Skip to main content

Advertisement

Log in

Prognostic and predictive biomarkers in lung cancer. A review

  • Review and Perspectives
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

In lung cancer, clinically relevant prognostic information is provided by staging. Staging forms the basis for the treatment options and this is briefly summarized in the introduction. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase are biomarkers used for prediction of chemotherapy and prediction of targeted treatment. Other driver biomarkers in lung cancer (point mutations and rearrangements in specific genes including Her2, BRAF, NUT, MET, ROS1, DDR2, FGFR1, KRAS, and PTEN) might potentially provide additional information for clinical decision making. Owing to the low prevalence of mutations in predictive markers, patient numbers in studies are usually small, with the exception of EGFR. These mutations increase our understanding of the biology of lung cancer. Mutation analysis as a basis for treatment choice can have an impressive clinical impact with dramatic responses. However, as yet the impact of these approaches to overall survival is less striking.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Vallières E, Shepherd FA, Crowley J et al (2009) The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 4:1049–1059. doi:10.1097/JTO.0b013e3181b27799

    PubMed  Google Scholar 

  2. Travis WD, Giroux DJ, Chansky K et al (2008) The IASLC Lung Cancer Staging Project: proposals for the inclusion of broncho-pulmonary carcinoid tumors in the forthcoming (seventh) edition of the TNM Classification for Lung Cancer. J Thorac Oncol 3:1213–1223. doi:10.1097/JTO.0b013e31818b06e3

    PubMed  Google Scholar 

  3. Zhu C-Q, Shih W, Ling C-H, Tsao M-S (2006) Immunohistochemical markers of prognosis in non-small cell lung cancer: a review and proposal for a multiphase approach to marker evaluation. J Clin Pathol 59:790–800. doi:10.1136/jcp.2005.031351

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Kanters SDJM, Lammers J-WJ, Voest EE (1995) Molecular and biological factors in the prognosis. Eur Respir J 8:1389–1397. doi:10.1183/09031936.95.08081389

    CAS  PubMed  Google Scholar 

  5. Botling J, Edlund K, Lohr M et al (2013) Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis, and tissue microarray validation. Clin Cancer Res 19:194–204. doi:10.1158/1078-0432.CCR-12-1139

    CAS  PubMed  Google Scholar 

  6. Van Meerbeeck JP, Fennell DA, De Ruysscher DKM (2011) Small-cell lung cancer. Lancet 378:1741–1755. doi:10.1016/S0140-6736(11)60165-7

    PubMed  Google Scholar 

  7. Scagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551. doi:10.1200/JCO.2007.15.0375

    CAS  PubMed  Google Scholar 

  8. NSCLC Meta-Analyses Collaborative Group (2008) Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 26:4617–4625. doi:10.1200/JCO.2008.17.7162

    PubMed Central  Google Scholar 

  9. Vansteenkiste J, De Ruysscher D, Eberhardt WEE et al (2013) Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 21:1–10. doi:10.1093/annonc/mdt241

    Google Scholar 

  10. Soria J-C, Mauguen A, Reck M et al (2013) Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 24:20–30. doi:10.1093/annonc/mds590

    PubMed  Google Scholar 

  11. Lima ABC, Macedo LT, Sasse AD (2011) Addition of bevacizumab to chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis. PLoS One 6:e22681. doi:10.1371/journal.pone.0022681

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Travis W, Brambilla E, Muller-Hermelink H (2004) WHO classification of tumours, pathology and genetics: tumors of the lung, pleura thymus and heart. IARC Press, Lyon

    Google Scholar 

  13. Travis WD, Brambilla E, Noguchi M 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 6:244–285. doi:10.1097/JTO.0b013e318206a221

    PubMed  Google Scholar 

  14. Travis WD, Brambilla E, Noguchi M et al (2012) 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. doi:10.5858/arpa.2012-0263-RA

    Google Scholar 

  15. Thunnissen E, Boers E, Heideman DA et al (2012) Correlation of immunohistochemical staining p63 and TTF-1 with EGFR and K-ras mutational spectrum and diagnostic reproducibility in non small cell lung carcinoma. Virchows Arch. doi:10.1007/s00428-012-1324-x

    PubMed Central  Google Scholar 

  16. Bishop JA, Teruya-Feldstein J, Westra WH et al (2012) p40 (DeltaNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol 25:405–415. doi:10.1038/modpathol.2011.173

    CAS  PubMed  Google Scholar 

  17. Nonaka D (2012) A study of DeltaNp63 expression in lung non-small cell carcinomas. Am J Surg Pathol 36:895–899. doi:10.1097/PAS.0b013e3182498f2b

    PubMed  Google Scholar 

  18. Rekhtman N, Paik PK, Arcila ME et al (2012) Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations. Clin Cancer Res 18:1167–1176. doi:10.1158/1078-0432.CCR-11-2109.Clarifying

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Liu Y, Yin T-J, Zhou R et al (2013) Expression of thymidylate synthase predicts clinical outcomes of pemetrexed-containing chemotherapy for non-small-cell lung cancer: a systemic review and meta-analysis. Cancer Chemother Pharmacol. doi:10.1007/s00280-013-2299-2

