Familial pancreatic carcinoma

Familial pancreatic cancer (FPC or FaPaCa) is defined as the occurrence of pancreatic cancer in at least two first-degree relatives within a family, but in whom family history and clinical criteria for another hereditary syndrome are not present (Seufferlein 2021). However, if these criteria are present, it is a hereditary pancreatic cancer syndrome (Ganten 2013).

In 85-90% of cases, pancreatic carcinomas are ductal adenocarcinomas. Some of these adenocarcinomas show a familial clustering. A distinction is made among affected families between:

- Familial pancreatic carcinoma (without criteria of another hereditary syndrome)

- Hereditary pancreatic cancer syndrome (with criteria of another hereditary syndrome [Ganten 2013]).

FPC does not follow a specific Mendelian inheritance pattern (Rahmann 2019). Brückner (2021) describes the mode of inheritance as predominantly autosomal dominant with variable penetrance (Werner 2020).

In hereditary pancreatic cancer syndrome, defined as the occurrence of pancreatic cancer due to hereditary genetic predisposition syndromes and the most important differential diagnosis of FPC, Bartsch (2021) found autosomal dominant inheritance in up to 72% of affected families.

Compared to the more common sporadic pancreatic ductal carcinoma, FPC is a rare tumor syndrome (Bartsch 2021). Only about 1 - 3% of all pancreatic tumors fulfill the criteria of an FPC (Kaiser 2020).

FPC is clustered in Jews, significantly more common in Ashkenazi than in Caucasian Jews (Lynch 2004).

Until the late 1990s, equal numbers of men and women developed and died from FPC. Since then, both the rate of disease and death have increased in women (Brückner 2021).

The risk of developing FPC is increased up to 18-fold for 2 ill persons within a family, and 57-fold for 3 or more family members (Seufferlein 2021).

FPC is found in up to 16% (Kasper 2015) similar to other hereditary tumor diseases (Seufferlein 2021).

It has been shown in a prospective study that approximately 1 - 3% of all patients with pancreatic cancer fulfill the criteria of FPC (Seufferlein 2021). In patients with pancreatic ductal adenocarcinoma (PDAC), approximately 5% have FPC (Mintziras 2019).

The median age of onset is approximately 62 years. Thus, it is not significantly different from patients with sporadic tumors. However, it has been shown that children of FPC- patients show anticipation in up to 71% (Humphris 2014) and they may develop the disease up to 10 years earlier (Seufferlein 2021).

So far, a genetic cause for FPC could not be clearly identified (Brückner 2021). A specific genetic defect has been identified in only about 10% of cases (Kaiser 2020).

Affected may be the gene:

- PALB2 in 2.8 % (Herold 2022 / Bartsch 2021).

In cases of FPC, the following environmental factors have been found:

- Tobacco smoke

- asbestos

- Radon (Matsubayashi 2017).

Risks for the occurrence of FPC are:

- smoking

- recent onset of diabetes mellitus

- obesity

- chronic pancreatitis

- dilated main pancreatic duct

- pancreatic cyst

- intraductal papillary mucinous neoplasm (Matsubayashi 2017).

There are other germline mutations associated with a significantly increased risk of hereditary pancreatic cancer syndrome:

- ATM gene in 5.5 %

- BRCA1 gene in 2

- BRCA 2 gene in 6

- CDKN2A gene in 3,3 %

- CHEK2 gene in 5,4 %

- PALB2 gene in 2,8 % (Bartsch 2021)

- PRSS1 gene (serine protease 1) (Kasper 2015)

Most pancreatic cancers develop from microscopic ductal lesions called pancreatic intraepithelial neoplasia (PanIN). A smaller proportion arise from cystic lesions. The time it takes for precursor lesions to develop into the actual disease is estimated to be between 10-20 years (Humphris 2014).

Patients with FPC are significantly more likely (44.1%) to have at least one 1st-degree family member with an extrapancreatic malignancy (Humphris 2014).

