Subtyping of advanced lung cancer based on PD-L1 expression, tumor histopathology and mutation burden (EGFR and KRAS): a study from North India

Submitted: October 4, 2022
Accepted: December 13, 2022
Published: February 1, 2023
Abstract Views: 1011
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Immune checkpoint inhibitor (PD-L1) therapy of advanced non-small-cell lung cancer (NSCLC) has variable outcomes. Tumor subtypes based on PD-L1 expression, histopathology, mutation burden is required for patient stratification and formulation of treatment guidelines. Lung cancers (n=57) diagnosed at Pathology department, VPCI (2018-2021) were retrospectively analyzed. PD-L1(SP263) expressed by tumor cells [low (<1%), medium (1-49%), high (≥50%)] was correlated with histopathology, microenvironment, EGFR, KRAS expression. Patients were categorized into high and low risk based on their: i) gender: males (n=47, 30-89 years), females (n=10, 45-80 years); ii) smoking history: males 26/47 (45.61%), females 1/10 (10%); iii) tumor subtyping: squamous cell carcinoma 15/57 (26.32%), adenocarcinoma 6/57 (17.54%), NSCLC-undifferentiated 24/57 (42.10%), adenosquamous carcinoma 5/57 (8.77 %), carcinosarcoma 4/57 (7.02%), small cell carcinoma 1/57 (1.75%); iv) inflammatory tumor microenvironment/TILs 44/57 (77.1%); iv) PD-L1 positivity-31/57 (54.3%); v) concomitant EGFR/KRAS positivity. PD-L1positive cases showed squamous/undifferentiated histopathology, concomitant EGFR+ (9/20, 45%) and KRAS+ (8/15, 53.3%), smoking+ (21/31,67.74%).PD-L1 negative cases (26/57, 45.6%), were EGFR+ (2/14, 14.28%) and KRAS+ (6/19, 31.5%). The high-risk lung cancer subtypes show squamous/undifferentiated histopathology, inflammatory microenvironment, male preponderance, smoking history, higher concomitant PD-L1, KRAS and EGFR positivity. Lung cancer subtyping can predict clinical response/resistance of patients prior to initiation of PD-L1 inhibitor therapies and can be used to guide therapy.



