Skip to main content
Top

18-08-2016 | Lung and thoracic tumors | Article

Diagnosis and Molecular Classification of Lung Cancer

Authors: Jaime Rodriguez-Canales, Edwin Parra-Cuentas, Ignacio I. Wistuba

Publisher: Springer International Publishing

Abstract

Lung cancer is a complex disease composed of diverse histological and molecular types with clinical relevance. The advent of large-scale molecular profiling has been helpful to identify novel molecular targets that can be applied to the treatment of particular lung cancer patients and has helped to reshape the pathological classification of lung cancer. Novel directions include the immunotherapy revolution, which has opened the door for new opportunities for cancer therapy and is also redefining the classification of multiple tumors, including lung cancer. In the present chapter, we will review the main current basis of the pathological diagnosis and classification of lung cancer incorporating the histopathological and molecular dimensions of the disease.
Literature
1.
American Cancer Society (2015) Cancer facts & figures 2015. American Cancer Society, Atlanta
2.
Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359(13):1367–1380PubMedCrossRef
3.
Travis WD et al (2013) Diagnosis of lung adenocarcinoma in resected specimens: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med 137(5):685–705PubMedCrossRef
4.
Travis WD, Brambilla E, Riely GJ (2013) New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. J Clin Oncol 31(8):992–1001PubMedCrossRef
5.
Fujimoto J, Wistuba II (2014) Current concepts on the molecular pathology of non-small cell lung carcinoma. Semin Diagn Pathol 31(4):306–313
6.
Travis WD, Bambrilla E, Burke AP, Marx A, Nicholson AG (2015) WHO classification of tumours of the lung, pleura, thymus and heart, 4th edn. IARC WHO Classification of Tumours 2015: World Health Organization
7.
Biesalski HK et al (1998) European consensus statement on lung cancer: risk factors and prevention. Lung Cancer Panel. CA Cancer J Clin 48(3):167–76 (discussion 164–166)
8.
Hecht SS (2012) Lung carcinogenesis by tobacco smoke. Int J Cancer 131(12):2724–2732PubMedPubMedCentralCrossRef
9.
Khuder SA (2001) Effect of cigarette smoking on major histological types of lung cancer: a meta-analysis. Lung Cancer 31(2–3):139–148PubMedCrossRef
10.
Rosai J (2007) Why microscopy will remain a cornerstone of surgical pathology. Lab Invest 87(5):403–408PubMedCrossRef
11.
Kadota K et al (2015) Reevaluation and reclassification of resected lung carcinomas originally diagnosed as squamous cell carcinoma using immunohistochemical analysis. Am J Surg Pathol 9:1170–1180
12.
Rekhtman N et al (2011) Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol 24(10):1348–1359PubMedCrossRef
13.
Travis WD, Rekhtman N (2011) Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing. Semin Respir Crit Care Med 32(1):22–31PubMedCrossRef
14.
Travis WD et al (2011) International association for the study of lung cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 6(2):244–285PubMedPubMedCentralCrossRef
15.
Dela Cruz CS, Tanoue LT, Matthay RA (2011) Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med 32(4):605–644
16.
Shimosato Y et al (1980) Prognostic implications of fibrotic focus (scar) in small peripheral lung cancers. Am J Surg Pathol 4(4):365–373PubMedCrossRef
17.
Russell PA et al (2011) Does lung adenocarcinoma subtype predict patient survival? A clinicopathologic study based on the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol 6(9):1496–1504PubMedCrossRef
18.
Russell PA et al (2013) Correlation of mutation status and survival with predominant histologic subtype according to the new IASLC/ATS/ERS lung adenocarcinoma classification in stage III (N2) patients. J Thorac Oncol 8(4):461–468PubMedCrossRef
19.
Voldborg BR et al (1997) Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol 8(12):1197–1206PubMedCrossRef
20.
Lynch TJ et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21):2129–2139PubMedCrossRef
21.
Paez JG et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497–1500PubMedCrossRef
22.
Pao W et al (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci US A 101(36):13306–13311CrossRef
23.