    PubMed Central  Google Scholar 

  20. Nicolson MC, Fennell DA, Ferry D et al (2013) Thymidylate synthase expression and outcome of patients receiving pemetrexed for advanced nonsquamous non-small-cell lung cancer in a prospective blinded assessment phase II clinical trial. J Thorac Oncol 8:930–939. doi:10.1097/JTO.0b013e318292c500

    CAS  PubMed  Google Scholar 

  21. Olaussen KA, Dunant A, Fouret P et al (2006) DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355:983–991. doi:10.1056/NEJMoa060570

    CAS  PubMed  Google Scholar 

  22. Wachters FM, Wong LSM, Timens W et al (2005) ERCC1, hRad51, and BRCA1 protein expression in relation to tumour response and survival of stage III/IV NSCLC patients treated with chemotherapy. Lung Cancer 50:211–219. doi:10.1016/j.lungcan.2005.06.013

    CAS  PubMed  Google Scholar 

  23. Vilmar AC, Santoni-Rugiu E, Sørensen JB (2010) ERCC1 and histopathology in advanced NSCLC patients randomized in a large multicenter phase III trial. Ann Oncol 21:1817–1824. doi:10.1093/annonc/mdq053

    CAS  PubMed  Google Scholar 

  24. Reynolds C, Obasaju C, Schell MJ et al (2009) Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer. J Clin Oncol 27:5808–5815. doi:10.1200/JCO.2009.21.9766

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Booton R, Ward T, Ashcroft L et al (2007) ERCC1 mRNA expression is not associated with response and survival after platinum-based chemotherapy regimens in advanced non-small cell lung cancer. J Thorac Oncol 2:902–906. doi:10.1097/JTO.0b013e318155a637

    PubMed  Google Scholar 

  26. Cobo M, Isla D, Massuti B et al (2007) Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol 25:2747–2754. doi:10.1200/JCO.2006.09.7915

    CAS  PubMed  Google Scholar 

  27. Bepler G, Williams C, Schell MJ et al (2013) Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 31:2404–2412. doi:10.1200/JCO.2012.46.9783

    CAS  PubMed  Google Scholar 

  28. Maus MKH, Mack PC, Astrow SH et al (2013) Histology-related associations of ERCC1, RRM1, and TS biomarkers in patients with non-small-cell lung cancer: implications for therapy. J Thorac Oncol 8:582–586. doi:10.1097/JTO.0b013e318287c3c5

    CAS  PubMed  Google Scholar 

  29. Jakobsen JN, Santoni-Rugiu E, Ravn J, Sørensen JB (2013) Intratumour variation of biomarker expression by immunohistochemistry in resectable non-small cell lung cancer. Eur J Cancer 49:2494–2503. doi:10.1016/j.ejca.2013.04.003

    CAS  PubMed  Google Scholar 

  30. Vilmar A, Garcia-Foncillas J, Huarriz M et al (2012) RT-PCR versus immunohistochemistry for correlation and quantification of ERCC1, BRCA1, TUBB3 and RRM1 in NSCLC. Lung Cancer 75:306–312. doi:10.1016/j.lungcan.2011.08.016

    CAS  PubMed  Google Scholar 

  31. Mok TS, Wu Y-L, Thongprasert S et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957. doi:10.1056/NEJMoa0810699

    CAS  PubMed  Google Scholar 

  32. Sequist LV, Yang JC-H, Yamamoto N et al (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327–3334. doi:10.1200/JCO.2012.44.2806

    CAS  PubMed  Google Scholar 

  33. Zhou C, Wu Y-L, Chen G et al (2011) Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12:735–742. doi:10.1016/S1470-2045(11)70184-X

    CAS  PubMed  Google Scholar 

  34. Mitsudomi T, Morita S, Yatabe Y et al (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11:121–128. doi:10.1016/S1470-2045(09)70364-X

    CAS  PubMed  Google Scholar 

  35. Rosell R, Carcereny E, Gervais R et al (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239–246. doi:10.1016/S1470-2045(11)70393-X

    CAS  PubMed  Google Scholar 

  36. Shaw AT, Kim D-W, Nakagawa K et al (2013) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:130601060020006. doi:10.1056/NEJMoa1214886

    Google Scholar 

  37. Govindan R, Ding L, Griffith M et al (2013) Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150:1121–1134. doi:10.1016/j.cell.2012.08.024.GENOMIC

    Google Scholar 

  38. Imielinski M, Berger AH, Hammerman PS et al (2013) Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150:1107–1120. doi:10.1016/j.cell.2012.08.029.Mapping

    Google Scholar 

  39. Ding L, Getz G, Wheeler DA et al (2009) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075. doi:10.1038/nature07423.Somatic

    Google Scholar 

  40. Lindeman NI, Cagle PT, Beasley MB et al (2013) 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 Patho. Arch Pathol Lab Med 137:828–860. doi:10.5858/arpa.2012-0720-OA

