Advertisement

Tumor Biology

, Volume 36, Issue 2, pp 861–869 | Cite as

Pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR genotypes

  • Xiangli Jiang
  • Bo Yang
  • Jiuqin Lu
  • Zhongli Zhan
  • Kai Li
  • Xiubao Ren
Research Article

Abstract

Advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) activating mutations usually are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs), but whether EGFR-mutant lung adenocarcinoma is also responsive to pemetrexed-based chemotherapy remains controversial. We conducted a retrospective study to evaluate the efficacy and outcome of pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR mutation statuses. Sixty-nine EGFR-mutant and 89 wild-type patients with advanced lung adenocarcinoma were enrolled. They all had received pemetrexed-based treatments. Chemotherapy objective response rate (ORR), median progression-free survival (mPFS), and thymidylate synthase (TS) expression levels of EGFR-mutant patients were compared with those of EGFR-wild-type patients. For the EGFR-mutant patients treated with first-line platinum/pemetrexed combinations, the ORR was significantly higher than that of the wild-type patients treated with similar regimens (43 vs. 21 %, p = 0.039). Nonetheless, for the patients treated with pemetrexed monotherapy, the difference in ORR was not significant between patients with EGFR mutations and those with wild-type EGFR in any line of treatments (in the first-line setting 20 vs. 13 %, p = 0.715; in the second-/third-line setting 13 vs. 8 %, p = 0.655). On the other hand, the mPFS for the EGFR-mutant patients treated with first-line combinations was also obviously prolonged (8.3 vs. 6.7 months, p = 0.004). However, among the patients receiving second-line platinum/pemetrexed combinations or any line of single-agent pemetrexed, there was no difference in PFS between EGFR-mutant and wild-type patients. Our results indicated that the efficacies and outcomes of pemetrexed treatment in advanced lung adenocarcinoma patients with EGFR activating mutations were similar to those in patients with EGFR-wild-type genotype, except in the setting of first-line platinum/pemetrexed combination chemotherapy.

Keywords

Lung adenocarcinoma Epidermal growth factor receptor Activating mutation Pemetrexed Thymidylate synthase 

Notes

Acknowledgments

This work was supported by the National Basic Research Program of China (973 program, No. 2012CB9333004) and Tianjin Science and Technology Project (Crucial Special Anticancer Program, No.12ZCDZSY15600).

