Cancer Res Treat.  2025 Jan;57(1):70-82. 10.4143/crt.2024.046.

Association of TP53 Mutation Status and Sex with Clinical Outcome in Non–Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study

• Choi S
• Kim SH
• Lee S
• Seo J
• Kang M
• Jung EH
• Kim SA
• Suh KJ
• Lee JY
• Kim JW
• Kim JW
• Lee JO
• Kim YJ
• Lee KW
• Kim JH
• Bang SM
• Lee JS

• KMID: 2564582
• DOI: http://doi.org/10.4143/crt.2024.046

Abstract

Purpose
Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non–small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC.
Materials and Methods
Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of The Cancer Genome Atlas and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed.
Results
In SNUBH cohort, no statistically significant difference was observed in the median progression-free survival (PFS) according to TP53 mutation status (p=0.930); however, female patients with TP53 mutations (MT) had a significantly prolonged median PFS compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). Programmed death-ligand 1 (PD-L1) high (≥ 50%) expression was significantly enriched in female patients with TP53 MT (p=0.005). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p < 0.001). In The Cancer Genome Atlas analysis, expression of immune-related genes, and tumor mutation burden score in TP53 MT females were higher than in males without TP53 MT.
Conclusion
Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Keyword

mutation; Sex disparity; Lung neoplasms; Immune checkpoint inhibitors; PD-L1

Figure

• 

  Fig. 1. Diagrammatic representation of the study cohort selection process. NGS, next-generation sequencing; NSCLC, non–small cell lung cancer.

• 

  Fig. 2. Kaplan-Meier plots showing progression-free survival (PFS) of all patients with and without TP53 mutations after immune checkpoint inhibitor (ICI) treatment initiation (A), PFS of male patients with and without TP53 mutations after ICI treatment initiation (B), PFS of female patients with and without TP53 mutations after ICI treatment initiation (C), and progression-free survival of all patients (n=240) treated at Memorial Sloan Kettering Cancer Center stratified by TP53 mutation status and patients’ sex (D). CI, confidence interval; MT, mutated; WT, wild-type.

• 

  Fig. 3. Comparison of the distribution of programmed death-ligand 1 (PD-L1) expression level between male and female patients of Seoul National University Bundang Hospital cohorts (n=100) according to subgroups of patients with TP53 wild-type (A), TP53 mutations (B), TP53 missense mutations (C), and TP53 non-missense mutations (D).

• 

  Fig. 4. The boxplot of immune-related gene expression and tumor mutation burden (TMB) score in non–small cell lung cancer from The Cancer Genome Atlas subgroups stratified by TP53 mutations and patients’ sex. (A-E) Elevated expression of anticancer immunity gene expression level was observed in female patients with TP53 mutation. (F) Correlation of TP53 mutation with TMB expression stratified by sex (Sub 1: female TP53 MT; Sub 2: female TP53 WT; Sub 3: male TP53 MT; Sub 4: male TP53 WT). MT, mutated; PD-L1, programmed death-ligand 1; WT, wild-type.

Reference

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020; 70:7–30.

2. Duma N, Santana-Davila R, Molina JR. Non-small cell lung cancer: epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc. 2019; 94:1623–40.

3. Brahmer J, Reckamp KL, Baas P, Crino 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.

4. 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.

5. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016; 375:1823–33.

6. 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.

7. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015; 372:2509–20.

8. Bykov VJN, Eriksson SE, Bianchi J, Wiman KG. Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer. 2018; 18:89–102.

9. Mello SS, Attardi LD. Deciphering p53 signaling in tumor suppression. Curr Opin Cell Biol. 2018; 51:65–72.

10. Jiang L, Hickman JH, Wang SJ, Gu W. Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses. Cell Cycle. 2015; 14:2881–5.

11. 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.

12. 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.

13. Haupt S, Caramia F, Herschtal A, Soussi T, Lozano G, Chen H, et al. Identification of cancer sex-disparity in the functional integrity of p53 and its X chromosome network. Nat Commun. 2019; 10:5385.

14. Ye Y, Jing Y, Li L, Mills GB, Diao L, Liu H, et al. Sex-associated molecular differences for cancer immunotherapy. Nat Commun. 2020; 11:1779.

15. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45:228–47.

16. Rimm DL, Han G, Taube JM, Yi ES, Bridge JA, Flieder DB, et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol. 2017; 3:1051–8.

17. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012; 2:401–4.

18. Rizvi H, Sanchez-Vega F, La K, Chatila W, Jonsson P, Halpenny D, et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol. 2018; 36:633–41.

19. Lyu H, Li M, Jiang Z, Liu Z, Wang X. Correlate the TP53 mutation and the HRAS mutation with immune signatures in head and neck squamous cell cancer. Comput Struct Biotechnol J. 2019; 17:1020–30.

20. Zhao L, Qu X, Wu Z, Li Y, Zhang X, Guo W. TP53 somatic mutations are associated with poor survival in non-small cell lung cancer patients who undergo immunotherapy. Aging (Albany NY). 2020; 12:14556–68.

21. Delbridge AR, Kueh AJ, Ke F, Zamudio NM, El-Saafin F, Jansz N, et al. Loss of p53 causes stochastic aberrant X-chromosome inactivation and female-specific neural tube defects. Cell Rep. 2019; 27:442–54.

22. Conforti F, Pala L, Bagnardi V, De Pas T, Martinetti M, Viale G, et al. Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol. 2018; 19:737–46.

23. Wallis CJ, Butaney M, Satkunasivam R, Freedland SJ, Patel SP, Hamid O, et al. Association of patient sex with efficacy of immune checkpoint inhibitors and overall survival in advanced cancers: a systematic review and meta-analysis. JAMA Oncol. 2019; 5:529–36.

24. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016; 16:626–38.