    CAS  PubMed  Google Scholar 

  41. Lee CK, Brown C, Gralla RJ et al (2013) Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. J Natl Cancer Inst 105:595–605. doi:10.1093/jnci/djt072

    CAS  PubMed  Google Scholar 

  42. Gahr S, Stoehr R, Geissinger E et al (2013) EGFR mutational status in a large series of Caucasian European NSCLC patients: data from daily practice. Br J Cancer. doi:10.1038/bjc.2013.511

    PubMed  Google Scholar 

  43. Dearden S, Stevens J, Wu Y-L, Blowers D (2013) Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol 24:2371–2376. doi:10.1093/annonc/mdt205

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Thunnissen E, Kerr KM, Herth FJ et al (2012) The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group. Lung Cancer 76:1–18. doi:10.1016/j.lungcan.2011.10.017

    PubMed  Google Scholar 

  45. Brevet M, Arcila M, Ladanyi M (2010) Assessment of EGFR mutation status in lung adenocarcinoma by immunohistochemistry using antibodies specific to the two major forms of mutant EGFR. J Mol Diagn 12:169–176. doi:10.2353/jmoldx.2010.090140

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Yu J, Kane S, Wu J et al (2009) Mutation-specific antibodies for the detection of EGFR mutations in non-small-cell lung cancer. Clin Cancer Res 15:3023–3028. doi:10.1158/1078-0432.CCR-08-2739

    CAS  PubMed  Google Scholar 

  47. Simonetti S, Molina MA, Queralt C et al (2010) Detection of EGFR mutations with mutation-specific antibodies in stage IV non-small-cell lung cancer. J Transl Med 8:135. doi:10.1186/1479-5876-8-135

    PubMed Central  PubMed  Google Scholar 

  48. Kawahara A, Yamamoto C, Nakashima K et al (2010) Molecular diagnosis of activating EGFR mutations in non-small cell lung cancer using mutation-specific antibodies for immunohistochemical analysis. Clin Cancer Res 16:3163–3170. doi:10.1158/1078-0432.CCR-09-3239

    CAS  PubMed  Google Scholar 

  49. Kitamura A, Hosoda W, Sasaki E et al (2010) Immunohistochemical detection of EGFR mutation using mutation-specific antibodies in lung cancer. Clin Cancer Res 16:3349–3355. doi:10.1158/1078-0432.CCR-10-0129

    CAS  PubMed  Google Scholar 

  50. Kawahara A, Taira T, Azuma K et al (2012) A diagnostic algorithm using EGFR mutation-specific antibodies for rapid response EGFR-TKI treatment in patients with non-small cell lung cancer. Lung Cancer 78:39–44. doi:10.1016/j.lungcan.2012.07.002

    PubMed  Google Scholar 

  51. Jiang G, Fan C, Zhang X et al (2013) Ascertaining an appropriate diagnostic algorithm using EGFR mutation-specific antibodies to detect EGFR status in non-small-cell lung cancer. PLoS One 8:e59183. doi:10.1371/journal.pone.0059183

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Sequist LV, Waltman BA, Dias-santagata D et al (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3:75ra26. doi:10.1126/scitranslmed.3002003.Genotypic

    PubMed Central  PubMed  Google Scholar 

  53. Zhang Z, Lee JCJ, Lin L et al (2013) Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat Genet 44:852–860. doi:10.1038/ng.2330.Activation

    Google Scholar 

  54. Wang S, Takayama K, Tanaka K, Takeshita M, Nakagaki N, Ijichi K, Li H, Nakanishi Y (2013) Nicotine induces resistance to epidermal growth factor receptor tyrosine kinase inhibitor by α1 nicotinic acetylcholine receptor-mediated activation in PC9 cells. J Thorac Oncol 8(6):719–725. doi:10.1097/JTO.0b013e31828b51d4

    Google Scholar 

  55. Terai H, Soejima KN, Yasuda H et al (2013) Activation of the FGF2-FGFR1 autocrine pathway: a novel mechanism of acquired resistance to gefitinib in NSCLC cells. Mol Cancer Res. doi:10.1158/1541-7786.MCR-12-0652

    PubMed  Google Scholar 

  56. Ware KE, Hinz TK, Kleczko E et al (2013) A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop. Oncogenesis 2:e39. doi:10.1038/oncsis.2013.4

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Popat S, Wotherspoon A, Nutting CM et al (2013) Transformation to “high grade” neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma. Lung Cancer 80:1–4. doi:10.1016/j.lungcan.2012.12.019

    CAS  PubMed  Google Scholar 

  58. Van Riel S, Thunnissen E, Heideman D et al (2012) A patient with simultaneously appearing adenocarcinoma and small-cell lung carcinoma harbouring an identical EGFR exon 19 mutation. Ann Oncol 23:3188–3189. doi:10.1093/annonc/mds525

    PubMed  Google Scholar 

  59. Thunnissen E, Bubendorf L, Dietel M et al (2012) EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations. Virchows Arch 461:245–257. doi:10.1007/s00428-012-1281-4

