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

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

Jan Budczies  1   2   3 , Eva Romanovsky  4 , Martina Kirchner  4 , Olaf Neumann  4 , Miriam Blasi  5   6 , Johannes Schnorbach  5   6 , Rajiv Shah  5   6 , Farastuk Bozorgmehr  5   6 , Rajkumar Savai  7   8 , Thorsten Stiewe  9 , Solange Peters  10 , Peter Schirmacher  4   11 , Michael Thomas  5   6 , Daniel Kazdal  4   11   5 , Petros Christopoulos  5   6 , Albrecht Stenzinger  4   11   5
Affiliations

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

Jan Budczies et al. Br J Cancer. 2024 Aug.

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.

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Conflict of interest statement

Daniel Kazdal, Petros Christopoulos, Peter Schirmacher, Martina Kirchner, Jan Budczies, Solange Peters, Rajiv Shah, Thorsten Stiewe, Albrecht Stenzinger, and Michael Thomas report the following details of their affiliation or involvement with any organisation or entity that has a financial or non-financial interest in the topic or material covered in this manuscript: Daniel Kazdal reports personal fees for speaker’s honoraria from AstraZeneca, and Pfizer, personal fees for Advisory Board from Bristol-Myers Squibb, outside the submitted work. Petros Christopoulos has received research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Novartis, Roche, and Takeda, speaker’s honoraria from AstraZeneca, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. Peter Schirmacher reports personal fees for speaker honoraria BMS, grants from BMS, AstraZeneca, MSD, and boards from BMS, AstraZeneca, MSD, outside the submitted work. Martina Kirchner has received personal fees for speaker’s honoraria and support for attending meetings or travel from Veracyte Inc., outside the submitted work. Jan Budczies reports grants from German Cancer Aid and consulting from MSD, outside the submitted work. Solange Peters reports grants or research support from Amgen, Arcus, AstraZeneca, Beigene, Bristol-Myers Squibb, GSK, iTeos, Merck Sharp and Dohme, Mirati, Pharma Mar, Promontory Therapeutics, Roche/Genentech, Seattle Genetics, provided consultation and attended advisory boards from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, Beigene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Fishawack, Foundation Medicine, Galenica, Genzyme, Gilead, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Nykode Therapeutics, Novartis, Novocure, Pharma Mar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, and personal fees for speaker’s honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Foundation Medicine, GSK, Illumina, Ipsen, Merck Sharp and Dohme, Mirati, Novartis, Pfizer, Roche/Genentech, Sanofi, Takeda, outside the submitted work. Rajiv Shah has received grants from Bristol Myers-Sqiubb and personal fees for speaker’s honoraria from AstraZeneca, Roche, outside the submitted work. Thorsten Stiewe reports grants from German Centre for Lung Research, Deutsche Forschungsgemeinschaft, and Deutsche Krebshilfe, outside the submitted work. Albrecht Stenzinger has received advisory boards from Agilent, Aignostics, Amgen, Astra Zeneca, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Qlucore, Roche, Seagen, Takeda, Thermo Fisher, and grants from Bayer, BMS, Chugai, Incyte, outside the submitted work. Michael Thomas reports grants from AstraZeneca, Bristol-Myers Squibb, Merck, Roche, Takeda, personal fees for participating to advisory boards from Amgen, AstraZeneca, Beigene, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda, and support for attending meeting and travel from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda. All remaining authors declare that they have no conflict of interest, outside the submitted work.

Figures

Fig. 1
Fig. 1. KRAS and TP53 co-mutation status as predictive marker for benefit from ICI in lung adenocarcinoma.
a,b Heidelberg cohort (HD-ICI): prognostic impact of co-mutations status in patients treated with ICI. c,d TCGA cohort (TCGA-LUAD): absence of the prognostic impact of co-mutations status in patients that underwent surgery.
Fig. 2
Fig. 2. In-depth analysis of the prognostic and predictive impact of dual KRAS and TP53 mutation.
a Subgroups analysis of HD-ICI confirming longer OS after ICI in most of the analysed subgroups. b Longer OS in the study cohort (HD-ICI) and two external cohorts (SU2C-ICI and MSK-ICI) of patients treated with ICI. By contrast, no prolongation of survival was observed in two external cohorts (TCGA-LUAD and MSK-LUAD) of conventionally treated patients.
Fig. 3
Fig. 3. Analysis of KRAS and TP53 mutation types in HD-ICI.
a Distribution of the mutations in KRAS. b Distribution of the mutations in TP53. c Univariate analysis of OS comparing tumours having specific KRAS mutations with KRASwt tumours, of the tumour having specific TP53 mutations with TP53wt tumours, and of tumours having specific types of KRAS/TP53 co-mutation with the basket of not double-mutated tumours. *without G12C mutation
Fig. 4
Fig. 4. Molecular tumour features associated with KRAS and TP53 co-mutation status (TCGA-LUAD cohort).
a Association of TMB with co-mutations status. b–e Association of TOP2A mRNA, PD-L1 mRNA, mast cells, and CX3CL1 mRNA with co-mutation status. f Numbers of differentially expressed genes between KRASmut/TP53mut tumours and KRASmut/TP53wt tumours (blue), KRASwt/TP53wt tumours (green), and KRASwt/TP53mut tumours (red). g Heatmap display of the significantly enriched and depleted categories of the GSEA cancer hallmark catalogue in the sets of differentially expressed genes. ↑ = overexpressed genes, ↓ = underexpressed genes
See this image and copyright information in PMC

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