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Validation of early detection cancer biomarkers has proven to be disappointing when initial promising claims have often not been reproducible in diagnostic samples or did not extend to prediagnostic samples. The previously reported lack of rigorous internal validity (systematic differences between compared groups) and external validity (lack of generalizability beyond compared groups) may be effectively addressed by utilizing blood specimens and data collected within well-conducted cohort studies. Cohort studies with prediagnostic specimens (eg, blood specimens collected prior to development of clinical symptoms) and clinical data have recently been used to assess the validity of some early detection biomarkers. With this background, the Division of Cancer Control and Population Sciences (DCCPS) and the Division of Cancer Prevention (DCP) of the National Cancer Institute (NCI) held a joint workshop in August 2013. The goal was to advance early detection cancer research by considering how the infrastructure of cohort studies that already exist or are being developed might be leveraged to include appropriate blood specimens, including prediagnostic specimens, ideally collected at periodic intervals, along with clinical data about symptom status and cancer diagnosis. Three overarching recommendations emerged from the discussions: 1) facilitate sharing of existing specimens and data, 2) encourage collaboration among scientists developing biomarkers and those conducting observational cohort studies or managing healthcare systems with cohorts followed over time, and 3) conduct pilot projects that identify and address key logistic and feasibility issues regarding how appropriate specimens and clinical data might be collected at reasonable effort and cost within existing or future cohorts., (© Published by Oxford University Press 2015.)

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.

Background: The relationship among chronic inflammation, innate immunity, and cancer is well established. Mannose-binding lectin (MBL) is a key player in innate immunity. Five polymorphisms in the promoter and first exon of the MBL2 gene alter the expression and function of MBL in humans and are associated with inflammation-related disease susceptibility. These five polymorphisms create six well-characterized haplotypes that result in lower (i.e., LYB, LYC, HYD, and LXA) or higher (i.e., HYA and LYA) serum MBL concentrations. We investigated whether survival of patients with lung cancer was associated with these polymorphisms., Methods: We used a multivariable Cox proportional hazards model to study the association between MBL2 polymorphisms and their haplotypes and diplotypes in 558 white and 173 African American patients with non-small-cell lung cancer in the Baltimore, MD, area and lung cancer mortality. Smoking history and race were obtained from interviews, tumor stage was obtained from medical records, and cause of death was obtained from the National Death Index. All statistical tests were two-sided., Results: We found a statistically significant association between the X allele of the promoter Y/X polymorphism (which results in a lower serum MBL concentration) and improved lung cancer survival among white patients (risk ratio [RR] of death from lung cancer with X/X or X/Y genotype compared with Y/Y genotype = 0.61, 95% confidence interval [CI] = 0.46 to 0.81) but not among African American patients (RR = 1.11, 95% CI = 0.69 to 1.77). The associations among white patients were strongest in heavy smokers and were independent of stage. We also found a statistically significant interaction between the Y/X polymorphism and race for lung cancer survival (P(interaction) = .019). The MBL2 LXA haplotype and XA/B diplotype, which are also associated with low serum MBL levels, were statistically significantly associated with improved lung cancer survival among white patients., Conclusion: The functional Y/X polymorphism of the innate-immunity gene MBL2 and MBL2 haplotypes and diplotypes appear to be associated with lung cancer survival among white patients.

Background: A 17-cytokine gene expression signature in noncancerous hepatic tissue from patients with metastatic hepatocellular carcinoma (HCC) was recently found to predict HCC metastasis and recurrence. We examined whether the cytokine gene expression profile of noncancerous lung tissue could predict the metastatic capability of adjacent lung adenocarcinoma., Methods: We analyzed a 15-cytokine gene expression profile in noncancerous lung tissue and corresponding lung tumor tissue from 80 US lung adenocarcinoma patients using real-time quantitative reverse transcription-polymerase chain reaction. We then used unsupervised hierarchical clustering and Prediction Analysis of Microarray classification to test the prognostic ability of the 15-cytokine gene profile in the US patients and in an independent validation set comprising 50 Japanese patients with stage I disease. Survival was analyzed by the Kaplan-Meier method using the log-rank test, and univariate and multivariable Cox proportional hazards modeling were used to analyze the association of clinical variables with patient survival. All statistical tests were two-sided., Results: A 15-cytokine gene signature in noncancerous lung tissue primarily reflected the lymph node status of 80 lung adenocarcinoma patients, whereas the gene signature of the corresponding lung tumor tissue was associated with prognosis independent of lymph node status. Cytokine Lung Adenocarcinoma Survival Signature of 11 genes (CLASS-11), a refined 11-gene signature, accurately classified patients, including those with stage I disease, according to risk of death from adenocarcinoma. CLASS-11 prognostic classification was statistically significantly associated with survival and was an independent prognostic factor for stage I patients (hazard ratio for death in the high-risk CLASS-11 group compared with the low-risk CLASS-11 reference group = 7.46, 95% confidence interval = 2.14 to 26.05; P = .002). CLASS-11 also classified patients in the validation set according to risk of recurrence., Conclusion: CLASS-11, which consists of genes for pro- and anti-inflammatory cytokines, identifies stage I lung adenocarcinoma patients who have a poor prognosis.