METABOLOMICS OF PANCREATIC CANCER

A dynamic portrait of metabolic profiles known as "metabolomics" has been used to identify new blood-derived metabolite biomarkers that can distinguish between pancreatic ductal adenocarcinoma and chronic pancreatitis with a high degree of accuracy and at an earlier disease stage than conventional diagnostic testing, researchers say.

"In patients with chronic pancreatitis with an increased risk for pancreatic cancer, the biomarker signature detected 98% of resectable pancreatic cancers (55 out of 78, stages IA to IIB) with an accuracy of 90.4%," the researchers report, adding that "this can be regarded as a significant advance in the field."

The reserachers, led by Markus M. Lerch, MD, professor of medicine at University Medicine Greifswald in Germany, also note that the pancreatic cancer was detected at an early stage, when surgical resection could increase survival by 30% to 40%.

The negative predictive value of the biomarker signature was 99.8%.

The report was published online January 20 in Gut.

The biomarker signature includes 9 metabolites as well as the carbohydrate antigen 19-9 (CA19-9), which is currently the only blood-based biomarker in clinical use for pancreatic cancer.

At present, the test is a research tool. Technical validation as a test for pancreatic cancer has been completed, and plans are underway to have it externally validated. In addition, patent applications for the identified biomarkers have been filed, the reserachers note.

The biomarker signature distinguished pancreatic cancer from chronic pancreatitis, assuming a cumulative incidence of 1.95%, with an area under the curve of 0.96, a sensitivity of 89.9%, and a specificity of 91.3%, the researchers report. This successfully validates the biomarker signature, they add.

"In one third of our patients, the clinical use of this biomarker signature would have improved diagnosis and treatment stratification in comparison to CA19-9," they say.

The biomarker signature also detected 9% of false-positives compared with 23% for CA19-9. "Theoretically, the latter patients would have undergone unnecessary pancreatic resection with a reported mortality of up to 8%," they note.

Conversely, the new test identified 15% more patients in whom the diagnosis of pancreatic cancer was missed with standard diagnostic methods.

Transabdominal ultrasonography, blood tests, and transsectional imaging are also standard for the diagnosis of chronic pancreatitis. The study showed that abdominal ultrasonography had a sensitivity of 68% and a specificity of 75%.

Previously, it has been reported that CA19-9 has a sensitivity of 80.3% and a specificity of 80.2% when discriminating between patients with pancreatic cancer and healthy controls.

When separating out patients who have pancreatic cancer from those who have benign pancreatic disease, the test's sensitivity is 78.2% and its specificity is 82.8%, the researchers point out. The sensitivity of CA19-9 can't surpass 92%, they emphasize, because the carbohydrate antigen is not expressed in Lewis blood type–negative patients.

Greater Accurary

The current 5-year survival rate for pancreatic adenocarcinoma is about 6%, and pancreatic cancer is projected to be the third leading cause of cancer-related death by 2030, thanks to delayed diagnosis and few new treatment options, the researchers note.

"The results demonstrate the feasibility of developing a diagnostic test that can detect pancreatic cancer with greater accuracy (>90%) than has previously been achieved with either conventional tumour markers or a micro RNA panel," Dr Lerch and colleagues say.

For the study, which was designed according to the REMARK guidelines for diagnostic tumor marker development, the researchers prospectively enrolled 914 patients from three tertiary care centers. A total of 271 patients had pancreatic ductal adenocarcinoma, 282 patients had chronic pancreatitis, and 100 had cirrhosis of the liver; there were 261 healthy controls without pancreatic disease.

In the patients with pancreatic cancer, blood was drawn as presurgical samples in 135 patients who had resectable disease and as prechemotherapy samples in 136 patients with unresectable pancreatic cancer.

To generate metabolomic profiles of plasma and serum samples, the researchers used gas chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry to identify 477 metabolites.

Of these metabolites, 10 compounds made up the final panel. These compounds included 2 sphingomyelins, 1 phosphatidylcholine, 1 sphinganine-phosphate, and 1 ceramide, a finding that further supports the role of ceramides in human pancreatic cancer, the researchers say.

"The fact that there was no loss of diagnostic accuracy when only patients with resectable pancreatic cancer were analyzed suggests that total tumor burden has little influence on the metabolic signature of pancreatic cancer," they point out.

Metabolomics has just begun to enter the field of cancer diagnostics and tumor biology, the researchers note, adding that this study may be "the largest metabolome investigation of any kind of cancer to date."

A metabolic biomarker signature may also have the potential for screening in other high-risk cohorts, such as patients older than 45 years of age with newly diagnosed diabetes, they suggest.

This study was supported by the Deutsche Krebshilfe/Dr. Mildred-Scheel-Stiftung, the Deutsche Forschungsgemeinschaft, the Federal Ministry of Education and Research, the European Union, the Wilhelm Sander Stiftung and EFRE-State Ministry of Economics MV, and the German Ministry for Education and Research. The study authors have disclosed no relevant financial relationships.