Precision Oncology for Pancreatic Ductal Adenocarcinoma: Germline Mutations and High-Risk Surveillance

(1) Background: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer mortality, largely due to late-stage diagnosis and early metastatic progression. Identification of patients with hereditary pancreatic cancer syndromes and familial pancreatic cancer (FPC) provides an opportunity to establish routine surveillance aimed at detecting precursor lesions and early-stage disease. (2) Methods: A narrative review was conducted to evaluate hereditary PDAC susceptibility genes, current screening recommendations, prospective surveillance studies in high-risk individuals, and emerging biomarker, artificial intelligence, risk stratification, and early cancer interception strategies. (3) Results: Germline pathogenic variants, including BRCA1, BRCA2, PALB2, ATM, CDKN2A, STK11, and PRSS1 are associated with increased lifetime PDAC risk. Guidelines recommend surveillance with magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) for defined high-risk individuals (HRIs). Surveillance programs detect earlier-stage, more frequently resectable disease with encouraging rates of 5-year overall survival. Serum carbohydrate antigen 19-9 (CA 19-9) remains the only current guideline-referenced biomarker, with emerging liquid biopsy, artificial intelligence (AI)/machine learning (ML), and risk-enrichment strategies aimed at improving early-stage detection. (4) Conclusions: Germline testing and high-risk surveillance facilitate earlier PDAC detection and are associated with longer survival in non-randomized studies. Ongoing efforts seek to refine patient selection, resource utilization, surveillance strategies, and biomarker integration to further enhance outcomes.