Targeting pancreatic cancer screening by identification of pathogenic variants of BRCA2/ BRCA1 in healthy individuals who have no known family history of pancreatic cancer: The arguments for and against.

The majority of patients with pancreatic ductal adenocarcinoma (PDAC) are no longer suitable for treatment with curable intent at the time of diagnosis resulting in a 5-year survival of less than 10 %. Imaging of asymptomatic individuals could identify early cancers, but only with a risk of falsely identifying a benign lesion as malignant. Screening of an unselected population would result in far more such false positives than true early cancers. Selection before screening is therefore essential, but there are very few populations at high enough risk to make screening more beneficial than counterproductive. These populations include carriers of specific mutations in BRCA2, and arguably BRCA1, who have a family history of PDAC. These pathogenic mutations all have a predictable effect in making loss of Homologous Recombination Repair (HRR) likely in a carrier’s lifetime. In this review the impact of such loss of HRR function on the likelihood of PDAC development will be discussed. Furthermore, it will be discussed whether the identification of a germline pathogenic mutation is sufficient to justify carrier surveillance for the development of the malignancy, or whether the current practice of screening only those carriers with a close relative diagnosed with PDAC is justifiable, as only a proportion of carriers are at high risk. The review will go beyond this to discuss whether there is an essential need to better define and stratify those at high risk, so that only high-risk carriers are put on surveillance.