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Boost in Plasma Levels of Chain Amino Acids Is Associated With Increased Risk of Pancreatic Cancer

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Key Points

  • Researchers have found that elevated plasma levels of branched chain amino acids are associated with a greater than twofold increased risk of a future pancreatic cancer diagnosis.
  • The findings provide an important lead for scientists studying how pancreatic tumors interact with patients’ normal tissues.
  • Detecting pancreatic cancer earlier in its development may improve the ability to treat the disease.

In a recent study reported in Nature Medicine, scientists from Dana-Farber Cancer Institute, the Massachusetts Institute of Technology, and the Harvard School of Public Health, among other institutions, investigated whether pancreatic ductal adenocarcinoma produces metabolic changes that can be detected before the disease is diagnosed. Mayers et al found that elevated plasma levels of branched chain amino acids are associated with a greater than twofold increased risk of a future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors. Detecting pancreatic cancer earlier in its development may improve the ability to treat the disease.

Study Methodology

The study population included pancreatic cancer cases and controls from four prospective cohort studies: Health Professionals Follow-Up Study, The Nurses’ Health Study, Physicians’ Health Study, and Women’s Health Initiative-Observational Study. The researchers analyzed blood samples from 1,500 study participants for more than 100 different metabolites and compared the results from participants who had gone on to develop pancreatic cancer and those who had not.

The researchers assessed heterogeneity of metabolite associations with pancreatic cancer risk across cohorts using Cochran’s Q-statistic and examined associations in predefined subgroups by sex, smoking status, body mass index, and fasting status. Associations were also examined for circulating branched chain amino acids with previously explored risk factors for pancreatic cancer in the cohorts and with cancer stage at diagnosis.

Study Findings

In conditional logistic regression models, 15 plasma metabolites were associated with future diagnosis of pancreatic ductal adenocarcinoma to P < .05; three metabolites— the branched chain amino acids isoleucine, leucine, and valine—were significant to P ≤ .0006, the predefined significance threshold after correction for multiple-hypothesis testing.

To evaluate the magnitude of risk for pancreatic ductal adenocarcinoma diagnosis, the researchers divided participants into quintiles of increasing branched chain amino acid levels. They found compared to the bottom quintile, subjects in the top quintile had at least a twofold increased risk of developing pancreatic ductal adenocarcinoma.

The amount of time that elapsed before those individuals were diagnosed with pancreatic cancer ranged from 2 to 25 years, although the highest risk was in the several years before diagnosis, found the researchers.

Findings May Lead to Improved Treatment of Deadly Disease

“These findings led us to hypothesize that the increase in branched chain amino acids is due to the presence of an early pancreatic tumor,” said Brian Wolpin, MD, MPH, Assistant Professor, Medical Oncology at Dana-Farber Cancer Institute, and a co–senior author of the study, in a statement. The theory was confirmed in laboratory experiments showing that mice with newly formed pancreatic tumors had above-normal blood levels of these amino acids.

The researchers found that the increase was due to a breakdown of muscle tissue, which caused branched amino acids to be released into the bloodstream, a process that is similar to what occurs in patients with cancer-related cachexia.

The findings provide an important lead to scientists studying how pancreatic tumors interact with patients’ normal tissues, concluded the study authors.

“Most people with pancreatic ductal adenocarcinoma are diagnosed after the disease has reached an advanced stage, and many die within a year of diagnosis. Detecting the disease earlier in its development may improve our ability to treat it successfully,” said Dr. Wolpin in a statement.

Major support for the study was provided by the Howard Hughes Medical Institute and the Lustgarten Foundation. Additional support was provided by the National Institutes of Health; the Nestle Research Center; the Robert T. and Judith B. Hale Fund for Pancreatic Cancer; the Perry S. Levy Fund for Gastrointestinal Cancer Research; the Pappas Family Research Fund for Pancreatic Cancer; Cambridge Isotope Laboratories; the Burroughs Wellcome Fund; the Damon Runyon Cancer Research Foundation; the Smith Family; the Stern Family; the American Society of Clinical Oncology Conquer Cancer Foundation; and Promises for Purple.

The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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