The German National Case Collection for Familial Pancreatic Cancer (FaPaCa)

Knowledge Gained in 20 Years

Background: Familial pancreatic carcinoma (FPC) is a rare hereditary tumor syndrome with a heterogeneous clinical phenotype. The study of FPC also contributes to a better understanding of the more common sporadic pancreatic ductal adenocarcinoma (PDAC). We report on the past 20 years’ experience of the German National Case Collection for Familial Pancreatic Carcinoma (FaPaCa) of the German Cancer Aid (Deutsche Krebshilfe).

Methods: From 1999 onward, families in which at least two first-degree relatives had PDAC, and which did not meet the criteria for any other tumor syndrome, have been entered into the FaPaCa registry and analyzed both clinically and with molecular genetic techniques. Persons at risk are offered the opportunity to participate in an early detection program.

Results: From June 1999 to June 2019, 227 families (a total of 2579 persons) met the criteria for entry into the FaPaCa registry. PDAC was the sole tumor entity present in 37% of the families (95% confidence interval [31.1; 44.1]); in the remaining 63% [55.9; 68.9], other tumor types were present as well, particularly breast cancer (70 families, 31% [24.9; 37.3]), colon carcinoma (25 families, 11% [7.3; 15.8]), and melanoma (22 families, 9.7% [6.2; 14.3]). The mode of inheritance of PDAC was autosomal dominant in 72% [65.5; 77.6] of the families. Predisposing germ-line mutations were found in 25 of the 150 (16.7%) families studied, in the following genes: BRCA2 (9 families), CDKN2A (5 families), PALB2 (4 families), BRCA1 (3 families), ATM (2 families), and CHEK2 (2 families). The early detection program revealed high-grade cancer precursor lesions or a PDAC in 5 of the participating 110 persons at risk (4.5%, [1.5; 10.3] during a period of observation of at least five years.

Conclusion: The care of families with FPC is complex and should be provided in centers with the necessary expertise. Prospective, controlled longitudinal studies are needed to determine whether the screening of persons at risk for PDAC truly lessens mortality and is cost-effective.

By the year 2030, pancreatic ductal adenocarcinoma (PDAC) will probably be the second leading cause of cancer-related deaths in Germany (1). PDAC is an aggressive tumor with a 5-year overall survival rate that is below 10% (2). According to two prospective studies from Sweden and Germany in the early 2000s, 3%–6% of all cases of PDAC occur in patients with a strong genetic predisposition (2, 3), which, given the incidence of PDAC in Germany of 22/100 000 per year (Statistisches Bundesamt, www.krebsdaten.de/abfrage, retrieved December 2019), means around 700 cases/year. So far as is known today, an inherited predisposition toward developing PDAC occurs in three different scenarios (summarized in [4], Table 1):

Table 1

Clinical scenarios for familial pancreatic cancer

• Hereditary cancer syndromes, such as hereditary breast and ovarian cancer
• Hereditary pancreatitis and cystic fibrosis
• Familial pancreatic cancer

The last accounts for approximately 75% of all cases of hereditary PDAC and characterizes families with at least two first-degree relatives with PDAC who do not fulfill the criteria for any other hereditary cancer syndrome (5, 6, 7). Although familial pancreatic cancer is rare, clinical and genetic investigation of rare hereditary cancer syndromes can also provide important insights for the much more common sporadic forms of the cancers (around 95% in the case of PDAC), e.g., regarding progression of precursor lesions.

The German National Case Collection for Familial Pancreatic Cancer (FaPaCa) was established in 1999 to investigate the clinical and genetic characteristics of familial pancreatic cancer (FPC). In addition, since 2001, high-risk individuals in these families have been offered a screening program for the detection of PDAC or its precursor lesions to enable early curative therapy. The 5-year and 15-year results of the screening program have already been reported (8, 9), the latter in cooperation with two other European centers. This article now presents the 20-year overall clinical and genetic findings of the FaPaCa registry, which provide a good overview of the genotypic and phenotypic heterogeneity of FPC and the efficacy of a screening program.

