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

• Verfasst von: Budczies, Jan [VerfasserIn]
• Verfasst von: Romanovsky, Eva [VerfasserIn]
• Verfasst von: Kirchner, Martina [VerfasserIn]
• Verfasst von: Neumann, Olaf [VerfasserIn]
• Verfasst von: Blasi, Miriam [VerfasserIn]
• Verfasst von: Schnorbach, Johannes [VerfasserIn]
• Verfasst von: Shah, Rajiv [VerfasserIn]
• Verfasst von: Bozorgmehr, Farastuk [VerfasserIn]
• Verfasst von: Savai, Rajkumar [VerfasserIn]
• Verfasst von: Stiewe, Thorsten [VerfasserIn]
• Verfasst von: Peters, Solange [VerfasserIn]
• Verfasst von: Schirmacher, Peter [VerfasserIn]
• Verfasst von: Thomas, Michael [VerfasserIn]
• Verfasst von: Kazdal, Daniel [VerfasserIn]
• Verfasst von: Christopoulos, Petros [VerfasserIn]
• Verfasst von: Stenzinger, Albrecht [VerfasserIn]
• Titel: KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma
• Verf.angabe: Jan Budczies, Eva Romanovsky, Martina Kirchner, Olaf Neumann, Miriam Blasi, Johannes Schnorbach, Rajiv Shah, Farastuk Bozorgmehr, Rajkumar Savai, Thorsten Stiewe, Solange Peters, Peter Schirmacher, Michael Thomas, Daniel Kazdal, Petros Christopoulos and Albrecht Stenzinger
• E-Jahr: 2024
• Jahr: 12 June 2024
• Umfang: 10 S.
• Illustrationen: Illustrationen
• Fussnoten: Gesehen am 27.11.2024
• Titel Quelle: Enthalten in: British journal of cancer
• Ort Quelle: Edinburgh : Nature Publ. Group, 1999
• Jahr Quelle: 2024
• Band/Heft Quelle: 131(2024), 3, Seite 524-533
• ISSN Quelle: 1532-1827
• DOI: doi:10.1038/s41416-024-02746-z
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Cancer genomics
• Sach-SW: Non-small-cell lung cancer
• Sach-SW: Predictive markers
• Sach-SW: Statistical methods
• K10plus-PPN: 1909612928

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.