Tumors originating in different regions of the pancreas have significant molecular differences, according to a Houston Methodist-led study that provides promise for transforming the therapeutic landscape for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC).

The study, one of pancreatic cancer research's largest molecular profiling efforts to date, distinguishes the molecular intricacies of PDAC tumors based on whether they started in either the head or body/tail of the pancreas. The hope is that targeting either root site could provide better tailored treatment for the aggressive disease.

"We found that tumors in the head of the pancreas are often associated with jaundice, while those in the body and tail are more likely to present with weight loss and are often diagnosed at a later stage," said Dr. Maen Abdelrahim, the paper's first author and a prominent gastrointestinal oncologist at Houston Methodist. "These differences are compounded by the distinct embryonic origins, blood supply and lymphatic drainage of these regions, factors that may contribute to the divergent molecular characteristics observed in our study."

The study, published recently in Precision Oncology, provides much-needed insight into the divergent molecular characteristics of the two origin locations of PDAC, matching the profiles with corresponding variances in clinical presentation, prognosis and potential therapeutic response.

Dr. Abdelrahim said more tailored treatment would be a huge advance, given that pancreatic ductal adenocarcinoma "continues to rank among the world's deadliest forms of cancer, with an alarming rise in incidence that closely parallels global increases in obesity and diabetes." PDAC makes up 92% of all pancreatic cancer cases worldwide.

Pancreatic cancer recently surpassed breast cancer as the third leading cause of cancer-related death in the United States after lung and colon cancer. It is expected to overtake colon cancer as the second-deadliest form of the disease by 2030.

The research team employed next-generation sequencing of DNA and RNA, coupled with immunohistochemistry, to explore the tumor immune microenvironment and gene expression profiles of some 3,499 PDAC samples. Their findings suggest that the immune landscape and the expression of immune-oncology related genes differ significantly between tumors in the head and body/tail regions of the pancreas.

"Such differences are likely to influence the efficacy of various immunotherapies, which are increasingly being investigated as potential treatments for PDAC," Dr. Abdelrahim explained.

Currently, treatment regimens for PDAC do not typically differentiate based on the tumor's location within the pancreas. The study's results suggest the approach may be hindering results.

"The differences we've observed in gene expression and immune response between tumors in the head versus the body and tail of the pancreas suggest that a more nuanced approach to treatment could be beneficial," said Dr. Abdelrahim.

By illuminating the heterogeneity within PDAC, the study raises the possibility that personalized treatment strategies, tailored to the tumor's site of origin, could improve patient outcomes. This would be particularly significant given the five-year survival rate for PDAC has remained below 10% for decades.

In their report, Dr. Abdelrahim and his colleagues call for future clinical trials to further investigate the tumor immune microenvironment and molecular differences between head and body/tail tumors. Such research could lead to the development of refined therapeutic strategies that consider the biological nuances of PDAC, potentially enhancing the effectiveness of immunotherapies and other treatment modalities.

"As pancreatic cancer rates continue to rise, there's an urgent need to better understand the molecular underpinnings of the disease," Dr. Abdelrahim said. "By analyzing one of the largest cohorts of pancreatic ductal adenocarcinoma tumors ever to undergo extensive molecular profiling, our hope is that better, more targeted, and ultimately more effective interventions will be developed as a result."