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

Jennifer M. Giltnane, Katherine E. Hutchinson, Thomas P. Stricker, Luigi Formisano, Christian D. Young, Monica V. Estrada, Mellissa J. Nixon, Liping Du, Violeta Sanchez, Paula Gonzalez Ericsson, Maria G. Kuba, Melinda E. Sanders, Xinmeng J. Mu, Eliezer M. Van Allen, Nikhil Wagle, Ingrid A. Mayer, Vandana Abramson, Henry Gómez, Monica Rizzo, Weiyi ToySarat Chandarlapaty, Erica L. Mayer, Jason Christiansen, Danielle Murphy, Kerry Fitzgerald, Kai Wang, Jeffrey S. Ross, Vincent A. Miller, Phillip J. Stephens, Roman Yelensky, Levi Garraway, Yu Shyr, Ingrid Meszoely, Justin M. Balko, Carlos L. Arteaga

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30 Citations (Scopus)

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.

Original languageEnglish
Article numberaai7993
JournalScience Translational Medicine
Volume9
Issue number402
DOIs
Publication statusPublished - 2017 Aug 9

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Giltnane, J. M., Hutchinson, K. E., Stricker, T. P., Formisano, L., Young, C. D., Estrada, M. V., Nixon, M. J., Du, L., Sanchez, V., Ericsson, P. G., Kuba, M. G., Sanders, M. E., Mu, X. J., Van Allen, E. M., Wagle, N., Mayer, I. A., Abramson, V., Gómez, H., Rizzo, M., ... Arteaga, C. L. (2017). Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance. Science Translational Medicine, 9(402), [aai7993]. https://doi.org/10.1126/scitranslmed.aai7993