Pancreatic Cancer: Why Consider Screening?

Pancreatic cancer remains one of the most deadly diseases, despite significant advances in medicine over the past decade. Pancreatic adenocarcinoma is the fourth leading cause of cancer deaths in the United States for both males and females, with an estimated 44,030 new cases and 37,660 deaths in 2011. In contrast to the death rates for other leading causes of cancer death (lung, colorectal, breast, and prostate), which have declined since 2003, the death rate from pancreatic adenocarcinoma has increased during the same time period. Unfortunately, the majority of symptomatic patients are incurable. The prognosis for patients with pancreatic adenocarcinoma remains poor: a 5-year relative survival rate of 6% for all stages combined, most likely because of the late stage of disease at the time of diagnosis. Hence, there has been a strong interest in detecting precursor lesions or small asymptomatic cancers that are potentially curable. A widespread screening program does not seem feasible or cost effective given the relatively low incidence of the disease, accounting for 3% of all new cancer cases in the United States, and the lack of accurate, inexpensive, and noninvasive diagnostic tests for early lesions. However, screening may be desirable in the selected population at increased risk for developing pancreatic adenocarcinoma.

Genetic Predisposition to Pancreatic Cancer

Although the great majority of pancreatic adenocarcinoma cases are thought to be sporadic in nature, up to 10% of cases can be attributed to genetic factors. In fact, familial clustering of pancreatic cancer was noted as early as 1967, when Lynch and colleagues reported on an adenocarcinoma-prone family. Familial pancreatic cancer (FPC) is characterized by two or more first-degree relatives (FDRs) with pancreatic adenocarcinoma in the absence of known cancer syndromes or other diseases with known genetic defect. Individuals from a family with a pair of affected FDRs have a higher risk (6.4-fold to 32-fold) of developing pancreatic cancer. Thus far, the key causative gene or genes leading to the inherited predisposition in familial pancreatic cancer have not yet been fully elucidated. Complex segregation analysis suggests that this predisposition may be due to a novel rare major gene with an autosomal dominant inheritance with reduced penetrance.

Initial linkage analysis suggested that the mutation of the palladin gene may be involved in the development of pancreatic cancer in a specific kindred. However, the initial excitement has been tempered by the failure of population-based studies in Canada and Europe to demonstrate that mutations in the palladin gene are more common in those with FPC as compared to controls. Further, a study evaluating the pattern of palladin protein expression in 177 cases of pancreatic adenocarcinoma determined that although the palladin protein is overexpressed in the stroma, it is not overexpressed in the neoplastic cells in pancreatic cancer.

To date, germline breast cancer 2 ( BRCA2 ) mutation appears to be the most common genetic abnormality in patients from FPC kindreds who develop pancreatic adenocarcinoma, but still have been reported in only 6% to 19% of all FPC kindreds. Mutations in the BRCA2 gene can be present even in the absence of breast or ovarian cancer, and in apparently sporadic pancreatic cancer. Recent studies have identified another associated inheritable gene mutation, partner and localizer for breast cancer 2 gene ( PALB2 ), as a pancreatic adenocarcinoma susceptibility gene, which may be causative for 3% to 4% of FPC. The PALB2 protein directly binds to the breast cancer 1 gene ( BRCA1 ) and acts as a bridge between BRCA1 and BRCA2 to form a complex involved in double-strand break repair. The PALB2 gene is present in 1% to 2% of patients with familial breast cancer. Subsequent testing of patients with a personal history of breast and pancreatic cancer and also of non- BRCA1 and non- BRCA2 breast cancer women with a personal or family history of pancreatic cancer has shown the PALB2 mutation to be a very uncommon mutation. The clinical utility of routine testing of FPC patients for PALB2 has not been proven.