Tumor Biology

, Volume 36, Issue 8, pp 5943–5951 | Cite as

CEA serum level as early predictive marker of outcome during EGFR-TKI therapy in advanced NSCLC patients

  • Francesco Facchinetti
  • Raffaella Aldigeri
  • Rosalia Aloe
  • Beatrice Bortesi
  • Andrea Ardizzoni
  • Marcello Tiseo
Research Article


Considering the role of carcinoembryonic antigen (CEA) serum levels as potential useful predictive marker during chemotherapy treatment, we studied its applicability in advanced non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). Our retrospective cohort consists of 79 patients (33 EGFR mutated and 46 EGFR wild type or unknown) affected by advanced NSCLC, for whom CEA serum values at the beginning of TKI therapy and after the first month of treatment were available, regardless of treatment line. Baseline CEA value, percentage of CEA reduction after 1 month, and percentage of patients with ≥20 % CEA decrease after 1 month (CEA response) were correlated with disease control rate (DCR), progression-free (PFS), and overall (OS) survival, according to EGFR mutational status. Median baseline CEA levels were significantly higher in EGFR mutated (40.9 ng/ml; interquartile range (IQR) 8.9–197.6) than in wild-type cases (6.2 ng/ml; IQR 2.8–12.8; p = 0.003). Both percentage reduction in CEA levels (−10.7 vs. +13.4 %) and percentage of cases with CEA response (42 vs. 20 %) were significantly higher in mutated vs. wild-type/unknown patients (p = 0.007 and p = 0.027, respectively). In wild-type/unknown patients, CEA response was significantly correlated with DCR (p = 0.001) and resulted as a significant predictor of PFS both in univariate (p = 0.002) and in multivariate analyses (hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.11–0.66; p = 0.004); only a trend was found for OS prediction (p = 0.082). In EGFR-mutated group, CEA reduction did not show any correlation either with PFS or OS. CEA response after 1 month of EGFR-TKI therapy could be a useful marker, worthy to further studies, as early predictor of treatment outcome in EGFR wild-type/unknown unselected NSCLC cases for which no molecular predictor is yet available.


Non-small cell lung cancer Epidermal growth factor receptor Carcinoembryonic antigen Early predictive marker 


