Familial Pancreatic Cancer: Current Perspectives

Abstract

Pancreatic cancer (PC) is a highly lethal disease, mostly incurable when detected. Thus, despite advances in PC treatments, only around 7% of patients survive 5-years after diagnosis. This morbid outcome is secondary to multifactorial reasons, such as late-stage diagnosis, rapid progression and minimal response to chemotherapy. Based on these factors, it is of special relevance to identify PC high-risk individuals in order to establish preventive and early detection measures. Although most PC are sporadic, approximately 10% cases have a familial basis. No main causative gene of PC has been identified but several known germline pathogenic mutations are related with an increased risk of this tumor. These inherited cancer syndromes represent 3% of all PC. On the other hand, in 7% of cases of PC, there is a strong family history without a causative germline mutation, a situation known as familial pancreatic cancer (FPC). In recent years, there is increasing evidence supporting the benefit of genetic germline analysis in PC patients, and periodic pancreatic screening in PC high-risk patients (mainly those with a lifetime risk greater than 5%), although there is no general agreement in the group of patients and individuals to study and screen. In the present review, we expose an update in the field of hereditary and FPC, with the aim of describing the current strategies and implications in genetic counseling, surveillance and therapeutic interventions.

Keywords: familial; hereditary; mutation; pancreatic cancer; personalized medicine; screening.

Figure 1

Diagnosis flow-chart of hereditary/familial pancreatic cancer. Conventional approach to rule out a hereditary PC (left part of the figure) is based on the fulfillment of clinical criteria for known hereditary conditions. New proposal suggests performing germline genetic testing in all PC cases or, at least, in early onset PC or if family meets criteria of FPC. PSJ, HP, FAMMM, HBOC, FAP, LS, LFS, AT, CF.BRCA1, BRCA2, PALB2, CDKN2A, ATM, TP53, MLH1, MSH2, MSH6, PMS2, STK11, as well as PRSS1/SPINK1 and CFTR if the clinical is suggestive of hereditary pancreatitis or cystic fibrosis, respectively. Clinical criteria of familiar pancreatic cancer (FPC): ≥2 first-degree relatives (FDRs). Abbreviations: PC, pancreatic cancer; PSJ, Peutz Jeghers syndrome; HP, hereditary pancreatitis; FAMMM, familial atypical multiple mole melanoma; HBOC, hereditary breast-ovarian cancer syndrome; FAP, familial polyposis syndrome; LS, Lynch syndrome; LFS, Li-Fraumeni syndrome; AT, Ataxia telangiectasia; CF, cystic fibrosis; FPC, familial pancreatic cancer.

Figure 2

Candidates for pancreatic cancer screening. *Evidence and consensus for screening in these mutation carriers is not solid. PC, pancreatic cancer; FPC, familial pancreatic cancer.

Figure 3

Classification of pancreatic cancer high-risk individuals and screening recommendation based upon CAPS5 study. The Cancer of the Pancreas Screening-5. Abbreviations: PC, pancreatic cancer; SDR, second degree relative.