Purpose: Single-agent immune checkpoint inhibitor (IO) therapy is the standard for non-oncogene-addicted advanced non-small cell lung cancer (aNSCLC) with PD-L1 tumor proportion score ≥ 50%. Smoking-induced harm generates high tumor mutation burden (H-TMB) in smoking patients (S-pts), while never-smoking patients (NS-pts) typically have low TMB (L-TMB) and are unresponsive to IO. However, the molecular characterization of NS-pts with H-TMB remains unclear.Experimental design: Clinical data of 142 aNSCLC patients with PD-L1 ≥ 50% treated with first line pembrolizumab were retrospectively collected. Next-generation sequencing was performed using the FoundationOne®CDx assay to correlate genomic alterations with clinical characteristics and response outcomes. Detected mutations were classified into eleven main pathways and enrichment analysis identified patient subgroups based on mutated pathways. Additionally, a patient similarity network was constructed to analyze molecular characterization. Results were validated using data from 853 aNSCLC patients in POPLAR and OAK trials.Results: Among the patients, S-pts had higher TMB than NS-pts. Interestingly, 11 (8%) NS-pts exhibited H-TMB and were enriched in β-catenin/Wnt and DDR pathway mutations. DDR pathway mutations were confirmed to be enriched in NS-pts with H-TMB using data from POPLAR and OAK trials. In the real-world cohort, the NS/H-TMB subgroup with DDR pathway mutations demonstrated improved IO outcome. Patient similarity network analysis confirmed the clustering of NS/H-TMB patients with DDR mutations and their association with improved overall survival in both the real-world cohort and the trials.Conclusions: The DDR signature has a potential role as an additional generator of H-TMB in NS-pts. This subgroup of IO-responsive NS-pts may have better prognosis. Our findings suggest that DDR-based mutational profiling may help identify NS-pts who could benefit from IO therapy.
目的：单药免疫检查点抑制剂（IO）疗法是PD-L1肿瘤比例评分≥50%的非致癌基因成瘾性晚期非小细胞肺癌（aNSCLC）的标准治疗方案。吸烟导致的损害使吸烟患者（S-pts）产生高肿瘤突变负荷（H-TMB），而从不吸烟患者（NS-pts）通常具有低TMB（L-TMB）且对IO治疗无反应。然而，具有H-TMB的NS-pts的分子特征仍不明确。 实验设计：回顾性收集了142例接受一线帕博利珠单抗治疗且PD-L1≥50%的aNSCLC患者的临床数据。使用FoundationOne®CDx检测进行二代测序，以将基因组改变与临床特征和反应结果相关联。检测到的突变被分为十一个主要通路，并通过富集分析根据突变通路识别患者亚组。此外，构建了患者相似性网络以分析分子特征。结果使用POPLAR和OAK试验中853例aNSCLC患者的数据进行了验证。 结果：在患者中，S-pts的TMB高于NS-pts。有趣的是，11例（8%）NS-pts表现出H-TMB，并且在β-连环蛋白/Wnt和DDR通路突变中富集。使用POPLAR和OAK试验的数据证实，DDR通路突变在具有H-TMB的NS-pts中富集。在真实世界队列中，具有DDR通路突变的NS/H-TMB亚组显示出改善的IO治疗结果。患者相似性网络分析证实了具有DDR突变的NS/H-TMB患者的聚类，以及他们在真实世界队列和试验中与改善的总生存期之间的关联。 结论：DDR特征在NS-pts中可能作为H-TMB的额外产生因素发挥作用。这一对IO治疗有反应的NS-pts亚组可能具有更好的预后。我们的研究结果表明，基于DDR的突变谱分析可能有助于识别可从IO治疗中获益的NS-pts。
肿瘤(癌症)患者之家