Genomic profiling of ER(+) breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance Journal Article
| Authors: | 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.; Toy, W.; Chandarlapaty, S.; Mayer, E. L.; Christiansen, J.; Murphy, D.; Fitzgerald, K.; Wang, K.; Ross, J. S.; Miller, V. A.; Stephens, P. J.; Yelensky, R.; Garraway, L.; Shyr, Y.; Meszoely, I.; Balko, J. M.; Arteaga, C. L. |
| Article Title: | 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 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. © 2017 The Authors. |
| Journal Title: | Science Translational Medicine |
| Volume: | 9 |
| Issue: | 402 |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2017-08-09 |
| Start Page: | eaai7993 |
| Language: | English |
| DOI: | 10.1126/scitranslmed.aai7993 |
| PROVIDER: | scopus |
| PUBMED: | 28794284 |
| PMCID: | PMC5723145 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 5 September 2017 -- Source: Scopus |
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