Sarah Cannon Research Institute, Nashville, TN, USA.
Genospace, Boston, MA, USA.
Oncologist. 2022 Mar 11;27(3):175-182. doi: 10.1093/oncolo/oyab064.
Tumor mutation burden (TMB), a biomarker for immune checkpoint inhibitor (CPI) response, is reported by both blood- and tissue-based next-generation sequencing (NGS) vendors. However, the agreement between TMB from blood (bTMB) and tissue (tTMB) in real-world settings, both in absolute value and association with CPI response, is not known.
This study utilizes Sarah Cannon's precision medicine platform, Genospace, to harmonize clinico-genomic data from 17 206 patients with cancer with NGS results from September 2015 to August 2021. A subset of patients have both bTMB and tTMB results. Statistical analyses are performed in R and include (1) correlation (r) and concordance (ρ) between patient-matched bTMB-tTMB pairs, (2) distribution of total bTMB and tTMB values, and (3) association of bTMB and tTMB with time to CPI therapy failure.
In 410 patient-matched bTMB-tTMB pairs, the median bTMB (m = 10.5 mut/Mb) was significantly higher than the median tTMB (m = 6.0 mut/Mb, P < .001) leading to conflicting "high" and "low" statuses in over one-third of cases at a threshold of 10 mut/Mb (n = 410). Significant differences were observed in the distribution of bTMB values from blood-NGS vendors, with guardant health (GH) reporting higher (m = 10.5 mut/Mb, n = 2183) than Foundation Medicine (FMI, m = 3.8 mut/Mb, n = 462, P < .001). bTMB from GH required a higher threshold (≥40 mut/Mb) than bTMB from FMI (≥12 mut/Mb) in order to be associated with CPI response.
This study uncovers variability in bTMB reporting among commercial NGS platforms, thereby evidencing a need for assay-specific thresholds in identifying patients who may respond to CPI therapy.
肿瘤突变负荷（TMB）是免疫检查点抑制剂（CPI）反应的生物标志物，可通过血液和组织下一代测序（NGS）供应商进行报告。然而，在真实环境中，血液（bTMB）和组织（tTMB）的 TMB 之间的一致性，无论是在绝对值上还是与 CPI 反应的相关性上，尚不清楚。
本研究利用 Sarah Cannon 的精准医学平台 Genospace，对 2015 年 9 月至 2021 年 8 月期间来自 17206 例癌症患者的临床基因组数据与 NGS 结果进行了协调。部分患者同时具有 bTMB 和 tTMB 结果。统计分析在 R 中进行，包括（1）患者匹配的 bTMB-tTMB 对之间的相关性（r）和一致性（ρ），（2）总 bTMB 和 tTMB 值的分布，以及（3）bTMB 和 tTMB 与 CPI 治疗失败时间的相关性。
在 410 对患者匹配的 bTMB-tTMB 中，bTMB 的中位数（m = 10.5 mut/Mb）明显高于 tTMB 的中位数（m = 6.0 mut/Mb，P <.001），导致在 10 mut/Mb 的阈值下，超过三分之一的病例存在“高”和“低”的不一致状态（n = 410）。血液-NGS 供应商的 bTMB 值分布存在显著差异，Guardant Health（GH）报告的 bTMB 更高（m = 10.5 mut/Mb，n = 2183），而 Foundation Medicine（FMI）报告的 bTMB 更低（m = 3.8 mut/Mb，n = 462，P <.001）。与 FMI 相比，GH 的 bTMB 需要更高的阈值（≥40 mut/Mb）才能与 CPI 反应相关。
本研究揭示了商业 NGS 平台报告 bTMB 的变异性，从而证明在确定可能对 CPI 治疗有反应的患者时，需要针对特定检测方法设定阈值。