Patients and methods

The FaPaCa registry was established in 1999 with support from German Cancer Aid (Deutsche Krebshilfe) as a national case collection for familial pancreatic cancer (10). Families with two or more first-degree relatives with a histologically confirmed diagnosis of PDAC who did not fulfill the criteria of any other hereditary cancer syndrome were enrolled. Between June 1999 and June 2019, potential FPC families were recruited either through an initial multicenter study (2); through direct referral from specialists in general medicine, human genetics, surgery, or gastroenterology; through contact in person with the FaPaCa Study Center; or via contact over the internet (www.fapaca.de). All those seeking advice received genetic counseling, and a three-generation family tree including first- and second-degree relatives was prepared. All PDAC diagnoses in the family were confirmed by reviewing medical and pathology reports and death certificates. Newly occurring tumors in a family were registered in an ongoing manner from interviews with high-risk individuals as part of the screening program, and/or from reports by family members to the Study Center.

Because no principal genetic defect is currently known for familial pancreatic cancer, in affected index patients over the years the association with cancer predisposition genes that were known known at the time of presentation – such as ATM, BRCA1, BRCA2, CHEK2, CDKN2A, PALLD, and PALB2 – was repeatedly investigated by mutation analysis of all coding exons, including exon/intron boundaries (11, 12, 13, 14, Box). If a predisposing pathogenic germline mutation was detected, after receiving genetic counseling and giving written informed consent, family members were offered predictive genetic testing.

Box

Mutation analysis: technical details

Adult high-risk members of FPC families (first-degree relatives of affected individuals or carriers of a predisposing germline mutation) were invited to take part in a prospective screening program. If the underlying genetic defect in the family was known, screening was restricted to mutation carriers. Screening by the FaPaCa registry included a clinical examination, determination of certain blood values (which included liver enzymes, the tumor marker CA 19–9, glucose, and HbA_1c), and annual imaging studies (magnetic resonance imaging [MRI] plus MR cholangiopancreatography with diffusion weighting and high-resolution endoscopic ultrasonography) (for details, see [8]). Suspect lesions were further investigated by these methods and also by endoscopic ultrasound-guided fine-needle aspiration cytology (FNAC) where appropriate (8, 9). If a suspect pancreatic lesion was identified in any of the imaging modalities, a multidisciplinary conference involving surgeons, radiologists, gastroenterologists, and pathologists was called to determine the next course of action – intensified surveillance, FNAC, or surgery. The presence of any of the following was an indication for surgery: solid lesion; cystic lesion >30 mm; cystic lesion <30 mm with a solid component; indeterminate lesion with indistinct margins; suspect FNAC; and, finally, the patient’s wish because of lesions of concern and/or a fear of cancer (8). Initially (2002–2016) screening began at the age of 40; since 2017 it has begun at the age of 50 or else 10 years before the youngest age at onset recorded in the family (8). The 5-year and 15-year results of the screening program have been published previously (8, 9).

The collection of data and clinical examination of families and the implementation of the prospective screening program were approved by the Ethics Board of the Philipps University of Marburg in 1999 (no. 36/97, last amended in September 2010).

Results

Over the past 20 years, 1150 potential FPC families have contacted the FaPaCa study office. So far, 227 families totaling 2579 individuals have met the strict inclusion criteria. A representative family is shown in the Figure. Of the individuals diagnosed with PDAC, 51.1% (283/554; 95% confidence interval: [46.8; 55.3]) were women. The median age at diagnosis of PDAC in the families was 64 years (range, 18–91 years), although 53 families (23.3% [18.0; 29.4]) had at least one person with an early age at onset (<50 years of age). In 163 families (72% [65.5; 77.6]) the mode of inheritance was autosomal dominant, as at least two consecutive generations were affected by PDAC. In 85 families (37% [31.1; 44.1]) PDAC was the only type of cancer, whereas in 142 families (63% [55.9; 68.9]) other types of cancer occurred, especially breast cancer (70 families, 31% [24.9; 37.3]), colon cancer (25 families, 11% [7.2; 15.8]), and melanoma (22 families, 9.7% [6.2; 14.3]; Table 2). There were 153 families with 2 family members with PDAC in, 54 families with 3, 15 families with 4, 4 families with 5, and 1 family with 6.

