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Molecular pathology of lung cancer in routine diagnostic practice: 2017 update


Authors: Radoslav Matěj 1,2;  Zdeněk Rohan 1,2;  Kristýna Němejcová 2;  Pavel Dundr 2
Authors‘ workplace: Oddělení patologie a molekulární medicíny, Thomayerova nemocnice, Praha 1;  Ústav patologie, 1. lékařská fakulta, Univerzita Karlova a VFN v Praze 2
Published in: Čes.-slov. Patol., 53, 2017, No. 4, p. 159-166
Category: Reviews Article

Overview

The group of non–small cell lung carcinomas includes tumors that are variable at the clinical, histopathological and molecular levels. Advances in the understanding of molecular pathology of lung adenocarcinomas in particular led to changes in their histopathological classification and treatment. Patients diagnosed with lung adenocarcinoma harboring specific mutations benefit from the administration of specific targeted therapy. Analysis of EGFR gene mutations and ALK rearrangement in lung adenocarcinomas are already routinely performed and are closely related to the indication for the administration of tyrosinkinase inhibitors. Besides EGFR mutations and ALK rearrangement there are also available other potential markers for analyzing, e.g. b-raf – BRAF, ROS1. Moreover, immunotherapy needs standardization of detection of crucial molecules, namely PD-L1. The aim of this review is to summarize the role of the most relevant molecules that could also serve as the therapeutic target for practicing pathologists.

Keywords:
NSCLC – lung adenocarcinoma – EGFR – ALK – BRAF – KRAS – RET – MET – PD-L1 – ROS1


Sources

1. Rohan Z, Matejčková M, Matěj R. Molekulární patologie plicních karcinomů. Cesk Patol 2014; 50(2): 71-75.

2. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Fourth edition. Lyon, France: IARC Press; 2015.

3. Soo RA, Stone EC, Cummings KM, et al. Scientific Advances in Thoracic Oncology 2016. J Thorac Oncol 2017.

4. Drilon A, Rekhtman N, Ladanyi M, Paik P. Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy. The Lancet Oncology 2012; 13(10): e418-e426.

5. Gandara DR, Hammerman PS, Sos ML, Lara PN, Jr., Hirsch FR. Squamous cell lung cancer: from tumor genomics to cancer therapeutics. Clin Cancer Res 2015; 21(10): 2236-2243.

6. Liao RG, Jung J, Tchaicha J, et al. Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma. Cancer Res 2013; 73(16): 5195-5205.

7. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373(17): 1627-1639.

8. Herbst RS, Baas P, Kim DW, 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(10027): 1540-1550.

9. Roskoski R, Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res 2014; 79: 34-74.

10. Wee P, Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers (Basel) 2017; 9(5).

11. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005; 97(5): 339-346.

12. Chapman AM, Sun KY, Ruestow P, Cowan DM, Madl AK. Lung cancer mutation profile of EGFR, ALK, and KRAS: Meta-analysis and comparison of never and ever smokers. Lung Cancer 2016; 102: 122-134.

13. Castellanos E, Feld E, Horn L. Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer. J Thorac Oncol 2017; 12(4): 612-623.

14. Lee DH. Treatments for EGFR-mutant non-small cell lung cancer (NSCLC): The road to a success, paved with failures. Pharmacol Ther 2017; 174: 1-21.

15. Pirker R. Third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr Opin Oncol 2016; 28(2): 115-121.

16. Zakowski MF, Hussain S, Pao W, et al. Morphologic features of adenocarcinoma of the lung predictive of response to the epidermal growth factor receptor kinase inhibitors erlotinib and gefitinib. Arch Pathol Lab Med 2009; 133(3): 470-477.

17. Sartori G, Cavazza A, Sgambato A, et al. EGFR and K-ras mutations along the spectrum of pulmonary epithelial tumors of the lung and elaboration of a combined clinicopathologic and molecular scoring system to predict clinical responsiveness to EGFR inhibitors. Am J Clin Pathol 2009; 131(4): 478-489.

18. Yousem SA. Role of molecular studies in the diagnosis of lung adenocarcinoma. Mod Pathol 2012; 25 Suppl 1: S11-17.

19. Rekhtman N, Ang DC, Riely GJ, Ladanyi M, Moreira AL. KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma. Mod Pathol 2013; 26(10): 1307-1319.

