April 01, 2025
Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer death in the United States, and incidence rates continue to rise, according to the Centers for Disease Control and Prevention. More than half the people with PDAC are diagnosed at a stage when the cancer already has spread outside the pancreas and treatment options are limited. Shounak Majumder, M.D., and Mayo Clinic colleagues are working to change this. Dr. Majumder is a gastroenterologist and pancreatologist and leads the High-Risk Pancreas Clinic and the Pancreatic Cancer Early Detection Research Program at Mayo Clinic in Rochester, Minnesota.
Dr. Majumder and colleagues are conducting studies focused on the development of novel diagnostic tests to aid in the detection of pancreatic cancer when it's at an early stage and amenable for potentially curative treatment.
Liquid biopsy approach for detecting pancreatic ductal adenocarcinoma (PDAC)
Dr. Majumder and colleagues are developing a liquid biopsy approach for detecting PDAC using methylated DNA markers assayed in secretin-stimulated pancreatic juice collected from the duodenum during upper GI endoscopy, without the need to canulate the pancreatic duct or perform a pancreatic biopsy.
Precursors of pancreatic cancer arise in the pancreatic ductal system, in close proximity to pancreatic juice. In previous studies, Dr. Majumder and colleagues developed a novel liquid biopsy approach for detecting PDAC using methylated DNA markers (MDMs) assayed in secretin-stimulated pancreatic juice (PJ) collected from the duodenum during upper GI endoscopy, without the need to canluate the pancreatic duct or perform a pancreatic biopsy.
Building on that work, Dr. Majumder and colleagues conducted a prospective multicenter study to evaluate the sensitivity and specificity characteristics of this panel of PJ-MDMs in an independent set of samples, both as a stand-alone and in combination with plasma carbohydrate antigen 19-9 (CA 19-9). The results of the multicenter study were published in Clinical Gastroenterology and Hepatology in 2024, with Dr. Majumder serving as the corresponding author.
Methods
The researchers assayed paired PJ and plasma from 88 study participants with biopsy-confirmed PDAC and from a control group of 134 participants that included 53 with a healthy pancreas, 23 with chronic pancreatitis and 58 with intraductal papillary mucinous neoplasm.
The researchers analyzed bisulfite-converted DNA from buffered PJ using long-probe quantitative amplified signal assay that targeted 14 previously identified MDMs and a reference gene (methylated B3GALT6). They then used logistic regression to fit a previously identified panel of three PJ-MDMs (FER1L4, C13orf18 and BMP3), and they summarized discrimination accuracy using area under the receiver operating characteristic (AUROC) curve with a corresponding 95% confidence interval (CI).
Results
"Overall, we determined that a panel combining the three MDMs in pancreatic juice with plasma CA 19-9 differentiates PDAC from both healthy and diseased pancreas, with a high degree of sensitivity and specificity, and the discrimination accuracy for this combination was higher compared to either stand-alone," says Dr. Majumder.
- Methylated FER1L4 had the highest individual AUROC of 0.83 (95% CI; range, 0.78 to 0.89).
- The AUROC for the three PJ-MDMs plus plasma CA 19-9 model was 0.95 (95% CI, 0.92 to 0.98). This was higher than the AUROC for both the panel of three PJ-MDMs (0.87; 95% CI; 0.82 to 0.92) alone and plasma CA 19-9 alone (0.91; 95% CI, 0.87 to 0.96).
- At a specificity of 88% (95% CI; 81% to 93%), the sensitivity of the combined three-MDM PJ and plasma CA 19-9 model was 89% (95% CI, 80% to 94%) for all PDAC stages and 83% (95% CI, 64% to 94%) for early stages (1 and 2) of PDAC.
Conclusion
A panel combining methylated DNA markers in pancreatic juice and plasma CA 19-9 discriminates PDAC from both healthy and disease control groups with high accuracy. "These results indicate that a multimodal approach of combining biomarkers from different biofluids in the same patient, pancreatic juice and blood in this case, can be an effective approach for early detection of pancreatic cancer," says Dr. Majumder.
Dr. Majumder and his team are currently engaged in additional studies exploring this approach in individuals with pancreatic cysts and in high-risk individuals with familial and genetic risk of PDAC who are undergoing pancreatic surveillance.
For more information
Engels MML, et al. Multimodal pancreatic cancer detection using methylated DNA biomarkers in pancreatic juice and plasma CA 19-9: A prospective multicenter study. Clinical Gastroenterology and Hepatology. In press.
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