BACKGROUND Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized. METHODS Using a standardized approach, we quantify the robustness of TMB as a metric and its potential as a predictor of immunotherapy response and survival among a diverse cohort of cancer patients. We also explore the additive predictive potential of RNA-derived variants and neoepitope burden, incorporating several novel metrics of immunogenic potential. RESULTS We find that TMB is a partial predictor of immunotherapy response in melanoma and non-small cell lung cancer, but not renal cell carcinoma. We find that TMB is predictive of overall survival in melanoma patients receiving immunotherapy, but not in an immunotherapy-naive population. We also find that it is an unstable metric with potentially problematic repercussions for clinical cohort classification. We finally note minimal additional predictive benefit to assessing neoepitope burden or its bulk derivatives, including RNA-derived sources of neoepitopes. CONCLUSIONS We find sufficient cause to suggest that the predictive clinical value of TMB should not be overstated or oversimplified. While it is readily quantified, TMB is at best a limited surrogate biomarker of immunotherapy response. The data do not support isolated use of TMB in renal cell carcinoma.

中文翻译：

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肿瘤突变、新表位和其他变异的负担是癌症免疫治疗反应和总体生存率的弱预测因素。

背景肿瘤突变负荷（TMB；给定肿瘤可能含有的异常核苷酸序列的数量）与免疫检查点抑制剂治疗的反应相关，并因此获得广泛接受。然而，TMB 在不同癌症类型之间存在内在差异，其评估和解释标准化程度较差。方法 使用标准化方法，我们量化了 TMB 作为指标的稳健性及其作为不同癌症患者群体中免疫治疗反应和生存预测因子的潜力。我们还探索了 RNA 衍生变体和新表位负荷的附加预测潜力，结合了免疫原性潜力的几种新指标。结果我们发现 TMB 是黑色素瘤和非小细胞肺癌免疫治疗反应的部分预测因子，但不是肾细胞癌。我们发现 TMB 可以预测接受免疫治疗的黑色素瘤患者的总生存期，但不能预测未接受过免疫治疗的人群的总生存期。我们还发现这是一个不稳定的指标，可能会对临床队列分类产生问题。最后，我们注意到评估新表位负荷或其大量衍生物（包括 RNA 衍生的新表位来源）的额外预测益处微乎其微。结论 我们有足够的理由表明 TMB 的预测临床价值不应被夸大或过度简化。虽然很容易量化，但 TMB 充其量只是免疫治疗反应的有限替代生物标志物。该数据不支持单独使用 TMB 治疗肾细胞癌。