Conflicts of interest



  1. 1.
    Shepherd FA, Rodriguez Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. National cancer institute of Canada clinical trials group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–32.CrossRefPubMedGoogle Scholar
  2. 2.
    Mok TS, Wu Y-L, 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
  3. 3.
    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;13:239–46.CrossRefPubMedGoogle Scholar
  4. 4.
    Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med. 2005;353:133–44.CrossRefPubMedGoogle Scholar
  5. 5.
    Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled, phase III study. Lancet Oncol. 2010;11:521–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Kelly WK, Scher HI, Mazumdar M, Vlamis V, Schwartz M, Fossa SD. Prostate-specific antigen as a measure of disease outcome in hormone-refractory prostatic cancer. J Clin Oncol. 1993;11:607–15.CrossRefPubMedGoogle Scholar
  7. 7.
    Bridgewater JA, Nelstrop AE, Rustin GJ, Gore ME, McGuire WP, Hoskins WJ. Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxel. J Clin Oncol. 1999;17:501–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Grunnet M, Sorensen JB. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer. Lung Cancer. 2012;76:138–43.CrossRefPubMedGoogle Scholar
  9. 9.
    Stieber P, Zimmermann A, Reinmiedl J, Muller C, Hoffmann H, Dienemann H. CYFRA 21–1 in the early diagnosis of recurrent disease in non-small-cell lung carcinomas (NSCLC). Anticancer Res. 1999;19:665–8.Google Scholar
  10. 10.
    Pujol JL, Molinier O, Ebert W, Daurès JP, Barlesi F, Buccheri G, et al. CYFRA 21–1 is a prognostic determinant in non-small-cell lung cancer: results of a meta-analysis in 2063 patients. Br J Cancer. 2004;90:2097–105.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Vollmer RT, Govindan R, Graziano SL, Gamble G, Garst J, Kelley MJ, et al. Serum CYFRA 21–1 in advanced stage non-small cell lung cancer: an early measure of response. Clin Cancer Res. 2003;9:1728–33.PubMedGoogle Scholar
  12. 12.
    Holdenrieder S, Von Pawel J, Dankelmann E, Duell T, Faderl B, Markus A, et al. Nucleosomes and CYFRA 21–1 indicate tumor response after one cycle of chemotherapy in recurrent non-small cell lung cancer. Lung Cancer. 2008;63:128–35.CrossRefPubMedGoogle Scholar
  13. 13.
    Ardizzoni A, Cafferata MA, Tiseo M, Filiberti R, Marroni P, Grossi F, et al. Decline in serum carcinoembryonic antigen and cytokeratin 19 fragment during chemotherapy predicts objective response and survival in advanced non-small-cell lung cancer. Cancer. 2006;107:2842–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Tiseo M, Rossi G, Capelletti M, Sartori G, Spiritelli E, Marchioni A, et al. Predictors of gefitinib outcomes in advanced non-small cell lung cancer (NSCLC): study of a comprehensive panel of molecular markers. Lung Cancer. 2010;67:355–60.CrossRefPubMedGoogle Scholar
  15. 15.
    Therasse P, Arbuck SG, Esenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92:205–16.CrossRefGoogle Scholar
  16. 16.
    Chiu CH, Shih YN, Tsai CM, Liou JL, Chen YM, Perng RP. Serum tumor markers as predictors for survival in advanced non-small cell lung cancer patients treated with gefitinib. Lung Cancer. 2007;57:213–21.CrossRefPubMedGoogle Scholar
  17. 17.
    Zhang Y, Jin B, Shao M, Dong Y, Lou Y, Huang A, et al. Monitoring of carcinoembryonic antigen levels is predictive of EGFR mutations and efficacy of EGFR-TKI in patients with lung adenocarcinoma. Tumor Biol. 2014;35:4921–8.CrossRefGoogle Scholar
  18. 18.
    Barlési F, Tchouhadjian C, Doddoli C, Torre JP, Astoul P, Kleisbauer JP. CYFRA 21–1 level predicts survival in non-small-cell lung cancer patients receiving gefitinib as third-line therapy. Br J Cancer. 2005;92:13–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Okamoto T, Nakamura T, Ikeda J, Maruyama R, Shoji F, Miyake T, et al. Serum carcinoembryonic antigen as a predictive marker for sensitivity to gefitinib in advanced non-small cell lung cancer. Eur J Cancer. 2005;41:1286–90.CrossRefPubMedGoogle Scholar
  20. 20.
    Shoji F, Yoshino I, Yano T, Kometani T, Ohba T, Kouso H, et al. Serum carcinoembryonic antigen level is associated with epidermal growth factor receptor mutations in recurrent lung adenocarcinomas. Cancer. 2007;110:2793–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Kappers I, Vollebergh MA, Van Tinteren H, Korse CM, Nieuwenhuis LL, Bonfrer JM, et al. Soluble epidermal growth factor receptor (sEGFR) and carcinoembryonic antigen (CEA) concentration in patients with non-small cell lung cancer: correlation with survival after erlotinib and gefitinib treatment. Ecancermedicalscience. 2010;4:178.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Jung M, Kim SH, Lee YJ, Hong S, Kang YA, Kim SK, et al. Prognostic and predictive value of CEA and CYFRA 21–1 levels in advanced non-small cell lung cancer patients treated with gefitinib or erlotinib. Exp Ther Med. 2011;2:685–93.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Tanaka K, Hata A, Kaji R, Fujita S, Otoshi T, Fujimoto D, et al. Cytokeratin 19 fragment predicts the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor in non-small-cell lung cancer harboring EGFR mutation. J Thorac Oncol. 2013;8:892–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Fiala O, Pesek M, Finek J, Benesova L, Minarik M, Bortlicek Z, et al. Predictive role of CEA and CYFRA 21–1 in patients with advanced-stage NSCLC treated with erlotinib. Anticancer Res. 2014;34:3205–10.PubMedGoogle Scholar
  25. 25.
    Wirth T, Soeth E, Czubayko F, Juhl H. Inhibition of endogenous carcinoembryonic antigen (CEA) increases the apoptotic rate of colon cancer cells and inhibits metastatic tumor growth. Clin Exp Metastasis. 2002;19:155–60.CrossRefPubMedGoogle Scholar
  26. 26.
    Ordonez C, Screaton RA, Ilantzis C, Stanners CP. Human carcinoembryonic antigen functions as a general inhibitor of anoikis. Cancer Res. 2000;60:3419–24.PubMedGoogle Scholar
  27. 27.
    Zander T, Scheffler M, Nogova L, Kobe C, Engel-Riedel W, Hellmich M, et al. Early prediction of nonprogression in advanced non–small-cell lung cancer treated with erlotinib by using [18F] Fluorodeoxyglucose and [18F]fluorothymidine positron emission tomography. J Clin Oncol. 2011;29:1701–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Tiseo M, Ippolito M, Scarlattei M, Spadaro P, Cosentino S, Latteri F, et al. Predictive and prognostic value of early response assessment using 18FDG-PET in advanced non-small cell lung cancer patients treated with erlotinib. Cancer Chemother Pharmacol. 2014;73:299–307.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Francesco Facchinetti
    • 1
  • Raffaella Aldigeri
    • 2
  • Rosalia Aloe
    • 3
  • Beatrice Bortesi
    • 1
  • Andrea Ardizzoni
    • 4
  • Marcello Tiseo
    • 1
  1. 1.Medical Oncology UnitUniversity Hospital of ParmaParmaItaly
  2. 2.Department of Clinical and Experimental MedicineUniversity of ParmaParmaItaly
  3. 3.Biochemistry at High Automation UnitUniversity Hospital of ParmaParmaItaly
  4. 4.Medical Oncology UnitUniversity Hospital of BolognaBolognaItaly

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