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Author Notes:

Carlos L. Arteaga, MD, Div. of Oncology, Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN 37232-6307, Tel. 615.343.6653, carlos.arteaga@vanderbilt.edu

Author Contributions: Trial design/conception: IM, CLA

Clinical research procedures/regulatory approvals: IM, CLA, MR, HG, JMG

Data acquisition / analysis: All authors

Writing manuscript: JMG, KEH, TPS, CLA

The authors declare no competing interests.

Data And Material Access. RNA sequencing data generated in this study can be accessed through dbGaP number phs000857.

Whole exome sequencing data have been deposited and the dbGaP number is pending assignment.

Subjects:

Research Funding:

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.

SC is supported by a DOD Breast Cancer Research Program award W81XWH-14-1-0359 and NCI Cancer Center Support Grant P30 CA08748.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • ACTIVATING ESR1 MUTATIONS
  • ADJUVANT TREATMENT
  • POSTMENOPAUSAL WOMEN
  • RECEPTOR-ALPHA
  • EXPRESSION
  • TAMOXIFEN
  • TRIAL
  • AMPLIFICATION
  • QUANTIFICATION
  • COMBINATION

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

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Journal Title:

Science Translational Medicine

Volume:

Volume 9, Number 402

Publisher:

, Pages eaai7993-eaai7993

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2017 The Authors.

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