Tumor Biology

, Volume 33, Issue 6, pp 2061–2068 | Cite as

EGFR exon mutation distribution and outcome in non-small-cell lung cancer: a Portuguese retrospective study

  • Ramon Andrade de Mello
  • Filipa Soares Pires
  • Dânia Sofia Marques
  • Júlio Oliveira
  • Ana Rodrigues
  • Marta Soares
  • Isabel Azevedo
  • Ana Peixoto
  • Catarina Santos
  • Carla Pinto
  • Venceslau Hespanhol
  • Manuel R Teixeira
  • Teresina Amaro
  • Henrique Queiroga
  • António Araújo
Research Article

Abstract

Epidermal growth factor receptor (EGFR) mutations play a predictive role in advanced stages of non-small-cell lung cancer (NSCLC) patients. We conducted this study in order to assess EGFR status in a Portuguese population and its role in NSCLC patients' outcomes. Patients were submitted to EGFR assessment by high-resolution melting and/or direct sequencing. Kaplan–Meier curve was used to assess overall survival and progression-free survival (PFS). Two hundred forty eight out of 322 participants were assessed for EGFR status. Forty-two patients (16.9 %) presented EGFR-mutated status: one patient (2.4 %) presented exon 18; 21 patients (50 %), exon 19; one patient (2.4 %), exon 20; and 18 patients (45.2 %), exon 21 mutations, p < 0.001. PFS was not assessed (n.a.) for patient with exon 18 mutation, and for the other patients with mutations, it was 7 months (3.96–10.03) (exon 19), <1 month (exon 20), and 7 months (0–14.2) (exon 21) (p = 0.027). Overall survival (OS) was 11 months (exon 18), 11 months (1–18) (exon 19), 1 month (exon 20), and 7.5 months (2–70) (exon 21) (p = n.a). This study suggests that the EGFR mutation is herein observed in a higher proportion than expected for a Caucasian population, and OS is a little less than that published in the literature.

Keywords

EGFR Erlotinib Gefitinib Lung cancer Biomarkers EGFR exons 

Notes

Acknowledgments

The authors would like to acknowledge all colleagues from Portuguese Oncology Institute, Porto, Portugal, and from São João Hospital Center, University of Porto, Porto, Portugal for their help with patient treatment and data acquisition. Furthermore, we would like to acknowledge Catarina Cruz, PhD, Faculty of Medicine, University of Porto, for her critical comments and English review. This work was supported by the participant institutions' funding.