20. Allo G, Bandarchi B, Yanagawa N, et al. Epidermal growth factor receptor mutation-specific immunohistochemical antibodies in lung adenocarcinoma. Histopathology 2014; 64(6): 826-839.

21. Isaksson S, Bendahl PO, Salomonsson A, et al. Detecting EGFR alterations in clinical specimens-pitfalls and necessities. Virchows Arch 2013; 463(6): 755-764.

22. Wen YH, Brogi E, Hasanovic A, et al. Immunohistochemical staining with EGFR mutation-specific antibodies: high specificity as a diagnostic marker for lung adenocarcinoma. Mod Pathol 2013; 26(9): 1197-1203.

23. Lawrence B, Perez-Atayde A, Hibbard MK, et al. TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am J Pathol 2000; 157(2): 377-384.

24. Griffin CA, Hawkins AL, Dvorak C, Henkle C, Ellingham T, Perlman EJ. Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res 1999; 59(12): 2776-2780.

25. Debelenko LV, Raimondi SC, Daw N, et al. Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum. Mod Pathol 2011; 24(3): 430-442.

26. Horn L, Pao W. EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 2009; 27(26): 4232-4235.

27. Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol 2008; 3(1): 13-17.

28. Ou SH, Bartlett CH, Mino-Kenudson M, Cui J, Iafrate AJ. Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist 2012; 17(11): 1351-1375.

29. Choi YL, Takeuchi K, Soda M, et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res 2008; 68(13): 4971-4976.

30. Sasaki T, Rodig SJ, Chirieac LR, Janne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 2010; 46(10): 1773-1780.

31. Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 2009; 15(9): 3143-3149.

32. Togashi Y, Soda M, Sakata S, et al. KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One 2012; 7(2): e31323.

33. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013; 368(25): 2385-2394.

34. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014; 370(13): 1189-1197.

35. Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 2009; 15(16): 5216-5223.

36. Zhao F, Xu M, Lei H, et al. Clinicopathological characteristics of patients with non-small-cell lung cancer who harbor EML4-ALK fusion gene: a meta-analysis. PLoS One 2015; 10(2): e0117333.

37. Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol 2009; 22(4): 508-515.

38. Popat S, Gonzalez D, Min T, et al. ALK translocation is associated with ALK immunoreactivity and extensive signet-ring morphology in primary lung adenocarcinoma. Lung Cancer 2012; 75(3): 300-305.

39. Yoshida A, Tsuta K, Watanabe S, et al. Frequent ALK rearrangement and TTF-1/p63 co-expression in lung adenocarcinoma with signet-ring cell component. Lung Cancer 2011; 72(3): 309-315.

40. To KF, Tong JH, Yeung KS, et al. Detection of ALK rearrangement by immunohistochemistry in lung adenocarcinoma and the identification of a novel EML4-ALK variant. J Thorac Oncol 2013; 8(7): 883-891.

41. Han XH, Zhang NN, Ma L, et al. Immunohistochemistry reliably detects ALK rearrangements in patients with advanced non-small-cell lung cancer. Virchows Arch 2013; 463(4): 583-591.

42. Mino-Kenudson M, Chirieac LR, Law K, et al. A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res 2010; 16(5): 1561-1571.

43. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417(6892): 949-954.

44. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 2003; 63(7): 1454-1457.

45. Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 2011; 29(15): 2046-2051.

46. Chetty R, Govender D. Gene of the month: KRAS. J Clin Pathol 2013; 66(7): 548-550.

47. Sun JM, Hwang DW, Ahn JS, Ahn MJ, Park K. Prognostic and predictive value of KRAS mutations in advanced non-small cell lung cancer. PLoS One 2013; 8(5): e64816.

48. Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc 2009; 6(2): 201-205.

49. Campos-Parra AD, Zuloaga C, Manriquez ME, et al. KRAS mutation as the biomarker of response to chemotherapy and EGFR-TKIs in patients with advanced non-small cell lung cancer: clues for its potential use in second-line therapy decision making. Am J Clin Oncol 2015; 38(1): 33-40.

50. Naidoo J, Drilon A. KRAS-Mutant Lung Cancers in the Era of Targeted Therapy. Adv Exp Med Biol 2016; 893: 155-178.

51. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013; 8(7): 823-859.

52. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA 2007; 104(52): 20932-20937.

53. Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med 2012; 18(3): 375-377.

54. Pan ZW, Li JC. Advances in molecular genetics of Hirschsprung’s disease. Anat Rec (Hoboken) 2012; 295(10): 1628-1638.

55. Kim HS, Mitsudomi T, Soo RA, Cho BC. Personalized therapy on the horizon for squamous cell carcinoma of the lung. Lung Cancer 2013; 80(3): 249-255.

56. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991; 174(3): 561-569.

57. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711-723.

58. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372(21): 2018-2028.

59. Lee CK, Man J, Lord S, et al. Checkpoint Inhibitors in Metastatic EGFR-Mutated Non-Small Cell Lung Cancer-A Meta-Analysis. J Thorac Oncol 2017; 12(2): 403-407.

60. 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.

61. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 2014; 20(19): 5064-5074.

62. Bishop JA, Taube JM, Su A, et al. Secretory Carcinoma of the Skin Harboring ETV6 Gene Fusions: A Cutaneous Analogue to Secretory Carcinomas of the Breast and Salivary Glands. Am J Surg Pathol 2017; 41(1): 62-66.

63. Scheel AH, Dietel M, Heukamp LC, et al. Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas. Mod Pathol 2016; 29(10): 1165-1172.

64. Kerr KM, Tsao MS, Nicholson AG, et al. Programmed Death-Ligand 1 Immunohistochemistry in Lung Cancer: In what state is this art? J Thorac Oncol 2015; 10(7): 985-989.

65. Kerr KM, Hirsch FR. Programmed Death Ligand-1 Immunohistochemistry: Friend or Foe? Arch Pathol Lab Med 2016; 140(4): 326-331.

66. Rehman JA, Han G, Carvajal-Hausdorf DE, et al. Quantitative and pathologist-read comparison of the heterogeneity of programmed death-ligand 1 (PD-L1) expression in non-small cell lung cancer. Mod Pathol 2017; 30(3): 340-349.

67. Lim SH, Hong M, Ahn S, et al. Changes in tumour expression of programmed death-ligand 1 after neoadjuvant concurrent chemoradiotherapy in patients with squamous oesophageal cancer. Eur J Cancer 2016; 52: 1-9.

68. Kim S, Koh J, Kwon D, et al. Comparative analysis of PD-L1 expression between primary and metastatic pulmonary adenocarcinomas. Eur J Cancer 2017; 75: 141-149.

69. CAP/IASLC/AMP Molecular Testing Guideline: Open Comment Period [Available from: https://www.iaslc.org/articles/capiaslcamp-molecular-testing-guideline-open-comment-period.

70. Rachiglio AM, Esposito Abate R, Sacco A, et al. Limits and potential of targeted sequencing analysis of liquid biopsy in patients with lung and colon carcinoma. Oncotarget 2016; 7(41): 66595-66605.

71. Reck M, Hagiwara K, Han B, et al. ctDNA Determination of EGFR Mutation Status in European and Japanese Patients with Advanced NSCLC: The ASSESS Study. J Thorac Oncol 2016; 11(10): 1682-1689.

72. Oxnard GR, Thress KS, Alden RS, et al. Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2016; 34(28): 3375-3382.

73. Jiang L, Yang H, He P, et al. Improving Selection Criteria for ALK Inhibitor Therapy in Non-Small Cell Lung Cancer: A Pooled-Data Analysis on Diagnostic Operating Characteristics of Immunohistochemistry. Am J Surg Pathol 2016; 40(5): 697-703.

74. Zhou J, Zhao J, Sun K, et al. Accurate and economical detection of ALK positive lung adenocarcinoma with semiquantitative immunohistochemical screening. PLoS One 2014; 9(3): e92828.

75. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18(3): 378-381.

76. Matsuura S, Shinmura K, Kamo T, et al. CD74-ROS1 fusion transcripts in resected non-small cell lung carcinoma. Oncol Rep 2013; 30(4): 1675-1680.

77. Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project. J Thorac Oncol 2017; 12(2): 208-222.

78. Sholl LM, Aisner DL, Allen TC, et al. Programmed Death Ligand-1 Immunohistochemistry--A New Challenge for Pathologists: A Perspective From Members of the Pulmonary Pathology Society. Arch Pathol Lab Med 2016; 140(4): 341-344.

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