Abstract 3300: Pre-diagnosis neutrophil-to-lymphocyte ratio and lung cancer mortality
Authors: Grieshober Laurie , Graw Stefan , Barnett Matt J. , Thornquist Mark D. , Goodman Gary E. , Chen Chu , Koestler Devin , Marsit Carmen , Doherty Jennifer 
Published: August 2019

Abstract
The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that has been reported to be associated with smoking status as well as survival outcomes from chronic diseases including lung cancer. Most prior studies have examined NLR measured in blood collected at diagnosis, which may therefore reflect disease-related inflammation. Although blood cell type counts, and therefore NLR, cannot be quantified in stored samples, algorithms have been developed to estimate blood cell type counts based on lineage-specific DNA methylation patterns across the genome as methylation-derived NLR (mdNLR). We hypothesize that the inflammatory profile reflected by pre-diagnosis mdNLR may be associated with lung cancer mortality. To test this hypothesis, we examined mdNLR and lung cancer-specific mortality, overall and by histotype, among 293 cases from the Beta Carotene and Retinol Efficacy Trial (CARET) of heavy smokers (≥20 pack years). We used the ratio of predicted neutrophil and lymphocyte proportions derived from DNA methylation signatures in whole blood samples collected on average 4.1 years prior to diagnosis, to estimate mdNLR, which was discretized as quartiles ranging from lowest to highest; i.e. low to high levels of systemic inflammation. We fit Cox proportional hazards models adjusted for age, sex, race (white vs non-white), smoking status, intervention arm, asbestos exposure, and pack years smoked to examine the association between mdNLR lung cancer-specific mortality. We also adjusted for time between blood draw and diagnosis and included early versus late stage as a stratification variable. mdNLR was not associated with mortality for all cases combined, nor squamous cell carcinoma (N=100) or small cell lung cancer (N=59). In contrast, for adenocarcinoma (N=122), we observed a statistically significant linear trend (p=0.02) for increasing quartiles of mdNLR and adenocarcinoma-specific mortality, with a hazard ratio (HR) of 2.03 (95% Confidence Interval (CI): 1.03-4.03) comparing the highest (Q4) to lowest (Q1) mdNLR quartiles. Though subgroup analyses were sparse, we observed associations of larger magnitude (Q4 compared to Q1) for those who were younger at blood draw (HR=4.70, 95% CI: 1.73-12.76) and at diagnosis (HR=6.09, 95% CI: 1.98-18.72), as well as those with smoking histories lower than the median of 53 pack years (HR=2.91, 95% CI: 1.03-8.22) and those in the active intervention arm (HR=3.32, 95% CI: 1.11-9.93). Our findings suggest that an inflammatory response prior to diagnosis as indicated by higher mdNLR levels may be associated with mortality in heavy smokers who go on to develop lung adenocarcinoma. Since indicators of survival may be used to guide treatment decisions and gauge response to treatment, further research into the association between mdNLR and lung adenocarcinoma-specific survival is needed to understand its potential clinical utility.
Citation Format: Laurie Grieshober, Stefan Graw, Matt J. Barnett, Mark D. Thornquist, Gary E. Goodman, Chu Chen, Devin Koestler, Carmen Marsit, Jennifer Doherty. Pre-diagnosis neutrophil-to-lymphocyte ratio and lung cancer mortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3300.