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Pancreatic cancer is the fourth leading cause of cancer death in the United States and is associated with a poor prognosis. Endocrine tumors affecting the pancreas are discussed in Chap. 49. Infiltrating ductal adenocarcinomas, the subject of this chapter, account for the vast majority of cases and arise most frequently in the head of the pancreas. At the time of diagnosis, 85–90% of patients have inoperable or metastatic disease, which is reflected in the 5-year survival rate of only 5% for all stages combined. An improved 5-year survival of up to 20% may be achieved when the tumor is detected at an early stage and when complete surgical resection is accomplished.
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Pancreatic cancer represents 3% of all newly diagnosed malignancies in the United States. The most common age group at diagnosis is 60–79 years for both sexes. It was estimated that pancreatic cancer would be diagnosed in approximately 43,140 patients and account for 36,800 deaths in 2010. Over the past 30 years, 5-year survival rates have not improved substantially.
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Cigarette smoking may be the cause of up to 20–25% of all pancreatic cancers and is the most common environmental risk factor for this disease. Other risk factors are not well established due to inconsistent results from epidemiologic studies but include chronic pancreatitis and diabetes. It is difficult to evaluate whether these conditions are causally related or develop as a consequence of cancer. Alcohol does not appear to be a risk factor unless excess consumption gives rise to chronic pancreatitis.
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GENETIC CONSIDERATIONS
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Pancreatic cancer is associated with a number of well-defined molecular hallmarks. The most frequent genetic aberrations comprise KRAS mutations, mostly affecting codon 12, which are observed in 60–75% of pancreatic cancers. The tumor-suppressor genes p16, p53, and SMAD4 are frequently inactivated; the p16 gene locus on chromosome 9p21 is deleted in up to 95% of tumors, the p53 gene is inactivated by mutation or deleted in 50–70% of tumors, and the SMAD4 gene is deleted in 55% of pancreatic tumors. Furthermore, SMAD4 gene inactivation is associated with poorer survival in patients with surgically resected pancreatic adenocarcinoma. IGF-1R and focal adhesion kinase (FAK) interact to promote cell proliferation and survival, and their simultaneous inhibition synergistically inhibits pancreatic cell growth. Overexpression and/or aberrant activation of c-Src is frequently observed, which results in cell adhesion, enhanced migration, invasion, and cell proliferation. Survivin is overexpressed in more than 80% of pancreatic tumors, which results in resistance to apoptosis, and genomic sequencing has identified PALB2 as a susceptibility gene for pancreatic cancer.
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Up to 16% of pancreatic cancers are thought to be inherited. This occurs in three separate clinical settings: (1) familial multiorgan cancer syndromes; (2) genetically driven chronic diseases; and (3) familial pancreatic cancer with as yet unidentified genetic abnormalities, ...