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Conklin CMJ, Craddock KJ, Have C et al (2013) Immunohistochemistry is a reliable screening tool for identification of ALK rearrangement in non-small-cell lung carcinoma and is antibody dependent. J Thorac Oncol 8:45–51. doi:10.1097/JTO.0b013e318274a83e

    CAS  PubMed  Google Scholar 

  61. Mino-Kenudson M, Chirieac LR, Law K et al (2010) A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res 16:1561–1571. doi:10.1158/1078-0432.CCR-09-2845

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Yi ES, Boland JM, Maleszewski JJ 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 6:459–465. doi:10.1097/JTO.0b013e318209edb9

    PubMed  Google Scholar 

  63. Wallander ML, Geiersbach KB, Tripp SR, Layfield LJ (2012) Comparison of reverse transcription-polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization methodologies for detection of echinoderm microtubule-associated proteinlike 4-anaplastic lymphoma kinase fusion-positive non-small. Arch Pathol Lab Med 136:796–803. doi:10.5858/arpa.2011-0321-OA

    CAS  PubMed  Google Scholar 

  64. Park HS, Lee JK, Kim D-W et al (2012) Immunohistochemical screening for anaplastic lymphoma kinase (ALK) rearrangement in advanced non-small cell lung cancer patients. Lung Cancer 77:288–292. doi:10.1016/j.lungcan.2012.03.004

    PubMed  Google Scholar 

  65. Yang P, Kulig K, Boland JM et al (2012) Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma. J Thorac Oncol 7:90–97. doi:10.1097/JTO.0b013e31823c5c32

    PubMed Central  PubMed  Google Scholar 

  66. Paik JH, Choi C-M, Kim H et al (2012) Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: a proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma. Lung Cancer 76:403–409. doi:10.1016/j.lungcan.2011.11.008

    PubMed  Google Scholar 

  67. McLeer-Florin A, Moro-Sibilot D, Melis A et al (2012) Dual IHC and FISH testing for ALK gene rearrangement in lung adenocarcinomas in a routine practice: a French study. J Thorac Oncol 7:348–354. doi:10.1097/JTO.0b013e3182381535

    PubMed  Google Scholar 

  68. Mino-Kenudson M, Mark EJ (2011) Reflex testing for epidermal growth factor receptor mutation and anaplastic lymphoma kinase fluorescence in situ hybridization in non-small cell lung cancer. Arch Pathol Lab Med 135:655–664. doi:10.1043/2011-0029-RAI.1

    CAS  PubMed  Google Scholar 

  69. Kim H, Yoo S-B, Choe J-Y et al (2011) Detection of ALK gene rearrangement in non-small cell lung cancer: a comparison of fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression. J Thorac Oncol 6:1359–1366. doi:10.1097/JTO.0b013e31821cfc73

    PubMed  Google Scholar 

  70. Just P-A, Cazes A, Audebourg A et al (2012) Histologic subtypes, immunohistochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: a comprehensive study of Caucasian non-smokers. Lung Cancer 76:309–315. doi:10.1016/j.lungcan.2011.11.004

    PubMed  Google Scholar 

  71. Firat S, Pleister A, Byhardt R et al (2012) Immunohistochemistry to identify EGFR mutations or ALK rearrangements in patients with lung adenocarcinoma. Ann Oncol 23:1738–1743. doi:10.1093/annonc/mdr535

    Google Scholar 

  72. Wu Y-C, Chang I-C, Wang C-L et al (2013) Comparison of IHC, FISH and RT-PCR methods for detection of ALK rearrangements in 312 non-small cell lung cancer patients in Taiwan. PLoS One 8:e70839. doi:10.1371/journal.pone.0070839

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Han X-H, Zhang N-N, Ma L et al (2013) Immunohistochemistry reliably detects ALK rearrangements in patients with advanced non-small-cell lung cancer. Virchows Arch. doi:10.1007/s00428-013-1472-7

    Google Scholar 

  74. Takamochi K, Takeuchi K, Hayashi T et al (2013) A rational diagnostic algorithm for the identification of ALK rearrangement in lung cancer: a comprehensive study of surgically treated Japanese patients. PLoS One 8:e69794. doi:10.1371/journal.pone.0069794

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Peled N, Palmer G, Hirsch FR et al (2012) Next-generation sequencing identifies and immunohistochemistry confirms a novel crizotinib-sensitive ALK rearrangement in a patient with metastatic non-small-cell lung cancer. J Thorac Oncol 7(9):e14–e16

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Sun J-M, Choi Y-L, Won J-K et al (2012) A dramatic response to crizotinib in a non-small-cell lung cancer patient with IHC-positive nd FISH-negative ALK. J Thorac Oncol 7(12):e36–e38

    PubMed  Google Scholar 

  77. Sholl LM, Weremowicz S, Gray SW et al (2013) Combined use of ALK immunohistochemistry and FISH for optimal detection of ALK-rearranged lung adenocarcinomas. J Thorac Oncol 8:322–328. doi:10.1097/JTO.0b013e31827db604

