Table 2_Genomic profiling of NSCLC tumors with the TruSight oncology 500 assay provides broad coverage of clinically actionable genomic alterations and detection of known and novel associations between genomic alterations, TMB, and PD-L1.xlsx

IntroductionMatching patients to an effective targeted therapy or immunotherapy is a challenge for advanced and metastatic non-small cell lung cancer (NSCLC), especially when relying on assays that test one marker at a time. Unlike traditional single marker tests, comprehensive genomic profiling (CGP) can simultaneously assess NSCLC tumors for hundreds of genomic biomarkers and markers for immunotherapy response, leading to quicker and more precise matches to therapeutics.
MethodsIn this study, we performed CGP on 7,606 patients with advanced or metastatic NSCLC using the Illumina TruSight Oncology 500 (TSO 500) CGP assay to show its coverage and utility in detecting known and novel features of NSCLC.
ResultsTesting revealed distinct genomic profiles of lung adenocarcinoma and squamous cell carcinomas and detected variants with a current targeted therapy or clinical trial in >72% of patient tumors. Known associations between genomic alterations and immunotherapy markers were observed including significantly lower TMB levels in tumors with therapy-associated alterations and significantly higher PD-L1 levels in tumors with ALK, MET, BRAF, or ROS1 driver mutations. Co-occurrence analysis followed by network analysis with gene module detection revealed known and novel co-occurrences between genomic alterations. Further, certain modules of genes with co-occurring genomic alterations had dose-dependent relationships with histology and increasing or decreasing levels of PD-L1 and TMB, suggesting a complex relationship between PD-L1, TMB, and genomic alterations in these gene modules.
DiscussionThis study is the largest clinical study to date utilizing the TSO 500. It provides an opportunity to further characterize the landscape of NSCLC using this newer technology and show its clinical utility in detecting known and novel facets of NSCLC to inform treatment decision-making.

引言
为晚期及转移性非小细胞肺癌（non-small cell lung cancer, NSCLC）患者匹配有效的靶向治疗或免疫治疗方案，是临床实践中的一大挑战，尤其是当依赖单次仅检测单一标志物的检测实验时。与传统单标志物检测不同，全面基因组测序分析（comprehensive genomic profiling, CGP）可同时对NSCLC肿瘤的数百种基因组生物标志物及免疫治疗应答相关标志物进行评估，从而实现更快速、精准的治疗方案匹配。
方法
本研究采用Illumina TruSight Oncology 500（TSO 500）全面基因组测序分析（CGP）试剂盒，对7606例晚期或转移性NSCLC患者开展CGP检测，以验证该技术在检测NSCLC已知及新型分子特征方面的覆盖范围与应用价值。
结果
检测结果显示，肺腺癌与鳞状细胞癌具有截然不同的基因组特征；在超过72%的患者肿瘤样本中，检测到了当前已有对应靶向治疗或处于临床试验阶段的基因组变异。研究观察到基因组改变与免疫治疗标志物间的已知关联：携带治疗相关基因组改变的肿瘤，其肿瘤突变负荷（tumor mutational burden, TMB）水平显著更低；而携带ALK、MET、BRAF或ROS1驱动突变的肿瘤，其程序性死亡配体1（PD-L1）表达水平显著更高。通过基因组改变共发生分析，随后开展结合基因模块检测的网络分析，本研究揭示了基因组改变间已知及新型的共发生关联。进一步分析发现，部分携带共发生基因组改变的基因模块，与肿瘤组织学类型、PD-L1及TMB水平的升降呈现剂量依赖关系，这表明上述基因模块中PD-L1、TMB与基因组改变间存在复杂的调控关联。
讨论
本研究是目前为止采用TSO 500开展的规模最大的临床研究。本研究为利用该新兴技术进一步刻画NSCLC的分子特征图谱提供了契机，并证实了该技术在检测NSCLC已知及新型分子特征、辅助临床治疗决策制定方面的临床应用价值。