Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
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TMB 和 CNA 的组合对转移性癌症免疫治疗的预后和预测反应进行分层
DOI：
10.1158/1078-0432.ccr-19-0558
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发表时间：
2019-12-15
影响因子：
11.5
通讯作者：
Dong, Zhong-Yi
中科院分区：
文献类型：
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作者：
Liu, Li;Bai, Xue;Dong, Zhong-Yi
目的：虽然肿瘤突变负荷（TMB）已被公认为预测免疫检查点抑制剂（ICI）的反应，但缺乏随机临床试验数据限制了其临床应用。本研究旨在探讨基于TMB和拷贝数改变（copy-number alteration，CNA）的生物标志物组合对转移性泛癌环境中各肿瘤预后和ICI治疗预测的意义和可行性。三个独立的免疫治疗队列，包括非小细胞肺癌（n = 240），皮肤皮肤黑色素瘤（n = 174），混合癌（Dana-Farber，n = 98）患者从以前的研究，ICI therapy.Results的疗效进行了分析：TMB和CNA显示最佳组合的预后转移性癌症类型，TMB（低）CNA（低）患者表现出更好的生存。在预测分析中，TMB和CNA均为ICI治疗的独立预测因素。值得注意的是，当TMB和CNA联合分析时，TMB（高）CNA（低）的患者对ICI治疗表现出良好的反应。同时，TMB（高）CNA（低）作为一种新的生物标志物显示出更好的预测ICI疗效相比，无论是TMB-高或CNA-低。此外，非ICI治疗MSK泛癌症队列的分析支持，联合分层TMB和CNA可以用来分类肿瘤不同的敏感性ICI治疗跨pan-tumors.Conclusions：TMB和CNA的组合可以共同分层多个转移性肿瘤组不同的预后和异质性的临床反应ICI治疗。TMB（高）CNA（低）癌症患者可能是ICI治疗的最佳亚组。
Purpose: Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu.Experimental Design: Non-ICI-treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non-small cell lung cancer (n = 240), skin cutaneous melanoma (n = 174), and mixed cancer (Dana-Farber, n = 98) patients from previous studies, were analyzed for efficacy of ICI therapy.Results: TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMB(low)CNA(low) showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMB(high)CNA(low) showed favorable responses to ICI therapy. Meanwhile, TMB(high)CNA(low) as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI-treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors.Conclusions: The combination ofTMBandCNAcan jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMB(high)CNA(low) cancer can be an optimal subgroup for ICI therapy.