Pancreatic Cancer by Manuel Hidalgo, M.D. - Spain -

Volume 362:1605-1617 April 29, 2010 Number 17
Pancreatic Cancer
Manuel Hidalgo, M.D.

Deaths from pancreatic ductal adenocarcinoma, also known as pancreatic cancer, rank fourth among cancer-related deaths in the United States. In 2008, the estimated incidence of pancreatic cancer in the United States was 37,700 cases, and an estimated 34,300 patients died from the disease.1 Pancreatic cancer is more common in elderly persons than in younger persons, and less than 20% of patients present with localized, potentially curable tumors. The overall 5-year survival rate among patients with pancreatic cancer is <5%.1,2

The causes of pancreatic cancer remain unknown. Several environmental factors have been implicated, but evidence of a causative role exists only for tobacco use. Smokers have a 2.5 to 3.6% increase in the risk of pancreatic cancer, as compared with nonsmokers; the risk increases with greater tobacco use and longer exposure to smoke.3 Data are limited on the possible roles of moderate intake of alcohol, intake of coffee, and use of aspirin as contributing factors. Some studies have shown an increased incidence of pancreatic cancer among patients with a history of diabetes or chronic pancreatitis, and there is also evidence, although less conclusive, that chronic cirrhosis, a high-fat, high-cholesterol diet, and previous cholecystectomy are associated with an increased incidence.4,5,6,7 More recently, an increased risk has been observed among patients with blood type A, B, or AB as compared with blood type O.8

Approximately 5 to 10% of patients with pancreatic cancer have a family history of the disease.9 In some patients, pancreatic cancer develops as part of a well-defined cancer-predisposing syndrome for which germ-line genetic alterations are known (see Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). In addition, in some families with an increased risk of pancreatic cancer, a genetic rather than an environmental cause is suspected. The risk of pancreatic cancer is 57 times as high in families with four or more affected members as in families with no affected members.10 The genetic bases for these associations are not known, although a subgroup of such high-risk kindred carry germ-line mutations of DNA repair genes such as BRCA2 and the partner and localizer of BRCA2 (PALB2).11,12,13

In recent years, there have been important advances in the understanding of the molecular biology of pancreatic cancer as well as in diagnosis, staging, and treatment in patients with early-stage tumors. Minimal progress has been made, however, in prevention, early diagnosis, and treatment in patients with advanced disease. This review summarizes recent progress in the understanding and management of pancreatic cancer.

The Biology of Pancreatic Cancer

Data suggest that pancreatic cancer results from the successive accumulation of gene mutations.14 The cancer originates in the ductal epithelium and evolves from premalignant lesions to fully invasive cancer. The lesion called pancreatic intraepithelial neoplasia is the best-characterized histologic precursor of pancreatic cancer.15 The progression from minimally dysplastic epithelium (pancreatic intraepithelial neoplasia grades 1A and 1B) to more severe dysplasia (pancreatic intraepithelial neoplasia grades 2 and 3) and finally to invasive carcinoma is paralleled by the successive accumulation of mutations that include activation of the KRAS2 oncogene, inactivation of the tumor-suppressor gene CDKN2A (which encodes the inhibitor of cyclin-dependent kinase 4 [INK4A]), and, last, inactivation of the tumor-suppressor genes TP53 and deleted in pancreatic cancer 4 (DPC4, also known as the SMAD family member 4 gene [SMAD4]).16 This sequence of events in pancreatic carcinogenesis is supported by studies in genetically engineered mouse models in which targeted activation of Kras2 with concomitant inactivation of Trp53 or Cdkn2A/Ink4A results in the development of pancreatic cancer that is identical to the cognate human disease.17,18,19 Other premalignant lesions of the pancreas, which are less well characterized, include intrapancreatic mucinous neoplasia and mucinous cystic neoplasia.20

Almost all patients with fully established pancreatic cancer carry one or more of four genetic defects.21 Ninety percent of tumors have activating mutations in the KRAS2 oncogene. Transcription of the mutant KRAS gene produces an abnormal Ras protein that is "locked" in its activated form, resulting in aberrant activation of proliferative and survival signaling pathways. Likewise, 95% of tumors have inactivation of the CDKN2A gene, with the resultant loss of the p16 protein (a regulator of the G1–S transition of the cell cycle) and a corresponding increase in cell proliferation. TP53 is abnormal in 50 to 75% of tumors, permitting cells to bypass DNA damage control checkpoints and apoptotic signals and contributing to genomic instability. DPC4 is lost in approximately 50% of pancreatic cancers, resulting in aberrant signaling by the transforming growth factor β (TGF-β) cell-surface receptor. A recent comprehensive genetic analysis of 24 pancreatic cancers showed that the genetic basis of pancreatic cancer is extremely complex and heterogeneous.11 In that study, an average of 63 genetic abnormalities per tumor, mainly point mutations, were classified as likely to be relevant. These abnormalities can be organized in 12 functional cancer-relevant pathways (Figure 1). However, not all tumors have alterations in all pathways, and the key mutations in each pathway appear to differ from one tumor to another.

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