Upstate Cancer Center, Upstate Medical University, Syracuse, New York, USA.
Foundation Medicine, Cambridge, Massachusetts, USA.
Cancer Med. 2023 Jan;12(2):1157-1166. doi: 10.1002/cam4.4971. Epub 2022 Jun 23.
New treatment strategies for advanced non-small-cell lung carcinoma (NSCLC) include synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of genomic loss of methylthioadenosine phosphorylase (MTAP).
Twenty nine thousand three hundred seventy nine advanced NSCLC cases underwent hybrid-capture based comprehensive genomic profiling between June 1, 2018 and May 31, 2020. PD-L1 expression was determined by immunohistochemistry (Dako 22C3 PharmDx assay).
13.4% (3928/29,379) NSCLC cases exhibited MTAP loss distributed in adenocarcinoma (59%), squamous cell carcinoma (22%), NSCLC not otherwise specified (16%), and 1% each for large-cell neuroendocrine, sarcomatoid, and adenosquamous carcinoma. Statistically significant differences in mitogenic driver alterations included more KRAS G12C mutations in MTAP-intact versus MTAP-lost (12% vs. 10%, p = 0.0003) and fewer EGFR short variant mutations in MTAP-intact versus MTAP-lost NSCLC (10% vs. 13%, p < 0.0001). Statistically significant differences in currently untargetable genomic alterations included higher frequencies of TP53 (70% vs. 63%, p < 0.0001) and RB1 inactivation (10% vs. 2%, p < 0.0001) in MTAP-intact compared to MTAP-lost NSCLC. SMARCA4 inactivation (7% vs. 10%, p < 0.0001) was less frequent in MTAP-intact versus MTAP-lost NSCLC. Alterations in ERBB2, MET, ALK, ROS1, and NTRK1 did not significantly differ between the two groups. Predictors of immunotherapy efficacy were higher in MTAP-intact versus MTAP-lost NSCLC including tumor mutational burden (9.4 vs. 8.6 mut/Mb, p = 0.001) and low (30% vs. 28%, p = 0.01) and high PD-L1 (32% vs. 30%, p = 0.01) expression. Alterations in biomarkers potentially predictive of immune checkpoint inhibitor resistance (STK11, KEAP1, and MDM2) were similar in the two groups.
MTAP loss occurs in 13% of NSCLC, supporting the development of targeted therapies to exploit PRMT5 hyper-dependence. MTAP loss is accompanied by small differences in targeted and immunotherapy options which may impact future combination strategies.
针对晚期非小细胞肺癌（NSCLC）的新治疗策略包括针对蛋白精氨酸甲基转移酶（如 PRMT5）的合成致死性靶点，这些靶点利用了甲基硫腺苷磷酸酶（MTAP）基因组缺失的影响。
29379 例晚期 NSCLC 病例于 2018 年 6 月 1 日至 2020 年 5 月 31 日期间接受了基于杂交捕获的综合基因组分析。PD-L1 表达通过免疫组织化学（Dako 22C3 PharmDx 检测）确定。
13.4%（3928/29379）的 NSCLC 病例存在 MTAP 缺失，分布于腺癌（59%）、鳞状细胞癌（22%）、非特指型 NSCLC（16%）和 1%的大细胞神经内分泌癌、肉瘤样癌和腺鳞癌。在有丝分裂驱动改变方面，统计学上显著差异包括 MTAP 完整与 MTAP 缺失的 KRAS G12C 突变率更高（12%比 10%，p=0.0003），以及 MTAP 完整与 MTAP 缺失的 NSCLC 中 EGFR 短变体突变率更低（10%比 13%，p<0.0001）。目前无法靶向的基因组改变方面，统计学上显著差异包括 MTAP 完整与 MTAP 缺失的 NSCLC 中 TP53 失活频率更高（70%比 63%，p<0.0001）和 RB1 失活频率更高（10%比 2%，p<0.0001）。SMARCA4 失活（7%比 10%，p<0.0001）在 MTAP 完整与 MTAP 缺失的 NSCLC 中较少见。ERBB2、MET、ALK、ROS1 和 NTRK1 的改变在两组之间无显著差异。MTAP 完整与 MTAP 缺失的 NSCLC 中免疫治疗疗效的预测因子更高，包括肿瘤突变负担（9.4 比 8.6 mut/Mb，p=0.001）和低（30%比 28%，p=0.01）和高 PD-L1（32%比 30%，p=0.01）表达。两组之间免疫检查点抑制剂耐药的潜在生物标志物改变（STK11、KEAP1 和 MDM2）相似。
MTAP 缺失发生在 13%的 NSCLC 中，支持开发靶向治疗以利用 PRMT5 的过度依赖性。MTAP 缺失伴有靶向和免疫治疗选择的微小差异，这可能影响未来的联合治疗策略。
