Gene Activity May Change As Breast Cancer Progresses

A gene involved in many breast cancers may become more active during the course of the disease, and some patients will need additional medications that had been thought unnecessary, a new study indicates.

"Cancer is a moving target, and the oncologist has to know which bullet to put in his gun,'' said Dr. Jonathan Uhr of the University of Texas Southwestern Medical Center at Dallas.

Extra copies of the gene HER-2 occur in 20 percent to 25 percent of breast cancer cases. In these cases the cancer tends to resist chemotherapy and radiation, but the drug Herceptin, which blocks the gene, can help patients.

The primary tumor in breast cancer patients is tested for the HER-2 gene overactivity and those with negative tests don't get Herceptin.

In some cases, however, cancer cells circulating in the blood can develop this gene overactivity as the disease progresses, according to the study by a research team Uhr led.

The study, published Monday in Proceedings of the National Academy of Sciences, found HER-2 overactivity in nine of 24 patients whose primary cancer initially tested negative for the gene.

While the study is small and further research is needed, the findings call into question the assumption that test results on the primary tumor should be used to make treatment decisions at a later date, the researchers say.

"Cancer cells are genetically unstable and they do change,'' Uhr, a professor of microbiology and internal medicine, said in a telephone interview.

"Of course this is against current dogma. I'm sure there will be some reluctance in accepting this until more work is done, and more work should be done,'' he added.

Dr. Joseph Geradts of the Roswell Park Cancer Institute in Buffalo, N.Y., said the finding "adds to the evidence that what the oncologist treats is different from what the surgeon cuts out.''

The dogma has been that what is in the primary tumor is the same as what is in the cancer that spreads to other areas, Geradts said, but the new study indicates that may not be the case.

Dr. Stephen B. Edge, medical director of the breast center at Roswell Park, called the study "a small step ... but intriguing.''

Angela H. Brodie, a professor at the University of Maryland School of Medicine, said that while the paper is preliminary, "what is interesting is they're showing that patients can actually get (gene) amplification as the tumor progresses. It would serve as a marker for further treatment, different treatment.''

Uhr's team developed a sensitive blood test for overactivity of the HER-2 gene, allowing for tests of the circulating cancer cells. Even when the primary cancer is negative for HER-2 activity, some cancer cells may have the extra gene. Over time those could become dominant in the blood as chemotherapy and radiation destroy other cancer cells.

"The implications of tumor evolution over the course of treatment are significant,'' said Dr. Debasish Tripathy, professor of internal medicine and contributing author of the paper.

"A better understanding of this process will not only allow us to use available drugs in a more individualized fashion but also may point to new therapeutic approaches.''

Of the nine patients in Uhr's study who showed HER-2 activity in circulating cells, one had complete remission and two had partial remission when treated with Herceptin and chemotherapy.

For the blood test to be considered worthwhile, researchers said, they also must show that therapy with Herceptin alone or with chemotherapy can cause remissions in a significant number of patients.

The research was funded by the Nasher Cancer Research Program, the Cancer Immunobiology Center and the Komen Breast Cancer Center.

(Copyright 2004 by The Associated Press. All Rights Reserved.)