Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
Caris Life Sciences, Phoenix, USA.
Ann Oncol. 2021 Jul;32(7):906-916. doi: 10.1016/j.annonc.2021.03.203. Epub 2021 Mar 30.
The impact of molecular alterations on programmed death-ligand 1 (PD-L1) combined positive score (CPS) is not well studied in gastroesophageal adenocarcinomas (GEAs). We aimed to characterize genomic features of tumors with different CPSs in GEAs.
Genomic alterations of 2518 GEAs were compared in three groups (PD-L1 CPS ≥ 10, high; CPS = 1-9, intermediate; CPS < 1, low) using next-generation sequencing. We assessed the impact of gene mutations on the efficacy of immune checkpoint inhibitors (ICIs) and tumor immune environment based on the Memorial Sloan Kettering Cancer Center and The Cancer Genome Atlas databases.
High, intermediate, and low CPSs were seen in 18%, 54% and 28% of GEAs, respectively. PD-L1 positivity was less prevalent in women and in tissues derived from metastatic sites. PD-L1 CPS was positively associated with mismatch repair deficiency/microsatellite instability-high, but independent of tumor mutation burden distribution. Tumors with mutations in KRAS, TP53, and RAS-mitogen-activated protein kinase (MAPK) pathway were associated with higher PD-L1 CPSs in the mismatch repair proficiency and microsatellite stability (pMMR&MSS) subgroup. Patients with RAS-MAPK pathway alterations had longer overall survival (OS) from ICIs compared to wildtype (WT) patients [27 versus 13 months, hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.19-0.7, P = 0.016] and a similar trend was observed in the MSS subgroup (P = 0.11). In contrast, patients with TP53 mutations had worse OS from ICIs compared to TP53-WT patients in the MSS subgroup (5 versus 21 months, HR = 2.39, 95% CI: 1.24-4.61, P = 0.016).
This is the largest study to investigate the distinct genomic landscapes of GEAs with different PD-L1 CPSs. Our data may provide novel insights for patient selection using mutations in TP53 and RAS-MAPK pathway and for the development of rational combination immunotherapies in GEAs.
分子改变对程序性死亡配体 1（PD-L1）联合阳性评分（CPS）在胃食管腺癌（GEA）中的影响尚未得到充分研究。我们旨在描述 GEA 中不同 CPS 肿瘤的基因组特征。
使用下一代测序技术，将 2518 例 GEA 分为三组（PD-L1 CPS≥10，高；CPS=1-9，中；CPS<1，低），比较其基因组改变。我们基于纪念斯隆凯特琳癌症中心和癌症基因组图谱数据库评估基因突变更替疗法（ICIs）疗效和肿瘤免疫环境的影响。
高、中、低 CPS 在 GEA 中的比例分别为 18%、54%和 28%。女性和转移性部位组织中 PD-L1 阳性率较低。PD-L1 CPS 与错配修复缺陷/微卫星不稳定高呈正相关，但与肿瘤突变负担分布无关。KRAS、TP53 和 RAS-丝裂原激活蛋白激酶（MAPK）通路突变的肿瘤与错配修复功能正常和微卫星稳定（pMMR&MSS）亚组中更高的 PD-L1 CPS 相关。与野生型（WT）患者相比，RAS-MAPK 通路改变的患者接受 ICI 治疗的总生存期（OS）更长[27 个月对比 13 个月，风险比（HR）0.36，95%置信区间（CI）0.19-0.7，P=0.016]，在 MSS 亚组中也观察到类似趋势（P=0.11）。相比之下，在 MSS 亚组中，TP53 突变的患者接受 ICI 治疗的 OS 较 TP53-WT 患者更差[5 个月对比 21 个月，HR 2.39，95% CI 1.24-4.61，P=0.016]。
这是最大规模的研究，旨在调查不同 PD-L1 CPS 的 GEA 之间具有不同的基因组景观。我们的数据可能为利用 TP53 和 RAS-MAPK 通路突变进行患者选择以及为 GEA 开发合理的联合免疫疗法提供新的见解。
