Molecular Alterations in Pancreatic Cancer: Transfer to the Clinic

Pancreatic ductal adenocarcinoma (PDA) is the most common cancer of the exocrine pancreas and probably the tumor that has benefited the least from clinical progress in the last three decades. A consensus has been reached regarding the histologic classification of the ductal preneoplastic lesions (pancreatic intra-epithelial neoplasia—PanIN) and the molecular alterations associated with them. Mutations in KRAS and inactivation of CDKN2A, SMAD4 and TP53 are among the most prevalent alterations. Next generation sequencing studies are providing a broad picture of the enormous heterogeneity in this tumor type, describing new mutations less prevalent. These studies have also allowed the characterization of different subtypes with prognostic value. However, all this knowledge has not been translated into a clinical progress. Effective preventive and early diagnostic strategies are essential to improve the survival rates. The main challenge is, indeed, to identify new effective drugs. Despite many years of research and its limited success, gemcitabine is still the first line treatment of PDA. New drug combinations and new concepts to improve drug delivery into the tumor, as well as the development of preclinical predictive assays, are being explored and provide optimism and prospects for better therapies.