Figure

“Pure” FPC family with no identified germline mutation

Table 2

Cancer combinations in 227 FPC families with 2579 individual members (over three generations)

Mutation analysis of genes potentially predisposing to PDAC found pathogenic germline mutations in 25 of 150 families studied (16.6% [11.1; 23.6]) (Table 3). In descending order of frequency, the implicated genes were BRCA2 (9 families), CDKN2A (5 families), PALB2 (4 families), BRCA1 (3 families), CHEK2, and ATM (2 families each). Another 5 families showed previously unclassified gene variants of possible pathogenicity in the FANCM, POLQ, or SUFU genes. No mutations in the Palladin gene were found.

Table 3

Identified potentially deleterious germline mutations in families with familial pancreatic cancer

Between 2001 and 2019, 295 high-risk individuals (HRIs) with a median age of 55 years (range, 28–79 years) from 134 FPC families took part in the FaPaCa Registry prospective screening program, including 110 HRIs (37.3% [31.7; 43.1]) with an observation period of at least 5 years or 1008 observation-years and 28 germline mutation carriers (9.5% [6.4; 13.4]) (Table 4). A total of 182 HRIs (62% [55.9; 67.3]) had small (<10 mm) cystic pancreatic lesions on imaging that were consistent with branch duct intraductal papillary mucinous neoplasm (BD-IPMN). Five additional HRIs (1.7% [0.6; 3.9]) had pancreatic lesions that were solid or could not be definitely classified. So far, based on the imaging diagnosis and after detailed consultation, 16 HRIs have undergone pancreatic resection: in 7 cases total pancreatectomy and in 9 cases partial pancreatic resection. There were no postoperative deaths; clinically significant complications occurred in 5 of the 16 HRIs (31% [11.0; 58.7]). Histolopathogic workup of the resected pancreatic specimens revealed pancreatic ductal adenocarcinoma (UICC stages II and III [UICC, Union Internationale Contre le Cancer], Table 4) in 2 HRIs and pancreatic intraepithelial neoplasia with high-grade dysplasia (PanIN3, corresponding to a carcinoma in situ) in 3 HRIs. Six other HRIs had potentially concerning precancerous lesions with multifocal PanIN2 or intraductal papillary mucinous neoplasms (IPMN) with dysplasia, with 5 HRIs having benign lesions not regarded as precancerous, such as serous cystadenoma (n = 3) or focal fibrosis (n = 2). This resulted in diagnostic yields in accordance with the very strict criteria of an international consensus conference (15) of 1.7% [0.6; 3.9] overall (PDAC/PanIN3 in 5/295 HRIs) and 4.5% (5/110 HRIs [1.5; 10.3]) after an observation period of at least 5 years.

Table 4

Results of the FaPaCa screening program

Discussion

The FaPaCa registry provides the necessary infrastructure for the registration and clinical genetic analysis of FPC families at a national level. It also fulfills the requirement of international guidelines that screening examinations of high-risk members of these families be performed at a center of expertise as part of a screening program reviewed and controlled by an ethics committee (15). Registries of this nature with associated screening programs have become increasingly well established over the past 10 years in the United States, Japan, the United Kingdom, Italy, the Netherlands, and Sweden (5, 6, 14, 16, 17). The workup of the FPC families, who are very rare, is paradigmatic of other rare hereditary cancer syndromes, such as multiple endocrine neoplasia (MEN, types 1 and 2): important knowledge is gained not just regarding diagnosis and management in these families, but also about the sporadic types of the respective cancers. In recent years, the FPC registries have played an important part in the description of the phenotype and genotype of FPC families, which is very useful in the counseling and management of these families. Insights have also been derived for sporadic PDAC – for example that small branch-duct IPMN, which are potential precursors of PDAC, can remain stable for years and rarely require surgery.

