Cascade testing of first-degree relatives of patients with pancreatic cancer with confirmed germline genetic mutations: A simulation modeling study.

Abstract

10513 Background: Universal germline genetic testing is recommended for all patients with pancreatic ductal adenocarcinoma (PDAC). In addition to treatment implications for the patient, it is valuable for family members of the PDAC patient to undertake germline testing to understand their familial cancer risk. We evaluated the potential effectiveness of cascade testing of first-degree relatives (FDRs) of PDAC patients to guide MRI-based screening for PDAC. Methods: We used a microsimulation model of PDAC to estimate the potential life expectancy (LE) benefit of cascade genetic testing of FDRs of PDAC patients. Analysis was performed for eight mutations of interest (ATM, BRCA1, BRCA2, PALB2, Lynch, TP53, CDKN2A, STK11) with relative risk of PDAC ranging from 1.6 – 24. FDRs were defined by their sex, age, and information state (not informed, informed but not tested, test negative, or test positive). Family size and composition, communication of genetic testing results, and uptake of cascade testing were based on published studies. For each FDR group, we simulated multiple MRI-based screening strategies, defined by starting age (FDR age at patient diagnosis to age 75) and frequency (once or annual until age 75), and identified the strategy that resulted in the highest LE. Results: Each PDAC patient would have an average of 4.35 living FDRs. 1.32 of these living FDRs would be informed of the patient’s test results but not undergo testing themselves, and 1.03 would test positive for the mutation of interest. For lower risk mutations (ATM, BRCA2, PALB2), FDRs would only undergo screening if they test positive. For Lynch syndrome, not tested FDRs would undergo screening starting at age 65 or 70, whereas FDRs who test positive would start at 50 or 55. For STK11, the highest risk mutation, FDRs would start screening annually as soon as they are informed of the patient’s test results. The total LE gain for cascade testing of FDRs ranged from 0 (BRCA1) to 1.05 years (STK11). Conclusions: For each PDAC patient identified to have a germline genetic mutation, cascade testing of FDRs could add up to a year life expectancy for the family, in addition to the value of the germline information to the PDAC patient’s care. [Table: see text]