Conflicts of interest

None

References

  1. 1.
    Jemal A, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRefGoogle Scholar
  2. 2.
    De Mello RA, et al. Insights into angiogenesis in non-small cell lung cancer: molecular mechanisms, polymorphic genes, and targeted therapies. Recent Pat Anticancer Drug Discov. 2012;7:118–31.PubMedCrossRefGoogle Scholar
  3. 3.
    Lopez A, et al. A descriptive model of the cigarette epidemic in developed countries. Tob Control. 1994;3:242–7.CrossRefGoogle Scholar
  4. 4.
    De Mello RA, et al. Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies. World J Clin Oncol. 2011;2:367–76.PubMedCrossRefGoogle Scholar
  5. 5.
    Sculier J, et al. The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumors and the proposals for the 7th Edition. J Thorac Oncol. 2008;3:457–66.PubMedCrossRefGoogle Scholar
  6. 6.
    Carvalho L, et al. Projecto de estadiamento do cancro do pulmão pela IASLC: Estudo comparativo entre a 6. ª edição TNM em vigor ea 7. ª edição proposta. Rev Port Pneumol. 2009;15:67–76.PubMedGoogle Scholar
  7. 7.
    Brundage M, et al. Prognostic factors in non-small cell lung cancer. Chest. 2002;122:1037–57.PubMedCrossRefGoogle Scholar
  8. 8.
    Felip E, et al. ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC). Ann Oncol. 2005;16:i28–29.PubMedCrossRefGoogle Scholar
  9. 9.
    Eisenhauer E, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.PubMedCrossRefGoogle Scholar
  10. 10.
    Shepherd F, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–32.PubMedCrossRefGoogle Scholar
  11. 11.
    Cappuzzo F, et al. Epidermal growth factor receptor gene and protein and gefi tinib sensitivity in non-small-cell lung cancer. J Nat Cancer Inst. 2005;97:643–55.PubMedCrossRefGoogle Scholar
  12. 12.
    Lynch T, 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;350:2129–39.PubMedCrossRefGoogle Scholar
  13. 13.
    Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer. 2010;10:760–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Pao W, 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;2:225–35.CrossRefGoogle Scholar
  15. 15.
    Thatcher N, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366:1527–37.PubMedCrossRefGoogle Scholar
  16. 16.
    Zhou C, 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. Lancer Oncol. 2011;12:735–42.CrossRefGoogle Scholar
  17. 17.
    Mahalingam D, et al. Targeted therapy for advanced non-small cell lung cancers: historical perspective, current practices, and future development. Curr Probl Cancer. 2009;33:73–111.PubMedCrossRefGoogle Scholar
  18. 18.
    Olaussen KA, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006;355:983–91.PubMedCrossRefGoogle Scholar
  19. 19.
    Carvalho L, et al. ERCC1 and RRM1 genes in lung cancer. Rev Port Pneumol. 2009;15:683–96.PubMedGoogle Scholar
  20. 20.
    Mascaux C, 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. 2004;92:131–9.CrossRefGoogle Scholar
  21. 21.
    Roberts P, et al. Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol. 2010;28:4769–77.PubMedCrossRefGoogle Scholar
  22. 22.
    Paez JG, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–500.PubMedCrossRefGoogle Scholar
  23. 23.
    Sholl L, et al. EGFR Mutation is a better predictor of response to tyrosine kinase inhibitors in non-small cell lung carcinoma than FISH, CISH, and immunohistochemistry. Am J Clin Pathol. 2010;133:922–34.PubMedCrossRefGoogle Scholar
  24. 24.
    Miller V, et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol. 2008;26:1472–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Fukuoka M, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol. 2003;21:2237–46.PubMedCrossRefGoogle Scholar
  26. 26.
    Kosaka T, et al. Prognostic implication of EGFR, KRAS, and TP53 gene mutations in a large cohort of Japanese patients with surgically treated lung adenocarcinoma. J Thor Oncol. 2009;4:22.CrossRefGoogle Scholar
  27. 27.
    Kwak EL, et al. Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin Cancer Res. 2006;12:4283–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Rosell R, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361:958–67.PubMedCrossRefGoogle Scholar
  29. 29.
    Sunaga N, et al. Phase II prospective study of the efficacy of gefitinib for the treatment of stage III/IV non-small cell lung cancer with EGFR mutations, irrespective of previous chemotherapy. Lung Cancer. 2007;56:383–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Tanaka T, et al. Frequency of and variables associated with the EGFR mutation and its subtypes. Int J Cancer. 2010;126:651–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Cappuzzo F, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010;11:521–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Ichihara S, et al. The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer. Int J Cancer. 2007;120:1239–47.PubMedCrossRefGoogle Scholar
  33. 33.
    Maemondo M, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Mok T, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.PubMedCrossRefGoogle Scholar
  35. 35.
    Mitsudomi T, 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;11:121–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Zhu C, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR. 21. J Clin Oncol. 2008;26:4268–75.PubMedCrossRefGoogle Scholar
  37. 37.
    De Mello RA, et al. Association between EGF +61 genetic polymorphisms and non-small cell lung cancer increased risk in a Portuguese population: a case-control study. Tumour Biol. 2012. PMID:22457050.Google Scholar
  38. 38.
    Burnett J, et al. The rapidly advancing field of biodefense benefits many other, critical public health concerns. Discov Med. 2005;5:371–7.PubMedGoogle Scholar
  39. 39.
    Crabb S, et al. Tumor cavitation: impact on objective response evaluation in trials of angiogenesis inhibitors in non-small-cell lung cancer. J Clin Oncol. 2009;27:404.PubMedCrossRefGoogle Scholar
  40. 40.
    Natale R, et al. Vandetanib versus gefitinib in patients with advanced non-small-cell lung cancer: results from a two-part, double-blind, randomized phase II study. J Clin Oncol. 2009;27:2523–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Reck M, et al. A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer. Ann Oncol. 2011 doi: 10.1093/annonc/mdq618.
  42. 42.
    Bremnes R, et al. Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood. Lung Cancer. 2006;51:143–58.PubMedCrossRefGoogle Scholar
  43. 43.
    Dowlati A, et al. Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab—an Eastern Cooperative Oncology Group Study. Clin Cancer Res. 2008;14:1407–12.PubMedCrossRefGoogle Scholar
  44. 44.
    Rodig SJ, Shapiro GI. Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases. Curr Opin Investig Drugs. 2010;11:1477–90.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Ramon Andrade de Mello
    • 1
    • 2
  • Filipa Soares Pires
    • 3
  • Dânia Sofia Marques
    • 1
  • Júlio Oliveira
    • 1
  • Ana Rodrigues
    • 1
  • Marta Soares
    • 1
  • Isabel Azevedo
    • 1
  • Ana Peixoto
    • 4
  • Catarina Santos
    • 4
  • Carla Pinto
    • 4
  • Venceslau Hespanhol
    • 2
    • 3
  • Manuel R Teixeira
    • 4
  • Teresina Amaro
    • 5
  • Henrique Queiroga
    • 2
    • 3
  • António Araújo
    • 1
  1. 1.Department of Medical OncologyPortuguese Oncology InstitutePortoPortugal
  2. 2.Department of Medicine, Faculty of MedicineUniversity of PortoPortoPortugal
  3. 3.Department of Pneumology, São João Hospital Center, Faculty of MedicineUniversity of PortoPortoPortugal
  4. 4.Department of GeneticsPortuguese Oncology InstitutePortoPortugal
  5. 5.Department of PathologyPortuguese Oncology InstitutePortoPortugal

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