Skip to main content
SpringerLink
Log in

Role of Genotyping in Non-Small Cell Lung Cancer Treatment

Current Status

  • Current Opinion
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Non-small cell lung cancer (NSCLC) is a common malignant disease with an extremely poor prognosis. Chemotherapeutic treatment for advanced disease is currently based on histological subtyping, but recent discoveries of genetic alterations in subsets of NSCLC have already changed clinical practice with regard to Egfr mutations as predictive markers of response to gefitinib and erlotinib. This has also paved the way for the integration of molecular analyses into early phase clinical trials, as demonstrated by the clinical development of crizotinib, effective in lung cancer harbouring Alk rearrangements. Similarly, other subgroups of NSCLC carry potentially targetable molecular alterations and their study has the potential to change the diagnostic and therapeutic approach to lung cancer in the near future. In contrast to a wealth of knowledge surrounding genomic alterations in lung adenocarcinomas, fewer data are available concerning squamous cell lung cancer (SCC), although recent data demonstrate that genotyping can provide new therapeutic perspectives in SCC treatment. Moreover, the study of molecular predictive markers of response to chemotherapy aims to improve chemotherapeutic treatment, increasing efficacy and limiting toxicity.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Fig. 1
Fig. 2
Fig. 3
Table IV

Similar content being viewed by others

References

  1. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol 2007 Aug; 2(8): 706–14

    Article  PubMed  Google Scholar 

  2. Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 2010 Nov; 10(11): 760–74

    Article  PubMed  CAS  Google Scholar 

  3. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002 Jan 10; 346(2): 92–8

    Article  PubMed  CAS  Google Scholar 

  4. Travis WD, Brambilla E, Müller-Hermelink HK, et al. WHO histological classification of tumours of the lung. In: Travis WD, Brambilla E, Müller-Hermelink HK, et al. World Health Organization classification of tumours: pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press, 2004: 10–11

    Google Scholar 

  5. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011 Feb; 6(2): 244–85

    Article  PubMed  Google Scholar 

  6. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006 Dec 14; 355(24): 2542–50

    Article  PubMed  CAS  Google Scholar 

  7. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009 Mar 10; 27(8): 1227–34

    Article  PubMed  CAS  Google Scholar 

  8. Scagliotti GV, Parikh P, von Pawel J, et al. 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 2008 Jul 20; 26(21): 3543–51

    Article  PubMed  CAS  Google Scholar 

  9. Gronberg BH, Bremnes RM, Flotten O, et al. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2009 Jul 1; 27(19): 3217–24

    Article  PubMed  CAS  Google Scholar 

  10. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004 May 1; 22(9): 1589–97

    Article  PubMed  CAS  Google Scholar 

  11. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009 Oct 24; 374(9699): 1432–40

    Article  PubMed  CAS  Google Scholar 

  12. Scagliotti GV, Selvaggi G. New data integrating multi-targeted antifolates into treatment of first-line and relapsed non-small-cell lung cancer. Clin Lung Cancer 2008; 9 Suppl. 3: S122–8

    Article  PubMed  Google Scholar 

  13. Crino L, Dansin E, Garrido P, et al. Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Lancet Oncol 2010 Aug; 11(8): 733–40

    Article  PubMed  CAS  Google Scholar 

  14. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004 Jun 1; 22(11): 2184–91

    Article  PubMed  CAS  Google Scholar 

  15. Weinstein IB. Cancer: addiction to oncogenes. The Achilles heal of cancer. Science 2002 Jul 5; 297(5578): 63–4

    CAS  Google Scholar 

  16. Weinstein IB, Joe AK. Mechanisms of disease: oncogene addiction. A rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 2006 Aug; 3(8): 448–57

    CAS  Google Scholar 

  17. Ding L, Getz G, Wheeler DA, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008 Oct 23; 455(7216): 1069–75

    Article  PubMed  CAS  Google Scholar 

  18. Sharma SV, Haber DA, Settleman J. Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents. Nat Rev Cancer 2010 Apr; 10(4): 241–53

    Article  PubMed  CAS  Google Scholar 

  19. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004 Jun 4; 304(5676): 1497–500

    Article  PubMed  CAS  Google Scholar 

  20. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004 May 20; 350(21): 2129–39

    Article  PubMed  CAS  Google Scholar 

  21. Pao W, Miller V, Zakowski M, et al. 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 U S A 2004 Sep 7; 101(36): 13306–11

