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Pancreatic Cancer: Epidemiology, Genetics, and Approaches to Screening

Pancreatic Cancer: Epidemiology, Genetics, and Approaches to Screening


The review by Drs. Konner and O’Reilly addresses a number of important issues in pancreatic cancer. Adenocarcinoma of the pancreas is a devastating disease,[1] not only because it will occur in approximately 30,000 Americans this year, and perhaps 200,000 people worldwide, but also because of its high associated mortality. Pancreatic adenocarcinoma is one of the least treatable and, therefore, most lethal of all cancers. Fully 95% of all patients with an established diagnosis of adenocarcinoma of the pancreas will die of their disease.

In addressing a disease as lethal as pancreatic cancer, one would think that a review written in 2002 would emphasize treatment strategies. However, the review by Konner and O’Reilly does not discuss treatment. This lack of an analysis of therapeutic options is not an omission, but rather, an admission of the fact that all current treatment strategies are poor and result in significant benefit in only a small number of patients.

Given that for clinicians and clinical investigators, pancreatic adenocarcinoma is a serious and therapeutically frustrating disease, one could well ask what aspects of pancreatic cancer the oncologic community should be interested in at the present time. The answer, strongly implied by the work of Konner and O’Reilly, is that understanding the epidemiology, molecular genetics, prevention, and screening issues of pancreatic cancer is currently more important than reviewing treatment effects. I fully concur with this conclusion.

It is reasonable to hope—and one must have hope in oncology—that treatment will improve in the future and that we will see articles written about effective treatments in the years to come. For now, increasing our understanding of causation and molecular carcinogenesis may lead to clinical strategies capable of either preventing or effectively screening for the disease so that the cancer and/or precancer could be detected at an early stage, when treatment might be effective.

The K-ras Mutation Connection

Rapidly developing knowledge about molecular genetics and molecular carcinogenesis of pancreatic cancer raises many interesting points. Knowledge of the molecular changes leading to carcinoma of the pancreas has increased greatly over the past 10 to 15 years. The disease is associated with a high frequency of mutations in the K-ras proto-oncogene,[2] which codes for a guanosine triphosphate (GTP)-dependent signal transduction mediator for receptor tyrosine kinases. In roughly 90% of pancreatic adenocarcinomas, this gene is mutated. Mutations have also been detected in premalignant conditions such as pancreatic ductal hyperplasia.

Of interest, 80% to 90% of mutations in the K-ras gene are located in codon 12. This finding is in contradistinction to K-ras mutations in other malignancies, in which many different codons are affected. The high incidence of K-ras mutations, the fact that these mutations occur with high frequency in one codon, and the finding that mutant K-ras can be demonstrated in premalignant conditions[3] obviously tell us something important about carcinogenesis in the pancreas. The challenge in the future is to use our knowledge of the apparent centrality of K-ras mutation in pancreatic carcinogenesis to develop strategies for clinical intervention.


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