![]() However, only 7% of these individuals had received a matched, precision-based therapy 15. ![]() Recently, the ‘Know Your Tumor’ initiative reported that 28% of patients with available clinical outcomes had an actionable mutation, defined as a genetic aberration for which a specific targeted therapy existed 14. In addition, The Cancer Genome Atlas (TCGA) program reported the presence of 20 genes mutated at a frequency of less than 10%, which included chromatin modification genes (such as ARID1A, KMT2D and KMT2C), DNA repair genes (for example, BRCA1, BRCA2 and PALB2) and additional oncogenes ( BRAF, MYC, FGFR1 and others) 13. The International Cancer Genome Consortium (ICGC) confirmed these findings and described several structural variations 12. ![]() Early next-generation sequencing (NGS) studies of resected PDAC tumors revealed that KRAS, TP53, CDKN2A and SMAD4 displayed the highest mutation frequencies, with >90% of individuals having oncogenic KRAS mutations 10, 11. Several large-scale genomic efforts have cataloged potential driver mutations in PDAC, enabling genomic-guided clinical decisions and therapeutic development. In this section, we review efforts toward the molecular characterization of PDAC and the strategies aimed at targeting potential vulnerabilities. Identifying key oncogenic drivers and dependencies may yield novel approaches for PDAC. Here, we review our current understanding of the molecular features and immune landscape of PDAC to develop targeted and immune-based therapies and improve outcomes for patients with PDAC. There is a critical unmet need to translate our understanding of PDAC biology to the clinic to improve survival and quality of life. However, an improved understanding of the biology and genetics of PDAC have spurred the advent of new targeted and immune-based therapies that may be available for patients with PDAC in the near future. In stark contrast to other tumor types, multiple large-scale trials using targeted agents have been unsuccessful for PDAC 7, 8, 9. The past decade has cemented gemcitabine and fluoropyrimidine-based combination regimens as standard of care chemotherapy for patients with metastatic pancreatic cancer 4, although median OS (mOS) rates remain at approximately 1 year (refs. Recent progress in chemotherapy regimens has improved outcomes in resectable PDAC 2 however, 80% of patients are diagnosed at an advanced stage, precluding them from curative intent surgery 3. PDAC is a devastating disease with a 5-year overall survival (OS) of only 11% (ref.
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