The observed phenotype of the families in the FaPaCa registry supports the hypothesis that in familial pancreatic cancer, the families can basically be divided into 2 groups: “pure” FPC families (37%) and those in which other types of cancer also occur (63%). The three most common associated cancers are breast cancer (30.8%), colorectal cancer (11%), and melanoma (9.7%). Thus, the phenotype of these FPC families is very heterogeneous. The age at onset did not differ significantly between families; an early age at onset (before 50 years of age) was seen in 23% of families [18.0; 29.4]. The phenotypes of FPC families cannot be clearly assigned to specific genotypes (for example, BRCA1/2 mutation only in families with breast and/ or ovarian cancer), as pure FPC families may also have a BRCA2 mutation. An autosomal dominant inheritance pattern is seen in 72% of families [65.5; 77.6]. This is slightly higher than the 58% seen in the families of the European EUROPAC registry [18]; the difference is most likely due to the much stricter inclusion criteria of the FaPaCa registry. However, the possibility cannot actually be ruled out that the familial clustering of PDAC, alone or in combination with the more frequent breast and/or colon carcinoma, is just a coincidence, especially when no predisposing germline mutation is detected.

The FaPaCa registry has enabled numerous genetic analyses to be carried out in a total of 150 FPC families. In 16.7% of FPC families [11.1; 23.6], a pathogenic germline mutation predisposing to PDAC was detected in the predisposition gene BRCA1/2, CDKN2A, PALB2, CHEK2, or ATM. The most frequently found was a BRCA2 mutation, which at 6% [2,8; 11,1] was found twice as often as in investigated patients with presumed sporadic PDAC (19). In the FaPaCa registry the proportion of FPC families shown to carry a mutation is comparatively high, which is likely related in part to the registry’s strict inclusion criteria. In a US study (20), for example, 8% (41/512) of FPC subjects were identified as having a germline mutation in BRCA1/2, PALB2, or CDKN2A, compared with 14% (21/150) in the FaPaCa registry. Another US study, during genome sequencing of FPC patients without a previously identified mutation, found germline mutations in the predisposition genes ATM, BRCA2, CDKN2A, and PALB2 in 9.8%, but also found potentially pathogenic variants in BUB1B, CPA1, FANCC and FANCG, POLQ, and SUFU in some other families (21). Variants of previously undetermined pathogenicity in FANCM, POLQ, or SUFU were also identified in 5 families in the FaPaCa registry. The above studies demonstrate that FPC is a genetically very heterogeneous familial cancer syndrome that lacks a single principal genetic defect. Individual affected members of FPC families may even carry germline mutations in 2 or more genes (for example, BRCA2, FANCM, and BLM) (21).

According to an international consensus conference, HRIs from FPC families should be offered a screening program for the diagnosis of early PDAC or its high-grade precursor lesions (intraductal papillary mucinous neoplasm [IPMN], pancreatic intraepithelial neoplasia types 2 and 3 [PanIN3]) (15). Detection and treatment of stage I PDAC, PanIN3 lesions, and IPMN with high-grade dysplasia are considered to represent diagnostic success of a screening program (15). All first-degree relatives of a person with PDAC from an FPC family, and all carriers of a predisposing germline mutation (for example, BRCA2) from an FPC family, are considered as HRIs (7, 15), since they have at least a 5– to 10-fold increased risk of developing PDAC. In most centers, the screening program is based on MRI and endoscopic ultrasonography of the pancreas (7, 8, 17). In the screening program of the FaPaCa registry, 182 of 295 HRIs (62% [55.9; 67.3]) had small cystic pancreatic lesions (mostly <10 mm) on imaging, which is comparable to observations from other large screening programs (22). Only 16 (5.4%) of the 295 HRIs have undergone surgery to date. This is a significantly lower surgery rate than the recently reported rates of 15.5% among 1660 HRIs in a meta-analysis of 19 prospective cohort studies from the United States, Germany, Italy, Israel, and Sweden (23), and of 13.6% in a US study (24). This is likely due to a very conservative approach to decisions for surgery in the FaPaCa registry. PDAC or carcinoma in situ (PanIN3) was found in 5 (31%) of the 16 HRIs in the FaPaCa registry who underwent surgery, corresponding to an overall diagnostic yield of 4.5% [1.5; 10.3] after an observation period of at least 5 years. This diagnostic yield is comparable to the 7% reported in a US study with an observation period of 16 years (22), and higher than the RR of 0.74 [0.33; 1.14] recently reported in the above-mentioned meta-analysis (23). However, it must also be noted that in both the FaPaCa registry and other screening programs (23, 25), up to 68% unnecessary pancreatic resections were performed, where histologic analysis detected neither PDAC nor high-grade precancerous lesions. For this reason, according to the recommendations of a consensus conference, these screening programs should only be carried out at centers of interdisciplinary expertise (15).

