). <i>FGFR1</i> 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; <i>P</i> = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61-7.75; <i>P</i> = 0.002) and in multivariable models adjusted for clinicopathologic factors. Postmenopausal women with hormone receptor-positive early breast cancer harboring <i>FGFR1</i> CNG had an increased risk of late recurrence despite extended therapy. <i>FGFR1</i> CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.