Pancreatic Cancer: "A Riddle Wrapped in a Mystery inside an Enigma"

• Published in: Clinical cancer research 2017-04, Vol.23 (7), p.1629-1637
• Main Authors: Borazanci, Erkut, Dang, Chi V, Robey, Robert W, Bates, Susan E, Chabot, John A, Von Hoff, Daniel D
• Format: Article
• Language: English
• Subjects: Aberration; Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma - surgery; Auditory defects; Cancer; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - surgery; Chemoresistance; Chemotherapy; Cyclin-Dependent Kinase Inhibitor p18 - genetics; Deoxyribonucleic acid; DNA; DNA repair; Epigenetics; Extracellular matrix; Genes; Humans; Immune system; Innovations; K-Ras protein; Medical innovations; Metastases; Mutation; Neoadjuvant Therapy; p53 Protein; Pancreatic cancer; Pancreatic Stellate Cells - pathology; Proto-Oncogene Proteins p21(ras) - genetics; Recognition; Smad4 protein; Smad4 Protein - genetics; Stellate cells; Tumor cells; Tumor Suppressor Protein p53 - genetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-2070

Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult-to-treat cancers. With an increasing incidence and inability to make major progress, it represents the very definition of unmet medical need. Progress has been made in understanding the basic biology-systematic genomic sequencing has led to the recognition that PDAC is not typically a heavily mutated tumor, although there are exceptions. The most consistently mutated genes are , and Study of familial PDAC has led to the recognition that a variety of defects in DNA repair genes can be associated with the emergence of pancreatic cancer. Recent studies suggest that epigenetics may play a larger role than previously recognized. A major new understanding is the recognition that PDAC should be considered a composite of tumor cells, as well as pancreatic stellate cells, immune cells, and extracellular matrix. The individual components contribute to metabolic aberration, immune dysfunction, and chemotherapy resistance, and therapeutic innovations may be needed to address them individually. It has also been recognized that metastatic seeding from PDAC occurs very early in the disease course-in an estimated 73% of cases, once the tumor reaches 2 cm. The implication of this is that therapies directed toward micrometastatic disease and increasing fractional cell kill are most needed. Neoadjuvant approaches have been taken to increase resectability and improve outcome. So much work remains, and most critical is the need to understand how this tumor originates and develops.