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Sadiq AA, Salgia R (2013) MET as a possible target for non-small-cell lung cancer. J Clin Oncol 31:1089–1096. doi:10.1200/JCO.2012.43.9422

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Bergethon K, Shaw AT, Ou S-HI et al (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30:863–870. doi:10.1200/JCO.2011.35.6345

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Marchetti A, Felicioni L, Malatesta S et al (2011) Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 29:3574–3579. doi:10.1200/JCO.2011.35.9638

    CAS  PubMed  Google Scholar 

  81. Oxnard GR, Binder A, Jänne PA (2013) New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol 31:1097–1104. doi:10.1200/JCO.2012.42.9829

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Mazières J, Peters S, Lepage B et al (2013) Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 31:1997–2003. doi:10.1200/JCO.2012.45.6095

    PubMed  Google Scholar 

  83. Pirker R, Pereira JR, von Pawel J et al (2012) EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 13:33–42. doi:10.1016/S1470-2045(11)70318-7

    CAS  PubMed  Google Scholar 

  84. Reungwetwattana T, Molina JR, Mandrekar SJ et al (2012) Brief report: a phase II “window-of-opportunity” frontline study of the MTOR inhibitor, temsirolimus given as a single agent in patients with advanced NSCLC, an NCCTG study. J Thorac Oncol 7:919–922. doi:10.1097/JTO.0b013e31824de0d6

    PubMed  Google Scholar 

  85. Ohashi K, Sequist LV, Arcila ME et al (2013) Characteristics of lung cancers harboring NRAS mutations. Clin Cancer Res 19:2584–2591. doi:10.1158/1078-0432.CCR-12-3173

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Martin P, Leighl NB, Tsao M-S, Shepherd FA (2013) KRAS mutations as prognostic and predictive markers in non-small cell lung cancer. J Thorac Oncol 8:530–542. doi:10.1097/JTO.0b013e318283d958

    CAS  PubMed  Google Scholar 

  87. Vaishnavi A, Capelletti M, Le AT et al (2013) Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. doi:10.1038/nm.3352

    PubMed  Google Scholar 

  88. Hammerman PS, Sos ML, Ramos AH et al (2011) Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov 1:78–89. doi:10.1158/2159-8274.CD-11-0005

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Ren M, Hong M, Liu G et al (2013) Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1. Oncol Rep 29:2181–2190. doi:10.3892/or.2013.2386

    CAS  PubMed  Google Scholar 

  90. Bellezza G, Del Sordo R, Colella R et al (2013) Co-expression of receptors of the HER family correlates with clinical outcome in non-small cell lung cancer (NSCLC). Virchows Arch. doi:10.1007/s00428-013-1445-x

    PubMed  Google Scholar 

  91. Liu L, Shao X, Gao W et al (2010) The role of human epidermal growth factor receptor 2 as a prognostic factor in lung cancer. J Thorac Oncol 5:1922–1932. doi:10.1097/JTO.0b013e3181f26266

    PubMed  Google Scholar 

  92. Shigematsu H, Takahashi T, Nomura M et al (2005) Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 65:1642–1646. doi:10.1158/0008-5472.CAN-04-4235

    CAS  PubMed  Google Scholar 

  93. Buttitta F, Barassi F, Fresu G 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 119:2586–2591. doi:10.1002/ijc.22143

    CAS  PubMed  Google Scholar 

  94. Stephens P, Hunter C, Bignell G et al (2004) Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431:525–526. doi:10.1038/431525b

    CAS  PubMed  Google Scholar 

  95. Arcila ME, Chaft JE, Nafa K et al (2012) Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res 18:4910–4918. doi:10.1158/1078-0432.CCR-12-0912

    CAS  PubMed  Google Scholar 

  96. Ross HJ, Blumenschein GR, Aisner J et al (2010) Randomized phase II multicenter trial of two schedules of lapatinib as first- or second-line monotherapy in patients with advanced or metastatic non-small cell lung cancer. Clin Cancer Res 16:1938–1949. doi:10.1158/1078-0432.CCR-08-3328

    CAS  PubMed  Google Scholar 

  97. Cardarella S, Ogino A, Nishino M et al (2013) Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin Cancer Res 19:4532–4540. doi:10.1158/1078-0432.CCR-13-0657

    CAS  PubMed  Google Scholar 

  98. Davies H, Bignell GR, Cox C et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954. doi:10.1038/nature00766

    CAS  PubMed  Google Scholar 

  99. Sasaki H, Shimizu S, Tani Y et al (2013) Usefulness of immunohistochemistry for the detection of the BRAF V600E mutation in Japanese lung adenocarcinoma. Lung Cancer 82:51–54. doi:10.1016/j.lungcan.2013.06.014

    PubMed  Google Scholar 

  100. Gautschi O, Pauli C, Strobel K et al (2012) A patient with BRAF V600E lung adenocarcinoma responding to vemurafenib. J Thorac Oncol 7:e23–e24. doi:10.1097/JTO.0b013e3182629903

