Oncology Department, University Hospital of Geneva, Switzerland.
Oncology Department, University Hospital of Geneva, Switzerland; Clinique Générale Beaulieu, Geneva, Switzerland.
Crit Rev Oncol Hematol. 2021 Jul;163:103374. doi: 10.1016/j.critrevonc.2021.103374. Epub 2021 Jun 2.
Immune checkpoint inhibitors (ICIs) have revolutionized the landscape of therapeutic options for many cancers. These treatments have demonstrated improved efficacy and often a more favourable toxicity profile compared to standard cytotoxic chemotherapy. There are considerable differences among responders, with some patients experiencing durable long-term disease control and even remission. Given this variability, determining a proper biomarker to select patients for ICI therapy has become increasingly important. The only biomarker proven to be predictive of overall survival benefit with ICI therapy is PD-L1 expression level measured by immunohistochemistry. Several attempts have been made to identify different predictive biomarkers. One of the most intriguing and divisive is tumor mutational burden (TMB). TMB represents the number of mutations per megabase (Mut/Mb) of DNA that were sequenced in a specific cancer. With a higher number of mutations detected, and consequentially an increase in the number neo-epitopes, then it is more likely that one or more of those neo-antigens could be immunogenic and trigger a T cell response. Initially, TMB was identified as a biomarker for ICIs in melanoma and subsequent studies suggested a possible clinical role for TMB in non-small cell lung cancer. The initial data were not confirmed in a prospective study assessing OS as the primary endpoint. Recently, the FDA has approved pembrolizumab in all cancers with a TMB > 10Mut/Mb[12] based on findings from the phase 2 KEYNOTE-158. Much criticism has emerged about this pan-cancer approval, in particular about the use of TMB as biomarker to select patients. Here we review the data about the importance and role of TMB as possible pan-cancer one-size-fits-all biomarker. We highlight the strengths and intrinsic limitations of such a complex biomarker and its adoption in the daily practice.
免疫检查点抑制剂（ICIs）彻底改变了许多癌症的治疗选择格局。与标准细胞毒性化疗相比，这些治疗方法显示出更好的疗效，而且通常具有更有利的毒性特征。在反应者中存在相当大的差异，一些患者经历持久的长期疾病控制甚至缓解。鉴于这种可变性，确定适当的生物标志物来选择接受 ICI 治疗的患者变得越来越重要。唯一被证明可预测 ICI 治疗总生存获益的生物标志物是免疫组织化学检测到的 PD-L1 表达水平。已经进行了几次尝试来确定不同的预测性生物标志物。其中最引人关注和有争议的是肿瘤突变负担（TMB）。TMB 代表在特定癌症中测序的每兆碱基（Mut/Mb）的 DNA 中发生的突变数量。检测到的突变数量越多，随之而来的新抗原数量也会增加，那么其中一个或多个新抗原就更有可能具有免疫原性并引发 T 细胞反应。最初，TMB 被确定为黑色素瘤中 ICI 的生物标志物，随后的研究表明 TMB 在非小细胞肺癌中可能具有临床作用。在一项评估 OS 作为主要终点的前瞻性研究中，最初的数据并未得到证实。最近，FDA 根据 2 期 KEYNOTE-158 的研究结果，批准 pembrolizumab 用于所有 TMB > 10Mut/Mb 的癌症[12]。关于这种泛癌批准，特别是关于将 TMB 作为生物标志物选择患者的用途，出现了很多批评。在这里，我们回顾了 TMB 作为可能的泛癌一刀切生物标志物的重要性和作用的数据。我们强调了这种复杂生物标志物的优势和内在局限性及其在日常实践中的应用。