    Article  PubMed  CAS  Google Scholar 

  22. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009 Sep 3; 361(10): 958–67

    Article  PubMed  CAS  Google Scholar 

  23. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009 Sep 3; 361(10): 947–57

    Article  PubMed  CAS  Google Scholar 

  24. Mitsudomi T, Morita S, Yatabe Y, et al. 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 2010 Feb; 11(2): 121–8

    Article  PubMed  CAS  Google Scholar 

  25. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010 Jun 24; 362(25): 2380–8

    Article  PubMed  CAS  Google Scholar 

  26. Engelman JA, Zejnullahu K, Gale CM, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007 Dec 15; 67(24): 11924–32

    Article  PubMed  CAS  Google Scholar 

  27. Zhou C, Wu YL, Chen G, et al. 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 2011 Aug; 12(8): 735–42

    Article  PubMed  CAS  Google Scholar 

  28. Rosell R, Gervais R, Vergnenegre A, et al. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial [abstract no. 7503]. J Clin Oncol 2011; 29 Suppl.

  29. D’Addario G, Fruh M, Reck M, et al. Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010 May; 21 Suppl. 5: v116–9

    Article  PubMed  Google Scholar 

  30. Ettinger SE, Akerley W, Borghaei H, et al. NCCN clinical practice guidelines in oncology: non-small cell lung cancer. NCCN clinical practice guidelines in Oncology 2011 [online]. Available from URL: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp [Accessed 2011Oct 26]

  31. Azzoli CG, Baker Jr S, Temin S, et al. American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009 Dec 20; 27(36): 6251–66

    Article  PubMed  CAS  Google Scholar 

  32. Miyamae Y, Shimizu K, Hirato J, et al. Significance of epidermal growth factor receptor gene mutations in squamous cell lung carcinoma. Oncol Rep 2011 Apr; 25(4): 921–8

    PubMed  CAS  Google Scholar 

  33. Kang SM, Kang HJ, Shin JH, et al. Identical epidermal growth factor receptor mutations in adenocarcinomatous and squamous cell carcinomatous components of adenosquamous carcinoma of the lung. Cancer 2007 Feb 1; 109(3): 581–7

    Article  PubMed  CAS  Google Scholar 

  34. Toyooka S, Yatabe Y, Tokumo M, et al. Mutations of epidermal growth factor receptor and K-ras genes in adenosquamous carcinoma of the lung. Int J Cancer 2006 Mar 15; 118(6): 1588–90

    Article  PubMed  CAS  Google Scholar 

  35. Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 2010 Jan 10; 28(2): 357–60

    Article  PubMed  CAS  Google Scholar 

  36. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005 Feb 24; 352(8): 786–92

    Article  PubMed  CAS  Google Scholar 

  37. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005 Mar; 2(3): e73

    Article  PubMed  CAS  Google Scholar 

  38. Balak MN, Gong Y, Riely GJ, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006 Nov 1; 12(21): 6494–501

    Article  PubMed  CAS  Google Scholar 

  39. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 2008 Feb 12; 105(6): 2070–5

    Article  PubMed  CAS  Google Scholar 

  40. Kuang Y, Rogers A, Yeap BY, et al. Noninvasive detection of EGFR T790M in gefitinib or erlotinib resistant non-small cell lung cancer. Clin Cancer Res 2009 Apr 15; 15(8): 2630–6

    Article  PubMed  CAS  Google Scholar 

  41. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007 May 18; 316(5827): 1039–43

    Article  PubMed  CAS  Google Scholar 

  42. 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 U S A 2007 Dec 26; 104(52): 20932–7

    Article  PubMed  CAS  Google Scholar 

  43. Sequist LV, Waltman BA, Dias-Santagata D, et al. Geno-typic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011 Mar 23; 3(75): 75ra26

    Article  Google Scholar 

  44. Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 2005 May 24; 102(21): 7665–70

    Article  PubMed  CAS  Google Scholar 

  45. Carter TA, Wodicka LM, Shah NP, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A 2005 Aug 2; 102(31): 11011–6

    Article  PubMed  CAS  Google Scholar 

  46. Bean J, Riely GJ, Balak M, et al. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res 2008 Nov 15; 14(22): 7519–25

    Article  PubMed  CAS  Google Scholar 

  47. Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008 Aug 7; 27(34): 4702–11