In the diagnosis of FPC, endosonography or MRI represent the standard procedures (Hübner 2018) .

FPC tumors cannot be histologically distinguished from sporadic tumors (Seufferlein 2021).

In the majority of FPC, a ductal adenocarcinoma (PDAC) is found histologically.

- Hereditary pancreatic cancer syndrome

This is defined as the occurrence of pancreatic cancer due to hereditary genetic predisposition syndromes. (Kasuga 2022). These include, according to Kasper 2015:

- STK11 gene(Peutz- Jeghers syndrome).

- BRCA2 (increased risk for familial breast, ovarian and pancreatic cancer)

- p16 / CDKN2A in familial atypical multiple melanoma syndrome

- PALB2 (increased risk of breast and pancreatic cancer)

- hMLH1 and MSH2 (Lynch syndrome)

- ATM(ataxia telangiectasia)

- Chemotherapy:

The vast majority of FPCs are already unresectable at diagnosis. In this case, chemotherapy according to the FOLFIRINOX- regimen or gemcitabine-based regimens is recommended (Matsubayashi 2017).

- Radiatio:

Three randomized trials compared the efficacy of radiochemotherapy. The results of these trials were inconsistent (Seufferlein 2021).

Palliative radiotherapy is recommended for symptomatic metastases (Seufferlein 2021).

Surgical therapy in the form of pancreatectomy is the only potentially curative form of treatment (Seufferlein 2021).

However, most cases of FPC patients already show an advanced tumor stage or metastases at the time of diagnosis, so that surgical resection is no longer possible (Humphris 2014).

Pancreatic cancer is a leading cause of cancer-related deaths worldwide. Even today, despite advances in therapy, the 5-year survival rate is less than 10% (Kasuga 2022).

Of those patients in whom surgical resection of the tumor is still possible, approximately 80% still die from the disease, with a median survival of <2 years (Humphris 2014). Egawa (2012), on the other hand, describes that the 5-year survival rate can increase to 80.4 - 85.8%, provided the tumor size is ≤ 10 mm and appropriate therapy is given.

It is believed that pancreatic ductal adenocarcinoma will be the second leading cause of all cancer-related deaths in Germany by approximately 2030 (Bartsch 2021).

Because the management of FPC families is complex, monitoring at an expert center is recommended (Bartsch 2021).

Genetic testing is recommended for the following family members without manifest or symptomatic disease:

- Recommendation grade A:

- Family members with a known pathogenic gene variant predisposing to pancreatic cancer.

- Members who come from families that meet the criteria for genetic testing for previously known hereditary syndromes associated with pancreatic cancer

- Members of a family with a history of sporadic pancreatic cancer who are at increased risk. Increased risk is defined as:

- When pancreatic cancer has occurred in two blood relatives who are first-degree relatives and at least one of whom is first-degree related to the individual being evaluated.

- When two or more blood relatives on the same side of the family have developed pancreatic cancer, one of whom is first-degree related to the individual being evaluated (Seufferlein 2021).

Screening examinations should be performed from the age of 50 years or 10 years before the onset of disease in the youngest family member and should consist of endosonography or MRI / MRCP examination (Seufferlein 2021).

In 1999, the FaPaCa- Registry was established as a national case collection for FPA. In the meantime, about 1,150 FPC- families have reported to the secretariat of the registry (Bartsch 2021). The aim of the FaPaCa- Registry is to identify high-risk patients and to detect the genetic causes (Brückner 2021).

Genetic counseling is recommended for all patients, as for other hereditary diseases. However, no predictive genetic diagnostics, because so far a specific genetic defect could be detected in only about 10% of families affected by FPC (Seufferlein 2021).

Individuals at increased risk for FPC should be monitored regularly, as it has been shown that PFC is detected at a very early stage in these patients and often long-term survival may be possible (Saba 2022). However, the screening capabilities are not specific enough so far. Today, about half of the affected patients are still overlooked during screening (Sirtl 2022).

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