INTRODUCTION Blood-based tumor mutational burden (bTMB) has been studied to differentiate non-small cell lung cancer (NSCLC) patients who would benefit from anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration. METHODS Three independent cohorts of NSCLC patients treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N=211 and OAK, N=462) and further validated in the third National Cancer Center cohort (NCC, N=64). RESULTS bTMB-H (bTMB≥cut-off point) was not associated with favorable OS following immunotherapy regardless of the cut-off points in either the POPLAR and OAK or the NCC cohorts (P>0.05) due to its correlation with the circulating tumor DNA (ctDNA) amount, which was associated with poor OS. In the POPLAR and OAK cohorts, upon allele frequency (AF) adjustment, a high allele frequency bTMB (HAF-bTMB, mutation counts with an AF>5%) was strongly correlated with the ctDNA amount (Pearson's r=0.65), while a low allele frequency bTMB (LAF-bTMB, mutation counts with an AF≤5%) was not (Pearson's r=0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [[HR], 0.70; 95% confidence interval [CI], 0.52-0.95; P=0.02), progression-free survival (PFS) (HR, 0.62; 95% CI, 0.47-0.80; P<0.001), and the objective response rate (ORR) (P<0.001) following immunotherapy but not chemotherapy, with a cut-off point of 12 trained in the POPLAR cohort and validated in the OAK cohort. The LAF-bTMB algorithm was further validated in the NCC cohort in which LAF-bTMB-H was associated with OS (HR, 0.20; 95% CI, 0.05-0.84; P=0.02), PFS (HR, 0.30; 95% CI, 0.13-0.70; P=0.003), and the ORR (P=0.001). CONCLUSIONS We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and the ORR following anti-PD-1/PD-L1 therapies in NSCLC patients, which needs to be prospectively validated.

中文翻译：

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等位基因频率调整的基于血液的肿瘤突变负荷作为接受 PD-1/PD-L1 抑制剂治疗的非小细胞肺癌患者总生存期的预测指标

引言 已经研究了基于血液的肿瘤突变负荷 (bTMB) 以区分可从抗程序性细胞死亡蛋白 1 (PD-1)/程序性死亡配体 1 (PD-L1) 中受益的非小细胞肺癌 (NSCLC) 患者) 疗法。然而，它未能预测总生存 (OS) 益处，这值得进一步探索。方法 本研究使用了三个独立的接受免疫疗法治疗的 NSCLC 患者队列。新的 bTMB 算法首先在两个独立的队列（POPLAR，N=211 和 OAK，N=462）中开发，并在第三个国家癌症中心队列（NCC，N=64）中得到进一步验证。结果 bTMB-H（bTMB≥截止点）与免疫治疗后有利的 OS 无关，无论 POPLAR 和 OAK 或 NCC 队列中的截止点如何（P>0. 05) 因为它与循环肿瘤 DNA (ctDNA) 量相关，这与较差的 OS 相关。在 POPLAR 和 OAK 队列中，等位基因频率 (AF) 调整后，高等位基因频率 bTMB（HAF-bTMB，AF>5% 的突变计数）与 ctDNA 量（Pearson's r=0.65）密切相关，而 a低等位基因频率 bTMB（LAF-bTMB，AF≤5% 的突变计数）不是（Pearson's r=0.09）。LAF-bTMB-H 与有利的 OS（风险比 [[HR]，0.70；95% 置信区间 [CI]，0.52-0.95；P=0.02）、无进展生存期 (PFS)（HR，0.62；95 % CI, 0.47-0.80; P<0.001) 和免疫治疗后的客观缓解率 (ORR) (P<0.001)（P<0.001），在 POPLAR 队列中训练并在 OAK 队列中验证的截止点为 12 . LAF-bTMB 算法在 NCC 队列中得到进一步验证，其中 LAF-bTMB-H 与 OS（HR，0.20；95% CI，0.05-0.84；P=0.02），PFS（HR，0.30；95% CI）相关, 0.13-0.70; P=0.003) 和 ORR (P=0.001)。结论 我们开发并验证了一种新的 LAF-bTMB 算法，作为 NSCLC 患者抗 PD-1/PD-L1 治疗后 OS、PFS 和 ORR 的可行预测指标，需要前瞻性验证。