Tumor Biology

, Volume 37, Issue 1, pp 361–368 | Cite as

The elevated preoperative derived neutrophil-to-lymphocyte ratio predicts poor clinical outcome in breast cancer patients

  • Sabine Krenn-Pilko
  • Uwe Langsenlehner
  • Tatjana Stojakovic
  • Martin Pichler
  • Armin Gerger
  • Karin S. Kapp
  • Tanja Langsenlehner
Original Article

Abstract

Existing preclinical and clinical data suggest that the presence of a systemic inflammatory response plays a critical role in the progression of several solid tumors. The derived neutrophil-to-lymphocyte ratio (dNLR) represents an easily determinable marker of systemic inflammation and has been proposed as a potential prognostic marker. The present study was performed to validate and further clarify the prognostic relevance of an elevated pre-treatment dNLR in a large cohort of European breast cancer patients. Data from 762 consecutive female breast cancer patients treated from 1999 to 2004 were evaluated. Disease-free survival (DFS) and overall survival (OS) were assessed using the Kaplan–Meier method. To evaluate the prognostic relevance, univariate and multivariate Cox regression models were performed for each endpoint. Applying receiver operating characteristics (ROC) analysis, the optimal cutoff level for the dNLR was 3. In univariate analysis, a dNLR ≥3 was associated with poor DFS (hazard ratio (HR) 1.87, 95 % confidence interval (CI) 1.28–2.73, p = 0.001) and OS (HR 1.67, 95 % CI 1.07–2.63, p = 0.025). Multivariate analysis revealed a significant association between the elevated dNLR and poor DFS (hazard ratio (HR) 1.70, 95 % CI 1.09–2.65, p = 0.018) but did not show a significant association between the dNLR and OS (HR 1.54, 95 % CI 0.91–2.59, p = 0.106). The present study shows that the pre-treatment dNLR is an independent prognostic factor that could be useful for future individual risk assessment in breast cancer patients.

Keywords

Breast cancer Prognosis Inflammation Derived neutrophil-to-lymphocyte ratio 

Notes

Ethics statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The protocol has been approved by the Ethical Committee of the Medical University of Graz (approval number: EK 27-034 ex 13/14). As this is a retrospective nonintervention study, a formal consent is not required.

Conflicts of interest

None.