Initial studies now suggest that in HRIs with screening-detected PDAC, compared with HRIs with symptomatic PDAC diagnosed outside of a screening program, both resection rates and 5-year survival rates are significantly higher (respectively 75%–90% versus 15%–25% and 24%–60% versus 7%–25%) (17, 22). Ultimately, further prospective studies with long-term follow-up are needed to establish whether screening HRIs for PDAC actually reduces PDAC-related mortality and is cost-effective.

Many years of research into FPC have shown that there are basically two types of FPC family: “pure” FPC families and those in which there is an association with other types of cancer. A principal genetic defect is not yet known; however, predisposing germline mutations are found in approximately 15% of all FPC families, primarily in the ATM, BRCA2, and CDKN2A genes. Recent developments in sequencing techniques, such as multigene panel testing and “next-generation” sequencing, are likely in future to reveal more genes predisposing to PDAC, potentially making counseling and management of FPC families more complex. Screening programs allow detection of precancerous and asymptomatic PDAC, and this appears to reduce PDAC-related mortality. However, the cost-effectiveness of PDAC screening remains to be determined. Because of the complexity that has been mentioned, FPC families should be managed in centers of expertise.

Acknowledgments
We thank all the FPC families for their participation in the FaPaCa registry. We thank Prof. Johannes Schumacher and Dr. Karsten Haug of the Institute of Human Genetics, Marburg, for consultation on genetics. We gratefully acknowledge the support of the German Cancer Aid and the Gauff Foundation.

Conflict of interest
Dr. Slater was responsible for third-party funding from German Cancer Aid for conducting studies..

Prof. Bartsch was responsible for third-party funding from the German Cancer Aid, the Sander Foundation, and the Gauff Foundation for the conducting studies.

The other authors declare that they have no conflict of interest.

Submitted: 24 April 2020, revised version adopted: 28 September 2020

Translated from the original German by Kersti Wagstaff.

Corresponding author:
Prof. Dr. med. Detlef K. Bartsch
Klinik für Visceral-, Thorax- und Gefäßchirurgie
Philipps-Universität Marburg
Baldingerstr., 35043 Marburg, Germany

Cite this as:
Bartsch DK, Matthäi E, Mintziras I, Bauer C, Figiel J, Sina-Boemers M, Gress TM, Langer P, Slater EP: The German National Case Collection for Familial Pancreatic Carcinoma (FaPaCa)—knowledge gained in 20 years.
Dtsch Arztebl Int 2021; 118: 163–8. DOI:10.3238/arztebl.m2021.0004

References

1. Quante A, Ming C, Rottmann M, et al.: Projections of cancer incidence and cancer-related deaths in Germany by 2020 and 2030. Cancer Med 2016; 5: 2649–56

2. Bartsch DK, Kress R, Sina-Frey M, et al.: Prevalence of familial pancreatic cancer in Germany. Int J Cancer 2004; 110: 902–6

3. Hemminki K, Li X: Familial and second primary pancreatic cancers: a nationwide epidemiologic study from Sweden. Int J Cancer 2003; 103: 525–30

4. Bartsch DK, Gress TM, Langer P: Familial pancreatic cancer—current knowledge. Nat Rev Gastroenterol Hepatol 2012; 9: 445–53

5. Tersmette AC, Petersen GM, Offerhaus GJ, et al.: Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res 2001; 7: 738–44.

