Övgü AYDIN, Songül ŞAHİN, Şebnem BATUR, Akif TURNA, Büge ÖZ, Tülin ÖZTÜRK

Programmed Death-Ligand-1 Expression in Non-Small Cell Lung Cancer and Prognosis

Background: Prognostic significance of the programmed death-ligand-1 status in non-small cell lung carcinoma remains controversial.Aims: To show the programmed death-ligand-1 expression status in patients with non-small cell lung carcinoma and its effect on the prognosis and the relationship with clinicopathologic data.Study Design: Retrospective cross-sectional study.Methods: The study included 208 cases who were diagnosed with NSCLC and who underwent surgical resection between 2001 and 2012. Programmed death-ligand-1 (SP142 clone) was applied to the histological sections acquired from the microarray paraffin blocks with immunohistochemistry. Staining intensity was scored as weak (+, 1), moderate (++, 2), and strong (+++, 3). Percentage (0%-100%) was multiplied by staining intensity (1-2-3) to calculate the H score. Four different cut-off values were used; 1: ≥1% (independent of intensity), 2: ≥5% (independent of intensity), 3: ≥5% moderate/strong staining (except for weak staining), 4: H score ≥30 values were considered positive. In this study, staining a single cell at any intensity was considered positive.Results: Thirty-four out 208 cases (16.3%) had PDL-1 positive staining. PDL-1 expression was observed in patients with non-small cell lung carcinoma independent of the histological type or subtype (range; 0-25%). When the cut-off level was set to ≥5% with moderate and strong staining, the median overall survival was 45 months for the PD-L1 positive group and not reached for the PD-L1 negative group (p-value 0.024). PD-L1 positivity was significantly higher in patients over the age of 60 years and in cases with a tumor diameter of more than 5 cm (p=0.023 and 0.025, respectively).Conclusion: PD-L1 expression is positive in 16.3% of patients with non-small cell lung cancer and may have a negative prognostic value.

PDF

___

Cancer AS. Cancer Facts 2015 [cited 2016 14.04.2016]. Available from: http://www.cancer.org/acs/groups/content/@editorial/documents/document/ acspc-044552.pdf.
Turna H. Chemotheraphy in Non-Small Cell Lung Cancer: Current Status, Updates on Pulmonary Diseases 2013;1:115-23.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65.
Zitvogel L, Kroemer G. Targeting PD-1/PD-L1 interactions for cancer immunotherapy. Oncoimmunology 2012;1:1223-5.
He J, Hu Y, Hu M, Li B. Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci Rep 2015;5:13110.
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.
Zhang Y, Wang L, Li Y, Pan Y, Wang R, Hu H, et al. Protein expression of programmed death 1 ligand 1 and ligand 2 independently predict poor prognosis in surgically resected lung adenocarcinoma. OncoTargets Ther 2014;7:567-73.
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.
Herbst RS, Gordon MS, Fine GD, Sosman JA, Soria JC, Hamid O, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. ASCO Annual Meeting Proceedings; 2013.
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014;32:1020-30.
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.
Yang CY, Lin MW, Chang YL, Wu CT, Yang PC. Programmed cell death-ligand 1 expression is associated with a favourable immune microenvironment and better overall survival in stage I pulmonary squamous cell carcinoma. Eur J Cancer 2016;57:91-103.
Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res 2004;10:5094-100.
Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest 2014;94:107-16.
Mahoney KM, Sun H, Liao X, Hua P, Callea M, Greenfield EA, et al. PD-L1 Antibodies to Its Cytoplasmic Domain Most Clearly Delineate Cell Membranes in Immunohistochemical Staining of Tumor Cells. Cancer Immunol Res 2015;3:1308-15.
Cooper WA, Tran T, Vilain RE, Madore J, Selinger CI, Kohonen-Corish M, et al. PD-L1 expression is a favorable prognostic factor in early stage non-small cell carcinoma. Lung Cancer 2015;89:181-8.
Mao Y, Li W, Chen K, Xie Y, Liu Q, Yao M, et al. B7-H1 and B7-H3 are independent predictors of poor prognosis in patients with non-small cell lung cancer. Oncotarget 2015;6:3452-61.
Schmidt LH, Kümmel A, Görlich D, Mohr M, Bröckling 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.
Abdel-Rahman O. Correlation between PD-L1 expression and outcome of NSCLC patients treated with anti-PD-1/PD-L1 agents: A meta-analysis. Crit Rev Oncol Hematol 2016;101:75-85.
Martinez Marti A, Martinez P, Navarro A, Cedres S, Murtra-Garrell N, Salva F, et al. Concordance of PD-L1 expression by different immunohistochemistry (IHC) definitions and in situ hybridization (ISH) in squamous cell carcinoma (SCC) of the lung. ASCO Annual Meeting Proceedings; 2014.
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.
Kim MY, Koh J, Kim S, Go H, Jeon YK, Chung DH. Clinicopathological analysis of PD-L1 and PD-L2 expression in pulmonary squamous cell carcinoma: Comparison with tumor-infiltrating T cells and the status of oncogenic drivers. Lung Cancer 2015;88:24-33.
Ritprajak P, Azuma M. Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma. Oral Oncol 2015;51:221-8.
Kitazono S, Fujiwara Y, Tsuta K, Utsumi H, Kanda S, Horinouchi H, et al. Reliability of Small Biopsy Samples Compared With Resected Specimens for the Determination of Programmed Death-Ligand 1 Expression in Non-Small-Cell Lung Cancer. Clin Lung Cancer 2015;16:385-90.
Velcheti V, Rimm DL, Schalper KA. Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1). J Thorac Oncol. 2013;8:803-5.
Kim S, Kim MY, Koh J, Go H, Lee DS, Jeon YK, et al. Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: Comparison of sarcomatous and carcinomatous areas. Eur J Cancer 2015;51:2698-707.
Schultheis AM, Scheel AH, Ozretić L, George J, Thomas RK, Hagemann T, et al. PD- L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer 2015;51:421-6.
Zhang Y, Kang S, Shen J, He J, Jiang L, Wang W, et al. Prognostic significance of programmed cell death 1 (PD-1) or PD-1 ligand 1 (PD-L1) Expression in epithelial-originated cancer: a meta-analysis. Medicine (Baltimore) 2015;94:e515.
Gettinger SN, Kowanetz M, Koeppen H, Wistuba II, Kockx M, Kadel EE, et al. editors. Molecular, immune and histopathological characterization of NSCLC based on PDL1 expression on tumor and immune cells and association with response to the anti-PDL1 antibody MPDL3280A. ASCO Annual Meeting Proceedings; 2015.
Grosso J, Horak CE, Inzunza D, Cardona DM, Simon JS, Gupta AK, et al. editors. Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538). ASCO Annual Meeting Proceedings; 2013.