MedicalResearch: What is the background for this study?
Dr. Witkiewicz: Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis, with a five year survival rate of approximately 6%. This poor outcome is related to multiple factors, including the relatively late stage of diagnosis, many patients presenting with unresectable disease, and therapy recalcitrance resulting in disease recurrence in spite of operable disease and systemic therapy. Thus far, insights into how to target the treatment of Pancreatic ductal adenocarcinoma have remained unclear in spite of prior sequencing efforts.
MedicalResearch: What are the main findings?
Dr. Witkiewicz: The underlying critical finding of the study was that Pancreatic ductal adenocarcinoma is genetically diverse and that, in principle, this diversity could be exploited for the treatment of disease. Specifically, many cases harbored deregulation in pathways that are the target for drug development. For example, we identified cases that were driven by BRAF V600E and that were sensitive to the FDA approved drug Vemurafenib. Similarly, multiple cases harbored defects in DNA repair processes that impart sensitivity to select chemotherapeutic agents and PARP inhibitors. Common pathway deregulation was observed in reference to beta-catenin, notch, hedgehog, chromatin remodeling, and cell cycle regulatory pathways that are all targets for therapeutic intervention.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Witkiewicz: The data support the overall concept that knowledge of the genetics of Pancreatic ductal adenocarcinoma could be important for directing the care of the individual patient. This is an important advance when progressively more cancer cases are being referred for genetic analysis. Ongoing research and subsequent clinical trials will be required to fully leverage these findings into rationally targeted treatments yielding improved patient survival.
Agnieszka K. Witkiewicz, Elizabeth A. McMillan, Uthra Balaji, GuemHee Baek, Wan-Chi Lin, John Mansour, Mehri Mollaee, Kay-Uwe Wagner, Prasad Koduru, Adam Yopp, Michael A. Choti, Charles J. Yeo, Peter McCue, Michael A. White, Erik S. Knudsen. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nature Communications, 2015; 6: 6744 DOI: 10.1038/ncomms7744
MedicalResearch.com Interview with: Dr. Agnieszka Witkiewicz MD (2015). Genetic Diversity of Pancreatic Cancer May Lead To Therapeutic Targets