Abstract Background: Cancer-associated inflammation drives the progression, growth, and metastasis of many established tumors, including those of the head & neck, esophagus, and lung. Limited evidence from non-aerodigestive cancers suggests that quantifiable immunologic dysfunction may precede the emergence of some clinically detectable tumors. The Golestan region of Iran provides a unique opportunity to further study the relationship between chronic inflammation and aerodigestive cancer risk, as it features a very high incidence of esophageal squamous cell carcinoma despite remarkably low prevalence of typical confounders, including tobacco and alcohol use. This study tests the hypothesis that a comprehensive panel of cancer-associated serum inflammatory biomarkers can accurately predict risk of head & neck, esophageal, and lung cancers in a prospective, high-risk cohort. Methods: This is a nested case-control pilot study of subjects enrolled in the Golestan Cohort Study, an ongoing epidemiologic project assessing cancer trends in Golestan, Iran. We measured a broad panel of cytokines, chemokines, and inflammatory molecules using Luminex® technology in serum samples collected two or more years before cancer diagnosis in 78 aerodigestive cancer cases and 81 controls. Data was analyzed using Wilcoxon rank-sum test, ROC areas of discrimination, and multivariate analysis. Results: Mean age of 159 study subjects was 60 years. Median levels (pg/ml) of several biomarkers were profoundly elevated in future esophageal and lung cancer patients, respectively, as compared to controls, including FGF-2 (341.9 and 306.7 versus 139.6, p<0.0001), GM-CSF (63.7 and 63.3 versus 21.3, p<0.0001), IFN-α2 (245.3 and 251 versus 67.6, p<0.0001), and IL-1Rα (415 and 413.2 versus 116.2, p<0.0001). Receiver operating characteristic (ROC) areas demonstrated a strong ability to distinguish esophageal and lung cancer cases from controls for FGF-2, GM-CSF, IFN-α2, IL-1Rα, and TNF-β. The highest ROC area was 88% for esophageal cancer (GM-CSF and IFN-α2) and 85% for lung cancers (GM-CSF). The same trend was not observed among head and neck cancer cases, as no biomarker had a ROC area >69% as compared to controls. Among data-linked controls, biomarker levels tended to be higher with older age, Turkmen ethnicity, and cigarette smoking, but these correlations were non-significant. Conclusions: This study provides the first direct evidence that multiple inflammatory biomarkers are coordinately elevated in future lung and esophageal cancer patients at least two years before cancer diagnosis, suggesting that baseline serum levels of certain cancer-associated biomarkers may represent a useful adjunctive screening measure to determine aerodigestive cancer risk. Citation Format: Brieze R. Keeley, Farhad Islami, Akram Pourshams, Hossein Poustchi, Jamie S. Pak, Paul Brennan, Hooman Khademi, Shu-hsia Chen, Eric M. Genden, Christian C. Abnet, Sanford M. Dawsey, Paolo Boffetta, Reza Malekzadeh, Andrew G. Sikora. Serum inflammatory biomarkers predict esophageal and lung cancer risk two years prior to diagnosis in a prospective cohort. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 890. doi:10.1158/1538-7445.AM2014-890