    Article  PubMed  CAS  Google Scholar 

  48. Godin-Heymann N, Ulkus L, Brannigan BW, et al. The T790M ‘gatekeeper’ mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol Cancer Ther 2008 Apr; 7(4): 874–9

    Article  PubMed  CAS  Google Scholar 

  49. Sos ML, Rode HB, Heynck S, et al. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res 2010 Feb 1; 70(3): 868–74

    Article  PubMed  CAS  Google Scholar 

  50. Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 2008 Jul 24; 359(4): 366–77

    Article  PubMed  CAS  Google Scholar 

  51. Rosell R, Molina MA, Costa C, et al. Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin Cancer Res 2011 Mar1; 17(5): 1160–8

    Article  PubMed  CAS  Google Scholar 

  52. Bivona TG, Hieronymus H, Parker J, et al. FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR. Nature 2011 Mar 24; 471(7339): 523–6

    Article  PubMed  CAS  Google Scholar 

  53. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007 Aug 2; 448(7153): 561–6

    Article  PubMed  CAS  Google Scholar 

  54. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010 Oct 28; 363(18): 1693–703

    Article  PubMed  CAS  Google Scholar 

  55. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994 Mar 4; 263(5151): 1281–4

    Article  PubMed  CAS  Google Scholar 

  56. 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 Jul 1; 68(13): 4971–6

    Article  PubMed  CAS  Google Scholar 

  57. 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 May 1; 15(9): 3143–9

    Article  PubMed  CAS  Google Scholar 

  58. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008 Jul 1; 14(13): 4275–83

    Article  PubMed  CAS  Google Scholar 

  59. Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007 Dec 14; 131(6): 1190–203

    Article  PubMed  CAS  Google Scholar 

  60. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009 Sep 10; 27(26): 4247–53

    Article  PubMed  CAS  Google Scholar 

  61. 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 Aug 15; 15(16): 5216–23

    Article  PubMed  CAS  Google Scholar 

  62. Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res 2011 Apr 15; 17(8): 2081–6

    Article  PubMed  CAS  Google Scholar 

  63. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 2010 Oct 28; 363(18): 1734–9

    Article  PubMed  CAS  Google Scholar 

  64. Camidge DR, Kono SA, Flacco A, et al. Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. Clin Cancer Res 2010 Nov 15; 16(22): 5581–90

    Article  PubMed  CAS  Google Scholar 

  65. Yi ES, Boland JM, Maleszewski JJ, et al. Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma: IHC score algorithm for FISH. J Thorac Oncol 2011 Mar; 6(3): 459–65

    Article  PubMed  Google Scholar 

  66. Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 2005 Mar 1; 65(5): 1642–6

    Article  PubMed  CAS  Google Scholar 

  67. Liu L, Shao X, Gao W, et al. The role of human epidermal growth factor receptor 2 as a prognostic factor in lung cancer: a meta-analysis of published data. J Thorac Oncol 2010 Dec; 5(12): 1922–32

    Article  PubMed  Google Scholar 

  68. Gatzemeier U, Groth G, Butts C, et al. Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol 2004 Jan; 15(1): 19–27

    Article  PubMed  CAS  Google Scholar 

  69. Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc 2009 Apr 15; 6(2): 201–5

    Article  PubMed  CAS  Google Scholar 

  70. Riely GJ, Kris MG, Rosenbaum D, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 2008 Sep 15; 14(18): 5731–4

    Article  PubMed  CAS  Google Scholar 

  71. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005 Jan; 2(1): e17

    Article  PubMed  CAS  Google Scholar 

  72. Mao C, Qiu LX, Liao RY, et al. KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 2010 Sep; 69(3): 272–8

    Article  PubMed  Google Scholar 

  73. Mascaux C, Iannino N, Martin B, et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 2005 Jan 17; 92(1): 131–9

    Article  PubMed  CAS  Google Scholar 

  74. Garassino MC, Marabese M, Rusconi P, et al. Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer. Ann Oncol 2011 Jan; 22(1): 235–7

    Article  PubMed  CAS  Google Scholar 

  75. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002 Jun 27; 417(6892): 949–54

    Article  PubMed  CAS  Google Scholar 

  76. Naoki K, Chen TH, Richards WG, et al. Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res 2002 Dec 1; 62(23): 7001–3

    PubMed  CAS  Google Scholar 

  77. Pratilas CA, Hanrahan AJ, Halilovic E, et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 2008 Nov 15; 68(22): 9375–83

