Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Lung Cancer. 2023 Feb;176:103-111. doi: 10.1016/j.lungcan.2022.12.019. Epub 2022 Dec 31.
KRAS G12C is an oncogenic driver mutation, accounting for approximately 14% of Caucasian patients with non-small cell lung cancer (NSCLC). Recently, several KRAS G12C-targeted drugs have been developed; however, the clinico-genomic characteristics of NSCLC patients with KRAS G12C remain unclear.
Based on the large-scale prospective lung cancer genomic screening project (LC-SCRUM-Asia) database, the clinico-genomic characteristics and therapeutic outcomes of NSCLC patients with KRAS G12C were evaluated.
From March 2015 to March 2021, 10,023 NSCLC patients were enrolled in LC-SCRUM-Asia. KRAS mutations were detected in 1258 patients (14 %), including G12C in 376 (4.0 %), G12D in 289 (3.1 %) and G12V in 251 (2.7 %). The proportions of males and smokers were higher in patients with KRAS G12C than in those with KRAS non-G12C mutations (males: 73 % vs 63 %, p < 0.001; smokers: 89 % vs 76 %, p < 0.001). KRAS G12C-positive tumors showed a higher tumor mutation burden (TMB) (mean, 8.1 mut/Mb, p < 0.001) and a higher percentage of tumors with programmed cell death ligand-1 (PD-L1) expression ≥50 % (52 %, p = 0.08). The overall survival in patients with KRAS G12C (median, 24.6 months) was not different between patients with other mutation subtypes (G12V: 18.2 months, p = 0.23; G12D: 20.6 months, p = 0.65; other KRAS mutations: 18.3 months, p = 0.20). Among KRAS-mutated patients who received immune checkpoint inhibitors (ICIs), the progression-free survival in G12C-positive patients (median, 3.4 months) was similar to that in G12V-positive patients (4.2 months, p = 0.90), but significantly longer than that in G12D- (2.0 months, p = 0.02) and other KRAS mutation-positive patients (2.5 months, p = 0.02).
The frequencies of KRAS G12C were lower in Asian than in Caucasian NSCLC patients. Among the KRAS-mutated NSCLC patients, G12C-positive tumors showed increased immunogenicity, such as high TMB and high PD-L1 expression, and potential sensitivity to ICIs.
KRAS G12C 是一种致癌驱动突变，约占非小细胞肺癌（NSCLC）白种人群的 14%。最近，已经开发出几种 KRAS G12C 靶向药物；然而，KRAS G12C 阳性 NSCLC 患者的临床基因组特征尚不清楚。
基于大规模前瞻性肺癌基因组筛查项目（LC-SCRUM-Asia）数据库，评估了 KRAS G12C 阳性 NSCLC 患者的临床基因组特征和治疗结果。
2015 年 3 月至 2021 年 3 月，LC-SCRUM-Asia 项目纳入了 10023 例 NSCLC 患者。在 1258 例患者（14%）中检测到 KRAS 突变，包括 G12C 突变 376 例（4.0%）、G12D 突变 289 例（3.1%）和 G12V 突变 251 例（2.7%）。KRAS G12C 阳性肿瘤患者中男性和吸烟者的比例高于 KRAS 非 G12C 突变患者（男性：73%比 63%，p<0.001；吸烟者：89%比 76%，p<0.001）。KRAS G12C 阳性肿瘤的肿瘤突变负荷（TMB）更高（平均值为 8.1 mut/Mb，p<0.001），程序性死亡配体 1（PD-L1）表达≥50%的肿瘤比例更高（52%，p=0.08）。KRAS G12C 阳性患者的总生存期（中位 24.6 个月）与其他突变亚型患者（G12V：18.2 个月，p=0.23；G12D：20.6 个月，p=0.65；其他 KRAS 突变：18.3 个月，p=0.20）无差异。在接受免疫检查点抑制剂（ICIs）治疗的 KRAS 突变患者中，G12C 阳性患者的无进展生存期（中位 3.4 个月）与 G12V 阳性患者相似（4.2 个月，p=0.90），但明显长于 G12D 阳性患者（2.0 个月，p=0.02）和其他 KRAS 突变阳性患者（2.5 个月，p=0.02）。
亚洲 NSCLC 患者中 KRAS G12C 的频率低于白种人。在 KRAS 突变的 NSCLC 患者中，G12C 阳性肿瘤表现出更高的免疫原性，如高 TMB 和高 PD-L1 表达，并可能对 ICI 敏感。
