LAUSR

Simple Summary Although much progress has been made in recent years in the clinical management of solid tumors, pancreatic ductal adenocarcinoma (PDAC) remains a malignancy with limited therapeutical options. Indeed, responses to standard chemotherapy and targeted therapies vary widely when administered to unselected patient populations. This is in part due to the heterogeneous and variable molecular profile of PDAC. Here, we review current knowledge about the genomic heterogeneity of PDAC and its impact on disease behavior, and treatment including the molecular mechanisms of chemoresistance. Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death due to limited advances in recent years in early diagnosis and personalized therapy capable of overcoming tumor resistance to chemotherapy. In the last decades, significant advances have been achieved in the identification of recurrent genetic and molecular alterations of PDAC including those involving the KRAS, CDKN2A, SMAD4, and TP53 driver genes. Despite these common genetic traits, PDAC are highly heterogeneous tumors at both the inter- and intra-tumoral genomic level, which might contribute to distinct tumor behavior and response to therapy, with variable patient outcomes. Despite this, genetic and genomic data on PDAC has had a limited impact on the clinical management of patients. Integration of genomic data for classification of PDAC into clinically defined entities—i.e., classical vs. squamous subtypes of PDAC—leading to different treatment approaches has the potential for significantly improving patient outcomes. In this review, we summarize current knowledge about the most relevant genomic subtypes of PDAC including the impact of distinct patterns of intra-tumoral genomic heterogeneity on the classification and clinical and therapeutic management of PDAC.