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Defining determinants of pancreatic cancer risk: are we making progress?

Pancreatic cancer is the fourth leading cause of cancer-related mortality in the United States, and 80% – 85% of patients have incurable disease at the time of diagnosis. Furthermore, more than 95% of patients diagnosed with pancreatic cancer will ultimately die from the disease, highlighting the urgent need for novel insights into pancreatic tumorigenesis. Why has progress been so slow in defi ning predisposing factors for pancreatic cancer? First, its incidence rate is relatively low, when compared with other leading causes of cancer-related death, such as colorectal or breast cancer, so that fewer cases are available for study. Second, case – control studies have proved diffi cult. The rapid and nearly universal demise of patients with pancreatic cancer increases the susceptibility of retrospective studies to recall bias, selection bias, and exposure misclassifi cation, particularly when using proxy (ie, next of kin) respondents to collect eligibility and exposure data. In addition, studies in which plasma samples are collected at the time of diagnosis are diffi cult to interpret, due to the large alterations in patient nutritional and functional status caused by this malignancy. Third, although studies of families with high rates of pancreatic cancer have identifi ed several predisposing genetic variants, these variants are rare and contribute little to the overall population burden of pancreatic cancer. Fourth, no screening tests have been able to detect pancreatic cancer at an early, more treatable stage, leaving some to question whether risk factor identifi cation will impact patient outcomes, in the absence of a clear commitment to risk fac