6. Lynch HT, Brand RE, Deters CA, Shaw TG, Lynch JF: Hereditary pancreatic cancer. Pancreatology 2001; 1: 466–71

7. Canto MI, Harinck F, Hruban RH, et al.: International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013; 62: 339–47

8. Bartsch DK, Slater EP, Carrato A, et al.: Refinement of screening for familial pancreatic cancer. Gut 2016; 65: 1314–21

9. Langer P, Kann PH, Fendrich V, et al.: Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer. Gut 2009; 58: 1410–8

10. Bartsch DK, Sina-Frey M, Ziegler A, et al.: Update of familial pancreatic cancer in Germany. Pancreatology 2001; 1: 510–6

11. Hahn SA, Greenhalf B, Ellis I, et al.: BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 2003; 95: 214–21

12. Bartsch DK, Sina-Frey M, Lang S, et al.: CDKN2A germline mutations in familial pancreatic cancer. Ann Surg 2002; 236: 730–7

13. Slater EP, Langer P, Niemczyk E, et al.: PALB2 mutations in European familial pancreatic cancer families. Clin Genet 2010; 78: 490–4

14. Schneider R, Slater EP, Sina M, et al.: German national case collection for familial pancreatic cancer (FaPaCa)—ten years experience. Fam Cancer 2011; 10: 323–30

15. Goggins M, Overbeek KA, Brand R, et al.: Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut 2020; 69: 7–17

16. Applebaum SE, Kant JA, Whitcomb DC, Ellis IH: Genetic testing. Counseling, laboratory, and regulatory issues and the EUROPAC protocol for ethical research in multicenter studies of inherited pancreatic diseases. Med Clin North Am 2000; 84: 575–88

17. Vasen H, Ibrahim I, Ponce CG, et al.: Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers. J Clin Oncol 2016; 34: 2010–9

18. Greenhalf W, Malats N, Nilsson M, Bartsch D, Neoptolemos J: International registries of families at high risk of pancreatic cancer. Pancreatology 2008; 8: 558–65

19. Grant RC, Denroche RE, Borgida A, et al.: Exome-wide association study of pancreatic cancer risk. Gastroenterology 2018; 154: 719–22

20. Zhen DB, Rabe KB, Gallinger S, et al.: BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer (FPC): a PACGENE Study. Genet Med 2015; 17: 569–77

21. Roberts NJ, Norris AL, Petersen GM, et al.: Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov 2016; 6: 166–75

22. Canto MI, Almario JA, Schulick RD, et al.: Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology 2018; 155: 740–51

23. Corral JE, Mareth KF, Riegert-Johnson DL, Das A, Wallace MB: Diagnostic yield from screening asymptomatic individuals at high risk for pancreatic cancer: a meta-analysis of cohort studies. Clin Gastroenterol Hepatol 2019; 17: 41–53

24. Canto MI, Kerdsirichairat T, Yeo CJ, et al.: Surgical outcomes after pancreatic resection of screening-detected lesions in individuals at high risk for developing pancreatic cancer. J Gastrointest Surg 2020; 24: 1101–10

25. Paiella S, Salvia R, De Pastena M, et al.: Screening/surveillance programs for pancreatic cancer in familial high-risk individuals: a systematic review and proportion meta-analysis of screening results. Pancreatology 2018; 18: 420–8

26. Gospodarowicz MK, Brierley JD: TNM classification of malignant tumours; Wiley-Blackwell: Oxford, UK 2017.

27. Slater EP, Langer P, Fendrich V, et al.: Prevalence of BRCA2 and CDKN2a mutations in German familial pancreatic cancer families. Fam Cancer 2010; 9: 335–43

28. Slater E, Amrillaeva V, Fendrich V, et al.: Palladin mutation causes familial pancreatic cancer: absence in European families. PLoS Med 2007; 3: e516

29. Bartsch DK, Krysewski K, Sina-Frey M, et al.: Low frequency of CHEK2 mutations in familial pancreatic cancer. Fam Cancer 2006; 54: 305–8