The role of family history in predicting germline pathogenic variant carriers who develop pancreatic cancer: Results of a multicenter collaboration

BackgroundPancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations.MethodsIndividuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed.ResultsThe study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344).ConclusionsMost PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors.Results from this multicenter study show that individuals with pancreatic cancer and a germline pathogenic variant in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 are more likely to have a family history of pancreatic cancer, especially a first-degree relative, compared to individuals with pancreatic cancer and no germline pathogenic variant. However, most individuals diagnosed with pancreatic cancer who have a germline pathogenic variant in one of these genes would not have met current guidelines for pancreatic surveillance because of a lack of family history.