Women with early-stage breast cancer who have extra copies of the gene HER2 or its protein should be treated with chemotherapy and the drug trastuzumab (Herceptin), according to the results of three clinical trials reported in the October 20 New England Journal of Medicine (NEJM).

The results, from two trials in the United States and one in Europe, demonstrate that for many women with early-stage HER2-postive breast cancer, an aggressive disease that tends to recur, adding trastuzumab to chemotherapy can reduce the risk of recurrence by 50 percent compared with chemotherapy alone.

"We have made a radical advance in the treatment of breast cancer," says Dr. Edith A. Perez of the Mayo Clinic College of Medicine, who chaired the trial led by the North Central Cancer Treatment Group (NCCTG). "The publication of these results will show the tremendous impact this therapy has on people's lives now."

Preliminary results from the U.S. trials were reported in May at the American Society of Clinical Oncology annual meeting. The trials had been cut short after committees monitoring the interim results determined that trastuzumab plus chemotherapy was clearly superior to chemotherapy alone and should be made available to all participants.

The NCCTG trial and the National Surgical Adjuvant Breast and Bowel Project trial, both sponsored by NCI, evaluated regimens of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab. In Europe, the Herceptin Adjuvant Trial compared chemotherapy followed by trastuzumab with chemotherapy alone.

The findings in NEJM include detailed information about trastuzumab's safety, which had been questioned because 3 to 4 percent of women experienced symptoms of heart disease. The majority of these symptoms improved immediately with treatment, according to the researchers.

"The important message is that the efficacy of this treatment is so dramatic that while the safety issues should be followed closely, the therapeutic benefit completely outweighs the risk of toxicity for women with this disease," says Dr. Perez.

Approximately 50,000 women in the United States are diagnosed with HER2-positive breast cancer each year, representing about 20 percent of invasive breast cancers. Extra copies of the HER2 gene in tumor cells lead to abnormal levels of the HER2 protein.

Trastuzumab, made by Genentech, targets the mutant HER2 protein without causing damage to normal cells. In combination with chemotherapy, the targeted therapy alters the course of the disease, reversing a woman's prognosis from poor to good.

An editorial accompanying the studies calls the results "simply stunning." On the basis of these findings, "the care of patients with HER2-positive breast cancer must change today," writes Dr. Gabriel N. Hortobagyi of the University of Texas M.D. Anderson Cancer Center.

The editorial is "glowing" but deservedly so, says Dr. JoAnne Zujewski, who oversees breast cancer trials for NCI's Cancer Therapy Evaluation Program. It is now critical, she adds, that women diagnosed with breast cancer have their tumors tested by laboratories with validated technologies for detecting HER2 markers.

The researchers do not know whether women with small HER2-positive tumors would benefit from the treatment - or whether women diagnosed a year or longer ago would benefit. Future studies will further assess the risks and benefits of giving trastuzumab with chemotherapy or following chemotherapy.

Results from a fourth multicenter clinical trial now under way in the United States are to be presented in December at the San Antonio Breast Cancer Symposium.

By Edward R. Winstead