Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer.
Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer.
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DOI：
10.1093/jnci/djw306
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发表时间：
2017-07-01
期刊：
影响因子：
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通讯作者：
Boughey JC
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作者：
Goetz MP;Kalari KR;Suman VJ;Moyer AM;Yu J;Visscher DW;Dockter TJ;Vedell PT;Sinnwell JP;Tang X;Thompson KJ;McLaughlin SA;Moreno-Aspitia A;Copland JA;Northfelt DW;Gray RJ;Hunt K;Conners A;Sicotte H;Eckel-Passow JE;Kocher JP;Ingle JN;Ellingson MS;McDonough M;Wieben ED;Weinshilboum R;Wang L;Boughey JC
背景：新辅助化疗（NAC）后残留病灶的乳腺癌患者复发风险增加。分子表征、NAC反应的知识以及同时产生患者来源的异种移植物（PDX）可以加速药物开发。然而，这种方法的可行性是未知的。研究方法：我们对140例接受NAC治疗的乳腺癌患者进行了前瞻性研究，并进行了肿瘤和生殖细胞测序，并使用芯针活检产生了患者来源的异种移植物（PDX）。在手术时评估化疗反应。结果如下：复发性“靶向”改变在无病理完全缓解（pCR）的患者中未富集;然而，与基础亚型（60.0%，21/35）相比，在管腔雄激素受体（LAR）的三阴性乳腺癌（TNBC）患者中观察到类固醇受体信号传导上调和较低的pCR率（16.7%，1/6）。在TNBC中，TP 53突变频率（75.6%，31/41）与基础（74.3%，26/35）和LAR（83.3%，5/6）相比无差异;然而，TP 53停止增益突变在基础（22.9%，8/35）中比LAR（0.0%，0/6）中更常见，这在癌症基因组图谱和不列颠哥伦比亚省数据集中得到证实。在管腔型B肿瘤中，在携带内分泌耐药突变（p53、AKT和IKBKE）的肿瘤中观察到Ki-67反应。PDX摄取率（27.4%，31/113）根据肿瘤亚型而变化，在NAC治疗进展的患者中，测序数据告知药物选择（奥拉帕尼），在原发性和耐药（化疗后）PDX中观察到体内抗肿瘤活性。结论：在这项研究中，我们证明了肿瘤测序和PDX生成在NAC环境中的可行性。“靶向”改变在化疗耐药肿瘤中并不丰富;然而，基于序列数据的药物测试优先级可能会加速药物开发。
Background: Breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC) have increased recurrence risk. Molecular characterization, knowledge of NAC response, and simultaneous generation of patient-derived xenografts (PDXs) may accelerate drug development. However, the feasibility of this approach is unknown. Methods: We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient-derived xenografts (PDXs) using core needle biopsies. Chemotherapy response was assessed at surgery. Results: Recurrent “targetable” alterations were not enriched in patients without pathologic complete response (pCR); however, upregulation of steroid receptor signaling and lower pCR rates (16.7%, 1/6) were observed in triple-negative breast cancer (TNBC) patients with luminal androgen receptor (LAR) vs basal subtypes (60.0%, 21/35). Within TNBC, TP53 mutation frequency (75.6%, 31/41) did not differ comparing basal (74.3%, 26/35) and LAR (83.3%, 5/6); however, TP53 stop-gain mutations were more common in basal (22.9%, 8/35) vs LAR (0.0%, 0/6), which was confirmed in The Cancer Genome Atlas and British Columbia data sets. In luminal B tumors, Ki-67 responses were observed in tumors that harbored mutations conferring endocrine resistance (p53, AKT, and IKBKE). PDX take rate (27.4%, 31/113) varied according to tumor subtype, and in a patient with progression on NAC, sequencing data informed drug selection (olaparib) with in vivo antitumor activity observed in the primary and resistant (postchemotherapy) PDXs. Conclusions: In this study, we demonstrate the feasibility of tumor sequencing and PDX generation in the NAC setting. “Targetable” alterations were not enriched in chemotherapy-resistant tumors; however, prioritization of drug testing based on sequence data may accelerate drug development.