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Vrankar M, Kern I, Stanic K. Prognostic value of PD-L1 expression in patients with unresectable stage III non-small cell lung cancer treated with chemoradiotherapy. Radiat Oncol 2020;15:247. DOI:
Inge LJ, Dennis E. Development and applications of computer image analysis algorithms for scoring of PD-L1 immunohistochemistry. Immunooncol Technol 2020;6:2-8. DOI:
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018–28. DOI:
Ahn BC, So JW, Synn CB, et al. Clinical decision support algorithm based on machine learning to assess the clinical response to anti-programmed death-1 therapy in patients with non-small cell lung cancer. Eur J Cancer 2021;153:179-89. DOI:
Liu C, Zheng S, Jin R, et al. The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity. Cancer Lett 2019;470:95–105. DOI:
Lococo F, Torricelli F, Rossi G, et al. Inter-relationship between PD-L1 expression and clinic-pathological features and driver gene mutations in pulmonary sarcomatoid carcinomas. Lung Cancer 2017;113:93–101. DOI:
Armstrong SA, Liu SV. Dashing decades of defeat: Long anticipated advances in the first-line treatment of extensive-stage small cell lung cancer. Curr Oncol Rep 2020;22:20. DOI:
Cronin-Fenton D, Dalvi T, Movva N, et al. PD-L1 expression, EGFR and KRAS mutations and survival among stage III unresected non-small cell lung cancer patients: a Danish cohort study. Sci Rep 2021;11:16892. DOI:
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348:124-8. DOI:
Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol 2011;12:175–80. DOI:
Liu J, Zheng Q, Mu X, et al. Automated tumor proportion score analysis for PD-L1 (22C3) expression in lung squamous cell carcinoma. Sci Reps 2021;11:15907. DOI:
Qin T, Xia J, Liu S, et al. Clinical importance of VEGFC and PD-L1 co-expression in lung adenocarcinoma patients. Thorac Cancer 2020;11:1139-48. DOI:
Travis WD, Brambilla E, Burke AP, et al. Introduction to the 2015 World Health Organization classification of tumors of the lung, pleura, thymus, and heart. J Thorac Oncol 2015;10:1240-2. DOI:
Agilent Dako. Pd-L1 ihc 22c3 pharmdx interpretation manual. 2018. Available from:
Qu J, Mei Q, Liu L, et al. The progress and challenge of anti-PD-1/PD-L1 immunotherapy in treating non-small cell lung cancer. Ther Adv Med Oncol 2021;13:1758835921992968. DOI:
Tamiya M, Tamiya A, Hosoya K, et al. Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001). Invest New Drugs 2019;37:1266-73. DOI:
Sherwood JL, Brown H, Rettino A, et al. Key differences between 13 KRAS mutation detection technologies and their relevance for clinical practice. ESMO Open 2017;2:e000235. DOI:
Teramoto K, Igarashi T, Kataoka Y, et al. Biphasic prognostic significance of PD-L1 expression status in patients with early and locally advanced-stage non-small cell lung cancer. Cancer Immunol Immunother 2021;70:1063-74. DOI:
Miyazawa T, Marushima H, Saji H, et al. PD-L1 expression in non-small-cell lung cancer including various adenocarcinoma subtypes. Ann Thorac Cardiovasc Surg 2019;25:1-9. DOI:
Shien K, Papadimitrakopoulou VA, Wistuba II. Predictive biomarkers of response to PD-1/PD-L1 immune checkpoint inhibitors in non-small cell lung cancer. Lung Cancer 2016;99:79–87. DOI:
Iwai Y, Hamanishi J, Chamoto K, Honjo T. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 2017;24:26. DOI:
Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med 2016;8:328rv4. DOI:
Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 2002;99:12293-7. DOI:
Reck M, Luft A, Szczesna A, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol 2016;34:3740-8. DOI:
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PDL1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540–50. DOI:
Ng KeeKwong F, Laggner U, McKinney O, et al. Expression of PD-L1 correlates with pleomorphic morphology and histological patterns of non-small-cell lung carcinomas. Histopathology 2018;72:1024-32. DOI:
Wu Y, Ju Q, Jia K, et al. Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and CTLA-4 inhibitors). Int J Cancer 2018;14:45-51. DOI:
Wu Y, Ju Q, Qian B, et al. The effectiveness of PD-1 inhibitors in non-small cell lung cancer (NSCLC) patients of different ages. Oncotarget 2017;9:7942–8. DOI:
King-Kallimanis BL, Kanapuru B, Blumenthal GM, et al. Age-related differences in patient-reported outcomes in patients with advanced lung cancer receiving anti-PD-1/PD-L1 therapy. Semin Oncol 2018;45:201-9. DOI:
Sun L, Zhang L, Yu J, et al. Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and metaanalysis. Sci Rep 2020;10:2083. DOI:
Wang Q, Li M, Yang M, et al. Analysis of immune-related signatures of lung adenocarcinoma identified two distinct subtypes: implications for immune checkpoint blockade therapy. Aging 2020;12:3312-39. DOI:
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Eng J Med 2012;366:2455–65. DOI:
Herberth G, Bauer M, Gasch M, et al. Maternal and cord blood miR-223 expression associates with prenatal tobacco smoke exposure and low regulatory T-cell numbers. J Allergy Clin Immunol 2014;133:543-50. DOI:
Givi ME, Folkerts G, Wagenaar GT, et al. Cigarette smoke differentially modulates dendritic cell maturation and function in time. Respir Res 2015;16:131. DOI:
Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature 2013;500;415-21.
Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095-103. DOI:
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35. DOI:
Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 2018;379:2220-9. DOI:
Zito Marino F, Rossi G, Montella M, et al. Heterogeneity of PD-L1 expression in lung mixed adenocarcinomas and adenosquamous carcinomas. Am J Surg Pathol 2020;44:378-36. DOI:
Stanta G, Bonin S. Overview on clinical relevance of intra-tumor heterogeneity. Front Med (Lausanne) 2018;5:85. DOI:
Munari E, Zamboni G, Marconi M, et al. PD-L1 expression heterogeneity in non-small cell lung cancer: evaluation of small biopsies reliability. Oncotarget 2017;8:90123-31. DOI:
Vieira T, Antoine M, Hamard C, et al. Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1) and strong immune-cell infiltration by TCD3 cells and macrophages. Lung Cancer 2016;98:51-8. DOI:
Kroeze LI, de Voer RM, Kamping EJ, et al. Evaluation of a hybrid capture-based pan-cancer panel for analysis of treatment stratifying oncogenic aberrations and processes. J Mol Diagn 2020;22:757-69. DOI:

Supporting Agencies

The intramural funding was provided by Vallabhbhai Patel Chest Institute, University of Delhi

How to Cite

Kulshrestha, Ritu, Himanshi Saxena, Raj Kumar, Sonam Spalgais, Parul Mrigpuri, Nitin Goel, Balakrishnan Menon, Meenu Rani, Pawan Mahor, and Ishita Bhutani. 2023. “Subtyping of Advanced Lung Cancer Based on PD-L1 Expression, Tumor Histopathology and Mutation Burden (EGFR and KRAS): A Study from North India”. Monaldi Archives for Chest Disease 93 (4).