Characteristics of Pure Familial Pancreatic Cancer Families and Those with Additional Breast Cancer

Pancreatic ductal adenocarcinoma (PDAC) is a challenging
tumor entity with an increasing incidence and a dismal prognosis...


Familial Pancreatic Cancer (FaPaCa) and the European Registry of
Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) were established to investigate the phenotype and genotype of FPC families [6][7][8]. In the last years, studies focused mainly on the discovery of the underlying gene defects and the evaluation of diagnostic yield of prospective PDAC screening programs in individuals at risk (IAR) of such families [9][10][11][12][13][14][15][16][17]. Current sequencing and WES data suggest that FPC is genetically highly heterogeneous with no major predisposing gene [17]. The phenotypic variance of FPC families, however, is still not well-established. The current analysis was performed to analyze the phenotype and genotype and the diagnostic yield of prospective PDAC screening in pure FPC and FPC-breast cancer families.

Materials and Methods
The FaPaCa registry is a national case collection for familial pancreatic cancer families in Germany funded by the Deutsche Krebshilfe in 1999 [7][8][9][10][11][12][13][14][15][16][17][18]. Families with two or more first-degree relatives with a confirmed diagnosis of PDAC and without evidence of any other inherited tumor syndrome were collected. The current report analyzed the genotype and phenotype of FPC families with the occurrence of only PDAC (pure FPC families) and FPC families with the additional occurrence of breast cancer (FPC-breast) families. Members from FPC families were recruited between July 1999 and July 2019 by direct referral via their physicians or by personal contact to the FaPaCa study-office based on information about the study, e.g. via the internet (http://www.fapaca.de). All eligible persons and families were initially genetically counseled and a three-generation family pedigree was constructed. All PDAC diagnoses were confirmed by review of medical records, deaths certificates and by examination of the pathology slides when available. All patients with PDAC of FPC families with available blood samples who gave their informed consent were subjected to mutation analysis of the potential predisposing PDAC genes ATM, BRCA1/2, CDKN2A, PALB2, PLLD and CHEK2 as described previously [12][13][14][15][16][17][18]. In addition, whole exome sequencing (WES) was performed in 7 of those families (Slater et al., submitted). If a deleterious germline mutation was identified in the index patient, predictive genetic testing of this mutation was offered to all family members after genetic counseling. The result of the predictive testing was explained to the family members during another interdisciplinary counseling, involving a geneticist, a psychologist, a surgeon and gastroenterologist. Individuals at risk (IAR) older than 18 years were encouraged to participate in a prospective screening program that was conducted at our institution. Firstdegree relatives of an affected patient of a FPC family and members of a FPC-family carrying a predisposing mutation such as BRCA2, independent of the degree of relationship, were classified as IAR.
The screening started at age 40 years until 2016 and thereafter at age 50 years or 10 years before the earliest age of onset of PDAC in the family, whichever was first [19]. The screening program included an annual physical examination, determination of serum HbA1c, amylase, GOT, GPT, bilirubin and CA19-9, and imaging with magnetic resonance imaging plus MRCP and endosonography as described previously [19]. The screening program was restricted to mutation carriers, if the underlying gene defect was known in the family. Resection specimens were analyzed by experienced pathologists with special regard to the presence of PDAC, pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasia (IPMN) and atypical flat lesions (AFL). Previous screening results of some IAR have been already published [10,[18][19][20]. The        (Table 3). Thus, the diagnostic yield of the prospective PDAC screening was 0% and 3.7% in pure FPC and FPC-breast families according to the strict criteria of an international consensus conference [5,22].   insufficiently recorded in many patients' medical records, thereby compromising its clinical significance [24]. This is especially true for FPC families, since the phenotype is highly heterogeneous and affected patients die fast due to the aggressive disease. FPC can be mainly divided into two groups, namely pure PC families and those associated with other tumor types [4]. The most frequent other tumor type associated with FPC in the FaPaCa registry is breast cancer, in almost one third (30.7%) of FPC families. Therefore, we undertook a detailed analysis of the phenotype and genotype of pure FPC families and FPC with an additional occurrence of breast cancer. Initially, none of these families fulfilled the criteria for HBOC [21,22], but after a median follow-up of 7 years this was the case for 6 (8.6%) families due to the new development of additional breast and/or ovarian cancer cases. It has been previously reported that some HBOC families are associated with an increased risk for PDAC.
A retrospective analysis of 5143 Italian family trees with breast and/ or ovarian cancer, for example, showed that 392 (7.6%) families also had cases of PDAC [25]. It has also been postulated that the risk of PDAC is especially increased in those 25 to 30% of HBOC families who are associated with BRCA1 or BRCA2 germline mutations [25].  [28]. Analysis of the familial aggregation of PDAC with other malignancies using the updated Swedish Family-Cancer Database with more than 11.5 million individuals disclosed that a significantly increased the risk of PDAC was associated with earlyonset breast cancer in siblings [29].
Based on the present analysis one can postulate some phenotypic differences between pure FPC and FPC-breast families.  [26,27].
Comparing the FPC-breast families with the reported characteristics of HBOC families one can also note some phenotypical differences. The PDAC rate in FPC-breast families (18%) appears comparably high to HBOC families with 1.5 to 8% [24,25]. In the FPC-breast families the rate of breast cancer cases with mean 1.6 cases per family was lower than in German HBOC families [30,31].  [9,10,19]. In the present study it was obvious that IAR from FPC-breast families participated significantly more often in the recommended screening than IAR from pure FPC families (33.5% vs. 54.4%, p<0.0001). The reasons for this remain speculative and are probably multifactorial. The diagnostic yield of the screening program itself appears to be more efficient in FPC-breast families compared to pure FPC families (3.7% vs. 0%), although the prospective follow-up of less than 5 years is too short to draw any definitive conclusions. A recent North American study [33] reported that the cumulative incidence of PDAC and high grade dysplasia was significantly higher in the IAR group with predisposing germline mutations compared to those IAR without (RR 2.85, 95% CI 1.0-8.18, p=0.05). We can neither confirm nor reject this observation due to the limited number of mutation carriers (n=21) participating in screening.

Conclusion
In summary, there seems to be a distinct FPC-breast family phenotype, which might be associated with other solid cancers such as colon cancer and has at least a 30% prevalence of predisposing germline mutations in known susceptibility genes BRCA1/2, PALB2, CDKN2A and ATM. IAR of these families have a comparably high motivation to participate in PDAC screening, which in short term appears to be more effective than in pure FPC families. These data should be considered for the counseling and management of these families.