Soh J et al (2009) Oncogene mutations, copy number gains and mutant allele specific imbalance (MASI) frequently occur together in tumor cells. PLoS ONE 4(10):e7464PubMedPubMedCentralCrossRef
24.
Ladanyi M, Pao W (2008) Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol 21(Suppl 2):S16–S22PubMedCrossRef
25.
Sordella R et al (2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305(5687):1163–1167PubMedCrossRef
26.
Morris SW et al (1994) Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 263(5151):1281–1284PubMedCrossRef
27.
Roskoski R Jr (2013) Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition. Pharmacol Res 68(1):68–94PubMedCrossRef
28.
Kwak EL et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703PubMedPubMedCentralCrossRef
29.
Shinmura K et al (2008) EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. Lung Cancer 61(2):163–169PubMedCrossRef
30.
Wong DW et al (2009) The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 115(8):1723–1733PubMedCrossRef
31.
Choi YL et al (2008) Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res 68(13):4971–4976PubMedCrossRef
32.
Takeuchi K et al (2009) KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 15(9):3143–3149PubMedCrossRef
33.
Horn L, Pao W (2009) EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 27(26):4232–4235PubMedCrossRef
34.
Koivunen JP et al (2008) EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 14(13):4275–4283PubMedPubMedCentralCrossRef
35.
Soda M et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448(7153):561–566PubMedCrossRef
36.
Shaw AT et al (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27(26):4247–4253PubMedPubMedCentralCrossRef
37.
Mano H (2008) Non-solid oncogenes in solid tumors: EML4-ALK fusion genes in lung cancer. Cancer Sci 99(12):2349–2355PubMedCrossRef
38.
Rikova K et al (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131(6):1190–1203PubMedCrossRef
39.
Inamura K et al (2009) EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol 22(4):508–515PubMedCrossRef
40.
Yi ES et al (2011) Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. J Thorac Oncol 6(3):459–465PubMedCrossRef
41.
Bang YJ (2011) The potential for crizotinib in non-small cell lung cancer: a perspective review. Ther Adv Med Oncol 3(6):279–291PubMedPubMedCentralCrossRef
42.
Choi YL et al (2010) EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 363(18):1734–1739PubMedCrossRef
43.
Sasaki T et al (2010) The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res 70(24):10038–10043PubMedPubMedCentralCrossRef
44.
Popescu NC, King CR, Kraus MH (1989) Localization of the human erbB-2 gene on normal and rearranged chromosomes 17 to bands q12-21.32. Genomics 4(3):362–366PubMedCrossRef
45.
Buttitta F et al (2006) Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: mutations are mainly present in adenocarcinomas with bronchioloalveolar features. Int J Cancer 119(11):2586–2591PubMedCrossRef
46.
Shigematsu H et al (2005) Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 65(5):1642–1646PubMedCrossRef
47.
Stephens P et al (2004) Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431(7008):525–526PubMedCrossRef
48.
Serizawa M et al (2014) Assessment of mutational profile of Japanese lung adenocarcinoma patients by multitarget assays: a prospective, single-institute study. Cancer 120(10):1471–1481PubMedCrossRef
49.
Li C et al (2014) Prognostic value analysis of mutational and clinicopathological factors in non-small cell lung cancer. PLoS ONE 9(9):e107276PubMedPubMedCentralCrossRef
50.
Wang SE et al (2006) HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10(1):25–38PubMedCrossRef
51.
Bergethon K et al (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30(8):863–870PubMedPubMedCentralCrossRef
52.
Davies KD et al (2012) Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin Cancer Res 18(17):4570–4579PubMedPubMedCentralCrossRef
53.
Takeuchi K et al (2012) RET, ROS1 and ALK fusions in lung cancer. Nat Med 18(3):378–381PubMedCrossRef
54.
Shaw AT et al (2014) Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371(21):1963–1971PubMedPubMedCentralCrossRef
55.
Knowles PP et al (2006) Structure and chemical inhibition of the RET tyrosine kinase domain. J Biol Chem 281(44):33577–33587PubMedCrossRef
56.
Ju YS et al (2012) A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res 22(3):436–445PubMedPubMedCentralCrossRef
57.
