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The neutrophil-to-lymphocyte ratio in cancer: Beauty in simplicity

DII small banner By Warren R. Heymann, MD
Sept. 29, 2016

The world was stunned and saddened on January 28th, 1986 when the Space Shuttle Challenger exploded. Six months later, during the meeting of the Rogers Commission analyzing the disaster, the famed physicist Richard Feynman demonstrated how O-rings lost their resilience. By placing the sample material in ice water, he proved how the rings could no longer provide a seal. Simple. Direct. Brilliant.

Think of how we prognosticate cancer in 2016 — what did the PET/CT scan show? What genetic polymorphism did the tumor display? Imagine knowing future risk by looking at a CBC (complete blood count). Simple. Direct. Brilliant.
The prognostic role of an elevated blood neutrophil-to-lymphocyte ratio (NLR) has been associated with a poor prognosis in several malignancies, including melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, cholangiocarcinoma, glioblastoma, GIST, gastric, esophageal, lung, ovarian and head and neck cancer. A high baseline neutrophil count was identified as strong, independent risk factor for poor outcome in multivariate analyses (1).

The presumption is that increased neutrophils may enhance tumor growth and angiogenesis, while lymphopenia may inhibit tumor immunosurveillance. In an attempt to identify an upfront marker for treatment benefit of ipilimumab for melanoma, Ferrucci et al studied 187 metastatic melanoma patients. The NLR was calculated from pre-therapy full blood counts. Progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox models were applied, adjusting for confounders and other prognostic factors. Pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in multivariate analyses. Patients with baseline NLR<5 had a significantly improved PFS (HR=0.38; 95% CI: 0.22-0.66; P=0.0006) and OS (HR=0.24; 95% CI: 0.13-0.46; P<0.0001) compared with those with a NLR⩾5. Associations of low NLR with improved survival were confirmed in three validation cohorts of patients. The authors concluded that baseline NLR is strongly and independently associated with outcome of patients treated with ipilimumab, and may serve to identify patients most likely to benefit from this therapy (2).

In a retrospective study of 75 patients with Merkel Cell Carcinoma (MCC) a high NLR at baseline (NLR ≥4) was associated with death from MCC in univariate (hazard ratio 2.76, 95% confidence interval 1.15-6.62, P = .023) and multivariate (hazard ratio 3.30, 95% confidence interval 1.21-9.01, P = .020) analysis, but not with recurrence. An acknowledged limitation of the research was that because of the retrospective design, patients with missing data were excluded and not all confounding factors that may have influenced the NLR were available. Regardless, a high NLR at baseline was independently associated with specific mortality in patients with MCC, providing more evidence that the NLR may be an accessible, inexpensive prognostic biomarker at baseline (3).

I had never heard of a NLR being used for cancer prognostication until I read Zaragoza’s article. If you perform a PubMed search for “neutrophil-to-lymphocyte ratio and cancer” there are 1100 publications. Based on the simplicity and miniscule cost of a CBC, I have an inkling that we will be seeing NLR reports for many of our oncologic patients.

1. Donskov F. Immunomonitoring and prognostic relevance of neutrophils in clinical trials. Semin Cancer Biol 2013; 23: 200-7.
2. Ferrucci PF, et al. Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients. Br J Cancer 2015; 112: 1904-10.
3. Zaragoza J, et al. A high neutrophil-to-lymphocyte ratio as a potential marker of mortality in patients with Merkel cell carcinoma. J Am Acad Dermatol 2015; 75: 712-21.

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