Helsinki, Finland - Giving the breast-cancer drug trastuzumab (Herceptin, Roche) before treatment with anthracyclines appears to limit its cardiotoxicity but maintain its efficacy, a new study shows [1].

Dr Heikki Joensuu (Helsinki University Central Hospital, Finland) and colleagues report the results from their Finland Herceptin (FinHer) study in the February 23, 2006 issue of the New England Journal of Medicine.

Although the findings will need to be replicated in larger studies, this is the first proof that the toxic effects of this antibody can be dissociated from its therapeutic effects and has implications for the future design of other monoclonal antibodies, says Dr Kenneth R Chien (Cardiovascular Research Center, Massachusetts General Hospital, Boston) in an accompanying editorial [2].

Chien explained to heartwire that anthracyclines such as fluorouracil, epirubicin, and cyclophosphamide (FEC) "are the cornerstone of chemotherapy" for breast cancer, but they are also cardiotoxic. When the monoclonal antibody trastuzumab was launched, it was given after anthracycline therapy and improved survival for women with so-called HER2-positive breast cancer, a particularly aggressive form of the disease.

But unfortunately, Herceptin also exacerbated the cardiotoxicity of anthracyclines, with up to 5% of women treated with both regimens developing heart failure and 10% having a substantial decrease in left ventricular ejection fraction (LVEF).

And as Joensuu et al explain, "The long-term outcome of trastuzumab-related heart failure is unknown, although symptoms usually subside with cessation of treatment with trastuzumab and management of the condition."

Herceptin was initially licensed for use in those with metastatic (late-stage) breast cancer, and so some trade-off of survival for cardiotoxicity was tolerated, Chien says. But now that the drug is used more aggressively and much earlier in the course of the disease, it is even more important to try to limit the cardiotoxicity, he adds.

In their study, Joensuu and colleagues randomly assigned 1010 women with breast cancer to receive three cycles of docetaxel or vinorelbine followed by three cycles of anthracyclines (FEC) in both groups.

Of the 1010 women, 232 had HER2-positive breast cancer and were further assigned to receive or not to receive nine weekly trastuzumab infusions, in this case administered before the anthracyclines and concomitantly with the docetaxel or vinorelbine. The primary end point was recurrence-free survival.

Those who received trastuzumab had better three-year recurrence-free survival than those who did not get the antibody (89% vs 78%; hazard ratio for recurrence or death 0.42). Importantly, trastuzumab was not associated with decreased LVEF or cardiac failure.

As Joensuu et al observe: "None of the women who were treated with trastuzumab had cardiac failure, and unexpectedly, these women had slightly better maintenance of LVEF than did those who did not receive the antibody. Administration of trastuzumab before FEC . . . may have contributed to the preservation of cardiac function."

Chien told heartwirethat the Finnish researchers appear to have succeeded in dissociating the cardiotoxic effects of trastuzumab from its therapeutic ones. "The most likely explanation for the elimination of cardiotoxicity is the avoidance of either concomitant administration of trastuzumab and anthracycline or the use of trastuzumab after anthracycline."

He believes that cardiac stress signals are activated by anthracyclines, inducing myocyte loss. "It seems, therefore, that the risk of heart failure associated with trastuzumab was negated because cardiac stress signals had not been activated by anthracyclines.

"The study by Joensuu et al demonstrates that trastuzumab can be given in therapeutically active doses with negligible cardiac side effects, but whether a similar result might hold in . . . women with preexisting heart disease is now a pressing question," he notes.

"It will also be critical to see whether these results hold up in larger populations," he told heartwire.