Increased levels of circulating interleukin 6, interleukin 8, C-reactive protein, and risk of lung cancer

Abstract

Background: Previous studies that were based primarily on small numbers of patients suggested that certain circulating proinflammatory cytokines may be associated with lung cancer; however, large independent studies are lacking.

Methods: Associations between serum interleukin 6 (IL-6) and interleukin 8 (IL-8) levels and lung cancer were analyzed among 270 case patients and 296 control subjects participating in the National Cancer Institute-Maryland (NCI-MD) case-control study. Results were validated in 532 case patients and 595 control subjects in a nested case-control study within the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Association with C-reactive protein (CRP), a systemic inflammation biomarker, was also analyzed. Associations between biomarkers and lung cancer were estimated using logistic regression models adjusted for smoking, stage, histology, age, and sex. The 10-year standardized absolute risks of lung cancer were estimated using a weighted Cox regression model.

Results: Serum IL-6 and IL-8 levels in the highest quartile were associated with lung cancer in the NCI-MD study (IL-6, odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.88 to 5.77; IL-8, OR = 2.06, 95% CI = 1.19 to 3.57) and with lung cancer risk in the PLCO study (IL-6, OR = 1.48, 95% CI = 1.04 to 2.10; IL-8, OR = 1.57, 95% CI = 1.10 to 2.24), compared with the lowest quartile. In the PLCO study, increased IL-6 levels were only associated with lung cancer diagnosed within 2 years of blood collection, whereas increased IL-8 levels were associated with lung cancer diagnosed more than 2 years after blood collection (OR = 1.57, 95% CI = 1.15 to 2.13). The 10-year standardized absolute risks of lung cancer in the PLCO study were highest among current smokers with high IL-8 and CRP levels (absolute risk = 8.01%, 95% CI = 5.77% to 11.05%).

Conclusions: Although increased levels of both serum IL-6 and IL-8 are associated with lung cancer, only IL-8 levels are associated with lung cancer risk several years before diagnosis. Combination of IL-8 and CRP are more robust biomarkers than either marker alone in predicting subsequent lung cancer.

Figure 1

Associations of circulating interleukin 8 (IL-8) and C-reactive protein (CRP) levels with lung cancer risk. Associations across smoking status of Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial participants, and those participants diagnosed more than 2 years after baseline, are shown. High and low IL-8 and CRP levels were classified based on the median value among control subjects. Analyses were performed on 532 case patients and 595 control subjects. Odds ratios and 95% confidence intervals (CIs) are shown for all participants and were estimated by two-sided unconditional logistic regression analyses, adjusted for age, sex, smoking pack-years, smoking status (never, former quit ≤15 years, former quit >15 years, and current), year of random assignment, and number of years in the study. Vertical dashed lines represent an odds ratio of 1.0. Solid black circles represent the odds ratios and solid horizontal bars represent the 95% confidence intervals.