References

  1. 1.
    Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2012. doi: 10.1016/j.ejca.2012.12.027.PubMedGoogle Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012. doi: 10.3322/caac.20138.Google Scholar
  3. 3.
    Kraeima J, Siesling S, Vliegen IM, et al. Individual risk profiling for breast cancer recurrence: towards tailored follow-up schemes. Br J Cancer. 2013. doi: 10.1038/bjc.2013.401.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Proctor MJ, Morrison DS, Talwar D, et al. A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow inflammation outcome study. Eur J Cancer. 2011. doi: 10.1016/j.ejca.2011.03.028.PubMedGoogle Scholar
  5. 5.
    Azab B, Bhatt VR, Phookan J, et al. Usefulness of the neutrophil-to-lymphocyte ratio in predicting short-and long-term mortality in breast cancer patients. Ann Surg Oncol. 2012;19:217–24.CrossRefPubMedGoogle Scholar
  6. 6.
    Dirican A, Kucukzeybek BB, Alacacioglu A, et al. Do the derived neutrophil to lymphocyte ratio and the neutrophil to lymphocyte ratio predict prognosis in breast cancer? Int J Clin Oncol. 2015. doi: 10.1007/s10147-014-0672-8.PubMedGoogle Scholar
  7. 7.
    Mantovani A, Allavena P, Sica A, et al. Cancer-related inflammation. Nature. 2008;454:436–44.CrossRefPubMedGoogle Scholar
  8. 8.
    Szkandera J, Gerger A, Liegl-Atzwanger B, et al. Validation of the prognostic relevance of plasma C-reactive protein levels in soft-tissue sarcoma patients. Br J Cancer. 2013;109:2316–22.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Stotz M, Gerger A, Eisner F, et al. Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer. Br J Cancer. 2013. doi: 10.1038/bjc.2013.332.Google Scholar
  10. 10.
    Templeton AJ, McNamara MG, Šeruga B, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014. doi: 10.1093/jnci/dju124.Google Scholar
  11. 11.
    Pichler M, Hutterer GC, Stoeckigt C, et al. Validation of the pre-treatment neutrophil-lymphocyte ratio as a prognostic factor in a large European cohort of renal cell carcinoma patients. Br J Cancer. 2013. doi: 10.1038/bjc.2013.28.Google Scholar
  12. 12.
    Walsh SR, Cook EJ, Goulder F, et al. Neutrophil–lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol. 2005;91:181–4.CrossRefPubMedGoogle Scholar
  13. 13.
    Noh H, Eomm M, Han A. Usefulness of pretreatment neutrophil to lymphocyte ratio in predicting disease-specific survival in breast cancer patients. J Breast Cancer. 2013. doi: 10.4048/jbc.2013.16.1.55.Google Scholar
  14. 14.
    Kao SC, Pavlakis N, Harvie R, et al. High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. Clin Cancer Res. 2010;16:5805–13.CrossRefPubMedGoogle Scholar
  15. 15.
    Proctor MJ, McMillan DC, Morrison DS, et al. A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer. Br J Cancer. 2012. doi: 10.1038/bjc.2012.292.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Szkandera J, Stotz M, Eisner F, et al. External validation of the derived neutrophil to lymphocyte ratio as a prognostic marker on a large cohort of pancreatic cancer patients. PLoS One. 2013. doi: 10.1371/journal.pone.0078225.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Troppan K, Deutsch A, Gerger A, et al. The derived neutrophil to lymphocyte ratio is an independent prognostic factor in patients with diffuse large B-cell lymphoma. Br J Cancer. 2014. doi: 10.1038/bjc.2013.763.PubMedCentralGoogle Scholar
  18. 18.
    Dalpiaz O, Pichler M, Mannweiler S, et al. Validation of the pretreatment derived neutrophil-lymphocyte ratio as a prognostic factor in a European cohort of patients with upper tract urothelial carcinoma. Br J Cancer. 2014. doi: 10.1038/bjc.2014.180.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011; doi:  10.1093/annonc/mdr304
  20. 20.
    Jarnicki A, Putoczki T, Ernst M. Stat3: linking inflammation to epithelial cancer—more than a “gut” felling? Cell Div. 2010;5:14.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMedGoogle Scholar
  22. 22.
    Leitch EF, Chakrabarti M, Crozier JE, et al. Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer. Br J Cancer. 2007;97:1266–70.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    De Larco JE, Wuertz BRK, Furcht LT. The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin Cancer Res. 2004;10:4895–900.CrossRefPubMedGoogle Scholar
  24. 24.
    Rodriguez PC, Ernstoff MS, Hernandez C, et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 2009;69:1553–60.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Müller I, Munder M, Kropf P, et al. Polymorphonuclear neutrophils and T lymphocytes: strange bedfellows or brothers in arms? Trends Immunol. 2009;30:522–30.CrossRefPubMedGoogle Scholar
