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Genetic test can show whether drugs to treat colon cancer will work

Quebec David Spurgeon

A new study indicates that a simple genetic test can determine whether chemotherapy will be effective in treating colon cancer, the fourth commonest cancer in developed countries and the second leading cause of death from cancer in North America.

The study, led by doctors and researchers from Princess Margaret Hospital and Mount Sinai Hospital, Toronto, and involving other researchers in the United States and France, showed that patients with a mutation in their tumours did not benefit from chemotherapy, which can cause major unpleasant side effects (N Engl J Med 2003;349:247-57).

The mutation is called high frequency microsatellite instability. Microsatellites are stretches of DNA in which a short motif, usually one to five nucleotides long, is repeated several times. Microsatellite instability occurs when a germ line microsatellite allele has gained or lost repeated units.

The study’s lead author, Dr Steven Gallinger, a surgical oncologist at the Mount Sinai Hospital and University health network and a professor of surgery at the University of Toronto, said, "This study shows that the usual type of chemotherapy is effective for about 83% of colon cancer patients. Yet for nearly 17% of colon cancer patients the traditional chemotherapy treatment is not helpful and may even be harmful."

To conduct the investigation, tumour specimens were collected from patients with colon cancer who were enrolled in randomised trials of flourouracil based adjuvant chemotherapy.

The benefit of treatment differed significantly according to the microsatellite-instability status (P=0.01). Adjuvant chemotherapy improved overall survival among patients with microsatellite-stable tumours or tumours exhibiting low-frequency microsatellite instability, according to a multivariate analysis adjusted for stage and grade (hazard ratio for death, 0.72 [95 percent confidence interval, 0.53 to 0.99]; P=0.04). By contrast, there was no benefit of adjuvant chemotherapy in the group with high-frequency microsatellite instability.

Dr Malcolm Moore, a medical oncologist at Princess Margaret Hospital, said, "Undergoing chemotherapy is not an easy decision. Side effects can include sore throat and mouth, tiredness, increased risk of infection, and, in a small number of cases . . . serious life threatening illness. If we can select the patients most likely to benefit from therapy, we can restrict therapy to that population and spare the remaining patients the trauma of that type of treatment."

However, their report does not advocate altering clinical decision making on the basis of their findings: "If confirmed by other analyses of previous, well-designed clinical trials or by future prospective, randomised, controlled studies . . . our findings would indicate that microsatellite-instability testing should be conducted routinely and the results used to direct rational adjuvant chemotherapy in colon cancer."

An accompanying article (2003;349:209-210) says that testing for the mutation is straightforward: "DNA from the tumor and from normal tissue (blood, a buccal smear, or normal colonic mucosa) is tested by genotyping fluorescently labelled polymerase-chain-reaction products with the use of an automatic sequencer. A panel of five microsatellite markers is usually enough; microsatellite instability in two or more of them is a positive result."

Not only could such tests help doctors assess a patient’s prognosis and perhaps guide treatment, they could be a powerful method of screening for hereditary non-polyposis colorectal cancer, says the author of the accompanying article, Dr Albert de la Chapelle, of the human cancer genetics programme at Ohio State University’s Comprehensive Cancer Centre.
 

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bmj.com, 25 Jul 2003 [Full text]

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Collections under which this article appears: Cancer: gastroenterological Genetics

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