Genetic Testing Considerations

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Comprehensive genetic testing represents a critical component of modern pancreatic adenocarcinoma management, recommended for all patients at diagnosis. Current guidelines advocate for both germline and somatic tumor testing to identify actionable mutations that may influence treatment decisions. Germline testing should include a comprehensive hereditary cancer syndrome panel encompassing ATM, BRCA1/2, CDK2A, MLH1, PALB2, STK11, and TP53 mutations, which can guide treatment selection and family counseling.

Tumor profiling using NGS assays helps identify potentially actionable somatic mutations, though these remain relatively uncommon in pancreatic cancer. Key targets include BRAF mutations, BRCA1/2 alterations, KRAS mutations, and PALB2 changes. Additionally, immunohistochemistry testing for HER2 expression is increasingly performed to identify patients with HER2-positive disease who may benefit from targeted therapies.

Patients harboring specific germline mutations, particularly BRCA1/2 or PALB2 alterations, may demonstrate enhanced sensitivity to platinum-based chemotherapy regimens. For these patients, treatment options include FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin), modified FOLFIRINOX, or gemcitabine plus cisplatin combinations. The identification of these mutations not only impacts initial treatment selection but also has implications for maintenance therapy with PARP inhibitors and provides valuable information for genetic counseling of family members.