Dr. Steven Gallinger Discusses the Clinical Implications of Microsatellite Instability Studies

NEW ORLEANS—Colorectal cancer appears to be two distinct diseases at the molecular and natural history level, but what exactly does this mean in terms of clinical practice? Steven Gallinger, MD, of the Univesity of Toronto, attempted to answer that question in his overview of Dr. Elsaleh’s presentation on microsatellite instability (MSI).

“There are distinct differences between tumors with chromosomal instability and microsatellite instability,” Dr. Gallinger said. “These distinct differences appear at the histologic level, at the genetic level, at the anatomic level in terms of right side/left side, and certainly there’s now new evidence that there are significant differences at the chemotherapy-response levels as well.”

While genomic instability in cancer is a well-established field now, he said, the specific mechanisms by which these instabilities contribute to growth abnormalities are still not well understood. It is known that in leukemias and lymphomas, major interstitial deletions and translocations occur at the gross chromosomal level. In various epithelial tumors such as colon cancer, the changes occur differently, as major chromosomal arms have been shown to be lost.

Further, he said, “we now know of a new genome instability pathway called microsatellite instability whereby small insertions and deletions and point mutations have been shown to be important in various tumor systems.”

In colorectal cancer, there are two molecular pathways—the chromosomal instability pathway and the microsatellite instability pathway. “That’s the message of what we’re hearing today,” he said. “Tumors seem to progress down one pathway or the other but not both.”

The mechanisms of this process however, are still not known, although colorectal cancer serves as one of the best paradigms for understanding the progressive accumulation of changes from the adenoma to carcinoma sequence.

In 100 colorectal patients, about two will have germ-line mutations in mismatch repair genes and tumors that demonstrate high-frequency microsatellite instability, Dr. Gallinger said. About 85% of them will have tumors that appear to progress down the traditional chromosomal instability pathway.

“Of increasing importance is the knowledge that there is a fairly large and meaningful fraction of colon cancer patients who seem to have developed disease in a sporadic fashion, but whole tumors developed on the basis of the MSI pathway,” Dr. Gallinger explained. This fraction represents about 10% to 15% of all colon cancer patients.

Once this was recognized, he said, investigators began looking for phenotypic differences between high-frequency MSI tumors (MSI-H) and the traditional chromosomal instability tumors known as MSI-stable (MSS).

“It would be naïve for us to consider that patients whose tumors arose from two different pathways would have the same natural history, and that’s actually one of the points of today’s talk by Dr. Elsaleh and his group,” he said.

Dr. Gallinger described two main questions addressed by Dr. Elsaleh’s study and others: Do stage II and III colorectal cancer patients with MSI-positive tumors require adjuvant chemotherapy and radiotherapy? Do MSI-positive and MSS colorectal cancers actually respond similarly to standard adjuvant chemotherapy?

The strengths of the study by Elsaleh et al, Dr. Gallinger pointed out, are the large sample size, the fact that they all had Dukes’ C colon cancer, and there was a long follow-up.

The limitations were that the patients were not randomized, and the trial was not population based. While the latter is not of great significance, the fact that the patients were not randomized begs the question of how the oncologists chose the patients for adjuvant therapy. So, the question of bias is raised.

The use of a single marker for detecting MSI could be another limitation. According to the criteria set forth by an international committee in 1997, MSI analyses require the use of five MS markers —two mononucleotide repeats and three dinucleotide repeats. However, the researchers used the BAT26 marker, which has high sensitivity (92%) and specificity (100%), so according to Dr. Gallinger, it is probably adequate to define MSI. This actually could be considered a new finding of Elsaleh’s study, he said.

Elsaleh et al showed that the MSI phenotype seems to be primarily confined to the right colon. However, there are a few left-sided MSI tumors, Dr. Gallinger said.

But, the most interesting, albeit controversial, aspect of the study, Dr. Gallinger said, is the fact that it shows that the MSI phenotype appears to predict an improved response to chemotherapy.

“In fact, patients with the MSS tumors, the traditional chromosomal instability tumors, did not seem to derive much survival benefit from the use of 5-FU when compared with the MSI phenotype,” he said. According to Dr. Gallinger, this finding is both supported and not supported in the literature.

While the findings appear strong, Dr. Gallinger feels it might be premature to change clinical practice at this time. “Probably the most important research agenda is to examine ongoing and prospective studies,” he said. “I’m well aware that some of the current trials are including MSI and some of the molecular markers in their analysis. This will certainly provide a lot of information in the coming years.” If more studies validate Dr. Elsaleh’s study, colon cancer treatment can be further refined, he said.