Precision medicine advances in pancreatic cancer driven by genomic and molecular alterations.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies with limited treatment efficacy. Advances in precision oncology, enabled by next-generation sequencing, have highlighted key molecular targets. Kirsten rat sarcoma viral oncogene homolog mutations, present in up to 90% of cases, drive aggressive biology, though most variants remain undruggable; allele-specific inhibitors and exosome-based RNA interference are under exploration. Breast cancer susceptibility gene 1/2 mutations occur in 4%-7% of patients, conferring sensitivity to platinum agents and poly(ADP-ribose) polymerase inhibitors. Other rare but actionable alterations - such as v-raf murine sarcoma viral oncogene homolog B1 (V600), neurotrophic tyrosine receptor kinase, fibroblast growth factor receptor 2, and RET fusions - show benefit in tumor-agnostic trials, broadening options for selected subgroups. Immunotherapy is limited, as high tumor mutational burden and mismatch repair deficiency are uncommon in PDAC, though predictive when present. Co-mutations in tumor protein p53, cyclin-dependent kinase inhibitor 2A, and SMAD4 further stratify prognosis and influence therapy response. Cross-cancer analyses underscore the necessity of PDAC-specific strategies despite shared genomic drivers. Collectively, these insights support routine germline and somatic testing, enrollment in biomarker-matched trials, and rational combination strategies, establishing molecular profiling as central to advancing precision treatment in pancreatic cancer.