by
Jennifer Giltnane;
Katherine E. Hutchinson;
Thomas P. Stricker;
Luigi Formisano;
Christian Young;
Monica V. Estrada;
Mellissa J Nixon;
Liping Du;
Violeta Sanchez;
Paula Gonzales Ericsson;
Maria Kuba;
Melinda E. Sanders;
Xinmeng J. Mu;
Eliezer M. Van Allen;
Nikhil Wagle Wagle;
Ingrid A. Mayer;
Vandana Abramson;
Henry Gomez;
Monica Rizzo;
Weiyi Toy;
Sarat Chandarlapaty;
Eria L. Mayer;
Joseph Christiansen;
David J Murphy;
Kerry Fitzgerald;
Kai Wang;
Jeffrey S. Ross;
Vincent A. Miller;
Phillip Stephens;
Roman Yelensky;
Levi Garraway;
Yu Shyr;
Ingrid Meszoely;
Justin M. Balko;
Carlos L. Arteaga
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 FGFR1 and CCND1, 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+ FGFR1/CCND1 coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal ESR1 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.