    PubMed  Google Scholar 

  101. Peter S, Michielin O, Zimmermann S (2013) Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma. J Clin Oncol 1(20):e341–e344

    Google Scholar 

  102. Kohno T, Ichikawa H, Totoki Y et al (2012) KIF5B-RET fusions in lung adenocarcinoma. Nat Med 18:375–377. doi:10.1038/nm.2644

    CAS  PubMed  Google Scholar 

  103. Takeuchi K, Soda M, Togashi Y et al (2012) RET, ROS1 and ALK fusions in lung cancer. Nat Med 18:378–381. doi:10.1038/nm.2658

    CAS  PubMed  Google Scholar 

  104. Li F, Feng Y, Fang R et al (2012) Identification of RET gene fusion by exon array analyses in “pan-negative” lung cancer from never smokers. Cell Res 22:928–931. doi:10.1038/cr.2012.27

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Wang R, Hu H, Pan Y et al (2012) RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol 30:4352–4359. doi:10.1200/JCO.2012.44.1477

    CAS  PubMed  Google Scholar 

  106. Drilon A, Wang LL, Hasanovic A et al (2013) Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. doi:10.1158/2159-8290.CD-13-0035

    PubMed  Google Scholar 

  107. Seo J-S, Ju YS, Lee W-C et al (2012) The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 22:2109–2119. doi:10.1101/gr.145144.112

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Suehara Y, Arcila M, Wang L et al (2012) Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions. Clin Cancer Res 18:6599–6608. doi:10.1158/1078-0432.CCR-12-0838

    CAS  PubMed  Google Scholar 

  109. Lipson D, Capelletti M, Yelensky R et al (2012) Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 18:382–384. doi:10.1038/nm.2673

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Sasaki H, Shimizu S, Tani Y et al (2012) RET expression and detection of KIF5B/RET gene rearrangements in Japanese lung cancer. Cancer Med 1:68–75. doi:10.1002/cam4.13

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Suzuki M, Makinoshima H, Matsumoto S et al (2013) Identification of a lung adenocarcinoma cell line with CCDC6-RET fusion gene and the effect of RET inhibitors in vitro and in vivo. Cancer Sci. doi:10.1111/cas.12175

    Google Scholar 

  112. Gautschi O, Zander T, Keller FA et al (2013) A patient with lung adenocarcinoma and RET fusion treated with vandetanib. J Thorac Oncol 8:e43–e44. doi:10.1097/JTO.0b013e31828a4d07

    PubMed  Google Scholar 

  113. Gu T-L, Deng X, Huang F et al (2011) Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One 6:e15640. doi:10.1371/journal.pone.0015640

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Rimkunas VM, Crosby KE, Li D et al (2012) Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: identification of a FIG-ROS1 fusion. Clin Cancer Res 18:4449–4457. doi:10.1158/1078-0432.CCR-11-3351

    CAS  PubMed  Google Scholar 

  115. Rikova K, Guo A, Zeng Q et al (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131:1190–1203. doi:10.1016/j.cell.2007.11.025

    CAS  PubMed  Google Scholar 

  116. Matsuura S, Shinmura K, Kamo T et al (2013) CD74-ROS1 fusion transcripts in resected non-small cell lung carcinoma. Oncol Rep 30:1675–1680. doi:10.3892/or.2013.2630

    CAS  PubMed  Google Scholar 

  117. Kim HR, Lim SM, Kim HJ et al (2013) The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma. Ann Oncol 24:2364–2370. doi:10.1093/annonc/mdt220

    CAS  PubMed  Google Scholar 

  118. Yoshida A, Kohno T, Tsuta K et al (2013) ROS1-rearranged lung cancer. A clinicopathologic and molecular study of 15 surgical cases. Am J Surg Pathol 37:554–562

    PubMed  Google Scholar 

  119. Cai W, Li X, Su C et al (2013) ROS1 fusions in Chinese patients with non-small-cell lung cancer. Ann Oncol 24:1822–1827. doi:10.1093/annonc/mdt071

    CAS  PubMed  Google Scholar 

  120. Davies KD, Le AT, Theodoro MF et al (2012) Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin Cancer Res 18:4570–4579. doi:10.1158/1078-0432.CCR-12-0550

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Riess JW, Padda SK, Bangs CD et al (2013) A case series of lengthy progression-free survival with pemetrexed-containing therapy in metastatic non-small-cell lung cancer patients harboring ROS1 gene rearrangements. Clin Lung Cancer 14:592–595. doi:10.1016/j.cllc.2013.04.008

    PubMed  Google Scholar 

  122. Awad MM, Katayama R, McTigue M et al (2013) Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 368:2395–2401. doi:10.1056/NEJMoa1215530

    CAS  PubMed  Google Scholar 

  123. Wiesweg M, Ting S, Reis H et al (2013) Feasibility of preemptive biomarker profiling for personalised early clinical drug development at a comprehensive cancer center. Eur J Cancer. doi:10.1016/j.ejca.2013.06.014

