Genomic profiling of ER(+) breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance.
Genomic profiling of ER(+) breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance.
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DOI：
10.1126/scitranslmed.aai7993
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发表时间：
2017-08-09
影响因子：
17.1
通讯作者：
Arteaga CL
中科院分区：
文献类型：
--
作者：
Giltnane JM;Hutchinson KE;Stricker TP;Formisano L;Young CD;Estrada MV;Nixon MJ;Du L;Sanchez V;Ericsson PG;Kuba MG;Sanders ME;Mu XJ;Van Allen EM;Wagle N;Mayer IA;Abramson V;Gόmez H;Rizzo M;Toy W;Chandarlapaty S;Mayer EL;Christiansen J;Murphy D;Fitzgerald K;Wang K;Ross JS;Miller VA;Stephens PJ;Yelensky R;Garraway L;Shyr Y;Meszoely I;Balko JM;Arteaga CL
短期抗雌激素治疗后雌激素受体阳性(ER+)乳腺癌的增殖抑制与患者的长期预后相关。我们对143例患者的155例ER+/HER2-早期乳腺癌进行了分析，这些患者在手术前10-21天接受了芳香酶抑制剂来曲唑的治疗。21%的肿瘤保持高度增殖，这表明这些肿瘤存在与内分泌治疗抵抗有关的改变。全外显子组测序显示8p11-12和11q13基因扩增之间存在相关性，分别包括FGFR1和CCND1，以及高Ki67。我们在一系列治疗前、新辅助化疗后和复发ER+肿瘤的单独队列中证实了这些发现。联合抑制FGFR1和CDK4/6可逆转ER+FGFR1/CCND1共扩增的CAMA1乳腺癌细胞对雌激素的耐药性。来曲唑治疗的肿瘤的RNA测序显示，在Ki67高表达的癌症中，染色体内的ESR1融合转录本和基因表达特征，表明E2F介导的转录和细胞周期过程增强。这些数据表明，短期的术前雌激素剥夺和基因组图谱分析可以用来识别可能导致内分泌治疗抵抗的可用药改变。
Proliferative inhibition of estrogen-receptor positive (ER+) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER+/HER2– early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10-21 days before surgery. Twenty-one percent of tumors remained highly proliferative suggesting 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 pre-treatment, post-neoadjuvant chemotherapy, and recurrent ER+ tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER+ FGFR1/CCND1 co-amplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed intrachromosomal ESR1 fusion transcripts and gene expression signatures in cancers with high Ki67, indicative of enhanced E2F-mediated transcription and cell cycle processes. These data suggest short-term pre-operative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations potentially causal to intrinsic endocrine therapy resistance.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
Ellis, Matthew J.;Ding, Li;Shen, Dong;Luo, Jingqin;Suman, Vera J.;Wallis, John W.;Van Tine, Brian A.;Hoog, Jeremy;Goiffon, Reece J.;Goldstein, Theodore C.;Ng, Sam;Lin, Li;Crowder, Robert;Snider, Jacqueline;Ballman, Karla;Weber, Jason;Chen, Ken;Koboldt, Daniel C.;Kandoth, Cyriac;Schierding, William S.;McMichael, Joshua F.;Miller, Christopher A.;Lu, Charles;Harris, Christopher C.;McLellan, Michael D.;Wendl, Michael C.;DeSchryver, Katherine;Allred, D. Craig;Esserman, Laura;Unzeitig, Gary;Margenthaler, Julie;Babiera, G. V.;Marcom, P. Kelly;Guenther, J. M.;Leitch, Marilyn;Hunt, Kelly;Olson, John;Tao, Yu;Maher, Christopher A.;Fulton, Lucinda L.;Fulton, Robert S.;Harrison, Michelle;Oberkfell, Ben;Du, Feiyu;Demeter, Ryan;Vickery, Tammi L.;Elhammali, Adnan;Piwnica-Worms, Helen;McDonald, Sandra;Watson, Mark;Dooling, David J.;Ota, David;Chang, Li-Wei;Bose, Ron;Ley, Timothy J.;Piwnica-Worms, David;Stuart, Joshua M.;Wilson, Richard K.;Mardis, Elaine R.
通讯作者：
Mardis, Elaine R.
影响因子：
12.3
作者：
Fisher S;Barry A;Abreu J;Minie B;Nolan J;Delorey TM;Young G;Fennell TJ;Allen A;Ambrogio L;Berlin AM;Blumenstiel B;Cibulskis K;Friedrich D;Johnson R;Juhn F;Reilly B;Shammas R;Stalker J;Sykes SM;Thompson J;Walsh J;Zimmer A;Zwirko Z;Gabriel S;Nicol R;Nusbaum C
通讯作者：
Nusbaum C
影响因子：
64.5
作者：
Ciriello G;Gatza ML;Beck AH;Wilkerson MD;Rhie SK;Pastore A;Zhang H;McLellan M;Yau C;Kandoth C;Bowlby R;Shen H;Hayat S;Fieldhouse R;Lester SC;Tse GM;Factor RE;Collins LC;Allison KH;Chen YY;Jensen K;Johnson NB;Oesterreich S;Mills GB;Cherniack AD;Robertson G;Benz C;Sander C;Laird PW;Hoadley KA;King TA;TCGA Research Network;Perou CM
通讯作者：
Perou CM
影响因子：
14.9
作者：
Costello M;Pugh TJ;Fennell TJ;Stewart C;Lichtenstein L;Meldrim JC;Fostel JL;Friedrich DC;Perrin D;Dionne D;Kim S;Gabriel SB;Lander ES;Fisher S;Getz G
通讯作者：
Getz G