Kohno T et al (2012) KIF5B-RET fusions in lung adenocarcinoma. Nat Med 18(3):375–377PubMedCrossRef
58.
Lipson D et al (2012) Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 18(3):382–384PubMedPubMedCentralCrossRef
59.
Wang R et al (2012) RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol 30(35):4352–4359PubMedCrossRef
60.
Drilon A et al (2013) Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov 3(6):630–635PubMedPubMedCentralCrossRef
61.
Sossin WS (2006) Tracing the evolution and function of the Trk superfamily of receptor tyrosine kinases. Brain Behav Evol 68(3):145–156PubMedCrossRef
62.
Nakagawara A (2001) Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett 169(2):107–114PubMedCrossRef
63.
Alberti L et al (2003) RET and NTRK1 proto-oncogenes in human diseases. J Cell Physiol 195(2):168–186PubMedCrossRef
64.
Martin-Zanca D, Hughes SH, Barbacid M (1986) A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature 319(6056):743–748PubMedCrossRef
65.
Greco A, Miranda C, Pierotti MA (2010) Rearrangements of NTRK1 gene in papillary thyroid carcinoma. Mol Cell Endocrinol 321(1):44–49PubMedCrossRef
66.
Kim J et al (2014) NTRK1 fusion in glioblastoma multiforme. PLoS ONE 9(3):e91940PubMedPubMedCentralCrossRef
67.
Vaishnavi A et al (2013) Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med 19(11):1469–1472PubMedPubMedCentralCrossRef
68.
Doebele RC et al (2015) An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov 5(10):1049–1057PubMedPubMedCentralCrossRef
69.
Trusolino L, Bertotti A, Comoglio PM (2010) MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 11(12):834–848PubMedCrossRef
70.
Zhen Z et al (1994) Structural and functional domains critical for constitutive activation of the HGF-receptor (Met). Oncogene 9(6):1691–1697PubMed
71.
Yi S, Tsao MS (2000) Activation of hepatocyte growth factor-met autocrine loop enhances tumorigenicity in a human lung adenocarcinoma cell line. Neoplasia 2(3):226–234PubMedPubMedCentralCrossRef
72.
Cooper CS et al (1984) Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311(5981):29–33PubMedCrossRef
73.
Kong-Beltran M et al (2006) Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res 66(1):283–289PubMedCrossRef
74.
Ma PC et al (2003) c-MET mutational analysis in small cell lung cancer: novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res 63(19):6272–6281PubMed
75.
Kong-Beltran M, Stamos J, Wickramasinghe D (2004) The sema domain of met is necessary for receptor dimerization and activation. Cancer Cell 6(1):75–84PubMedCrossRef
76.
Ichimura E et al (1996) Expression of c-met/HGF receptor in human non-small cell lung carcinomas in vitro and in vivo and its prognostic significance. Jpn J Cancer Res 87(10):1063–1069PubMedCrossRef
77.
Olivero M et al (1996) Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas. Br J Cancer 74(12):1862–1868PubMedPubMedCentralCrossRef
78.
Benedettini E et al (2010) Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. Am J Pathol 177(1):415–423PubMedPubMedCentralCrossRef
79.
Nakamura Y et al (2007) c-Met activation in lung adenocarcinoma tissues: an immunohistochemical analysis. Cancer Sci 98(7):1006–1013PubMedCrossRef
80.
Onozato R et al (2009) Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol 4(1):5–11PubMedCrossRef
81.
Onitsuka T et al (2010) Comprehensive molecular analyses of lung adenocarcinoma with regard to the epidermal growth factor receptor, K-ras, MET, and hepatocyte growth factor status. J Thorac Oncol 5(5):591–596PubMedCrossRef
82.
Beau-Faller M et al (2008) MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naive cohort. J Thorac Oncol 3(4):331–339PubMedCrossRef
83.
Frampton GM et al (2015) Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov 5(8):850–859PubMedCrossRef
84.
McBride OW et al (1983) Regional chromosomal localization of N-ras, K-ras-1, K-ras-2 and myb oncogenes in human cells. Nucleic Acids Res 11(23):8221–8236PubMedPubMedCentralCrossRef
85.