    PubMed  Google Scholar 

  124. Pitini V, Arrigo C, Di Mirto C et al (2013) Response to dasatinib in a patient with SQCC of the lung harboring a discoid-receptor-2 and synchronous chronic myelogenous leukemia. Lung Cancer 82:171–172. doi:10.1016/j.lungcan.2013.07.004

    PubMed  Google Scholar 

  125. Khurshid H, Dipetrillo T, Ng T et al (2012) A phase I study of dasatinib with concurrent chemoradiation for stage III non-small cell lung cancer. Front Oncol 2:56. doi:10.3389/fonc.2012.00056

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Cardarella S, Ortiz TM, Joshi VA et al (2012) The introduction of systematic genomic testing for patients with non-small-cell lung cancer. J Thorac Oncol 7:1767–1774. doi:10.1097/JTO.0b013e3182745bcb

    CAS  PubMed  Google Scholar 

  127. Kawano O, Sasaki H, Endo K et al (2006) PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer 54:209–215. doi:10.1016/j.lungcan.2006.07.006

    PubMed  Google Scholar 

  128. Kawano O, Sasaki H, Okuda K et al (2007) PIK3CA gene amplification in Japanese non-small cell lung cancer. Lung Cancer 58:159–160. doi:10.1016/j.lungcan.2007.06.020

    PubMed  Google Scholar 

  129. Spoerke JM, O’Brien C, Huw L et al (2012) Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin Cancer Res 18:6771–6783. doi:10.1158/1078-0432.CCR-12-2347

    CAS  PubMed  Google Scholar 

  130. Chaft JE, Arcila ME, Paik PK et al (2012) Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling. Mol Cancer Ther 11:485–491. doi:10.1158/1535-7163.MCT-11-0692

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Zhang L, Shi L, Zhao X et al (2013) PIK3CA gene mutation associated with poor prognosis of lung adenocarcinoma. Onco Targets Ther 6:497–502. doi:10.2147/OTT.S41643

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Yu J, Bai H, Wang Z et al (2013) PIK3CA mutation in Chinese patients with lung squamous cell carcinoma. Chin J Cancer Res 25:416–422. doi:10.3978/j.issn.1000-9604.2013.08.03

    PubMed Central  PubMed  Google Scholar 

  133. Weiss J, Sos ML, Seidel D et al (2010) Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2:62ra93. doi:10.1126/scitranslmed.3001451

    CAS  PubMed  Google Scholar 

  134. Heist RS, Mino-Kenudson M, Sequist LV et al (2012) FGFR1 amplification in squamous cell carcinoma of the lung. J Thorac Oncol 7:1775–1780. doi:10.1097/JTO.0b013e31826aed28

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Tran TN, Selinger CI, Kohonen-Corish MRJ et al (2013) Fibroblast growth factor receptor 1 (FGFR1) copy number is an independent prognostic factor in non-small cell lung cancer. Lung Cancer 81:462–467. doi:10.1016/j.lungcan.2013.05.015

    PubMed  Google Scholar 

  136. Kohler LH, Mireskandari M, Knösel T et al (2012) FGFR1 expression and gene copy numbers in human lung cancer. Virchows Arch 461:49–57. doi:10.1007/s00428-012-1250-y

    CAS  PubMed  Google Scholar 

  137. Schildhaus H-U, Heukamp LC, Merkelbach-Bruse S et al (2012) Definition of a fluorescence in-situ hybridization score identifies high- and low-level FGFR1 amplification types in squamous cell lung cancer. Mod Pathol 25:1473–1480. doi:10.1038/modpathol.2012.102

    CAS  PubMed  Google Scholar 

  138. Gadgeel SM, Chen W, Cote ML et al (2013) Fibroblast growth factor receptor 1 amplification in non-small cell lung cancer by quantitative real-time PCR. PLoS One 8:e79820. doi:10.1371/journal.pone.0079820

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Dutt A, Ramos AH, Hammerman PS et al (2011) Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. PLoS One 6:e20351. doi:10.1371/journal.pone.0020351

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Kim HR, Kim DJ, Kang DR et al (2013) Fibroblast growth factor receptor 1 gene amplification is associated with poor survival and cigarette smoking dosage in patients with resected squamous cell lung cancer. J Clin Oncol 31:731–737. doi:10.1200/JCO.2012.43.8622

    PubMed  Google Scholar 

  141. Craddock KJ, Ludkovski O, Sykes J et al (2013) Prognostic value of fibroblast growth factor receptor 1 gene locus amplification in resected lung squamous cell carcinoma. J Thorac Oncol 8:1371–1377

    CAS  PubMed  Google Scholar 

  142. Preusser M, Berghoff AS, Berger W et al (2013) High rate of FGFR1 amplifications in brain metastases of squamous and non-squamous lung cancer. Lung Cancer 1:1–7. doi:10.1016/j.lungcan.2013.10.004

    Google Scholar 

  143. Sun W, Song L, Ai T et al (2013) Prognostic value of MET, cyclin D1 and MET gene copy number in non-small cell lung cancer. J Biomed Res 27:220–230. doi:10.7555/JBR.27.20130004

