Merck and Co, Kenilworth, New Jersey.
Foundation Medicine, Cambridge, Massachusetts.
JAMA Netw Open. 2020 Oct 1;3(10):e2025109. doi: 10.1001/jamanetworkopen.2020.25109.
Tumor mutational burden (TMB) is a potential biomarker associated with response to immune checkpoint inhibitor therapies. The prognostic value associated with TMB in the absence of immunotherapy is uncertain.
To assess the prevalence of high TMB (TMB-H) and its association with overall survival (OS) among patients not treated with immunotherapy with the same 10 tumor types from the KEYNOTE-158 study.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study evaluated the prognostic value of TMB-H, assessed by Foundation Medicine (FMI) and defined as at least 10 mutations/megabase (mut/Mb) in the absence of immunotherapy. Data were sourced from the deidentified Flatiron Health-FMI clinicogenomic database collected up to July 31, 2018. Eligible patients were aged 18 years or older with any of the following solid cancer types: anal, biliary, endometrial, cervical, vulvar, small cell lung, thyroid, salivary gland, mesothelioma, or neuroendocrine tumor. Patients with microsatellite instability-high tumors were excluded from primary analysis. For OS analysis, patients were excluded if immunotherapy started on the FMI report date or earlier or if patients died before January 1, 2012, and patients were censored if immunotherapy was started later than the FMI report date. Data were analyzed from November 2018 to February 2019.
Overall survival was analyzed using the Kaplan-Meier method and Cox proportional hazards model, adjusting for age, sex, cancer types, practice type, and albumin level.
Of 2589 eligible patients, 1671 (64.5%) were women, and the mean (SD) age was 63.7 (11.7) years. Median (interquartile range) TMB was 2.6 (1.7-6.1) mut/Mb, and 332 patients (12.8%) had TMB-H (≥10 mut/Mb). Prevalence of TMB-H was highest among patients with small cell lung cancer (40.0%; 95% CI, 34.7%-45.6%) and neuroendocrine tumor (29.3%; 95% CI, 22.8%-36.6%) and lowest was among patients with mesothelioma (1.2%; 95% CI, 0.3%-4.4%) and thyroid cancer (2.7%; 95% CI, 1.2%-5.7%). Adjusted hazard ratio for OS of patients not treated with immunotherapy with TMB-H vs those without TMB-H was 0.94 (95% CI, 0.77-1.13). Comparable results were observed when including patients with high microsatellite instability tumors and calculating OS from first observed antineoplastic treatment date.
These findings suggest that prevalence of TMB-H varies widely depending on tumor type and TMB-H does not appear to be a factor associated with OS among patients across these cancer types treated in the absence of immunotherapy.
肿瘤突变负担（TMB）是与免疫检查点抑制剂治疗反应相关的潜在生物标志物。在没有免疫治疗的情况下，TMB 与预后的相关性尚不确定。
评估在未接受免疫治疗的情况下，相同 10 种肿瘤类型的 KEYNOTE-158 研究中 TMB-H 的患病率及其与总生存期（OS）的关系。
设计、地点和参与者：这项回顾性队列研究评估了 TMB-H 的预后价值，TMB-H 由 Foundation Medicine（FMI）评估，并定义为在没有免疫治疗的情况下至少有 10 个突变/兆碱基（mut/Mb）。数据来自 Flatiron Health-FMI 临床基因组数据库，该数据库截至 2018 年 7 月 31 日进行了去标识处理。符合条件的患者年龄在 18 岁或以上，患有以下任何一种实体癌：肛门癌、胆管癌、子宫内膜癌、宫颈癌、外阴癌、小细胞肺癌、甲状腺癌、唾液腺癌、间皮瘤或神经内分泌肿瘤。排除微卫星不稳定性高的肿瘤患者进行主要分析。对于 OS 分析，如果患者在 FMI 报告日期或更早开始免疫治疗，或者如果患者在 2012 年 1 月 1 日前死亡，则排除患者，如果患者在 FMI 报告日期后开始免疫治疗，则对患者进行 censored。数据分析于 2018 年 11 月至 2019 年 2 月进行。
使用 Kaplan-Meier 方法和 Cox 比例风险模型分析总生存期，调整因素包括年龄、性别、癌症类型、实践类型和白蛋白水平。
在 2589 名符合条件的患者中，1671 名（64.5%）为女性，平均（SD）年龄为 63.7（11.7）岁。中位数（四分位距）TMB 为 2.6（1.7-6.1）mut/Mb，332 名（12.8%）患者 TMB-H（≥10 mut/Mb）。小细胞肺癌（40.0%；95%CI，34.7%-45.6%）和神经内分泌肿瘤（29.3%；95%CI，22.8%-36.6%）患者 TMB-H 的患病率最高，间皮瘤（1.2%；95%CI，0.3%-4.4%）和甲状腺癌（2.7%；95%CI，1.2%-5.7%）患者最低。与无 TMB-H 的患者相比，未接受免疫治疗的 TMB-H 患者的 OS 调整后危险比为 0.94（95%CI，0.77-1.13）。当包括高微卫星不稳定性肿瘤患者并从首次观察到的抗肿瘤治疗日期计算 OS 时，也观察到了类似的结果。
这些发现表明，TMB-H 的患病率因肿瘤类型而异，在没有免疫治疗的情况下，TMB-H 似乎不是这些癌症类型患者 OS 的相关因素。
