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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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