Derived neutrophil to lymphocyte ratio as a prognostic factor in patients with advanced colorectal cancer according to RAS and BRAF status: a post-hoc analysis of the MRC COIN study

The phase III Continuous or Intermittent (COIN) trial failed to show a benefit in overall survival (OS) of cetuximab in combination with chemotherapy for patients with metastatic colorectal cancer. High derived neutrophil to lymphocyte ratio (dNLR) has been shown to be prognostic in patients with metastatic colorectal cancer. The aim of this analysis is to evaluate dNLR as a predictive biomarker of the survival according to RAS and BRAF mutations status within the COIN trial. A post-hoc exploratory analysis of the COIN trial arms A and B was carried out. All patients with available white blood cell and neutrophil data were analysed. The dNLR was calculated using a formula that has previously shown predictive power in cancer patients: dNLR=ANC/(WBC−ANC). A high dNLR was defined as a value of 2.2 or more. dNLR was correlated with clinical outcomes using Kaplan–Meier and Cox regression analysis. A total of 1603 patients were assigned to the oxaliplatin-based chemotherapy (arm A, N=815) or oxaliplatin-based chemotherapy plus cetuximab (arm B, N=815) arms. There was a strong association between dNLR level and overall survival (OS) using Kaplan–Meier analysis. In all mutation groups, dNLR less than 2.2 was associated with better OS compared to dNLR of 2.2 or more. The median OS in patients with wild-type disease (dNLR<2.2 vs. dNLR≥2.2) was 22.8 versus 13.1 months [hazard ratio (HR)=1.33]; 16.9 versus 11.8 months (HR=1.36) in patients with RAS mutant tumours; and 12.6 versus 6.8 months (HR=1.67) in patients with BRAF mutant tumours. In patients with dNLR less than 2.2, the median OS was 19.2 months in arm A compared to 18.0 months in arm B (HR=1.11). Among patients with dNLR greater than or equal to 2.2, the median OS was 13.0 months in arm A compared with 13.1 months in arm B (HR=0.96). dNLR is strongly prognostic for survival in all mutation groups. dNLR does not predict for benefit from the addition of cetuximab.

[1]  S. Stintzing.  Faculty Opinions recommendation of Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. , 2018, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[2]  M. Delgado-Rodríguez,et al.  Systematic review and meta-analysis. , 2017, Medicina intensiva.

[3]  J. Bridgewater,et al.  Derived neutrophil lymphocyte ratio is predictive of survival from intermittent therapy in advanced colorectal cancer: a post hoc analysis of the MRC COIN study , 2016, British Journal of Cancer.

[4]  Marc Peeters,et al.  Analysis of KRAS/NRAS Mutations in a Phase III Study of Panitumumab with FOLFIRI Compared with FOLFIRI Alone as Second-line Treatment for Metastatic Colorectal Cancer , 2015, Clinical Cancer Research.

[5]  Sabine Tejpar,et al.  Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  J. Vauthey,et al.  Cytokine profile and prognostic significance of high neutrophil-lymphocyte ratio in colorectal cancer , 2015, British Journal of Cancer.

[7]  A. Dirican,et al.  Do the derived neutrophil to lymphocyte ratio and the neutrophil to lymphocyte ratio predict prognosis in breast cancer? , 2015, International Journal of Clinical Oncology.

[8]  M. Ychou,et al.  Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Fédération Francophone de Cancérologie Digestive, Fédération Nationale des Centres de Lutte Contre , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Ben Tran,et al.  Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. , 2014, Journal of the National Cancer Institute.

[10]  J. Barrett,et al.  Combined epiregulin (EREG) and amphiregulin (AREG) expression levels as a biomarker of prognosis and panitumumab benefit in RAS-wt advanced colorectal cancer (aCRC). , 2014 .

[11]  S. Imbeaud,et al.  Mir-31-3p as a predictive biomarker of cetuximab effects in a post hoc analysis of new EPOC phase III trial. , 2014 .

[12]  J. Tabernero,et al.  Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. , 2013, The New England journal of medicine.

[13]  Susan Richman,et al.  Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial , 2013, The Lancet. Oncology.

[14]  Gerald C. Chu,et al.  Mutant N-RAS protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression. , 2013, Cancer discovery.

[15]  Yan-wen Yao,et al.  Pretreatment neutrophil to lymphocyte ratio is associated with response to therapy and prognosis of advanced non-small cell lung cancer patients treated with first-line platinum-based chemotherapy , 2013, Cancer Immunology, Immunotherapy.

[16]  S. Clarke,et al.  A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer , 2012, British Journal of Cancer.

[17]  H. Sorbye,et al.  Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  V. Rusch,et al.  Prognostic Immune Markers in Non–Small Cell Lung Cancer , 2011, Clinical Cancer Research.

[19]  Harpreet Wasan,et al.  Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial , 2011, The Lancet. Oncology.

[20]  J. Thigpen.  Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial , 2011 .

[21]  Xiang Hu,et al.  The Baseline Ratio of Neutrophils to Lymphocytes is Associated with Patient Prognosis in Rectal Carcinoma , 2010, Journal of gastrointestinal cancer.

[22]  Dongsheng Tu,et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer. , 2008, The New England journal of medicine.

[23]  C. Tournigand,et al.  Metastatic colorectal cancer. , 2006, Gastroenterologie clinique et biologique.

[24]  M. ChB.,et al.  Neutrophil‐lymphocyte ratio as a prognostic factor in colorectal cancer , 2005, Journal of surgical oncology.

[25]  H. Dvorak.  Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. , 1986, The New England journal of medicine.