WEDNESDAY, Nov. 13 (HealthDay) -- Researchers in Houston have identified a marker that may determine those patients who have more aggressive forms of breast cancer, a finding that could present a target for new drug therapies.
In a retrospective study reported in tomorrow's issue of The New England Journal of Medicine, high levels of a truncated form of the protein cyclin E indicated poor survival prospects in women with breast cancer, while women with lower levels had decidedly better prospects. More aggressive cancer was also indicated when the regular form of the protein was present throughout the cell cycle.
In normal cells, cyclin E appears at certain times to give cells the "go" signal to replicate. In tumor cells, however, two things can go wrong: the regular cyclin E never goes away and, therefore, doesn't stop giving the "go" signal. Also, this regular or "full-length" cyclin E can generate a truncated or low molecular weight version.
"Low forms are more active versions of the full-length version, and give the go signal more strongly," says Khandan Keyomarsi, lead author of the paper and an associate professor in the experimental radiation oncology department at the University of Texas MD Anderson Cancer Center in Houston. "The low forms by themselves, without even taking into account the full form, are a strong predictor of poor outcomes, as are the two together."
Right now, the prognosis for women diagnosed with breast cancer is based largely on whether or not the cancer cells have spread into neighboring lymph glands. Unfortunately, this method is far from foolproof: About one-third of women whose cancer has not spread to the lymph nodes have a recurrence, while about one-third of women whose cancer has spread to the lymph nodes don't have a recurrence within 10 years.
"It's very encouraging. If this holds true, then perhaps we'll be able to tell which women we don't need to treat, who don't need to go through the pain, inconvenience and cost," says Dr. Jay Brooks, chief of hematology/oncology at the Ochsner Clinic Foundation in New Orleans. "Hopefully, the results can be expanded to larger groups of patients. We could then reassure women."
In this study, the researchers looked at total cyclin levels in the tumor tissue of 395 patients who had had breast cancer. One hundred twenty seven of these women had been diagnosed with Stage 1 breast cancer, where the disease had not spread to the lymph nodes, and 10 percent within this group had a poor prognosis.
The truncated forms of cyclin E were over expressed in the group with a poor outlook but not in any of the other Stage I patients. In fact, each one of the women with high levels of the abnormal cyclin E died from a recurrence within five years of being first diagnosed. All the women with low levels survived.
All told, women with high total cyclin levels had an eight-times higher risk of dying than those with low levels, the researchers report.
"Cyclin can identify those patients who would metastasize. It detected them all," says Keyomarsi.
The findings have a number of implications.
"The more general part of this study is that it would identify those patients who are not going to benefit from additional chemotherapy, and chemo is extremely debilitating," Keyomarsi says. "That's the very positive part because the majority of patients don't over express [cyclin E]."
Conversely, Keyomarsi adds, high expression of total cyclin E would indicate which patients require more aggressive treatment from the start.
The study also opens up the possibility of developing drugs to inhibit the generation of cyclin E.
"We have already identified the mechanism by which these lower [molecular weight] forms of cyclin E are generated. That actually opens the road for drug screening," Keyomarsi says. "We are in the process of trying to come up with compounds that would target the enzymes that generate these forms." Between 20 percent and 25 percent of women over express this altered form of cyclin E, which is about the same percentage of women who experience a recurrence.
The use of cyclin E as a predictor of more aggressive cancer is not ready for clinical use, however. The test that was used to identify the altered forms of cyclin E, called the Western blot analysis, is currently only used in research labs and would need to be incorporated into a clinical setting.
The findings also need to be validated with patients who are newly diagnosed, as opposed to patients who were previously diagnosed.
"If confirmed with larger groups of patients, then I believe this will come to be very helpful," Brooks says. "There has been a history over a number of years of various tumor markers being discovered, and many of them, when applied to larger groups, have not stood the test of time. Hopefully, this will."
What To Do
For more on breast cancer treatment, visit the Susan G. Komen Foundation or the National Cancer Institute
