Objective: To evaluate resected human pancreatic ductal adenocarcinoma (PDA) for selection of targeted adjuvant therapy.Background: Standard adjuvant therapy for PDA generates a small but significant improvement in post-resection survival. Recent data have shown that PDAs with defects in a DNA repair pathway, such as BRCA2, are hypersensitive to interstrand cross-linking agents including cis-platinum. The challenge is to efficiently select patients that will optimally benefit from targeted therapy.
Methods: Patients were chosen for this study by evaluating personal history, family history and ethnic background. Molecular assays were performed to determine a deficiency in the DNA repair pathway. Patients’ tumor samples were obtained immediately in the operating room, placed into media for cell culture and extracted for DNA, mRNA, and protein. DNA was also isolated from laser capture microdissected material of patient A’s tongue and endometrial cancers.
Results: Patient A had a strong family history of breast cancer and a personal history of tongue, endometrial, and breast cancers before presenting with pancreatic cancer. She was positive for a mutation in BRCA2 that causes a premature stop codon, and thus she was placed on cis-platinum therapy. Patient B presented with a medical and family history suggestive of a mutation in the BRCA2/FANC pathway. A cell line from patient B was generated and genetic analysis on several critical DNA repair genes including BLOOM, FANCC, BRCA2, and FANCA revealed no obvious alterations. However, the FANCD2 gene, showed markedly reduced protein and mRNA expression. Hence, this patient is also a candidate for targeted adjuvant therapy.
Conclusions: We present a model that provides promising and novel methods to appropriately select patients to receive targeted adjuvant therapy. Larger cohort studies involving patients with similar criteria will reveal whether patients who receive such optimized, targeted adjuvant therapies will have a survival advantage.