Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.
Cellworks Group, San Jose, CA.
JCO Precis Oncol. 2021 Nov;5:153-162. doi: 10.1200/PO.20.00172.
-mutated () non-small-cell lung cancer (NSCLC) is emerging as a heterogeneous disease defined by comutations, which may confer differential benefit to PD-(L)1 immunotherapy. In this study, we leveraged computational biological modeling (CBM) of tumor genomic data to identify PD-(L)1 immunotherapy sensitivity among NSCLC molecular subgroups.
In this multicohort retrospective analysis, the genotype clustering frequency ranked method was used for molecular clustering of tumor genomic data from 776 patients with NSCLC. These genomic data were input into the CBM, in which customized protein networks were characterized for each tumor. The CBM evaluated sensitivity to PD-(L)1 immunotherapy using three metrics: programmed death-ligand 1 expression, dendritic cell infiltration index (nine chemokine markers), and immunosuppressive biomarker expression index (14 markers).
Genotype clustering identified eight molecular subgroups and the CBM characterized their shared cancer pathway characteristics: /, ///, /, /, //, /, /, and without comutation. CBM identified PD-(L)1 immunotherapy sensitivity in the /, /, and alone subgroups and resistance in the containing subgroups. There was insufficient genomic information to elucidate PD-(L)1 immunotherapy sensitivity by the CBM in the ///, /, and / subgroups. In an exploratory clinical cohort of 34 patients with advanced NSCLC treated with PD-(L)1 immunotherapy, the CBM-assessed overall survival correlated well with actual overall survival ( = 0.80, < .001).
CBM identified distinct PD-(L)1 immunotherapy sensitivity among molecular subgroups of NSCLC, in line with previous literature. These data provide proof-of-concept that computational modeling of tumor genomics could be used to expand on hypotheses from clinical observations of patients receiving PD-(L)1 immunotherapy and suggest mechanisms that underlie PD-(L)1 immunotherapy sensitivity.
在这项多队列回顾性分析中，使用基因型聚类频率排名法对 776 名 NSCLC 患者的肿瘤基因组数据进行分子聚类。这些基因组数据被输入到 CBM 中，其中为每个肿瘤定制了蛋白质网络特征。CBM 使用三个指标评估对 PD-（L）1 免疫疗法的敏感性：程序性死亡配体 1 表达、树突状细胞浸润指数（9 种趋化因子标记物）和免疫抑制生物标志物表达指数（14 种标记物）。
基因型聚类确定了 8 个分子亚组，CBM 描述了它们共同的癌症途径特征：/，///，/，/，//，/，/，和无突变。CBM 在/，/和/单独亚组中识别出 PD-（L）1 免疫疗法的敏感性，而在包含突变的亚组中则存在耐药性。在 ///，/和/亚组中，CBM 缺乏足够的基因组信息来阐明 PD-（L）1 免疫疗法的敏感性。在接受 PD-（L）1 免疫疗法治疗的 34 名晚期 NSCLC 患者的探索性临床队列中，CBM 评估的总生存期与实际总生存期相关性良好（=0.80，<0.001）。
CBM 在 NSCLC 的分子亚组中确定了不同的 PD-（L）1 免疫疗法敏感性，与先前的文献一致。这些数据提供了概念验证，即肿瘤基因组学的计算模型可以用来扩展接受 PD-（L）1 免疫疗法治疗的患者的临床观察假设，并提出了 PD-（L）1 免疫疗法敏感性的潜在机制。
