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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.

SUBMITTER: Giltnane JM 

PROVIDER: S-EPMC5723145 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Giltnane Jennifer M JM   Hutchinson Katherine E KE   Stricker Thomas P TP   Formisano Luigi L   Young Christian D CD   Estrada Monica V MV   Nixon Mellissa J MJ   Du Liping L   Sanchez Violeta V   Ericsson Paula Gonzalez PG   Kuba Maria G MG   Sanders Melinda E ME   Mu Xinmeng J XJ   Van Allen Eliezer M EM   Wagle Nikhil N   Mayer Ingrid A IA   Abramson Vandana V   Gόmez Henry H   Rizzo Monica M   Toy Weiyi W   Chandarlapaty Sarat S   Mayer Erica L EL   Christiansen Jason J   Murphy Danielle D   Fitzgerald Kerry K   Wang Kai K   Ross Jeffrey S JS   Miller Vincent A VA   Stephens Phillip J PJ   Yelensky Roman R   Garraway Levi L   Shyr Yu Y   Meszoely Ingrid I   Balko Justin M JM   Arteaga Carlos L CL  

Science translational medicine 20170801 402


Inhibition of proliferation in estrogen receptor-positive (ER<sup>+</sup>) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER<sup>+</sup>/human epidermal growth factor receptor 2-negative (HER2<sup>-</sup>) 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 a  ...[more]

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