Cancer Res Treat.  2018 Jan;50(1):95-102. 10.4143/crt.2016.591.

Retrospective Molecular Epidemiology Study of PD-L1 Expression in Patients with EGFR-Mutant Non-small Cell Lung Cancer

• Cho JH
• Zhou W
• Choi YL
• Sun JM
• Choi H
• Kim TE
• Dolled-Filhart M
• Emancipator K
• Rutkowski
• Kim J

• KMID: 2403478
• DOI: http://doi.org/10.4143/crt.2016.591

Abstract

PURPOSE
Data are limited on programmed death ligand 1 (PD-L1) expression in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS
We retrospectively evaluated the relationship between PD-L1 expression and recurrence-free survival (RFS) and overall survival in 319 patients with EGFR-mutant NSCLC who were treated at Samsung Medical Center from 2006 to 2014. Membranous PD-L1 expression on tumor cells was measured using the PD-L1 IHC 22C3 pharmDx antibody and reported as tumor proportion score (TPS). Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis.
RESULTS
All patients had ≥1 EGFR mutation"”54% in exon 19 and 39% in exon 21. Overall, 51% of patients had PD-L1-positive tumors. The prevalence of PD-L1 positivity was higher among patients with stages II-IV versus stage I disease (64% vs. 44%) and among patients with other EGFR mutations (75%) than with L858R mutation (39%) or exon 19 deletion (52%). PD-L1 positivity was associated with shorter RFS, with an adjusted hazard ratio of 1.52 (95% confidence interval [CI], 0.81 to 2.84; median, 18 months) for the PD-L1 TPS ≥ 50% group, 1.51 (95% CI, 1.02 to 2.21; median, 31 months) for the PD-L1 TPS 1%-49% group, and 1.51 (95% CI, 1.05 to 2.18) for the combined PD-L1-positive groups (TPS ≥ 1%) compared with the PD-L1-negative group (median, 35 months).
CONCLUSION
PD-L1 expression is associated with disease stage and type of EGFR mutation. PD-L1 positivity might be associated with worse RFS among patients with surgically treated EGFR-mutant NSCLC.

Keyword

Programmed cell death 1 protein; Epidermal growth factor receptor; Non-small cell lung carcinoma

MeSH Terms

Carcinoma, Non-Small-Cell Lung*
Exons
Humans
Molecular Epidemiology*
Prevalence
Programmed Cell Death 1 Receptor
Proportional Hazards Models
Receptor, Epidermal Growth Factor
Retrospective Studies*
Programmed Cell Death 1 Receptor
Receptor, Epidermal Growth Factor

Figure

• 

  Fig. 1. Sample images of programmed death ligand 1 (PD-L1) staining in non-small cell lung cancer. (A) PD-L1 negative (tumor proportion score [TPS] < 1%). (B) PD-L1 TPS 1%-49%. (C) PD-L1 TPS ≥ 50%. All images are at original magnification ×20, blue counterstain is hematoxylin, and PD-L1 is identified by brown chromagen.

• 

  Fig. 2. Recurrence-free survival among patients with nonsmall cell lung cancer and epidermal growth factor receptor mutation, by programmed death ligand 1 status. TPS, tumor proportion score.

• 

  Fig. 3. Overall survival among patients with non-small cell lung cancer and epidermal growth factor receptor mutation, by programmed death ligand 1 status. TPS, tumor proportion score.

Reference

References

1. D’Addario G, Fruh M, Reck M, Baumann P, Klepetko W, Felip E, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010; 21 Suppl 5:v116–9.

2. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005; 97:339–46.

3. Bronte G, Rizzo S, La Paglia L, Adamo V, Siragusa S, Ficorella C, et al. Driver mutations and differential sensitivity to targeted therapies: a new approach to the treatment of lung adenocarcinoma. Cancer Treat Rev. 2010; 36 Suppl 3:S21–9.

4. Luo SY, Lam DC. Oncogenic driver mutations in lung cancer. Transl Respir Med. 2013; 1:6.

5. Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014; 9:154–62.

6. McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med. 2013; 2:662–73.

7. D’Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno A, Landi L, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015; 112:95–102.

8. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008; 8:467–77.

