A Finnish study on therapies for early breast cancer reports lower cardiac side effects among women who received a shorter than standard course of treatment with trastuzumab (Herceptin), according to a study published in the February 23 New England Journal of Medicine (NEJM).

To date, trastuzumab has been associated with heart failure among 1.7 to 4.1 percent of women taking the drug, and 10 percent of patients taking the drug have experienced substantial decreases in heart function.

The Finland Herceptin study administered trastuzumab to 116 women with HER2-positive tumors "before other cardiotoxic therapies and concomitantly with potentially synergistic chemotherapy for only 9 weeks to test the hypothesis that such a schedule would limit cardiotoxicity and maintain efficacy." This is different from previously published adjuvant studies in which anthracycline was given prior to trastuzumab. The patients were compared against a control group of 116 HER2-positive patients who received chemotherapy alone for 9 weeks without the addition of trastuzumab.

The trastuzumab group had better 3-year recurrence-free survival (89 versus 78 percent for the control group), the researchers report. None of the women who were treated with trastuzumab at the same time as the other chemotherapy had cardiac failure and, unexpectedly, these women had fewer decreases in heart function than the control group, they added.

"Our results indicate that a 9-week period of trastuzumab administration is effective in women with HER2/neu-positive breast cancer," note the researchers, led by Dr. Heikki Joensuu of Helsinki University Central Hospital. "Regimens in which only a few cycles of trastuzumab are administered concurrently with chemotherapy reduce the number of patient visits and may be more cost effective than regimens that require administration over a period of 12 to 24 months. In addition, such regimens may result in few cardiac adverse effects."

The Finnish study also compared docetaxel against vinorelbine in 1,010 breast cancer patients, including a subgroup of 232 HER2 patients. Docetaxel was found to have better recurrence-free survival than vinorelbine (91 versus 86 percent); however, docetaxel had more adverse effects than vinorelbine.

In an NEJM editorial, Harvard Medical School Professor Dr. Kenneth R. Chien comments on the findings in the HER2 arms of the study. He notes, "A longstanding question is whether it is possible to delineate the biologic pathways that link trastuzumab to the onset of cardiotoxic effects, so as to reveal approaches to the design of drugs that would dissociate the beneficial effects from the adverse ones." Dr. Chien says the Finnish study indicates "that the risk of heart failure associated with trastuzumab was negated because cardiac stress signals had not been activated" by the shortened course of anthracycline chemotherapy.

The study demonstrates that trastuzumab "can be given in therapeutically active doses with negligible cardiac side effects," Chien continues. "But whether a similar result might hold in larger numbers of patients or in women with preexisting heart disease is now a pressing question."

Dr. Sandra M. Swain, senior principal investigator in NCI's Medical Oncology Branch, also stressed the need for the Finnish study's findings to be confirmed "in a randomized trial in which a larger number of HER2-positive patients are evaluated." Nonetheless, she added, "It's a very interesting, well-designed study, and it's exciting because of the potential to give a short course of trastuzumab therapy with improved efficacy over chemotherapy alone and without creating cardiotoxicity."

The Finnish researchers acknowledged that the "small size of this subgroup and the short duration of the follow-up are limitations of the study." The optimal duration of adjuvant trastuzumab therapy is not known and may be clarified only in further randomized trials, the researchers add.

By Bill Robinson