TY - JOUR
T1 - Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance
AU - Giltnane, Jennifer M.
AU - Hutchinson, Katherine E.
AU - Stricker, Thomas P.
AU - Formisano, Luigi
AU - Young, Christian D.
AU - Estrada, Monica V.
AU - Nixon, Mellissa J.
AU - Du, Liping
AU - Sanchez, Violeta
AU - Ericsson, Paula Gonzalez
AU - Kuba, Maria G.
AU - Sanders, Melinda E.
AU - Mu, Xinmeng J.
AU - Van Allen, Eliezer M.
AU - Wagle, Nikhil
AU - Mayer, Ingrid A.
AU - Abramson, Vandana
AU - Gómez, Henry
AU - Rizzo, Monica
AU - Toy, Weiyi
AU - Chandarlapaty, Sarat
AU - Mayer, Erica L.
AU - Christiansen, Jason
AU - Murphy, Danielle
AU - Fitzgerald, Kerry
AU - Wang, Kai
AU - Ross, Jeffrey S.
AU - Miller, Vincent A.
AU - Stephens, Phillip J.
AU - Yelensky, Roman
AU - Garraway, Levi
AU - Shyr, Yu
AU - Meszoely, Ingrid
AU - Balko, Justin M.
AU - Arteaga, Carlos L.
N1 - Funding Information:
This study was funded by NIH Breast SPORE (Specialized Programs of Research Excellence) grant P50 CA098131, Vanderbilt-Ingram Cancer Center support grant P30 CA68485, Susan G. Komen for the Cure Foundation grant SAC100013 (C.L.A.), Vanderbilt Institute for Clinical and Translational Research Intramural Clinical and Translational Science Award VR2998, a grant from the Breast Cancer Research Foundation (C.L.A.), and a grant from Novartis (C.L.A.). T.P.S. was supported by NIH grant K08 CA148912. J.M.B. was supported by NIH/National Cancer Institute (NCI) R00 CA181491-01A1 grant, U.S. Department of Defense (DOD) grant BC131494, and Susan G. Komen Career Catalyst Research Award CCR 299052. S.C. was supported by U.S. DOD Breast Cancer Research Program award W81XWH-14-1-0359 and NCI Cancer Center Support Grant P30 CA08748.
Publisher Copyright:
© 2017 The Authors.
PY - 2017/8/9
Y1 - 2017/8/9
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.aai7993
DO - 10.1126/scitranslmed.aai7993
M3 - Article
C2 - 28794284
AN - SCOPUS:85027421288
VL - 9
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 402
M1 - aai7993
ER -