Jancik S et al (2010) Clinical relevance of KRAS in human cancers. J Biomed Biotechnol 2010:150960PubMedPubMedCentral
86.
Tam IY et al (2006) Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res 12(5):1647–1653PubMedCrossRef
87.
Guerra C et al (2003) Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4(2):111–120PubMedCrossRef
88.
Popescu NC et al (1985) Chromosomal localization of three human ras genes by in situ molecular hybridization. Somat Cell Mol Genet 11(2):149–155PubMedCrossRef
89.
Soung YH et al (2005) Mutational analysis of EGFR and K-RAS genes in lung adenocarcinomas. Virchows Arch 446(5):483–488PubMedCrossRef
90.
Riely GJ et al (2008) Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 14(18):5731–5734PubMedPubMedCentralCrossRef
91.
Sun Y et al (2010) Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. J Clin Oncol 28(30):4616–4620PubMedPubMedCentralCrossRef
92.
Pao W et al (2005) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2(1):e17PubMedPubMedCentralCrossRef
93.
Eberhard DA et al (2005) Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23(25):5900–5909PubMedCrossRef
94.
Massarelli E et al (2007) KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res 13(10):2890–2896PubMedCrossRef
95.
Riely GJ, Ladanyi M (2008) KRAS mutations: an old oncogene becomes a new predictive biomarker. J Mol Diagn 10(6):493–495PubMedPubMedCentralCrossRef
96.
Wan PT et al (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116(6):855–867PubMedCrossRef
97.
Brose MS et al (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62(23):6997–7000PubMed
98.
Cardarella S et al (2013) Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res 19(16):4532–4540PubMedPubMedCentralCrossRef
99.
Davies H et al (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954PubMedCrossRef
100.
Naoki K et al (2002) Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res 62(23):7001–7003PubMed
101.
Paik PK et al (2011) Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 29(15):2046–2051PubMedPubMedCentralCrossRef
102.
Pratilas CA et al (2008) Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 68(22):9375–9383PubMedPubMedCentralCrossRef
103.
Fang M et al (2014) A comparison of consistency of detecting BRAF gene mutations in peripheral blood and tumor tissue of nonsmall-cell lung cancer patients. J Cancer Res Ther 10(Suppl):C150–C154PubMed
104.
Gautschi O et al (2012) A patient with BRAF V600E lung adenocarcinoma responding to vemurafenib. J Thorac Oncol 7(10):e23–e24PubMedCrossRef
105.
Falchook GS et al (2012) Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379(9829):1893–1901PubMedPubMedCentralCrossRef
106.
Gautschi O et al (2015) Targeted therapy for patients with BRAF-mutant lung cancer: results from the European EURAF cohort. J Thorac Oncol 10(10):1451–1457PubMedCrossRef
107.
Hyman DM et al (2015) Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med 373(8):726–736PubMedCrossRef
108.
McCormick F (1995) Ras-related proteins in signal transduction and growth control. Mol Reprod Dev 42(4):500–506PubMedCrossRef
109.
Ding L et al (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455(7216):1069–1075PubMedPubMedCentralCrossRef
110.
Ohashi K et al (2013) Characteristics of lung cancers harboring NRAS mutations. Clin Cancer Res 19(9):2584–2591PubMedPubMedCentralCrossRef
111.
Sasaki H et al (2007) Nras and Kras mutation in Japanese lung cancer patients: genotyping analysis using lightcycler. Oncol Rep 18(3):623–628PubMed
112.
Reynolds SH et al (1991) Activated protooncogenes in human lung tumors from smokers. Proc Natl Acad Sci USA 88(4):1085–1089PubMedPubMedCentralCrossRef
113.
Huang MH et al (2013) MEK inhibitors reverse resistance in epidermal growth factor receptor mutation lung cancer cells with acquired resistance to gefitinib. Mol Oncol 7(1):112–120PubMedCrossRef
114.
Franke TF (2008) PI3K/Akt: getting it right matters. Oncogene 27(50):6473–6488PubMedCrossRef
115.
Bleeker FE et al (2008) AKT1 (E17K) in human solid tumours. Oncogene 27(42):5648–5650PubMedCrossRef
116.
