Skip to main content
Top
Published in: Tumor Biology 12/2015

01-12-2015 | Research Article

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

Authors: Ondrej Fiala, Milos Pesek, Jindrich Finek, Ondrej Topolcan, Jaroslav Racek, Marek Minarik, Lucie Benesova, Zbynek Bortlicek, Alexandr Poprach, Tomas Buchler

Published in: Tumor Biology | Issue 12/2015

Login to get access

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.
Literature
1.
go back to reference Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMed Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMed
2.
go back to reference Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46:765–81.CrossRefPubMed Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46:765–81.CrossRefPubMed
3.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
4.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
5.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
6.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
7.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
8.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
9.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
10.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
11.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
12.
go back to reference 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.CrossRef 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.CrossRef
13.
14.
go back to reference Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.CrossRefPubMed Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.CrossRefPubMed
15.
go back to reference Gabay C, Kushner I. Acute phase protein and other systemic responses to inflammation. N Engl J Med. 1999;340:448–54.CrossRefPubMed Gabay C, Kushner I. Acute phase protein and other systemic responses to inflammation. N Engl J Med. 1999;340:448–54.CrossRefPubMed
16.
go back to reference Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol. 2001;38(2–3):189–97.CrossRefPubMed Volanakis JE. Human C-reactive protein: expression, structure, and function. Mol Immunol. 2001;38(2–3):189–97.CrossRefPubMed
17.
go back to reference 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. 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.
18.
19.
go back to reference 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.PubMed 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.PubMed
20.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
21.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
22.
go back to reference 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.PubMed 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.PubMed
23.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
24.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
25.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
26.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
27.
go back to reference 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.PubMed 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.PubMed
28.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
29.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
30.
go back to reference 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.PubMed 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.PubMed
31.
go back to reference 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.PubMed 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.PubMed
32.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
33.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
34.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
35.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
36.
go back to reference Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98:295–303.CrossRefPubMed Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell. 1999;98:295–303.CrossRefPubMed
37.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
Metadata
Title
High serum level of C-reactive protein is associated with worse outcome of patients with advanced-stage NSCLC treated with erlotinib
Authors
Ondrej Fiala
Milos Pesek
Jindrich Finek
Ondrej Topolcan
Jaroslav Racek
Marek Minarik
Lucie Benesova
Zbynek Bortlicek
Alexandr Poprach
Tomas Buchler
Publication date
01-12-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3660-3

Other articles of this Issue 12/2015

Tumor Biology 12/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine