Elevated plasma levels of three branched-chain amino acids may predict the development of pancreatic ductal adenocarcinoma at least 2 years before diagnosis, and well before the onset of clinical cachexia, new data suggest.
Researchers retrospectively examined blood samples taken in four large prospective cohort studies, including the Nurses Health Study and the Women’s Health Initiative, and found significant associations between the levels of 15 metabolites and future diagnosis of pancreatic cancer.
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Elevated branched-chain amino acids may predict the development of pancreatic cancer at least 2 years before diagnosis.
In particular, elevated plasma levels of isoleucine, leucine, and valine were highly predictive of later pancreatic cancer, as patients in the top quintile of increasing levels had at least a twofold increase in the risk of pancreatic cancer, compared with those in the bottom quintile, according to a paper published online in Nature Medicine.
Researchers found that the associations between elevated branched-chain amino acids and future cancer diagnosis were most significant between 2 and 5 years before the diagnosis (Nature Med. 2014;20:1193-8 [doi:10.1038/nm.3686]).
Previous studies attempting to single out metabolite biomarkers predicting future risk of cancer have relied on a cross-sectional design, comparing affected patients with cancer-free individuals, which researchers said was likely to be complicated by the impact of advanced disease on circulating metabolite profiles.
“This is particularly true for patients with pancreatic cancer, who commonly have significant anorexia, weight loss, and pancreatic insufficiency at the time of diagnosis,” wrote Jared R. Mayers, Ph.D., from the Koch Institute for Integrative Cancer Research at MIT, Boston,and his colleagues.
“Increased muscle catabolism represents one aspect of cancer-associated cachexia, a wasting syndrome frequently affecting patients with advanced PDAC [pancreatic ductal adenocarcinoma] and contributing to worse outcomes.”“Our findings, however, suggest that protein breakdown begins much earlier than previously appreciated and predates onset of clinical cachexia.”
Elevated circulating branched-chain amino acids are known to be associated with a future risk of diabetes, and type 2 diabetes is also a predisposing factor for pancreatic cancer.
However, researchers found the results remained unchanged after excluding subjects who had diabetes at baseline, suggesting that the findings were not simply indicating the prevalent diabetes associated with the later development of pancreatic cancer.
The study showed circulating branched-chain amino acids (BCAA) were also modestly correlated with obesity and glucose intolerance; however, the relationship with future pancreatic cancer risk persisted after accounting for those markers.
Researchers also tested the possibility that occult pancreatic cancer may have already been present during the periods showing the strongest correlations between elevated BCAAs and later cancer risk, by conducting a prospective serial blood sampling study in mice genetically predisposed to pancreatic cancer.
They found the mice – which have a median survival of 21 weeks – initially showed similar levels of BCAAs to normal mice, but these increased significantly from 15 to 17 weeks before death.
“These data suggest circulating BCAA elevations accompany early PDAC,” the researchers wrote.
The study was supported by the Howard Hughes Medical Institute, the Lustgarten Foundation, and grants from the National Institutes of Health, the Nestle Research Center, the Robert T. and Judith B. Hale Fund for Pancreatic Cancer, Perry S. Levy Fund for Gastrointestinal Cancer Research, the Pappas Family Research Fund for Pancreatic Cancer, the Burroughs Wellcome Fund, the Damon Runyon Cancer Research Foundation, the Smith Family and the Stern Family, the American Society of Clinical Oncology Conquer Cancer Foundation, the Howard Hughes Medical Institute and Promises for Purple. There were no conflicts of interest declared.