Table Info

Variable	Whole cohort (n = 107)
Tumor cells
< 20%	7 (7%)
20–50%	45 (42%)
> 50%	40 (37%)
Missing	15 (14%)
Number of mutations
0	12 (11%)
1	39 (37%)
2	43 (40%)
≥ 3	13 (12%)

Declarations

Author contributions

HDSB: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. RE: Data curation, Writing—original draft, Writing—review & editing. ZM: Validation, Writing—review & editing. HB: Validation, Writing—review & editing, Supervision. RBD: Validation, Writing—review & editing. LG: Validation, Writing—review & editing. EF: Conceptualization, Investigation, Writing—original draft, Writing—review & editing, Supervision. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

The present study has been accepted and registered to the relevant institutional research (OncoHEGP: PRB-HEGP-URC NIF) and ethical committee (European Georges Pompidou Hospital) and has been conducted in accordance with the Declaration of Helsinki. All patients provided informed consent under the European Georges Pompidou Hospital approved protocol allowing collection and analysis of data.

Consent to participate

Informed consent to participate in the study was obtained from all participants.

Consent to publication

Informed consent to publication was obtained from relevant participants.

Availability of data and materials

The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.

Funding

Not applicable.

Copyright

References

Bayle A, Bonastre J, Chaltiel D, Latino N, Rouleau E, Peters S, et al. ESMO study on the availability and accessibility of biomolecular technologies in oncology in Europe. Ann Oncol. 2023;34:934–45. [DOI] [PubMed]

Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:1627–39. [DOI] [PubMed] [PMC]

Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373:123–35. [DOI] [PubMed] [PMC]

Pourmir I, Gazeau B, de Saint Basile H, Fabre E. Biomarkers of resistance to immune checkpoint inhibitors in non-small-cell lung cancer: myth or reality? Cancer Drug Resist. 2020;3:276–86. [DOI] [PubMed] [PMC]

Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity. 2013;39:61–73. [DOI] [PubMed] [PMC]

Chen N, Fang W, Lin Z, Peng P, Wang J, Zhan J, et al. KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma. Cancer Immunol Immunother. 2017;66:1175–87. [DOI] [PubMed] [PMC]

Li D, Zhu X, Wang H, Li N. Association between PD-L1 expression and driven gene status in NSCLC: A meta-analysis. Eur J Surg Oncol. 2017;43:1372–9. [DOI] [PubMed]

Shirasawa M, Yoshida T, Shimoda Y, Takayanagi D, Shiraishi K, Kubo T, et al. Differential Immune-Related Microenvironment Determines Programmed Cell Death Protein-1/Programmed Death-Ligand 1 Blockade Efficacy in Patients With Advanced NSCLC. J Thorac Oncol. 2021;16:2078–90. [DOI] [PubMed]

Kim JH, Kim HS, Kim BJ. Prognostic value of KRAS mutation in advanced non-small-cell lung cancer treated with immune checkpoint inhibitors: A meta-analysis and review. Oncotarget. 2017;8:48248–52. [DOI] [PubMed] [PMC]

10.

Lee CK, Man J, Lord S, Cooper W, Links M, Gebski V, et al. Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non-Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis. JAMA Oncol. 2018;4:210–6. [DOI] [PubMed] [PMC]

11.

Landre T, Justeau G, Assié JB, Chouahnia K, Davoine C, Taleb C, et al. Anti-PD-(L)1 for KRAS-mutant advanced non-small-cell lung cancers: a meta-analysis of randomized-controlled trials. Cancer Immunol Immunother. 2022;71:719–26. [DOI] [PubMed] [PMC]

12.

Sun L, Hsu M, Cohen RB, Langer CJ, Mamtani R, Aggarwal C. Association Between KRAS Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor-Based Therapy in Patients With Advanced Non-Small-Cell Lung Cancer. JAMA Oncol. 2021;7:937–9. [DOI] [PubMed] [PMC]

13.

Guaitoli G, Tiseo M, Di Maio M, Friboulet L, Facchinetti F. Immune checkpoint inhibitors in oncogene-addicted non-small cell lung cancer: a systematic review and meta-analysis. Transl Lung Cancer Res. 2021;10:2890–916. [DOI] [PubMed] [PMC]

14.

Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30:1321–8. [DOI] [PubMed] [PMC]

15.

Frost N, Kollmeier J, Vollbrecht C, Grah C, Matthes B, Pultermann D, et al. KRAS^G12C/TP53 co-mutations identify long-term responders to first line palliative treatment with pembrolizumab monotherapy in PD-L1 high (≥50%) lung adenocarcinoma. Transl Lung Cancer Res. 2021;10:737–52. [DOI] [PubMed] [PMC]

16.

Assoun S, Theou-Anton N, Nguenang M, Cazes A, Danel C, Abbar B, et al. Association of TP53 mutations with response and longer survival under immune checkpoint inhibitors in advanced non-small-cell lung cancer. Lung Cancer. 2019;132:65–71. [DOI] [PubMed]

17.

