Genomic profiling of ER⁺ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance.

Abstract

Inhibition of proliferation in estrogen receptor-positive (ER⁺) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER⁺/human epidermal growth factor receptor 2-negative (HER2^-) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including <i>FGFR1</i> and <i>CCND1</i>, respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pretreatment, postneoadjuvant chemotherapy, and recurrent ER⁺ tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER⁺<i>FGFR1</i>/<i>CCND1</i> coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal <i>ESR1</i> fusion transcripts and increased expression of gene signatures indicative of enhanced E2F-mediated transcription and cell cycle processes in cancers with high Ki67. These data suggest that short-term preoperative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations that may cause intrinsic endocrine therapy resistance.