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

Giltnane JM, Hutchinson KE, Stricker TP, Formisano L, Young CD, Estrada MV, Nixon MJ, Du L, Sanchez V, Ericsson PG, Kuba MG, Sanders ME, Mu XJ, Van Allen EM, Wagle N, Mayer IA, Abramson V, Gόmez H, Rizzo M, Toy W, Chandarlapaty S, Mayer EL, Christiansen J, Murphy D, Fitzgerald K, Wang K, Ross JS, Miller VA, Stephens PJ, Yelensky R, Garraway L, Shyr Y, Meszoely I, Balko JM, Arteaga CL
Sci Transl Med. 2017 9 (402)

PMID: 28794284 · PMCID: PMC5723145 · DOI:10.1126/scitranslmed.aai7993

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 and , 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/ coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal 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.

Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

MeSH Terms (11)

Breast Neoplasms Cell Line, Tumor Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase 6 Cyclin D1 Female Humans In Vitro Techniques Receptor, ErbB-2 Receptor, Fibroblast Growth Factor, Type 1 Receptors, Estrogen

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