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KRAS 和 TP53 共突变可预测肺腺癌免疫检查点阻断的获益。

KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma.

机构信息

Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Center for Personalized Medicine (ZPM), Heidelberg, Germany.

出版信息

Br J Cancer. 2024 Aug;131(3):524-533. doi: 10.1038/s41416-024-02746-z. Epub 2024 Jun 12.

DOI:10.1038/s41416-024-02746-z
PMID:38866964
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11300455/
Abstract

BACKGROUND

Predictive biomarkers in use for immunotherapy in advanced non-small cell lung cancer are of limited sensitivity and specificity. We analysed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information.

METHODS

The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas, negative for actionable genetic alterations. Additionally, two previously published immunotherapy and two surgical patient cohorts were analyzed. Therapy benefit was stratified by KRAS and TP53 mutations. Molecular characteristics underlying KRASmut/TP53mut tumours were revealed by the analysis of TCGA data.

RESULTS

An interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses of overall survival (Hazard ratio [HR] = 0.56, p = 0.0044 and HR = 0.53, p = 0.0021) resulting in a stronger benefit for KRASmut/TP53mut tumours (HR = 0.71, CI 0.55-0.92). This observation was confirmed in immunotherapy cohorts but not observed in surgical cohorts. Tumour mutational burden, proliferation, and PD-L1 mRNA were significantly higher in TP53-mutated tumours, regardless of KRAS status. Genome-wide expression analysis revealed 64 genes, including CX3CL1 (fractalkine), as specific transcriptomic characteristic of KRASmut/TP53mut tumours.

CONCLUSIONS

KRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumour features. Mutation testing of the two genes can be easily implemented using small NGS panels.

摘要

背景

在晚期非小细胞肺癌的免疫治疗中使用的预测性生物标志物的敏感性和特异性有限。我们分析了激活 KRAS 和致病性 TP53 突变提供额外预测信息的潜力。

方法

该研究队列包括 713 例连续的晚期肺腺癌免疫治疗患者，这些患者的基因改变无治疗作用。此外，还分析了两个之前发表的免疫治疗和两个手术患者队列。根据 KRAS 和 TP53 突变对治疗获益进行分层。通过分析 TCGA 数据揭示了 KRASmut/TP53mut 肿瘤的分子特征。

结果

在总生存的单变量和多变量分析中观察到 KRAS 和 TP53 突变之间存在相互作用（风险比[HR] = 0.56，p = 0.0044 和 HR = 0.53，p = 0.0021），导致 KRASmut/TP53mut 肿瘤的获益更强（HR = 0.71，CI 0.55-0.92）。这一观察结果在免疫治疗队列中得到了证实，但在手术队列中没有观察到。无论 KRAS 状态如何，TP53 突变的肿瘤突变负担、增殖和 PD-L1 mRNA 均显著升高。全基因组表达分析显示包括 CX3CL1（ fractalkine）在内的 64 个基因是 KRASmut/TP53mut 肿瘤的特异性转录组特征。

结论

KRAS/TP53 共突变预测 ICI 在单变量和多变量生存分析中的获益，并与独特的分子肿瘤特征相关。这两个基因的突变检测可以使用小型 NGS 面板轻松实现。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd8/11300455/f77c21bc472f/41416_2024_2746_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd8/11300455/38627d7b9c40/41416_2024_2746_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd8/11300455/c38327113251/41416_2024_2746_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd8/11300455/15873712596d/41416_2024_2746_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd8/11300455/f77c21bc472f/41416_2024_2746_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd8/11300455/38627d7b9c40/41416_2024_2746_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd8/11300455/c38327113251/41416_2024_2746_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd8/11300455/15873712596d/41416_2024_2746_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4cd8/11300455/f77c21bc472f/41416_2024_2746_Fig4_HTML.jpg

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