9. Sun JM, Zhou W, Choi YL, Choi SJ, Kim SE, Wang Z, et al. Prognostic significance of PD-L1 in patients with non-small cell lung cancer: a large cohort study of surgically resected cases. J Thorac Oncol. 2016; 11:1003–11.

10. Azuma K, Ota K, Kawahara A, Hattori S, Iwama E, Harada T, et al. Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Ann Oncol. 2014; 25:1935–40.

11. Sul J, Blumenthal GM, Jiang X, He K, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. Oncologist. 2016; 21:643–50.

12. Kazandjian D, Suzman DL, Blumenthal G, Mushti S, He K, Libeg M, et al. FDA approval summary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist. 2016; 21:634–42.

13. Genentech, Inc. Tecentriq [package insert]. South San Fransisco, CA: Genentech, Inc.;2016.

14. Boland JM, Kwon ED, Harrington SM, Wampfler JA, Tang H, Yang P, et al. Tumor B7-H1 and B7-H3 expression in squamous cell carcinoma of the lung. Clin Lung Cancer. 2013; 14:157–63.

15. Chen YB, Mu CY, Huang JA. Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study. Tumori. 2012; 98:751–5.

16. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol. 2011; 28:682–8.

17. Yang CY, Lin MW, Chang YL, Wu CT, Yang PC. Programmed cell death-ligand 1 expression in surgically resected stage I pulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes. Eur J Cancer. 2014; 50:1361–9.

18. Dolled-Filhart M, Roach C, Toland G, Stanforth D, Jansson M, Lubiniecki GM, et al. Development of a companion diagnostic for pembrolizumab in non-small cell lung cancer using immunohistochemistry for programmed death ligand-1. Arch Pathol Lab Med. 2016; Aug. 23. [Epub]. https://doi.org/10.5858/arpa.2015-0542-OA.

19. Roach C, Zhang N, Corigliano E, Jansson M, Toland G, Ponto G, et al. Development of a companion diagnostic PD-L1 immunohistochemistry assay for pembrolizumab therapy in non-small-cell lung cancer. Appl Immunohistochem Mol Morphol. 2016; 24:392–7.

20. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th ed. New York: Springer-Verlag;2010.

21. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015; 372:2018–28.

22. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016; 387:1540–50.

23. Sun JM, Zhou W, Choi YL, Choi SJ, Kim SE, Wang Z, et al. PD-L1 expression and survival in patients with non-small cell lung cancer (NSCLC) in Korea. J Clin Oncol. 2014; 32 Suppl 5:Abstr 8066.

24. Ji M, Liu Y, Li Q, Li X, Ning Z, Zhao W, et al. PD-1/PD-L1 expression in non-small-cell lung cancer and its correlation with EGFR/KRAS mutations. Cancer Biol Ther. 2016; 17:407–13.

25. Ji M, Liu Y, Li Q, Li XD, Zhao WQ, Zhang H, et al. PD-1/PD-L1 pathway in non-small-cell lung cancer and its relation with EGFR mutation. J Transl Med. 2015; 13:5.

26. Tang Y, Fang W, Zhang Y, Hong S, Kang S, Yan Y, et al. The association between PD-L1 and EGFR status and the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-TKIs. Oncotarget. 2015; 6:14209–19.

27. Lin K, Cheng J, Yang T, Li Y, Zhu B. EGFR-TKI down-regulates PD-L1 in EGFR mutant NSCLC through inhibiting NF-κB. Biochem Biophys Res Commun. 2015; 463:95–101.

28. Rizvi NA, Chow LQ, Borghaei H, Shen Y, Harbison C, Alaparthy S, et al. Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC. J Clin Oncol. 2014; 32 Suppl 5:Abstr 8022.

29. Sorensen SF, Zhou W, Dolled-Filhart M, Georgsen JB, Wang Z, Emancipator K, et al. PD-L1 expression and survival among patients with advanced non-small cell lung cancer treated with chemotherapy. Transl Oncol. 2016; 9:64–9.

30. Schmidt LH, Kummel A, Gorlich D, Mohr M, Brockling S, Mikesch JH, et al. PD-1 and PD-L1 expression in NSCLC indicate a favorable prognosis in defined subgroups. PLoS One. 2015; 10:e0136023.