NEWS

Molecular Markers May Improve Colon Cancer Staging, Screening

Jean McCann

With more sophisticated tests now available, the dilemma of just who needs adjuvant treatment for colon cancer and who does not is coming to the fore.

The problem of understaging in colon cancer patients is probably worse than previously thought, based on more sophisticated methods of detecting metastases. Many patients thought to be free of disease may not be.

"The theory is that many who have stage II colon cancer may actually have stage III, and should be getting adjuvant chemotherapy," said David Ota, M.D., medical director and chief of surgical oncology at the Ellis Fischel Cancer Center in Columbia, Mo., who chaired a session on colorectal cancer at a recent Society of Surgical Oncology meeting in New Orleans.

"Those who are truly node negative by histology, by [reverse transcription]–PCR, and by immunohistochemistry probably will not benefit from systemic chemotherapy because their risk of recurrence is so low," Ota said in an interview. "We’re not there yet, but if we can determine the high-risk patients, I think that will help out a lot in determining who gets treatment and who doesn’t." Ota said he thinks it will take a series of molecular markers to really determine who are high-risk patients.

Richard Goldberg, M.D., of the Mayo Clinic, Rochester, Minn., who spoke recently at the annual meeting of the American Society of Clinical Oncology, agreed that there are likely many patients whose lymph nodes are either not removed who have metastatic disease or whose nodes are removed but not looked at carefully enough to determine whether micrometastatic disease is present.



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Dr. Richard Goldberg

 
"In colon cancer lymphadenectomy is diagnostic as well as therapeutic, so maybe the best way is to take out as many nodes as is reasonable," he said. He added that understaging might also become less of an issue if all stage II patients, node negative as well as positive, were treated with chemotherapy.

Molecular Markers

On the other hand, Anton Bilchik, M.D., assistant director of surgical oncology at the John Wayne Cancer Institute in Santa Monica, Calif., told the surgeons’ group that so-called molecular staging may be the way to go. He added that using RT–PCR recently enabled his group to upstage 17% of a series of 75 patients.

Bilchik said that because colon tumors are heterogeneous, the eventual goal would be to test for a series of markers that are found in metastatic cancer but not in normal tissues or fluids. Our hypothesis is that a multiple-marker PCR assay can improve the treatment of systemic disease and may ultimately aid in the stratification for further adjuvant treatment," he said.

The markers his group used were c-Met (which is a hepatocyte growth factor receptor and has been shown to be important in GI metastases), u-Mage, and ß-human chorionic gonadotropin (ß-HCG). "We looked for the markers in healthy normal blood as well as in nonmalignant lymph nodes and normal colon and couldn’t find any expression in those without evidence of malignancy," he said.

He said his group then looked at tumor biopsy specimens in 38 patients and found at least one of the markers was expressed in 90%. They also recently looked at 49 patients with early colorectal cancer in whom lymph node mapping was successful and the sentinel node had been identified, and they found that 56% expressed ß-HCG, 49% expressed c-Met, and 35% expressed u-Mage.

In the meantime, what should be done with this information? As far as adjuvant therapy for ostensible stage II or III disease patients, "to treat or not to treat—that is the question," said Timothy Yeatman, M.D., associate professor of surgery, biochemistry and molecular biology at the H. Lee Moffitt Cancer Center, University of South Florida, Tampa.

He said the basic issue will be what to do with stage II patients, because about 50% will harbor occult metastases and about 20% of this group will die from their disease. He added that the corollary to the idea of doing more extensive testing would be also to determine if adjuvant treatment will extend their lives. He said the trials reported so far are conflicting, with both negative and positive results reported.

However, when the NSABP did a combined analysis of four trials, it showed that treatment resulted in a 30% reduction in death for Dukes’ B and 18% for Dukes’ C patients. He added that several trials also now show that RT–PCR can predict poor outcome.

In addition, there are other factors to look at in trying to identify the high-risk patient who needs additional treatment. Yeatman said that in the future he foresees molecular fingerprinting of tumors by microarrays, and phenotype-driven adjuvant chemotherapy.

Screening for Colon Cancer

Bernard Levin, M.D., of the University of Texas M. D. Anderson Cancer Center, Houston, said at an American Cancer Society seminar in Tampa, "molecular detection of gene abnormalities are also being investigated [in the United States] and in Europe, as is virtual colonoscopy and fast CT scanning of the abdomen."



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Dr. Bernard Levin

 
Still, "with the techniques we now have we could probably save half of the deaths now occurring," Levin said, because colon cancer typically takes decades to develop from the earliest biochemical changes in the colonic epithelium, followed subsequently by the development of polyps.

He added that a colorectal roundtable is coming together soon to develop public health initiatives, while the search goes on for molecular ways to detect the earliest changes in the colonic epithelium that eventually lead to cancer.

There is some suggestion that agents like COX-2 inhibitors might forestall such changes, but the answers are not in yet.



             
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