3598 Background: High blood neutrophil-to-lymphocyte ratio (NLR) has been previously identified as a poor prognostic marker in patients with metastatic colorectal cancer (mCRC). However, the underlying pathophysiology associated with this marker is not well defined. We validated this biomarker and investigated the relationship between circulating cytokines and high NLR. Methods: NLRs were calculated retrospectively from the ratio of peripheral blood absolute neutrophil and lymphocyte counts, and segregated based on previously determined cutoff of ≤5 and >5. Four cohorts with a total of 805 CRC pts were evaluated to confirm the prognostic clinical significance of NLR. Plasma cytokine levels were evaluated in exploratory (n=39) and validation cohorts (n=166) of previously untreated mCRC patients using multiplex-bead assays, and correlated with NLR. Results: High NLR is present in 20% of CRC patients and is associated with poor prognosis, independent of known prognostic factors (Table). Expression of 6 cytokines (IL-6, IL-8, IL-2Ra, HGF, M-CSF and VEGF) correlated with NLR>5 in both the exploratory and validation cohort. In the validation cohort, an additional 14 cytokines correlated with NLR>5, including high EREG,AREG, and TGF-α, and low TRAIL. By hierarchial clustering, these 20 cytokines fall into 3 overlapping major clusters: angiogenic cytokines, inflammatory cytokines, and epidermal growth factor ligands. In the validation cohort, pts with a composite cytokine score below the median have longer survival than patients with high scores (40.0 mo vs 20.0 mo, HR = 2.24; 95% CI=1.47–3.41; P<0.001). Conclusions: High peripheral blood neutrophil/lymphocyte ratio (NLR) is associated with poor outcomes independent of other known prognostic features. NLR correlates with discrete sets of cytokines which may reflect important biological features in poor prognosis mCRC. [Table: see text]
The decrease in NKG2D+ Natural Killer cells in peripheral blood of patients with metastatic colorectal cancer