Malanga D et al (2008) Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung. Cell Cycle 7(5):665–669PubMedCrossRef
117.
Carpten JD et al (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448(7152):439–444PubMedCrossRef
118.
Derijard B et al (1995) Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science 267(5198):682–685PubMedCrossRef
119.
Arcila ME et al (2015) MAP2K1 (MEK1) mutations define a distinct subset of lung adenocarcinoma associated with smoking. Clin Cancer Res 21(8):1935–1943PubMedCrossRef
120.
Marks JL et al (2008) Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res 68(14):5524–5528PubMedPubMedCentralCrossRef
121.
Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94(4):455–459PubMedPubMedCentralCrossRef
122.
Hiles ID et al (1992) Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit. Cell 70(3):419–429PubMedCrossRef
123.
Samuels Y, Ericson K (2006) Oncogenic PI3K and its role in cancer. Curr Opin Oncol 18(1):77–82PubMedCrossRef
124.
Kawano O et al (2006) PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer 54(2):209–215PubMedCrossRef
125.
Lee JW et al (2005) PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 24(8):1477–1480PubMedCrossRef
126.
Oxnard GR, Binder A, Janne PA (2013) New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol 31(8):1097–1104PubMedPubMedCentralCrossRef
127.
Sequist LV et al (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3(75):75ra26
128.
Chaft JE et al (2012) Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Mol Cancer Ther 11(2):485–491PubMedCrossRef
129.
Xu J et al (2011) Somatic mutation analysis of EGFR, KRAS, BRAF and PIK3CA in 861 patients with non-small cell lung cancer. Cancer Biomark 10(2):63–69PubMed
130.
Anagnostou VK et al (2009) Thyroid transcription factor 1 is an independent prognostic factor for patients with stage I lung adenocarcinoma. J Clin Oncol 27(2):271–278PubMedCrossRef
131.
Berghmans T et al (2006) Thyroid transcription factor 1–a new prognostic factor in lung cancer: a meta-analysis. Ann Oncol 17(11):1673–1676PubMedCrossRef
132.
Crum CP, McKeon FD (2010) p63 in epithelial survival, germ cell surveillance, and neoplasia. Annu Rev Pathol 5:349–371PubMedCrossRef
133.
Travis WD et al (2013) Diagnosis of lung cancer in small biopsies and cytology: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. Arch Pathol Lab Med 137(5):668–684PubMedCrossRef
134.
Collins FS, Varmus H (2015) A new initiative on precision medicine. N Engl J Med 372(9):793–795PubMedCrossRef
135.
Topalian SL et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454PubMedPubMedCentralCrossRef
136.
Brahmer JR et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465PubMedPubMedCentralCrossRef
137.
Massarelli E et al (2014) Immunotherapy in lung cancer. Transl Lung Cancer Res 3(1):53–63PubMedPubMedCentral
138.
Anagnostou VK, Brahmer JR (2015) Cancer immunotherapy: a future paradigm shift in the treatment of non-small cell lung cancer. Clin Cancer Res 21(5):976–984PubMedCrossRef
139.
Brahmer JR (2014) Immune checkpoint blockade: the hope for immunotherapy as a treatment of lung cancer? Semin Oncol 41(1):126–132PubMedCrossRef
140.
Velcheti V et al (2014) Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest 94(1):107–116PubMedCrossRef
141.
Schalper KA et al (2015) Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst 107(3):dju435
142.
Teng MW et al (2015) Classifying cancers based on T-cell Infiltration and PD-L1. Cancer Res 75(11):2139–2145PubMedPubMedCentralCrossRef
143.
Kerr KM et al (2015) Programmed death-ligand 1 immunohistochemistry in lung cancer: in what state is this art? J Thorac Oncol 10(7):985–989PubMedCrossRef
144.
Garon EB et al (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372(21):2018–2028PubMedCrossRef
145.
Brahmer J et al (2015) Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373(2):123–135PubMedPubMedCentralCrossRef
146.
Borghaei H et al (2015) Nivolumab versus Docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373(17):1627–1639PubMedCrossRef
147.
Herbst RS et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567PubMedPubMedCentralCrossRef
148.
Rizvi NA et al (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230):124–128PubMedCrossRef