Familial pancreatic cancer (FPC) is a rare hereditary tumor syndrome. The large phenotypic and genotypic heterogeneity is not
yet well-established. FPC families without (pure FPC) or with additional occurrence of breast cancer (FPC-breast) were analyzed
regarding phenotype, genotype and the diagnostic yield of prospective screening for pancreatic ductal adenocarcinoma (PDAC). The
total cohort of 227 FPC families included 85 (38%) pure FPC and 70 (30.7%) FPC-breast families. The proportions of affected family
members with PDAC (27.2%, 197/724 vs. 18.3%, 177/962, p<0.0001) and of 2 or more affected generations (84.2% vs. 62.9%,
p<0.05) were significantly higher in pure FPC families. In 48 (68.6%) FPC-breast families additional tumor types occurred, most
frequently colorectal cancer (n=16, 22.8%). Deleterious germline mutations (2 BRCA2, 1 PALB2) were detected in 3 of 53 (5.6%)
analyzed pure FPC and in 17 of 56 (30.4%) analyzed FPC-breast families (3 BRCA1, 6 BRCA2, 3 PALB2, 3 CDKN2A, 2 ATM; p=0.001).
Individuals at risk (IAR) from FPC-breast families participated significantly more often in a prospective PDAC screening program
(54.4% vs. 33.5%; p=0.0001) resulting in a diagnostic yield of 3.7% and 0% in FPC-breast and pure FPC families, respectively. The
phenotypic and genotypic characteristics of pure FPC and FPC-breast families should be considered for the genetic counseling and
management of these families.