  26. 26.
    El-Hag A, Clark RA. Immunosuppression by activated human neutrophils. Dependence on the myeloperoxidase system. J Immunol. 1987;139:2406–13.PubMedGoogle Scholar
  27. 27.
    Houghton AM. The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle. 2010;9:1732–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Jensen HK, Donskov F, Marcussen N, et al. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol. 2009;28:4709–17.CrossRefGoogle Scholar
  29. 29.
    Bekes EM, Schweighofer B, Kupriyanova TA, et al. Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am J Pathol. 2011. doi: 10.1016/j.ajpath.2011.05.031.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Kusumanto YH, Dam WA, Hospers GA, et al. Platelets and granulocytes, in particular the neutrophils, form important compartments for circulating vascular endothelial growth factor. Angiogenesis. 2003;6:283–7.CrossRefPubMedGoogle Scholar
  31. 31.
    An X, Ding PR, Li YH, et al. Elevated neutrophil to lymphocyte ratio predicts survival in advanced pancreatic cancer. Biomarkers. 2010;15:516–22.CrossRefPubMedGoogle Scholar
  32. 32.
    Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2003;21:137–48.CrossRefGoogle Scholar
  33. 33.
    Gooden MJ, de Bock GH, Leffers N, et al. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105:93–103.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29:1949–55.CrossRefPubMedGoogle Scholar
  35. 35.
    West NR, Milne K, Truong PT, et al. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res. 2011;13:R126.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ropponen KM, Eskelinen MJ, Lipponen PK, et al. Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol. 1997;182:318–24.CrossRefPubMedGoogle Scholar
  37. 37.
    Fogar P, Sperti C, Basso D, et al. Decreased total lymphocyte counts in pancreatic cancer: an index of adverse outcome. Pancreas. 2006;32:22–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Ray-Coquard I, Cropet C, Van Glabbeke M, et al. European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 2009; doi:  10.1158/0008-5472.CAN-08-3845
  39. 39.
    Ege H, Gertz MA, Markovic SN, et al. Prediction of survival using absolute lymphocyte count for newly diagnosed patients with multiple myeloma: a retrospective study. Br J Haematol. 2008;141:792–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Nieto Y, Nawaz S, Shpall EJ, et al. Long-term analysis and prospective validation of a prognostic model for patients with high-risk primary breast cancer receiving high-dose chemotherapy. Clin Cancer Res. 2004;10:2609–17.CrossRefPubMedGoogle Scholar
  41. 41.
    Buyukkaya E, Karakas MF, Karakas E, et al. Correlation of neutrophil to lymphocyte ratio with the presence and severity of metabolic syndrome. Clin Appl Thromb Hemost. 2014;20:159–63. doi: 10.1177/1076029612459675.CrossRefPubMedGoogle Scholar
  42. 42.
    Kaya H, Ertas F, Islamoglu Y, et al. Association between neutrophil to lymphocyte ratio and severity of coronary artery disease. Clin Appl Thromb Hemost. 2014;20:221. doi: 10.1177/1076029613499821.CrossRefPubMedGoogle Scholar
  43. 43.
    Lee GK, Lee LC, Chong E, et al. The long-term predictive value of the neutrophil-to-lymphocyte ratio in Type 2 diabetic patients presenting with acute myocardial infarction. QJM. 2012;105:1075–82.CrossRefPubMedGoogle Scholar
  44. 44.
    Demir M. The relationship between neutrophil lymphocyte ratio and non-dipper hypertension. Clin Exp Hypertens. 2013;35:570–3. doi: 10.3109/10641963.2013.764893.CrossRefPubMedGoogle Scholar
  45. 45.
    Okyay GU, Inal S, Onec¸ K, et al. Neutrophil to lymphocyte ratio in evaluation of inflammation in patients with chronic kidney disease. Ren Fail. 2013;35:29–36.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Sabine Krenn-Pilko
    • 1
  • Uwe Langsenlehner
    • 2
  • Tatjana Stojakovic
    • 3
  • Martin Pichler
    • 4
  • Armin Gerger
    • 4
  • Karin S. Kapp
    • 1
  • Tanja Langsenlehner
    • 1
  1. 1.Department of Therapeutic Radiology and Oncology, Comprehensive Cancer CenterMedical University of GrazGrazAustria
  2. 2.Division of Internal MedicineOutpatient Department GrazGrazAustria
  3. 3.Clinical Institute of Medical and Chemical Laboratory DiagnosticsMedical University of GrazGrazAustria
  4. 4.Division of Clinical Oncology, Department of Internal Medicine, Comprehensive Cancer CenterMedical University of GrazGrazAustria

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