Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets.
Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets.
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DOI：
10.1158/2159-8290.cd-13-0286
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发表时间：
2014-02
期刊：
影响因子：
28.2
通讯作者：
Arteaga CL
中科院分区：
文献类型：
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作者：
Balko JM;Giltnane JM;Wang K;Schwarz LJ;Young CD;Cook RS;Owens P;Sanders ME;Kuba MG;Sánchez V;Kurupi R;Moore PD;Pinto JA;Doimi FD;Gómez H;Horiuchi D;Goga A;Lehmann BD;Bauer JA;Pietenpol JA;Ross JS;Palmer GA;Yelensky R;Cronin M;Miller VA;Stephens PJ;Arteaga CL
新辅助化疗(NAC)在大约30%的三阴性乳腺癌(TNBC)患者中诱导病理完全应答(PCR)。在缺乏聚合酶链式反应的患者中，NAC选择对化疗耐药的肿瘤细胞亚群。为了了解耐药TNBCs的分子基础，我们对74例临床定义的TNBCs在NAC后的残留疾病(RD)进行了全面的分子分析，包括对20例配对的治疗前活检进行下一代测序(NGS)。结合NGS和数字RNA表达分析，在耐药肿瘤细胞中发现了不同的分子损伤和途径激活。90%的肿瘤包含一种基因改变，可能可以用目前可用的靶向治疗方法治疗。因此，分析NAC后残留的TNBCs可以确定肿瘤化疗耐药成分中的靶向分子病变，这些病变可能反映了临床上注定要复发的微转移。这些数据可以指导针对这些微转移的生物标记物驱动的辅助研究，以改善对NAC没有完全反应的TNBC患者的预后。
Neoadjuvant chemotherapy (NAC) induces a pathologic complete response (pCR) in approximately 30% of patients with triple-negative breast cancers (TNBC). In patients lacking a pCR, NAC selects a subpopulation of chemotherapy-resistant tumor cells. To understand the molecular underpinnings driving treatment-resistant TNBCs, we performed comprehensive molecular analyses on the residual disease (RD) of 74 clinically-defined TNBCs after NAC including next-generation sequencing (NGS) on 20 matched pre-treatment biopsies. Combined NGS and digital RNA expression analysis identified diverse molecular lesions and pathway activation in drug-resistant tumor cells. Ninety percent of the tumors contained a genetic alteration potentially treatable with a currently available targeted therapy. Thus, profiling residual TNBCs after NAC identifies targetable molecular lesions in the chemotherapy-resistant component of the tumor which may mirror micro-metastases destined to recur clinically. These data can guide biomarker-driven adjuvant studies targeting these micro-metastases to improve the outcome of patients with TNBC who do not respond completely to NAC.