Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer.
Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer.
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DOI：
10.1016/j.eururo.2015.07.009
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发表时间：
2015-12
期刊：
影响因子：
23.4
通讯作者：
Ross EA
中科院分区：
文献类型：
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作者：
Plimack ER;Dunbrack RL;Brennan TA;Andrake MD;Zhou Y;Serebriiskii IG;Slifker M;Alpaugh K;Dulaimi E;Palma N;Hoffman-Censits J;Bilusic M;Wong YN;Kutikov A;Viterbo R;Greenberg RE;Chen DY;Lallas CD;Trabulsi EJ;Yelensky R;McConkey DJ;Miller VA;Golemis EA;Ross EA
膀胱切除术前行以顺铂为基础的新辅助化疗（NAC）是肌层浸润性膀胱癌（MIBC）的标准治疗方法，预计25% - 50%的患者会出现病理反应。目前缺乏经过验证的可预测反应的生物标志物。
目的：发现并验证可预测MIBC对NAC反应的生物标志物。
从两项以顺铂为基础的NAC的独立临床试验中治疗的患者前瞻性收集的MIBC治疗前样本构成了发现集和验证集。在经临床实验室改进修正案认证的实验室中，对治疗前肿瘤组织的DNA进行287个癌症相关基因的所有编码外显子测序，并分析碱基替换、插入缺失、拷贝数改变以及选定的重排情况。
每个基因的变异数量均值和变异状态与反应相关。利用来自发现队列的变异数据构建分类树，以区分有反应者和无反应者。然后在独立验证集中测试所得的决策规则。
在发现集（p = 0.024）和验证集（p = 0.018）中，病理完全缓解的患者比有残留肿瘤的患者有更多的改变。在发现集中，三个DNA修复基因ATM、RB1和FANCC中一个或多个发生改变可预测病理反应（p < 0.001；敏感性87%，特异性100%）以及更好的总生存期（p = 0.007）。该检测在验证集中对病理反应仍有预测性（p = 0.033），且有总生存期更好的趋势（p = 0.055）。这些结果需要在更多样本集中进一步验证。结论：DNA修复相关基因ATM、RB1和FANCC的基因组改变可预测MIBC以顺铂为基础的化疗后的反应和临床获益。结果表明，DNA修复缺陷使肿瘤对顺铂敏感。
膀胱切除术前给予的化疗可提高部分但并非所有肌层浸润性膀胱癌患者的治愈机会。我们发现一组基因突变，当它们存在于肿瘤组织中时可预测从新辅助化疗中获益，这表明化疗前检测可能有助于选择推荐采用这种方法的患者。
Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25–50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. To discover and validate biomarkers predictive of response to NAC for MIBC. Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments–certified laboratory. The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p = 0.024) and validation (p = 0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p < 0.001; 87% sensitivity, 100% specificity) and better overall survival (p = 0.007). This test remained predictive for pathologic response in the validation set (p = 0.033), with a trend towards better overall survival (p = 0.055). These results require further validation in additional sample sets. Conclusions: Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.