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Sci Transl Med. 2017 Aug 9;9(402). pii: eaai7993. doi: 10.1126/scitranslmed.aai7993.

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

Author information

1
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
2
Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
3
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
4
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
5
Vanderbilt Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
6
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
8
Instituto Nacional de Enfermedades Neoplásicas, Surquillo 15038, Peru.
9
Department of Surgery, Emory University, Atlanta, GA 30322, USA.
10
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10022, USA.
11
Genoptix Medical Laboratories, Carlsbad, CA 92008, USA.
12
Foundation Medicine Inc., Cambridge, MA 02141, USA.
13
Department of Pathology, Albany Medical College, Albany, NY 12208, USA.
14
Joint Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
15
Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
16
Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA. carlos.arteaga@vanderbilt.edu.

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.

PMID:
28794284
PMCID:
PMC5723145
DOI:
10.1126/scitranslmed.aai7993
[Indexed for MEDLINE]
Free PMC Article

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