Bergamaschi D, Gasco M, Hiller L, Sullivan A, Syed N, Trigiante G, et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell. 2003;3:387–402. [DOI] [PubMed]

18.

Biton J, Mansuet-Lupo A, Pécuchet N, Alifano M, Ouakrim H, Arrondeau J, et al. TP53, STK11, and EGFR Mutations Predict Tumor Immune Profile and the Response to Anti-PD-1 in Lung Adenocarcinoma. Clin Cancer Res. 2018;24:5710–23. [DOI] [PubMed]

19.

Dong ZY, Zhong WZ, Zhang XC, Su J, Xie Z, Liu SY, et al. Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma. Clin Cancer Res. 2017;23:3012–24. [DOI] [PubMed]

20.

Hellmann MD, Nathanson T, Rizvi H, Creelan BC, Sanchez-Vega F, Ahuja A, et al. Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer. Cancer Cell. 2018;33:843–52.e4. [DOI] [PubMed] [PMC]

21.

Yang Y, Shen S, Sun Y, Husain H, Zhou H, Lu S, et al. The relationship between different subtypes of KRAS and PD-L1 & tumor mutation burden (TMB) based on next-generation sequencing (NGS) detection in Chinese lung cancer patients. Transl Lung Cancer Res. 2022;11:213–23. [DOI] [PubMed] [PMC]

22.

Pan M, Jiang C, Tse P, Achacoso N, Alexeeff S, Solorzano AV, et al. TP53 Gain-of-Function and Non-Gain-of-Function Mutations Are Differentially Associated With Sidedness-Dependent Prognosis in Metastatic Colorectal Cancer. J Clin Oncol. 2022;40:171–9. [DOI] [PubMed] [PMC]

23.

Sun H, Liu SY, Zhou JY, Xu JT, Zhang HK, Yan HH, et al. Specific TP53 subtype as biomarker for immune checkpoint inhibitors in lung adenocarcinoma. EBioMedicine. 2020;60:102990. [DOI] [PubMed] [PMC]

24.

Kim JY, Jung J, Kim KM, Lee J, Im YH. TP53 mutations predict poor response to immunotherapy in patients with metastatic solid tumors. Cancer Med. 2023;12:12438–51. [DOI] [PubMed] [PMC]

25.

Budczies J, Romanovsky E, Kirchner M, Neumann O, Blasi M, Schnorbach J, et al. KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma. Br J Cancer. 2024;131:524–33. [DOI] [PubMed] [PMC]

26.

Bischoff P, Reck M, Overbeck T, Christopoulos P, Rittmeyer A, Lüders H, et al.; National Network Genomic Medicine Lung Cancer (nNGM) Collaborator Group. Outcome of First-Line Treatment With Pembrolizumab According to KRAS/TP53 Mutational Status for Nonsquamous Programmed Death-Ligand 1-High (≥50%) NSCLC in the German National Network Genomic Medicine Lung Cancer. J Thorac Oncol. 2024;19:803–17. [DOI] [PubMed]

27.

Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8. [DOI] [PubMed] [PMC]

28.

Yang JC, Shepherd FA, Kim DW, Lee GW, Lee JS, Chang GC, et al. Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M-Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report. J Thorac Oncol. 2019;14:933–9. [DOI] [PubMed]

29.

Aramini B, Banchelli F, Bettelli S, Manfredini S, D’Amico R, Masciale V, et al. Overall survival in patients with lung adenocarcinoma harboring “niche” mutations: an observational study. Oncotarget. 2020;11:550–9. [DOI] [PubMed] [PMC]

30.

Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92. [DOI] [PubMed] [PMC]

31.

Lin A, Wei T, Meng H, Luo P, Zhang J. Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations. Mol Cancer. 2019;18:139. [DOI] [PubMed] [PMC]

32.

Isomoto K, Haratani K, Hayashi H, Shimizu S, Tomida S, Niwa T, et al. Impact of EGFR-TKI Treatment on the Tumor Immune Microenvironment in EGFR Mutation-Positive Non-Small Cell Lung Cancer. Clin Cancer Res. 2020;26:2037–46. [DOI] [PubMed]

33.

Offin M, Rizvi H, Tenet M, Ni A, Sanchez-Vega F, Li BT, et al. Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers. Clin Cancer Res. 2019;25:1063–9. [DOI] [PubMed] [PMC]

34.

Yang JC, Gadgeel SM, Sequist LV, Wu CL, Papadimitrakopoulou VA, Su WC, et al. Pembrolizumab in Combination With Erlotinib or Gefitinib as First-Line Therapy for Advanced NSCLC With Sensitizing EGFR Mutation. J Thorac Oncol. 2019;14:553–9. [DOI] [PubMed]

35.

Nakajima EC, Ren Y, Vallejo JJ, Akinboro O, Mishra-Kalyani PS, Larkins EA, et al. Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis. J Cli Oncol. 2022;40:9001. [DOI]