Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal ma-lignancies with limited treatment efficacy.Advances in precision oncology,enabled by next-generation sequencing,have highlighted key molecular ta...Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal ma-lignancies 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,con-ferring sensitivity to platinum agents and poly(ADP-ribose)polymerase inhi-bitors.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.展开更多
文摘Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal ma-lignancies 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,con-ferring sensitivity to platinum agents and poly(ADP-ribose)polymerase inhi-bitors.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.