Conflicts of interest

None

References

  1. 1.
    Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500.CrossRefPubMedGoogle Scholar
  2. 2.
    Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, 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(21):2129–39.CrossRefPubMedGoogle Scholar
  3. 3.
    Wu YL, Zhong WZ, Li LY, Zhang XT, Zhang L, Zhou CC, et al. Epidermal growth factor receptor mutations and their correlation with gefitinib therapy in patients with non-small cell lung cancer: a meta-analysis based on updated individual patient data from six medical centers in mainland China. J Thorac Oncol. 2007;2(5):430–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958–67.CrossRefPubMedGoogle Scholar
  5. 5.
    Marchetti A, Martella C, Felicioni L, Barassi F, Salvatore S, Chella A, et al. EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol. 2005;23(4):857–65.CrossRefPubMedGoogle Scholar
  6. 6.
    Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, 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(2):121–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang 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. Lancet Oncol. 2011;12(8):735–42.CrossRefPubMedGoogle Scholar
  8. 8.
    Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. 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. 2012;13(3):239–46.CrossRefPubMedGoogle Scholar
  9. 9.
    Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57.CrossRefPubMedGoogle Scholar
  10. 10.
    Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327–34.CrossRefPubMedGoogle Scholar
  12. 12.
    Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, 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;26(21):3543–51.CrossRefPubMedGoogle Scholar
  13. 13.
    Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, 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;22(9):1589–97.CrossRefPubMedGoogle Scholar
  14. 14.
    Esteban E, Casillas M, Cassinello A. Pemetrexed in first-line treatment of non-small cell lung cancer. Cancer Treat Rev. 2009;35(4):364–73.CrossRefPubMedGoogle Scholar
  15. 15.
    Wu SG, Yang CH, Yu CJ, Lee JH, Hsu YC, Chang YL, et al. Good response to pemetrexed in patients of lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Lung Cancer. 2011;72(3):333–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Kawano Y, Ohyanagi F, Yanagitani N, Kudo K, Horiike A, Tanimoto A, et al. Pemetrexed and cisplatin for advanced non-squamous non-small cell lung cancer in Japanese patients: phase II study. Anticancer Res. 2013;33(8):3327–33.PubMedGoogle Scholar
  17. 17.
    Jiang X, Liu Y, Chen C, Zhan Z, Yan Q, Guo Y, et al. The value of biomarkers in patients with sarcomatoid carcinoma of the lung: molecular analysis of 33 cases. Clin Lung Cancer. 2012;13(4):288–96.CrossRefPubMedGoogle Scholar
  18. 18.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRefPubMedGoogle Scholar
  19. 19.
    Takezawa K, Okamoto I, Okamoto W, Takeda M, Sakai K, Tsukioka S, et al. Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer. Br J Cancer. 2011;104(10):1594–601.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ceppi P, Volante M, Saviozzi S, Rapa I, Novello S, Cambieri A, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 2006;107(7):1589–96.CrossRefPubMedGoogle Scholar
  21. 21.
    Ceppi P, Volante M, Ferrero A, Righi L, Rapa I, Rosas R, et al. Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors. Clin Cancer Res. 2008;14(4):1059–64.CrossRefPubMedGoogle Scholar
  22. 22.
    Manegold C, Gatzemeier U, von Pawel J, Pirker R, Malayeri R, Blatter J, et al. Front-line treatment of advanced non-small-cell lung cancer with MTA (LY231514, pemetrexed disodium, ALIMTA) and cisplatin: a multicenter phase II trial. Ann Oncol. 2000;11(4):435–40.CrossRefPubMedGoogle Scholar
  23. 23.
    Scagliotti GV, Kortsik C, Dark GG, Price A, Manegold C, Rosell R, et al. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: a multicenter, randomized, phase II trial. Clin Cancer Res. 2005;11(2 Pt 1):690–6.PubMedGoogle Scholar
  24. 24.
    Zinner RG, Fossella FV, Gladish GW, Glisson BS, Blumenschein Jr GR, Papadimitrakopoulou VA, et al. Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced nonsmall cell lung cancer. Cancer. 2005;104(11):2449–56.CrossRefPubMedGoogle Scholar
  25. 25.
    Clarke SJ, Abratt R, Goedhals L, Boyer MJ, Millward MJ, Ackland SP. Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-naive patients with advanced non-small-cell lung cancer. Ann Oncol. 2002;13(5):737–41.CrossRefPubMedGoogle Scholar
  26. 26.
    Giovannetti E, Lemos C, Tekle C, Smid K, Nannizzi S, Rodriguez JA, et al. Molecular mechanisms underlying the synergistic interaction of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, with the multitargeted antifolate pemetrexed in non-small-cell lung cancer cells. Mol Pharmacol. 2008;73(4):1290–300.CrossRefPubMedGoogle Scholar
  27. 27.
    Papay J, Sapi Z, Egri G, Gyulai M, Szende B, Losonczy G, et al. Platinum-based chemotherapy in lung cancer affects the expression of certain biomarkers including ERCC1. Pathol Oncol Res POR. 2009;15(3):445–50.CrossRefPubMedGoogle Scholar
  28. 28.
    Yamashita F, Azuma K, Yoshida T, Yamada K, Kawahara A, Hattori S, et al. Prognostic value of EGFR mutation and ERCC1 in patients with non-small cell lung cancer undergoing platinum-based chemotherapy. PLoS One. 2013;8(8):e71356.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Dong X, Zhao X, Hao Y, Wei Y, Yin Q, Du J. Response to first-line chemotherapy in patients with non-small-cell lung cancer according to epidermal growth factor receptor and K-RAS mutation status. Clin Lung Cancer. 2013;14(6):680–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Li S, Zhou F, Ren S, Zhou C. Response to pemetrexed rechallenge after acquired resistance of EGFR-TKI in a patient with advanced NSCLC. Lung Cancer. 2014;84(2):203–5.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of Thoracic Medical OncologyTianjin Medical University Cancer Institute and HospitalTianjinChina
  2. 2.Department of PathologyTianjin Medical University Cancer Institute and HospitalTianjinChina
  3. 3.Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Immunology and BiotherapyNational Clinical Research Center of CancerTianjinChina
  4. 4.Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of CancerTianjinChina

Personalised recommendations