Circulating inflammation markers and prospective risk for lung cancer

Abstract

Background: Despite growing recognition of an etiologic role for inflammation in lung carcinogenesis, few prospective epidemiologic studies have comprehensively investigated the association of circulating inflammation markers with lung cancer.

Methods: We conducted a nested case-control study (n = 526 lung cancer patients and n = 592 control subjects) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Control subjects were matched to lung cancer case patients on age, sex, follow-up time (median = 2.9 years), randomization year, and smoking (pack-years and time since quitting). Serum levels of 77 inflammation markers were measured using a Luminex bead-based assay. Conditional logistic regression and weighted Cox models were used to estimate odds ratios (ORs) and cumulative risks, respectively.

Results: Of 68 evaluable markers, 11 were statistically significantly associated with lung cancer risk (P trend across marker categories < .05), including acute-phase proteins (C-reactive protein [CRP], serum amyloid A [SAA]), proinflammatory cytokines (soluble tumor necrosis factor receptor 2 [sTNFRII]), anti-inflammatory cytokines (interleukin 1 receptor antagonist [IL-1RA]), lymphoid differentiation cytokines (interleukin 7 [IL-7]), growth factors (transforming growth factor alpha [TGF-A]), and chemokines (epithelial neutrophil-activating peptide 78 [ENA 78/CXCL5], monokine induced by gamma interferon [MIG/CXCL9], B cell-attracting chemokine 1 [BCA-1/CXCL13], thymus activation regulated chemokine [TARC/CCL17], macrophage-derived chemokine [MDC/CCL22]). Elevated marker levels were associated with increased lung cancer risk, with odds ratios comparing the highest vs the lowest group ranging from 1.47 (IL-7) to 2.27 (CRP). For IL-1RA, elevated levels were associated with decreased lung cancer risk (OR = 0.71; 95% confidence interval = 0.51 to 1.00). Associations did not differ by smoking, lung cancer histology, or latency. A cross-validated inflammation score using four independent markers (CRP, BCA-1/CXCL13, MDC/CCL22, and IL-1RA) provided good separation in 10-year lung cancer cumulative risks among former smokers (quartile [Q] 1 = 1.1% vs Q4 = 3.1%) and current smokers (Q1 = 2.3% vs Q4 = 7.9%) even after adjustment for smoking.

Conclusions: Some circulating inflammation marker levels are associated with prospective lung cancer risk.

Figure 1.

Associations of 11 inflammation markers with lung cancer risk stratified by smoking status. Odds ratios and 95% confidence intervals comparing the highest level vs lowest level from conditional logistic regression models are shown. All models were adjusted for matching factors (age, sex, follow-up time, randomization year, pack-years of smoking, and time since quitting) as well as for personal history of bronchitis/emphysema, history of coronary heart disease or heart attack, family history of lung cancer, use of aspirin/ibuprofen, body mass index, race, and education. P values for trend across marker categories were estimated through the use of markers as ordinal variables with 1 degree of freedom. Multiplicative statistical interactions of inflammation marker associations across smoking status were evaluated using the Wald test. Statistically significant differences by smoking status were only observed for the association between interleukin 1 receptor antagonist (IL-1RA) and lung cancer. All P values were two-sided. BCA-1/CXCL13 = B cell–attracting chemokine 1; CRP = C-reactive protein; ENA78/CXCL5 = epithelial neutrophil-activating peptide 78; IL-7 = interleukin 7; MDC/CCL22 = macrophage-derived chemokine; MIG/CXCL9= monokine induced by gamma interferon; SAA = serum amyloid A; sTNFRII = soluble tumor necrosis factor receptor 2; TARC/CCL17 = thymus activation regulated chemokine; TGF-A = transforming growth factor alpha.

Figure 2.

Ten-year standardized cumulative risks of lung cancer separately among never smokers (NS; black lines), former smokers (FS; blue lines), and current smokers (CS; red lines) across an inflammation score which was based on four independent markers (C-reactive protein [CRP], B cell–attracting chemokine 1 [BCA-1/CXCL13], MDC/CCL22 [macrophage-derived chemokine], and interleukin 1 receptor antagonist [IL-1RA]). Cumulative risks were estimated using weighted Cox regression models and were standardized to the age, sex, and smoking (pack-years and time since quit) distributions of the 50862 Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial screening arm participants eligible for selection into our case–control study. The figure also shows relative risks of lung cancer for each inflammation score quartile (Q) and smoking status compared with never smokers with inflammation score in the fourth quartile. The cumulative risks of lung cancer estimated for never smokers in the first, second, and third quartiles of the inflammation score were 0.17%, 0.26%, and 0.12%, respectively. Overall estimated 10-year cumulative risks of lung cancer were 0.16% in never smokers, 1.8% in former smokers, and 5.0% in current smokers (data not shown in figure).