    Article  PubMed  CAS  Google Scholar 

  78. Sanchez-Cespedes M, Parrella P, Esteller M, et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 2002 Jul 1; 62(13): 3659–62

    PubMed  CAS  Google Scholar 

  79. Ji H, Ramsey MR, Hayes DN, et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 2007 Aug 16; 448(7155): 807–10

    Article  PubMed  CAS  Google Scholar 

  80. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008 Sep 25; 359(13): 1367–80

    Article  PubMed  CAS  Google Scholar 

  81. Sobottka SB, Haase M, Fitze G, et al. Frequent loss of heterozygosity at the 19p13.3 locus without LKB1/STK11 mutations in human carcinoma metastases to the brain. J Neurooncol 2000 Sep; 49(3): 187–95

    Article  PubMed  CAS  Google Scholar 

  82. Mahoney CL, Choudhury B, Davies H, et al. LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. Br J Cancer 2009 Jan 27; 100(2): 370–5

    Article  PubMed  CAS  Google Scholar 

  83. Weir BA, Woo MS, Getz G, et al. Characterizing the cancer genome in lung adenocarcinoma. Nature 2007 Dec 6; 450(7171): 893–8

    Article  PubMed  CAS  Google Scholar 

  84. Yamamoto H, Shigematsu H, Nomura M, et al. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 2008 Sep 1; 68(17): 6913–21

    Article  PubMed  CAS  Google Scholar 

  85. Kawano O, Sasaki H, Okuda K, et al. PIK3CA gene amplification in Japanese non-small cell lung cancer. Lung Cancer 2007 Oct; 58(1): 159–60

    Article  PubMed  Google Scholar 

  86. Angulo B, Suarez-Gauthier A, Lopez-Rios F, et al. Expression signatures in lung cancer reveal a profile for EGFR-mutant tumours and identify selective PIK3CA overexpression by gene amplification. J Pathol 2008 Feb; 214(3): 347–56

    Article  PubMed  CAS  Google Scholar 

  87. Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2010 Dec 15; 2(62): 62ra93

    Article  CAS  Google Scholar 

  88. Qian J, Massion PP. Role of chromosome 3q amplification in lung cancer. J Thorac Oncol 2008 Mar; 3(3): 212–5

    Article  PubMed  Google Scholar 

  89. Bass AJ, Watanabe H, Mermel CH, et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 2009 Nov; 41(11): 1238–42

    Article  PubMed  CAS  Google Scholar 

  90. Hussenet T, Dali S, Exinger J, et al. SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung squamous cell carcinomas. PLoS One 2010; 5(1): e8960

    Article  PubMed  CAS  Google Scholar 

  91. McCaughan F, Pole JC, Bankier AT, et al. Progressive 3q amplification consistently targets SOX2 in preinvasive squamous lung cancer. Am J Respir Crit Care Med 2010 Jul 1; 182(1): 83–91

    Article  PubMed  Google Scholar 

  92. Regala RP, Weems C, Jamieson L, et al. Atypical protein kinase C iota is an oncogene in human non-small cell lung cancer. Cancer Res 2005 Oct 1; 65(19): 8905–11

    Article  PubMed  CAS  Google Scholar 

  93. Chen Y, Shi L, Zhang L, et al. The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer. J Biol Chem 2008 Jun 27; 283(26): 17969–78

    Article  PubMed  CAS  Google Scholar 

  94. Que J, Luo X, Schwartz RJ, et al. Multiple roles for Sox2 in the developing and adult mouse trachea. Development 2009 Jun; 136(11): 1899–907

    Article  PubMed  CAS  Google Scholar 

  95. Wilbertz T, Wagner P, Petersen K, et al. SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer. Mod Pathol 2011 Jul; 24(7): 944–53

    Article  PubMed  CAS  Google Scholar 

  96. Hammerman PS, Sos ML, Ramos AH, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov 2011; 1(1): 77–87

    Article  CAS  Google Scholar 

  97. Vogel W, Gish GD, Alves F, et al. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1997 Dec; 1(1): 13–23

    Article  PubMed  CAS  Google Scholar 

  98. Vogel W. Discoidin domain receptors: structural relations and functional implications. FASEB J 1999; 13 Suppl.: S77–82

    PubMed  CAS  Google Scholar 

  99. Ikeda K, Wang LH, Torres R, et al. Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. J Biol Chem 2002 May 24; 277(21): 19206–12

