Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations.
Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations.
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DOI：
10.1158/1078-0432.ccr-17-3099
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发表时间：
2018-03-15
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影响因子：
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通讯作者：
O'Reilly EM
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作者：
Hu ZI;Shia J;Stadler ZK;Varghese AM;Capanu M;Salo-Mullen E;Lowery MA;Diaz LA Jr;Mandelker D;Yu KH;Zervoudakis A;Kelsen DP;Iacobuzio-Donahue CA;Klimstra DS;Saltz LB;Sahin IH;O'Reilly EM
免疫检查点抑制已被证明在MMR-D实体瘤中产生深刻而持久的反应，并引起了对指导治疗决策的检测工具和策略的兴趣。在此，我们解决的问题，适当的筛选，检测方法，病人的选择，并开始治疗MMR-D PDAC和评估的效用NGS提供额外的预后和预测信息MMR-D PDAC。使用基于杂交捕获的NGS测定法分析来自N= 833例PDAC病例的存档和前瞻性采集的样本和匹配的正常DNA，该测定法设计用于对341-468个癌症相关基因的所有外显子和选定内含子进行靶向深度测序。使用NGS数据的计算程序从肿瘤-正常配对基因组测序数据导出MSI状态。对可用的生殖系检测、IHC和MSI PCR结果进行审查，以评估和确认MMR-D和MSI状态。PDAC中的MMR-D是PDAC患者中的罕见事件（7/833），发生率为0.8%。免疫组化检测MMR蛋白表达缺失、高突变负荷和MSISensor评分升高与MMR-D PDAC相关。研究中的所有7例MMR-D PDAC患者均发现患有Lynch综合征。接受免疫检查点阻断治疗的4名（57%）MMR-D患者取得了治疗获益（1例完全缓解; 2例部分缓解; 1例病情稳定）。使用NGS对晚期PDAC中的肿瘤组织进行生殖细胞检测和体细胞分析的综合方法可能有助于指导PDAC患者的免疫和分子定向治疗的未来发展。
Immune checkpoint inhibition has been shown to generate profound and durable responses in MMR-D solid tumors and has elicited interest in detection tools and strategies to guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D PDAC and assess the utility of NGS in providing additional prognostic and predictive information for MMR-D PDAC. Archival and prospectively acquired samples and matched normal DNA from N= 833 PDAC cases were analyzed using a hybridization capture based, NGS assay designed to perform targeted deep sequencing of all exons and selected introns of 341-468 cancer-associated genes. A computational program using NGS data derived the MSI status from the tumor-normal paired genome sequencing data. Review of available germline testing, IHC, and MSI PCR results were performed to assess and confirm MMR-D and MSI status. MMR-D in PDAC is a rare event among PDAC patients (7/833) occurring at a frequency of 0.8%. Loss of MMR protein expression by IHC, high mutational load and elevated MSIsensor scores were correlated with MMR-D PDAC. All 7 MMR-D PDAC patients in the study were found to have Lynch Syndrome. Four (57%) of the MMR-D patients treated with immune checkpoint blockade had treatment benefit (1 complete response; 2 partial responses; 1 stable disease). An integrated approach of germline testing and somatic analyses of tumor tissues in advanced PDAC using NGS may help guide future development of immune and molecularly directed therapies in PDAC patients.