    PubMed Central  PubMed  Google Scholar 

  144. Wang S, An T, Duan J et al (2013) Alterations in EGFR and related genes following neo-adjuvant chemotherapy in Chinese patients with non-small cell lung cancer. PLoS One 8:e51021. doi:10.1371/journal.pone.0051021

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Cully M, You H, Levine AJ, Mak TW (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6:184–192. doi:10.1038/nrc1819

    CAS  PubMed  Google Scholar 

  146. Buckingham L, Penfield Faber L, Kim A et al (2010) PTEN, RASSF1 and DAPK site-specific hypermethylation and outcome in surgically treated stage I and II nonsmall cell lung cancer patients. Int J Cancer 126:1630–1639. doi:10.1002/ijc.24896

    CAS  PubMed  Google Scholar 

  147. Jin G, Kim MJ, Jeon H-S et al (2010) PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers. Lung Cancer 69:279–283. doi:10.1016/j.lungcan.2009.11.012

    PubMed  Google Scholar 

  148. Marsit CJ, Zheng S, Aldape K et al (2005) PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol 36:768–776. doi:10.1016/j.humpath.2005.05.006

    CAS  PubMed  Google Scholar 

  149. Cumberbatch M, Tang X, Beran G et al (2013) Identification of a subset of human non-small cell lung cancer patients with high PI3Kβ and low PTEN expression, more prevalent in SCC. Clin Cancer Res. doi:10.1158/1078-0432.CCR-13-1638

    PubMed  Google Scholar 

  150. Lee AC, Kwong YI, Fu KH et al (1993) Disseminated mediastinal carcinoma with chromosomal translocation (15;19). A distinctive clinicopathologic syndrome. Cancer 72:2273–2276

    CAS  PubMed  Google Scholar 

  151. Kubonishi I, Takehara N, Iwata J et al (1991) Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma. Cancer Res 51:3327–3328

    CAS  PubMed  Google Scholar 

  152. Kees UR, Mulcahy MT, Willoughby ML (1991) Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19). Am J Pediatr Hematol Oncol 13:459–464

    CAS  PubMed  Google Scholar 

  153. Evans AG, French CA, Cameron MJ et al (2012) Pathologic characteristics of NUT midline carcinoma arising in the mediastinum. Am J Surg Pathol 36:1222–1227. doi:10.1097/PAS.0b013e318258f03b

    PubMed Central  PubMed  Google Scholar 

  154. Bauer DE, Mitchell CM, Strait KM et al (2012) Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin Cancer Res 18:5773–5779. doi:10.1158/1078-0432.CCR-12-1153

    PubMed Central  PubMed  Google Scholar 

  155. Schwartz BE, Hofer MD, Lemieux ME et al (2011) Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer Res 71:2686–2696. doi:10.1158/0008-5472.CAN-10-3513

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Clauditz TS, Gontarewicz A, Wang C-J et al (2012) 11q21 rearrangement is a frequent and highly specific genetic alteration in mucoepidermoid carcinoma. Diagn Mol Pathol 21:134–137. doi:10.1097/PDM.0b013e318255552c

    CAS  PubMed  Google Scholar 

  157. Von Holstein SL, Fehr A, Heegaard S et al (2012) CRTC1-MAML2 gene fusion in mucoepidermoid carcinoma of the lacrimal gland. Oncol Rep 27:1413–1416. doi:10.3892/or.2012.1676

    Google Scholar 

  158. Fehr A, Löning T, Stenman G (2011) Mammary analogue secretory carcinoma of the salivary glands with ETV6-NTRK3 gene fusion. Am J Surg Pathol 35:1600–1602. doi:10.1097/PAS.0b013e31822832c7

    PubMed  Google Scholar 

  159. Stenman G (2013) Fusion oncogenes in salivary gland tumors: molecular and clinical consequences. Head Neck Pathol 7(Suppl 1):S12–S19. doi:10.1007/s12105-013-0462-z

    PubMed  Google Scholar 

  160. Connor A, Perez-Ordoñez B, Shago M et al (2012) Mammary analog secretory carcinoma of salivary gland origin with the ETV6 gene rearrangement by FISH: expanded morphologic and immunohistochemical spectrum of a recently described entity. Am J Surg Pathol 36:27–34. doi:10.1097/PAS.0b013e318231542a

    PubMed  Google Scholar 

  161. Skálová A, Vanecek T, Sima R et al (2010) Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol 34:599–608. doi:10.1097/PAS.0b013e3181d9efcc

    PubMed  Google Scholar 

Download references

Conflict of interest

E. Thunnissen is consultant for Pfizer. The other authors have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Erik Thunnissen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thunnissen, E., van der Oord, K. & den Bakker, M. Prognostic and predictive biomarkers in lung cancer. A review. Virchows Arch 464, 347–358 (2014). https://doi.org/10.1007/s00428-014-1535-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-014-1535-4

Keywords

Navigation