    Article  PubMed  CAS  Google Scholar 

  100. Olaso E, Labrador JP, Wang L, et al. Discoidin domain receptor 2 regulates fibroblast proliferation and migration through the extracellular matrix in association with transcriptional activation of matrix metalloproteinase-2. J Biol Chem 2002 Feb 1; 277(5): 3606–13

    Article  PubMed  CAS  Google Scholar 

  101. Haura EB, Tanvetyanon T, Chiappori A, et al. Phase I/II study of the Src inhibitor dasatinib in combination with erlotinib in advanced non-small-cell lung cancer. J Clin Oncol 2010 Mar 10; 28(8): 1387–94

    Article  PubMed  CAS  Google Scholar 

  102. Johnson FM, Bekele BN, Feng L, et al. Phase II study of dasatinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2010 Oct 20; 28(30): 4609–15

    Article  PubMed  CAS  Google Scholar 

  103. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004 Apr 23; 304(5670): 554

    Article  PubMed  CAS  Google Scholar 

  104. Kawano O, Sasaki H, Endo K, et al. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer 2006 Nov; 54(2): 209–15

    Article  PubMed  Google Scholar 

  105. Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007 Jul 26; 448(7152): 439–44

    Article  PubMed  CAS  Google Scholar 

  106. Malanga D, Scrima M, De Marco C, et al. Activating E17K mutation in the gene encoding the protein kinase AKT1 in a subset of squamous cell carcinoma of the lung. Cell Cycle 2008 Mar 1; 7(5): 665–9

    Article  PubMed  CAS  Google Scholar 

  107. Lord RV, Brabender J, Gandara D, et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 2002 Jul; 8(7): 2286–91

    PubMed  CAS  Google Scholar 

  108. Cobo M, Isla D, Massuti B, et al. 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 2007 Jul 1; 25(19): 2747–54

    Article  PubMed  CAS  Google Scholar 

  109. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006 Sep 7; 355(10): 983–91

    Article  PubMed  CAS  Google Scholar 

  110. Zheng Z, Chen T, Li X, et al. DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med 2007 Feb 22; 356(8): 800–8

    Article  PubMed  CAS  Google Scholar 

  111. Lee KH, Min HS, Han SW, et al. ERCC1 expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer. Lung Cancer 2008 Jun; 60(3): 401–7

    Article  PubMed  Google Scholar 

  112. Simon GR, Sharma S, Cantor A, et al. ERCC1 expression is a predictor of survival in resected patients with nonsmall cell lung cancer. Chest 2005 Mar; 127(3): 978–83

    Article  PubMed  Google Scholar 

  113. Okuda K, Sasaki H, Dumontet C, et al. Expression of excision repair cross-complementation group 1 and class III beta-tubulin predict survival after chemotherapy for completely resected non-small cell lung cancer. Lung Cancer 2008 Oct; 62(1): 105–12

    Article  PubMed  Google Scholar 

  114. Bartolucci R, Wei J, Sanchez JJ, et al. XPG mRNA expression levels modulate prognosis in resected non-small-cell lung cancer in conjunction with BRCA1 and ERCC1 expression. Clin Lung Cancer 2009 Jan; 10(1): 47–52

    Article  PubMed  CAS  Google Scholar 

  115. Ceppi P, Volante M, Novello S, et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol 2006 Dec; 17(12): 1818–25

    Article  PubMed  CAS  Google Scholar 

  116. Hwang IG, Ahn MJ, Park BB, et al. ERCC1 expression as a prognostic marker in N2(+) nonsmall-cell lung cancer patients treated with platinum-based neoadjuvant concurrent chemoradiotherapy. Cancer 2008 Sep 15; 113(6): 1379–86

    Article  PubMed  CAS  Google Scholar 

  117. Reynolds C, Obasaju C, Schell MJ, et al. 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 2009 Dec 1; 27(34): 5808–15

    Article  PubMed  CAS  Google Scholar 

  118. Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010 Jul 24; 376(9737): 245–51

    Article  PubMed  CAS  Google Scholar 

  119. Quinn JE, James CR, Stewart GE, et al. BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy. Clin Cancer Res 2007 Dec 15; 13(24): 7413–20

    Article  PubMed  CAS  Google Scholar 

  120. Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 2010 May 20; 28(15): 2512–9

