Molecular tag pinpoints which breast cancer tumors are most likely to spread

A new molecular tag discovered by scientists at The University of Texas M. D. Anderson Cancer Center may help doctors decide which breast cancer patients need more aggressive treatment and which can forego the potentially toxic course of chemotherapy.

Khandan Keyomarsi, Ph.D., associate professor in experimental radiation at M. D. Anderson, and her colleagues report in the November 14, 2002, issue of the New England Journal of Medicine that high levels of a protein called cyclin E are closely associated with aggressive, invasive breast cancer. The study, conducted with tissue samples of current or former breast cancer patients, appears to show that cyclin E is a much better predictor of patient outcome than any current predictive marker. However, says Keyomarsi, the study must be repeated with newly diagnosed patients to determine its true predictive value.

The ability to predict which breast cancer tumors will recur or spread throughout the body is an important aspect of breast cancer treatment, says Keyomarsi. Currently, the prognosis for women diagnosed with breast cancer is determined by whether tumor cells have spread to lymph nodes. But some women who have cancer cells in the lymph nodes never have a recurrence, while others whose cancer has not spread do have a recurrence. Yet many women, after discussions with their doctors, opt to undergo grueling chemotherapy in hopes of ensuring any rogue cancer cells that may be present are killed. If an accurate predictive marker were available, many women could be spared chemotherapy, she says.

In the study, Keyomarsi and her colleagues looked for the presence of cyclin E because when this protein is present at high levels inside cancer cells it signals cells to multiply all the time. In normal cells, cyclin E is present only for a short time and helps keep cell division under tight control. In addition, the scientists discovered smaller versions of cyclin E that are not present in normal cells. These low molecular weight versions are generated by an enzyme that chops up the normal cyclin E and in the process creates a new form that is even better at signaling cells to divide.

“We have shown the occurrence of low molecular weight forms of cyclin E that are not found in normal cells and are present throughout cell cycle in cancer cells,” says Keyomarsi. “These abnormal forms of cyclin E are always giving the ’go’ signal, telling cells to divide.”

The scientists examined tumor tissue from 395 patients with breast cancer. Of those patients with stage one breast cancer, in which a single tumor is found and the cancer has not yet spread, about 10 percent had high levels of cyclin E in their cancer cells. All of these patients had died from a recurrence of breast cancer within five years of diagnosis, while none of the patients who had low levels of cyclin E had died. The proportion of tumors that had high levels of cyclin E increased with increasing extent of disease.

“This study shows that the presence of low molecular weight forms of cyclin E has a very powerful prognostic value,” says Keyomarsi. “However, we have to validate the study using newly diagnosed patients in which we are blinded to the diagnosis. We are in the midst of that study now. If it bears out our initial results, we will try to get it into the clinic as soon as possible, though it may be at least one year.”

Keyomarsi points out, however, that the specialized laboratory technique, called a western blot, used in her study is not available in most clinical laboratories that test patient samples. In order for the results to be used, testing laboratories would need to learn how do use the new technique.

“My hope is that this technique may help ease the burden of chemotherapy among breast cancer patients,” says Keyomarsi. “Women who don’t overexpress cyclin E may not need chemotherapy, which kills all dividing cells and can do significant damage to other tissues and organs.”

For those patients who have high levels of cyclin E more aggressive treatment would be indicated, she says. And intensive research is now underway at M. D. Anderson to find ways to stop production or block cyclin E in those patients where it is present.

Keyomarsi’s research was supported by grants from the U.S. Army Medical Research and Material Command and the National Cancer Institute. Dr. Keyomarsi holds U.S. patents (#5,543,291 and #5,763,219) on the use of cyclin E to detect and treat cancer.