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High serum level of C-reactive protein is associated with worse outcome of patients with advanced-stage NSCLC treated with erlotinib

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Tumor Biology

Abstract

Erlotinib is a low molecular weight tyrosine kinase inhibitor (TKI) directed at epidermal growth factor receptor (EGFR), widely used in the treatment of locally advanced or metastatic-stage non-small cell lung cancer (NSCLC). Although introduction of EGFR-TKIs have significantly extended survival of advanced-stage NSCLC patients, their efficacy in the entire patient population is relatively low. Aside from activating EGFR mutations, no reliable biochemical or molecular predictors of response to erlotinib have been established. The aim of our retrospective study was to evaluate the association of baseline serum levels of C-reactive protein (CRP) with outcomes in patients with advanced-stage NSCLC treated with erlotinib. We retrospectively analyzed clinical data of 595 patients with advanced-stage NSCLC (IIIB or IV) treated with erlotinib. Serum CRP was measured using an immunoturbidimetric method. High baseline levels of CRP (≥10 mg/l) were measured in 387 (65 %) patients, and normal levels (<10 mg/l) were measured in 208 (35 %) patients. The median progression-free survival (PFS) and overall survival (OS) for patients with high CRP was 1.8 and 7.7 compared to 2.8 and 14.4 months for patients with low CRP (p < 0.001 and p < 0.001). The multivariable Cox proportional hazards model revealed that CRP was significantly associated with PFS and also with OS (hazard ratio (HR) = 1.57, p < 0.001, and HR = 1.63, p < 0.001, respectively). In conclusion, the results of the conducted retrospective study suggest that high baseline level of CRP was independently associated with worse outcome of patients with advanced-stage NSCLC treated with erlotinib. CRP is a commonly used biomarker which is simple and easy to detect, and thus, it is feasible for the use in the routine clinical practice.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46:765–81.

    Article  CAS  PubMed  Google Scholar 

  3. Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur Respir J. 2001;18:1059–68.

    Article  CAS  PubMed  Google Scholar 

  4. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–32.

    Article  CAS  PubMed  Google Scholar 

  5. Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, et al. Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study. Lancet Oncol. 2012;13:300–8.

    Article  CAS  PubMed  Google Scholar 

  6. 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;12:735–42.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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;350:2129–39.

    Article  CAS  PubMed  Google Scholar 

  9. Paez JG, Jänne 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;304:1497–500.

    Article  CAS  PubMed  Google Scholar 

  10. Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu N, 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.

    Article  CAS  PubMed  Google Scholar 

  11. Hirsch FR, Varella-Garcia M, Bunn Jr PA, Franklin WA, Dziadziuszko R, Thatcher N, et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small cell lung cancer. J Clin Oncol. 2006;24:5034–42.

    Article  CAS  PubMed  Google Scholar 

  12. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumours. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.

    Article  CAS  Google Scholar 

  13. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–45.

    Article  CAS  PubMed  Google Scholar 

  14. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.

    Article  CAS  PubMed  Google Scholar 

  15. Gabay C, Kushner I. Acute phase protein and other systemic responses to inflammation. N Engl J Med. 1999;340:448–54.

    Article  CAS  PubMed  Google Scholar 

  16. Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol. 2001;38(2–3):189–97.

    Article  CAS  PubMed  Google Scholar 

  17. Egenhofer C, Alsdorff K, Fehsel K, Kolb-Bachofen V. Membrane associated C-reactive protein on rat liver macrophages is synthesized within the macrophages, expressed as neo-C-reactive protein and bound through a C-reactive protein-specific membrane receptor. Hepatology. 1995;18:1216–23.

    Google Scholar 

  18. Weinhold B, Rüther U. Interleukin-6-dependent and independent regulation of the human C-reactive protein gene. Biochem J. 1997;327:425–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gresser I, Delers F, Tran Quangs N, et al. Tumor necrosis factor induces acute phase protein in rats. J Biol Regul Homeost Agents. 1987;1:173–6.

    CAS  PubMed  Google Scholar 

  20. Kuta AE, Baum LL. C-reactive protein is produced by a small number of normal human peripheral blood lymphocytes. J Exp Med. 1986;164:321–6.

    Article  CAS  PubMed  Google Scholar 

  21. Ikeda M, Natsugoe S, Ueno S, Baba M, Aikou T. Significant host- and tumor-related factors for predicting prognosis in patients with esophageal carcinoma. Ann Surg. 2003;238:197–202.

    PubMed  PubMed Central  Google Scholar 

  22. Shimura T, Kitagawa M, Yamada T, Ebi M, Mizoshita T, Tanida S, et al. C-reactive protein is a potential prognostic factor for metastatic gastric cancer. Anticancer Res. 2012;32:491–6.

    CAS  PubMed  Google Scholar 

  23. Koike Y, Miki C, Okugawa Y, Yokoe T, Toiyama Y, Tanaka K, et al. Preoperative C-reactive protein as a prognostic and therapeutic marker for colorectal cancer. J Surg Oncol. 2008;98:540–4.

    Article  CAS  PubMed  Google Scholar 

  24. Pine JK, Fusai KG, Young R, Sharma D, Davidson BR, Menon KV, et al. Serum C-reactive protein concentration and the prognosis of ductal adenocarcinoma of the head of pancreas. Eur J Surg Oncol. 2009;35:605–10.

    Article  CAS  PubMed  Google Scholar 

  25. Karakiewicz PI, Hutterer GC, Trinh QD, Jeldres C, Perrotte P, Gallina A, et al. C-reactive protein is an informative predictor of renal cell carcinoma-specific mortality: a European study of 313 patients. Cancer. 2007;110:1241–7.