    Article  PubMed  CAS  Google Scholar 

  121. Bhattacharyya A, Ear US, Koller BH, et al. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem 2000 Aug 4; 275(31): 23899–903

    Article  PubMed  CAS  Google Scholar 

  122. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005 Apr 14; 434(7035): 917–21

    Article  PubMed  CAS  Google Scholar 

  123. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009 Jul 9; 361(2): 123–34

    Article  PubMed  CAS  Google Scholar 

  124. Rottenberg S, Jaspers JE, Kersbergen A, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A 2008 Nov 4; 105(44): 17079–84

    Article  PubMed  CAS  Google Scholar 

  125. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010 Jul 24; 376(9737): 235–44

    Article  PubMed  CAS  Google Scholar 

  126. Abbott DW, Thompson ME, Robinson-Benion C, et al. BRCA1 expression restores radiation resistance in BRCA 1-defective cancer cells through enhancement of transcription-coupled DNA repair. J Biol Chem 1999 Jun 25; 274(26): 18808–12

    Article  PubMed  CAS  Google Scholar 

  127. Mullan PB, Quinn JE, Gilmore PM, et al. BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents. Oncogene 2001 Sep 27; 20(43): 6123–31

    Article  PubMed  CAS  Google Scholar 

  128. Taron M, Rosell R, Felip E, et al. BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer. Hum Mol Genet 2004 Oct 15; 13(20): 2443–9

    Article  PubMed  CAS  Google Scholar 

  129. Rosell R, Skrzypski M, Jassem E, et al. BRCA1: a novel prognostic factor in resected non-small-cell lung cancer. PLoS One 2007; 2(11): e1129

    Article  PubMed  CAS  Google Scholar 

  130. Rosell R, Perez-Roca L, Sanchez JJ, et al. Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression. PLoS One 2009; 4(5): e5133

    Article  PubMed  CAS  Google Scholar 

  131. Boukovinas I, Papadaki C, Mendez P, et al. Tumor BRCA1, RRM1 and RRM2mRNA expression levels and clinical response to first-line gemcitabine plus docetaxel in non-small-cell lung cancer patients. PLoS One 2008; 3(11): e3695

    Article  PubMed  CAS  Google Scholar 

  132. Camps C, Sirera R, Iranzo V, et al. Gene expression and polymorphisms of DNA repair enzymes: cancer susceptibility and response to chemotherapy. Clin Lung Cancer 2007 May; 8(6): 369–75

    Article  PubMed  CAS  Google Scholar 

  133. Shiraishi K, Kohno T, Tanai C, et al. Association of DNA repair gene polymorphisms with response to platinum-based doublet chemotherapy in patients with non-small-cell lung cancer. J Clin Oncol 2010 Nov 20; 28(33): 4945–52

    Article  PubMed  CAS  Google Scholar 

  134. Thomas RK, Weir B, Meyerson M. Genomic approaches to lung cancer. Clin Cancer Res 2006 Jul 15; 12 (14 Pt 2): 4384–91s

    Article  Google Scholar 

  135. Pao W, Kris MG, Iafrate AJ, et al. Integration of molecular profiling into the lung cancer clinic. Clin Cancer Res 2009 Sep 1; 15(17): 5317–22

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Kate Williams, assistant to Dr Rosell, for help in revising the English in this manuscript.

No sources of funding were used to conduct this study or prepare this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this article.

Author information

Authors and Affiliations

  1. Medical Oncology 2, Instituto Oncologico Veneto-IRCCS, Padua, Italy

    Laura Bonanno & Adolfo Favaretto

  2. Department of Medical Diagnostic Sciences and Special Therapies, Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy

    Massimo Rugge

  3. Baylor College of Medicine, Houston, TX, USA

    Massimo Rugge

  4. Pangaea Biotech, USP Dexeus University Institute, Barcelona, 08028, Spain

    Miquel Taron &  Rafael Rosell MD

  5. Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Ctra Canyet s/n, Badalona, Spain

    Miquel Taron &  Rafael Rosell MD

Authors
  1. Laura Bonanno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adolfo Favaretto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Massimo Rugge
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miquel Taron
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rafael Rosell MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rafael Rosell MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bonanno, L., Favaretto, A., Rugge, M. et al. Role of Genotyping in Non-Small Cell Lung Cancer Treatment. Drugs 71, 2231–2246 (2011). https://doi.org/10.2165/11597700-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11597700-000000000-00000

Keywords

Search

Navigation