KRAS and TP53 Co-mutation Predicts Benefit of Immune Checkpoint Blockade in Lung Adenocarcinoma

Overview

Journal Br J Cancer

Specialty Oncology

Date 2024 Jun 12

PMID 38866964

Authors

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

Albrecht Stenzinger

Affiliations

Soon will be listed here.

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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References

Chang H, Sasson A, Srinivasan S, Golhar R, Greenawalt D, Geese W . Bioinformatic Methods and Bridging of Assay Results for Reliable Tumor Mutational Burden Assessment in Non-Small-Cell Lung Cancer. Mol Diagn Ther. 2019; 23(4):507-520. PMC: 6675777. DOI: 10.1007/s40291-019-00408-y. View

Goldschmid H, Kluck K, Ball M, Kirchner M, Allgauer M, Winter H . Spatial profiling of the microenvironment reveals low intratumoral heterogeneity and STK11-associated immune evasion in therapy-naïve lung adenocarcinomas. Lung Cancer. 2023; 180:107212. DOI: 10.1016/j.lungcan.2023.107212. View

Caso R, Sanchez-Vega F, Tan K, Mastrogiacomo B, Zhou J, Jones G . The Underlying Tumor Genomics of Predominant Histologic Subtypes in Lung Adenocarcinoma. J Thorac Oncol. 2020; 15(12):1844-1856. PMC: 7704768. DOI: 10.1016/j.jtho.2020.08.005. View

Bocanegra A, Fernandez-Hinojal G, Ajona D, Blanco E, Zuazo M, Garnica M . Plasma fractalkine contributes to systemic myeloid diversity and PD-L1/PD-1 blockade in lung cancer. EMBO Rep. 2023; 24(8):e55884. PMC: 10398648. DOI: 10.15252/embr.202255884. View

Havel J, Chowell D, Chan T . The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer. 2019; 19(3):133-150. PMC: 6705396. DOI: 10.1038/s41568-019-0116-x. View

Zhang F, Wang J, Xu Y, Cai S, Li T, Wang G . Co-occurring genomic alterations and immunotherapy efficacy in NSCLC. NPJ Precis Oncol. 2022; 6(1):4. PMC: 8766442. DOI: 10.1038/s41698-021-00243-7. View

Mino-Kenudson M, Schalper K, Cooper W, Dacic S, Hirsch F, Jain D . Predictive Biomarkers for Immunotherapy in Lung Cancer: Perspective From the International Association for the Study of Lung Cancer Pathology Committee. J Thorac Oncol. 2022; 17(12):1335-1354. DOI: 10.1016/j.jtho.2022.09.109. View

Kazdal D, Endris V, Allgauer M, Kriegsmann M, Leichsenring J, Volckmar A . Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology From Technical Artifacts. J Thorac Oncol. 2019; 14(11):1935-1947. DOI: 10.1016/j.jtho.2019.07.006. View

Bazan J, Bacon K, Hardiman G, Wang W, Soo K, Rossi D . A new class of membrane-bound chemokine with a CX3C motif. Nature. 1997; 385(6617):640-4. DOI: 10.1038/385640a0. View

10.

Skoulidis F, Goldberg M, Greenawalt D, Hellmann M, Awad M, Gainor J . Mutations and PD-1 Inhibitor Resistance in -Mutant Lung Adenocarcinoma. Cancer Discov. 2018; 8(7):822-835. PMC: 6030433. DOI: 10.1158/2159-8290.CD-18-0099. View

11.

Gainor J, Shaw A, Sequist L, Fu X, Azzoli C, Piotrowska Z . EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res. 2016; 22(18):4585-93. PMC: 5026567. DOI: 10.1158/1078-0432.CCR-15-3101. View

12.

Camidge D, Doebele R, Kerr K . Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC. Nat Rev Clin Oncol. 2019; 16(6):341-355. DOI: 10.1038/s41571-019-0173-9. View

13.

Ricciuti B, Arbour K, Lin J, Vajdi A, Vokes N, Hong L . Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status. J Thorac Oncol. 2021; 17(3):399-410. PMC: 10980559. DOI: 10.1016/j.jtho.2021.10.013. View

14.

Romanovsky E, Kluck K, Ourailidis I, Menzel M, Beck S, Ball M . Homogenous TP53mut-associated tumor biology across mutation and cancer types revealed by transcriptome analysis. Cell Death Discov. 2023; 9(1):126. PMC: 10104808. DOI: 10.1038/s41420-023-01413-1. View

15.

. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014; 511(7511):543-50. PMC: 4231481. DOI: 10.1038/nature13385. View

16.

Mok T, Lopes G, Cho B, Kowalski D, Kasahara K, Wu Y . Associations of tissue tumor mutational burden and mutational status with clinical outcomes in KEYNOTE-042: pembrolizumab versus chemotherapy for advanced PD-L1-positive NSCLC. Ann Oncol. 2023; 34(4):377-388. DOI: 10.1016/j.annonc.2023.01.011. View

17.

Conroy M, Lysaght J . CX3CL1 Signaling in the Tumor Microenvironment. Adv Exp Med Biol. 2020; 1231:1-12. DOI: 10.1007/978-3-030-36667-4_1. View

18.

Danaher P, Warren S, Dennis L, DAmico L, White A, Disis M . Gene expression markers of Tumor Infiltrating Leukocytes. J Immunother Cancer. 2017; 5:18. PMC: 5319024. DOI: 10.1186/s40425-017-0215-8. View

19.

Budczies J, Kazdal D, Allgauer M, Christopoulos P, Rempel E, Pfarr N . Quantifying potential confounders of panel-based tumor mutational burden (TMB) measurement. Lung Cancer. 2020; 142:114-119. DOI: 10.1016/j.lungcan.2020.01.019. View

20.

Zhu L, Ye D, Lei T, Wu J, Wang W, Xu B . Cancer mutation profiles predict ICIs efficacy in patients with non-small cell lung cancer. Expert Rev Mol Med. 2022; 24:e16. DOI: 10.1017/erm.2022.9. View