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Precision medicine advances in pancreatic cancer driven by genomic and molecular alterations
Xiang Li1, Yan Jiao2, Ya-Hui Liu3
1Department of First Operation Room, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China.
Abstract:
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.
Insights
Precision oncology advances in pancreatic cancer reveal key molecular targets. Molecular profiling guides personalized treatment strategies for this lethal malignancy, improving patient outcomes.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited therapeutic options.
- Next-generation sequencing has identified critical molecular targets driving PDAC's aggressive nature.
- Understanding the genomic landscape is crucial for developing effective precision treatments.
Purpose of the Study:
- To review the current molecular targets and therapeutic strategies in pancreatic cancer.
- To highlight the role of molecular profiling in advancing precision oncology for PDAC.
- To discuss the implications of genetic mutations and co-mutations for treatment selection and prognosis.
Main Methods:
- Review of next-generation sequencing data and clinical trial outcomes.
- Analysis of common and rare actionable alterations in PDAC.
- Evaluation of the efficacy of targeted therapies and immunotherapy in PDAC subgroups.
Main Results:
- Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are prevalent but largely undruggable, with novel inhibitors under investigation.
- BRCA1/2 mutations sensitize PDAC to platinum agents and PARP inhibitors.
- Rare alterations (BRAF V600, NTRK, FGFR2, RET fusions) benefit selected patients in tumor-agnostic trials.
- Immunotherapy efficacy is limited due to low tumor mutational burden and mismatch repair deficiency.
- Co-mutations in TP53, CDKN2A, and SMAD4 impact prognosis and treatment response.
Conclusions:
- Molecular profiling, including germline and somatic testing, is essential for personalized PDAC treatment.
- Biomarker-matched clinical trials and rational combination strategies are key to advancing PDAC therapy.
- PDAC-specific strategies are necessary despite shared genomic drivers with other cancers.
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