    Article  CAS  PubMed  Google Scholar 

  26. Hefler LA, Concin N, Hofstetter G, Marth C, Mustea A, Sehouli J, et al. Serum C-reactive protein as independent prognostic variable in patients with ovarian cancer. Clin Cancer Res. 2008;14:710–4.

    Article  CAS  PubMed  Google Scholar 

  27. Hara M, Matsuzaki Y, Shimuzu T, Tomita M, Ayabe T, Enomoto Y, et al. Preoperative serum C-reactive protein level in non-small-cell lung cancer. Anticancer Res. 2007;27:3001–4.

    CAS  PubMed  Google Scholar 

  28. Koch A, Fohlin H, Sorenson S. Prognostic significance of C-reactive protein and smoking in patients with advanced non-small cell lung cancer treated with first-line palliative chemotherapy. J Thorac Oncol. 2009;4:326–32.

    Article  PubMed  Google Scholar 

  29. Scott HR, McMillan DC, Forrest LM, Brown DJF, McArdle CS, Milroy R. The systemic inflammatory response weight loss, performance status and survival in patients with inoperable non-small cell lung cancer. Br J Cancer. 2002;87:264–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wilop S, Crysandt M, Bendel M, Mahnken AH, Osieka R, Jost E. Correlation of C-reactive protein with survival and radiographic response to first-line platinum-based chemotherapy in advanced non-small cell lung cancer. Onkologie. 2008;31:665–70.

    CAS  PubMed  Google Scholar 

  31. Pircher A, Ulsperger E, Hack R, Jamnig H, Pall G, Zelger B, et al. Basic clinical parameters predict gefitinib efficacy in non-small cell lung cancer. Anticancer Res. 2011;31:2949–55.

    CAS  PubMed  Google Scholar 

  32. Masago K, Fujita S, Togashi Y, Kim YH, Hatachi Y, Fukuhara A, et al. Clinical significance of pretreatment C-reactive protein in patients with advanced nonsquamous, non-small cell lung cancer who received gefitinib. Oncology. 2010;79:355–62.

    Article  CAS  PubMed  Google Scholar 

  33. McKeown DJ, Brown DJ, Kelly A, Wallace AM, McMillan DC. The relationship between circulating concentrations of C-reactive protein, inflammatory cytokines and cytokine receptors in patients with non-small-cell lung cancer. Br J Cancer. 2004;91:1993–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Haura EB, Zheng Z, Song L, Cantor A, Bepler G. Activated epidermal growth factor receptor-Stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer. Clin Cancer Res. 2005;11:8288–94.

    Article  CAS  PubMed  Google Scholar 

  35. Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, et al. Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci. 2009;1171:59–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98:295–303.

    Article  CAS  PubMed  Google Scholar 

  37. Kim SM, Kwon OJ, Hong YK, Kim JH, Solca F, Ha SJ, et al. Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation. Mol Cancer Ther. 2012;11:2254–64.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank all the patients who voluntarily took part in the observational, population-based registry TULUNG. This study is supported by the Ministry of Health, Czech Republic [conceptual development of research organizations: Faculty Hospital in Pilsen - FNPl (00669806) and Masaryk Memorial Cancer Institute - MMCI (00209805)] and by the project CZ.1.05/2.1.00/03.0076 from European Regional Development Fund.

Conflicts of interest

JF has received honoraria from AstraZeneca, Roche and Novartis for consultations and lectures unrelated to this project. TB has received honoraria from Roche for consultations and lectures unrelated to this project. AP has received honoraria from GSK, Roche and Bayer for consultations and lectures unrelated to this project. OF, MP, OT, MM, LB, JR and ZB declare that they have no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations that could inappropriately influence this work.

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Authors and Affiliations

  1. Department of Oncology and Radiotherapy, Medical School and Teaching Hospital in Pilsen, Charles University in Prague, alej Svobody 80, 304 60, Pilsen, Czech Republic

    Ondrej Fiala & Jindrich Finek

  2. Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic

    Ondrej Fiala

  3. Department of Pneumology, Medical School and Teaching Hospital in Pilsen, Charles University in Prague, Pilsen, Czech Republic

    Milos Pesek

  4. Department of Nuclear Medicine, Medical School and Teaching Hospital in Pilsen, Charles University in Prague, Pilsen, Czech Republic

    Ondrej Topolcan

  5. Institute of Clinical Biochemistry and Hematology, Medical School and Teaching Hospital in Pilsen, Charles University in Prague, Pilsen, Czech Republic

    Jaroslav Racek & Lucie Benesova

  6. Center for Applied Genomics of Solid Tumours, Genomac Research Institute, Prague, Czech Republic

    Marek Minarik

  7. Department of Analytical Chemistry, Faculty of Sciences, Charles University in Prague, Pilsen, Czech Republic

    Marek Minarik

  8. Institute of Biostatistics and Analysis, Faculty of Medicine, Masaryk University, Brno, Czech Republic

    Zbynek Bortlicek

  9. Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute and Faculty of Medicine, Masaryk University, Brno, Czech Republic

    Alexandr Poprach

  10. Department of Oncology and First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic

    Tomas Buchler

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  1. Ondrej Fiala
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Correspondence to Ondrej Fiala.

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Fiala, O., Pesek, M., Finek, J. et al. High serum level of C-reactive protein is associated with worse outcome of patients with advanced-stage NSCLC treated with erlotinib. Tumor Biol. 36, 9215–9222 (2015). https://doi.org/10.1007/s13277-015-3660-3

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  • DOI: https://doi.org/10.1007/s13277-015-3660-3

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