Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months. PDAC has been linked with obesity and glucose intolerance, but whether changes in circulating metabolites are associated with early cancer progression had not been studied. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from pancreatic cancer cases and matched controls from four prospective cohort studies. We found that elevated plasma levels of branched chain amino acids (BCAAs) are associated with a greater than 2–fold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years prior to diagnosis when occult disease is likely present. Utilizing genetically engineered mouse models of PDAC, we have confirmed that these elevations represent a marker of early, sub-clinical disease. Furthermore, using these model systems, we demonstrate that the increase in plasma BCAAs reflects a breakdown of tissue protein that accompanies early stage disease. Together, these findings suggest that altered whole body amino acid metabolism is an early event in development of PDAC, and that elevations in BCAAs can be seen in patients years before their pancreatic cancer diagnosis.

Citation Format: Matthew G. Vander Heiden. Evidence for increased muscle breakdown associated with early pancreatic cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL04-03.

©2015 American Association for Cancer Research.
2015