Clinicopathologic characteristics, co-mutation landscape, and survival outcomes of KRAS-G12D mutant lung adenocarcinoma in comparison to KRAS-G12C and EGFR-mutated subtypes

IF 4.5 2区医学 Q1 ONCOLOGY

Lung Cancer Pub Date : 2025-05-27 DOI:10.1016/j.lungcan.2025.108596

Hanie Abolfathi , Manal Kordahi , Victoria Saavedra Armero , Andréanne Gagné , Patrice Desmeules , Michèle Orain , Pierre Oliver Fiset , Dominique K. Boudreau , Nathalie Gaudreault , Fabien Claude Lamaze , Yohan Bossé , Philippe Joubert

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Abstract

Given the ongoing clinical development of KRAS^G12D specific inhibitors, we aimed to explore the clinicopathologic characteristics of KRAS^G12D mutant tumors. We analyzed 1,225 surgically resected LUAD from a large cohort of a French-Canadian cohort. Tumors were classified into five mutually exclusive molecular groups: KRAS^G12D (n = 82), KRAS^G12C (n = 311), KRAS^{non-G12C/G12D} (n = 324), EGFR-mutant (n = 175), and WT (n = 333). Clinicopathological features, survival outcomes, and co-mutational profiles were compared across groups. KRAS^G12D tumors had the highest frequency of invasive mucinous adenocarcinoma (IMA) (17.1 %, p < 0.00001), spread through air spaces (STAS, p = 0.0001), lymphovascular invasion (LVI, p < 0.00001), and presentation at advanced stages compared to EGFR-mutant and other groups (p = 0.0031). TP53 was the most frequently co-mutated gene across all subgroups; however, it was significantly less frequent in KRAS^G12D tumors (47.8 %) compared to KRAS^G12C (68.1 %) and EGFR-mutant tumors (83.0 %) (p = 0.041). KRAS^G12D also exhibited a broader spectrum of low-frequency co-mutations, including BRAF (8.7 %) and GNAS (4.3 %). In the unstratified cohort, both KRAS^G12D and KRAS^G12C mutations were associated with significantly worse overall survival (OS) and recurrence-free survival (RFS) compared to EGFR-mutant tumors. In multivariable Cox models, KRAS^G12D remained independently associated with poorer OS (HR = 1.778, 95 % CI: 1.418–2.186, p = 0.021) and RFS (HR = 1.665, 95 % CI: 1.267–2.193, p = 0.045) when compared to EGFR. These associations were particularly evident in stage I disease. This study identifies KRAS^G12D as a clinically and pathologically distinct LUAD subtype, characterized by more aggressive histologic features, a unique co-mutation profile, and independently poorer survival outcomes compared to EGFR-mutant tumors. These findings support the need for refined molecular classification of LUAD and underscore the prognostic importance of KRAS^G12D mutations in risk stratification and clinical management, particularly in early-stage disease.

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与KRAS-G12C和egfr突变亚型相比，KRAS-G12D突变型肺腺癌的临床病理特征、共突变情况和生存结果

鉴于KRASG12D特异性抑制剂的持续临床开发，我们旨在探讨KRASG12D突变肿瘤的临床病理特征。我们分析了来自法裔加拿大队列的1225例手术切除的LUAD。肿瘤被分为5个相互排斥的分子组：KRASG12D （n = 82）、KRASG12C （n = 311）、KRASnon-G12C/G12D （n = 324）、egfr突变体（n = 175）和WT （n = 333）。比较各组的临床病理特征、生存结果和共突变概况。KRASG12D肿瘤中浸润性粘液腺癌（IMA）发生率最高(17.1%,p <；0.00001)，通过空气空间扩散（STAS, p = 0.0001），淋巴血管侵入(LVI, p <；0.00001)，与egfr突变和其他组相比，出现在晚期（p = 0.0031）。TP53是所有亚组中最常见的共突变基因；然而，与KRASG12C（68.1%）和egfr突变肿瘤（83.0%）相比，KRASG12D肿瘤（47.8%）的发生率明显较低（p = 0.041）。KRASG12D还表现出更广泛的低频共突变，包括BRAF（8.7%）和GNAS（4.3%）。在未分层的队列中，与egfr突变肿瘤相比，KRASG12D和KRASG12C突变与更差的总生存期（OS）和无复发生存期（RFS）相关。在多变量Cox模型中，与EGFR相比，KRASG12D仍然与较差的OS （HR = 1.778, 95% CI: 1.418-2.186, p = 0.021）和RFS （HR = 1.665, 95% CI: 1.267-2.193, p = 0.045）独立相关。这些关联在I期疾病中尤为明显。本研究将KRASG12D确定为临床和病理上独特的LUAD亚型，与egfr突变肿瘤相比，其特点是更具侵袭性的组织学特征，独特的共突变谱，以及独立较差的生存结果。这些发现支持了对LUAD进行精细分子分类的必要性，并强调了KRASG12D突变在风险分层和临床管理中的预后重要性，特别是在早期疾病中。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Lung Cancer 医学-呼吸系统

CiteScore

9.40

自引率

3.80%

发文量

407

审稿时长

25 days

期刊介绍： Lung Cancer is an international publication covering the clinical, translational and basic science of malignancies of the lung and chest region.Original research articles, early reports, review articles, editorials and correspondence covering the prevention, epidemiology and etiology, basic biology, pathology, clinical assessment, surgery, chemotherapy, radiotherapy, combined treatment modalities, other treatment modalities and outcomes of lung cancer are welcome.