Trastuzumab's cardio risk can be reduced, avoided.(Gynecology)

SAN ANTONIO -- Just when the use of trastuzumab (Herceptin) as first-line adjuvant therapy in breast cancer is expanding to a vastly larger patient population, investigators have hit on several novel means of avoiding the cardiotoxicity that is the drug's major side effect.

Roughly 25% of breast cancers overexpress human epidermal growth factor 2 (HER2); these tumors progress earlier and carry a worse prognosis than HER2-negative breast cancers. When trastuzumab was approved in the late 1990s for the treatment of metastatic HER2-positive breast cancer, the targeted monoclonal antibody therapy was recognized to be both far more effective and safer in most respects than conventional treatment options.

Now the use of trastuzumab is broadening from patients with metastatic disease to include the far larger population of women who have HER2-positive early-stage breast cancer. Last year's annual meeting of the American Society of Clinical Oncology saw the presentation of three very positive, large, randomized, phase III trials, which collectively demonstrated that a year of adjuvant trastuzumab in patients with HER2-positive early breast cancer resulted in roughly a 50% reduction in the relative risk of recurrence, compared with various conventional chemotherapy regimens. More recently, essentially the same results were found in an interim analysis of a fourth phase III trial--the 3,222-patient Breast Cancer International Research Group trial 006 (BCIRG 006).

But expanding the use of this very expensive agent to include patients with early-stage breast cancer creates a dilemma: Why expose all of these women to the risk of trastuzumab-induced cardiotoxicity, given that many would not go on to develop advanced breast cancer if initially treated instead with conventional adjuvant systemic therapy? Two promising methods of reducing trastuzumab's cardiotoxicity risk were presented at a breast cancer symposium sponsored by the Cancer Therapy and Research Center.

Dr. Dennis J. Slamon, who presented the interim BCIRG 006 results at the symposium, said the study provided both good news and bad regarding trastuzumab's cardiotoxicity. The bad news is that the problem appears to be significantly worse than previously reported by other investigators.

BCIRG 006 randomized 3,222 patients with HER2-positive breast cancer and positive lymph nodes or other high-risk features to one of three treatment arms: a control group given a standard potent anthracycline-based chemotherapy regimen consisting of four cycles of doxorubicin and cyclophosphamide followed by four of docetaxel, the same regimen with the addition of 1 year of adjuvant trastuzumab beginning concurrent with the docetaxel, or a year of trastuzumab starting at the outset of six cycles of docetaxel and carboplatin.

In terms of the primary efficacy end point, at a median follow-up of 23 months the disease-free survival rate was 84% with the anthracycline/trastuzumab regimen and 80% with docetaxel/carboplatin/trastuzumab--significantly better than the 73% rate among the controls, who received anthracycline-based chemotherapy without trastuzumab.