Fancelli Sara, Caliman Enrico, Mazzoni Francesca, Paglialunga Luca, Gatta Michelet Marta Rita, Lavacchi Daniele, Berardi Rossana, Mentrasti Giulia, Metro Giulio, Birocchi Ilaria, Delmonte Angelo, Priano Ilaria, Comin Camilla Eva, Castiglione Francesca, Bartoli Caterina, Voltolini Luca, Pillozzi Serena, Antonuzzo Lorenzo
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Clinical Oncology Unit, Careggi University Hospital, Florence, Italy.
Front Oncol. 2022 Nov 14;12:968064. doi: 10.3389/fonc.2022.968064. eCollection 2022.
KRAS is commonly mutated in non-small cell lung cancer (NSCLC); however, the prognostic and predictive impact of each G12 substitution has not been fully elucidated. The approval of specific G12C inhibitors has modified the idea of KRAS "undruggability", and although the first-line standard consists of immune checkpoint inhibitors (ICIs) with or without chemotherapy, as suggested at ASCO 2022, the outcome in KRAS-mutated population is still controversial.
We retrospectively described the clinical and pathological characteristics of a homogeneous G12 mutated cohort of 219 patients treated in four Italian oncologic units. We evaluated the outcome (PFS at 18 months and OS at 30 months) of those who underwent standard first-line treatment according to PD-L1 status, focusing on differences across single mutations.
In the study population, 47.9% of patients harbor the KRAS G12C mutation; 20.5%, G12V; 17.4%, G12D; and 8.2%, G12A. Smoking was a common behavior of patients harboring transversions and transition mutations. PD-L1 expression does not show particular distribution in the case series, although we recorded a prevalence of PD-L1 <1% in G12V (51.4%) compared to G12A (26.7%). ICIs alone was the clinician's choice in 32.7% of patients, and the chemo-immune combination in 17.3% of patients. We described the independent prognostic role of young age ( = 0.007), female gender ( = 0.016), and an ICI-based regimen ( = 0.034) regardless of mutations. Overall, our data confirm the worst prognostic value of G12V mutation apart from treatment choice unlike the other major mutations (C, D, and A) that showed a favorable trend in PFS.
KRAS G12 mutations are confirmed to have different characteristics, and the outcome is influenced by ICI first-line regimen. This study provides valuable information for further analysis in the future.
KRAS在非小细胞肺癌（NSCLC）中常见突变；然而，每种G12替代的预后和预测影响尚未完全阐明。特异性G12C抑制剂的获批改变了KRAS“不可成药”的观念，尽管2022年美国临床肿瘤学会（ASCO）建议一线标准治疗方案为含或不含化疗的免疫检查点抑制剂（ICI），但KRAS突变人群的治疗结果仍存在争议。
我们回顾性描述了在四个意大利肿瘤治疗单位接受治疗的219例G12突变同质性队列患者的临床和病理特征。我们根据PD-L1状态评估了接受标准一线治疗患者的结局（18个月时的无进展生存期和30个月时的总生存期），重点关注单一突变之间的差异。
在研究人群中，47.9%的患者携带KRAS G12C突变；20.5%为G12V；17.4%为G12D；8.2%为G12A。吸烟是携带颠换和转换突变患者的常见行为。在该病例系列中，PD-L1表达未显示出特定分布，尽管我们记录到G12V（51.4%）中PD-L1<1%的患病率高于G12A（26.7%）。32.7%的患者临床医生选择单独使用ICI，17.3%的患者选择化疗-免疫联合方案。我们描述了年轻（P=0.007）、女性（P=0.016）和基于ICI的治疗方案（P=0.034）与突变无关的独立预后作用。总体而言，我们的数据证实，与其他主要突变（C、D和A）在无进展生存期显示出有利趋势不同，G12V突变的预后价值最差，与治疗选择无关。
KRAS G12突变具有不同特征，且结局受ICI一线治疗方案影响。本研究为未来的进一步分析提供了有价值的信息。
