ETIOLOGIC FACTORS

Recent investigations have identified a number of factors that may contribute to the pathogenesis of pancreatic cancer. These factors can be organized into general areas of risk that include environmental factors, associated medical or surgical factors, heritable genetic factors (familial pancreatic cancer), and occupational exposures.

ENVIRONMENTAL FACTORS

A number of important environmental risk factors have been investigated for their role in the etiology of pancreatic cancer.

Cigarette Smoking.

Cigarette smoking is the most firmly established risk factor associated with pancreatic cancer. Pancreatic malignancies can be induced in animals through long-term administration of tobacco-specific N-nitrosamines or by parenteral administration of other N-nitroso compounds. These carcinogens are metabolized to electrophiles that readily react with DNA, leading to miscoding and activation of specific oncogenes such as K- ras. Induction of pancreatic cancer in these systems can be modulated by additional factors, including changes in bile acid composition, cholecystokinin (CCK) levels, and diet.

At the clinical level, numerous case-control and cohort studies have reported an increased risk of pancreatic cancer for smokers in both the United States and Europe, and current estimates suggest that approximately 30% of pancreatic cancer cases are due to cigarette smoking. Recent studies that have explored the dose-response relationship have shown that the risk of pancreatic cancer increases as the amount and duration of smoking increase and that long-term smoking cessation (more than 10 years) reduces risk by approximately 30% relative to the risk of current smokers. Application of molecular epidemiologic techniques that are being developed for lung cancer may provide greater specificity in linking tobacco exposure with the development of pancreatic cancer and may facilitate the study of chemopreventive strategies.

Dietary Factors

Over the past 10 years, numerous dietary factors have been implicated in pancreatic cancer development. Generally, high intakes of fat or meat increase risk, and diets high in fruits and vegetables reduce risk. When the available studies are analyzed in greater detail, the associations between dietary intake and pancreatic cancer become more complex. For example, high fat intake, usually in the form of high meat intake, increases risk. However, a recent study has suggested that the effect may vary by source of fat and by patient population. Investigators found that large amounts of fat from any source increase the risk of pancreatic cancer in men but that only fat from nonmeat or nondairy sources increases the risk in women. Other studies have reported an increased risk of pancreatic cancer with high total energy intake, high total cholesterol intake, or high ingestion of carbohydrates. These clinical observations are supported by laboratory studies in animal models in which high-fat and high-cholesterol diets have been shown to promote pancreatic carcinogenesis.

Decreased rates for pancreatic cancer have been associated with high consumption of vegetables, citrus fruits, fiber, and vitamin C. The association of diets high in citrus with a reduced risk of pancreatic cancer is particularly interesting given the recent observation that limonene, a natural product found in citrus fruits, is a potent inhibitor of the K- ras oncoprotein.

Data regarding the effect of coffee consumption and excessive alcohol consumption appear conflicting. For each of these factors, a few studies have suggested an increased risk of pancreatic cancer (coffee, alcohol), but most studies conducted over the past 10 years have failed to consistently demonstrate such a risk (coffee, alcohol). In some cases, significant methodologic problems may have confounded interpretation of the data, leading to erroneous conclusions.