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

• Type of Material: Article
• Authors: Jennifer Giltnane, Vanderbilt University; Katherine E. Hutchinson, Vanderbilt University; Thomas P. Stricker, Vanderbilt University; Luigi Formisano, Vanderbilt University; Christian Young, Vanderbilt University; Monica V. Estrada, Vanderbilt University; Mellissa J Nixon, Vanderbilt University; Liping Du, Vanderbilt University; Violeta Sanchez, Vanderbilt University; Paula Gonzales Ericsson, Vanderbilt University; Maria Kuba, Vanderbilt University; Melinda E. Sanders, Vanderbilt University; Xinmeng J. Mu, Broad Institute of MIT and Harvard; Eliezer M. Van Allen, Broad Institute of MIT and Harvard; Nikhil Wagle Wagle, Broad Institute of MIT and Harvard; Ingrid A. Mayer, Vanderbilt University; Vandana Abramson, Vanderbilt University; Henry Gomez, Instituto Nacional de Enfermedades Neoplásicas; Monica Rizzo, Emory University; Weiyi Toy, Memorial Sloan Kettering Cancer Center; Sarat Chandarlapaty, Memorial Sloan Kettering Cancer Center; Eria L. Mayer, Dana-Farber Cancer Institute; Joseph Christiansen, Emory University; David J Murphy, Emory University; Kerry Fitzgerald, Genoptix Medical Laboratories; Kai Wang, Foundation Medicine Inc.; Jeffrey S. Ross, Foundation Medicine Inc.; Vincent A. Miller, Foundation Medicine Inc.; Phillip Stephens, Foundation Medicine Inc.; Roman Yelensky, Foundation Medicine Inc.; Levi Garraway, Broad Institute of MIT and Harvard; Yu Shyr, Vanderbilt University School of Medicine; Ingrid Meszoely, Vanderbilt University; Justin M. Balko, Vanderbilt University; Carlos L. Arteaga, Vanderbilt University
• Language: English
• Date: 2017-08-09
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 The Authors.
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aai7993
• Title of Journal or Parent Work: Science Translational Medicine
• ISSN: 1946-6234
• Volume: 9
• Issue: 402
• Start Page: eaai7993
• End Page: eaai7993
• Grant/Funding Information: SC is supported by a DOD Breast Cancer Research Program award W81XWH-14-1-0359 and NCI Cancer Center Support Grant P30 CA08748.; This study was funded by NIH Breast SPORE grant P50 CA098131, Vanderbilt-Ingram Cancer Center Support grant P30 CA68485, Susan G. Komen for the Cure Foundation grant SAC100013 (CLA), Vanderbilt Institute for Clinical and Translational Research (VICTR) Intramural Clinical and Translational Science Award (CTSA) VR2998, and a grant from the Breast Cancer Research Foundation (CLA).; TPS is supported by NIH grant K08 CA148912. JMB is supported by NIH/NCI R00 CA181491-01A1 grant, Department of Defense (DOD) grant BC131494, and Susan G. Komen Career Catalyst Research award CCR 299052.; JMB is supported by NIH/NCI R00 CA181491-01A1 grant, Department of Defense (DOD) grant BC131494, and Susan G. Komen Career Catalyst Research award CCR 299052.
• Keywords: TAMOXIFEN; Cell Biology; QUANTIFICATION; COMBINATION; Medicine, Research & Experimental; ACTIVATING ESR1 MUTATIONS; EXPRESSION; Science & Technology; POSTMENOPAUSAL WOMEN; RECEPTOR-ALPHA; TRIAL; Research & Experimental Medicine; Life Sciences & Biomedicine; AMPLIFICATION; ADJUVANT TREATMENT
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery; Engineering, Biomedical

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 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.