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.

短期抗雌激素治疗后抑制雌激素受体阳性（ER ⁺）乳腺癌的增殖与患者的长期预后相关。我们评测的155 ER ⁺ /人表皮生长因子受体2阴性（HER2 ^- ）从术前用芳香酶抑制剂来曲唑治疗10到21天143例早期乳腺癌。21％的肿瘤仍保持高度增殖性，表明这些肿瘤具有与内分泌内在治疗抗性相关的改变。全外显子组测序揭示了8p11-12和11q13基因扩增之间的相关性，包括FGFR1和CCND1分别为高Ki67。我们在一系列连续预处理，新辅助化疗和复发性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乳腺癌细胞中的抗雌激素耐药性。来曲唑治疗的肿瘤的RNA测序揭示了染色体内ESR1的存在融合转录本和基因签名的增加表达，表明在高Ki67的癌症中E2F介导的转录和细胞周期过程增强。这些数据表明，术前短期雌激素剥夺和基因组图谱分析可用于鉴定可能引起内分泌内在治疗耐药性的药物改变。