October 28, 2014
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Branched-chain amino acids linked to future pancreatic cancer diagnosis

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Adults who had elevated plasma levels of branched-chain amino acids were at greater than twice the risk for pancreatic cancer, according to study results.

“The study demonstrates that increasing circulating branched-chain amino acids are a marker for future pancreatic cancer diagnosis,” Brian M. Wolpin, MD, MPH, assistant professor of medical oncology at Dana-Farber Cancer Institute, told HemOnc Today. “The association was particularly strong in the several years before diagnosis, leading us to hypothesize that early pancreatic tumors were impacting host metabolism to lead to elevated branched-chain amino acids.”

Brian Wolpin

Brian M. Wolpin

Wolpin and colleagues compared plasma metabolite samples from 454 patients with pancreatic cancer to samples from 908 matched controls who were enrolled on one of four prospective cohort studies. A median of 8.7 years passed between blood collection and pancreatic ductal adenocarcinoma diagnosis.

Overall, researchers identified 15 metabolites that were associated with a future pancreatic cancer diagnosis (P˂.05). Three circulating branched-chain amino acids —isoleucine, leucine and valine — met the researchers’ predefined significance threshold for an association with pancreatic cancer (P≤.0006).

Patients who were in the top quintile of branched-chain amino acid expression demonstrated more than twice the risk for pancreatic cancer compared with patients in the bottom quintile of expression (OR=2.13; 95% CI, 1.43-3.15). Researchers also noted the expression of isoleucine, leucine and valine were highly correlated.

Elevated branched-chain amino acid levels 2 to 5 years before diagnosis were associated with the strongest risk for pancreatic cancer, suggesting the presence of occult disease (OR=4.34; 95% CI, 1.82-10.35).

Stratified analyses indicated the association between branched-chain amino acid expression and pancreatic cancer persisted regardless of cohort, sex, smoking status, BMI and fasting status at blood collection (P≥.14).

Wolpin and colleagues sought to replicate this association in mice. They found plasma branched-chain amino acid expression was associated with KRAS-mutated early-stage pancreatic cancer, but not KRAS-mutated tumors in other tissues.

“[Our findings were] confirmed using two mouse models of pancreatic cancer, in which elevated branched-chain amino acids were seen with early tumors,” Wolpin said. “In further studies in mice, we discovered that branched-chain amino acids were coming for muscle wasting, which had developed before loss of weight or other outward signs of cancer.”

The tissue breakdown associated with increased branched-chain amino acid levels suggests that whole-body protein breakdown is an early sign of pancreatic cancer, researchers said.

“The primary implications are twofold,” Wolpin said. “One, better understanding the biology of early pancreatic ductal adenocarcinoma and the identified subclinical muscle wasting will enable further early detection markers to be developed. Circulating branched-amino acids on their own are not sufficiently sensitive or specific for population screening at this time. Two, if tumors are using the products liberated by muscle wasting to support their growth, interrupting this process could identify new treatments.”

Disclosure: The researchers report no relevant financial disclosures.