Ning Biao, Liu Yixin, Wang Miao, Li Yi, Xu Tianzi, Wei Yongchang
Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Hubei Key Laboratory of Tumor Biological Behaviors Zhongnan Hospital of Wuhan University, Wuhan, China.
Front Pharmacol. 2022 Mar 9;13:748674. doi: 10.3389/fphar.2022.748674. eCollection 2022.
Tumor mutational burden (TMB) is a genomic biomarker that can predict favorable responses to immune checkpoint inhibitors (ICIs). Although we have better understanding of TMB in cancer immunity and cancer immunotherapy, the relationship between TMB and the clinical efficacy of ICIs remains unknown in the treatment of melanoma patients. Here, we conduct a systematic review and meta-analysis to evaluate the predictive value of TMB on the efficacy of ICIs in patients with melanoma. We systematically collected data from PubMed, Embase, Cochrane Library, CNKI, China Biomedical Database (CBM), and Wanfang Database. The end date was set to 26 June 2021. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival and/or progression-free survival according to TMB. Data for 1,493 patients from 15 studies were included. In addition, pooled effect size, heterogeneity analysis, sensitivity analysis, publication bias detection, and subgroup analysis were performed based on the included data. Patients with high TMB showed significantly improved OS (HR = 0.49, 95% CI: 0.33, 0.73; = 0.001) and PFS (HR = 0.47, 95% CI: 0.33, 0.68; < 0.001) compared with patients with low TMB. This association was very good in patients treated with monotherapy, that is, anti-CTLA-4 or anti-PD-(L)-1 inhibitors, but not for the patients treated with a combination of the two drugs. The subgroup analysis results showed that heterogeneity was substantial in the targeted next-generation sequencing (NGS) group. Publication bias was detected, and the results were visualized using the funnel chart. And sensitivity analysis and trim-and-fill method analysis showed that our results were stable and reliable. High TMB is associated with improved OS and PFS in melanoma patients treated with mono-drug ICIs. TMB determined by NGS should be standardized to eliminate heterogeneity. Therefore, the role of TMB in identifying melanoma patients who may benefit from ICI should be further determined in more randomized controlled trials in the future.
肿瘤突变负荷（TMB）是一种基因组生物标志物，可预测对免疫检查点抑制剂（ICI）的良好反应。尽管我们对癌症免疫和癌症免疫治疗中的TMB有了更好的理解，但在黑色素瘤患者的治疗中，TMB与ICI临床疗效之间的关系仍然未知。在此，我们进行了一项系统评价和荟萃分析，以评估TMB对黑色素瘤患者ICI疗效的预测价值。我们系统地从PubMed、Embase、Cochrane图书馆、中国知网、中国生物医学数据库（CBM）和万方数据库收集数据。截止日期设定为2021年6月26日。我们纳入了报告了根据TMB得出的总生存期和/或无进展生存期风险比（HR）的ICI回顾性研究或临床试验。纳入了来自15项研究的1493例患者的数据。此外，基于纳入的数据进行了合并效应量、异质性分析、敏感性分析、发表偏倚检测和亚组分析。与低TMB患者相比，高TMB患者的总生存期（HR = 0.49，95%CI：0.33，0.73；P = 0.001）和无进展生存期（HR = 0.47，95%CI：0.33，0.68；P < 0.001）显著改善。这种关联在接受单药治疗的患者中非常明显，即抗CTLA-4或抗PD-（L）-1抑制剂，但在接受两种药物联合治疗的患者中不明显。亚组分析结果显示，靶向二代测序（NGS）组的异质性很大。检测到发表偏倚，并使用漏斗图对结果进行了可视化。敏感性分析和剪补法分析表明我们的结果稳定可靠。高TMB与接受单药ICI治疗的黑色素瘤患者总生存期和无进展生存期的改善相关。通过NGS确定的TMB应进行标准化以消除异质性。因此，未来应在更多随机对照试验中进一步确定TMB在识别可能从ICI中获益的黑色素瘤患者中的作用。
