Trastuzumab faces trials, clinical and otherwise.

296 NEWS Journal of the National Cancer Institute, Vol. 98, No. 5, March 1, 2006 Last spring’s eagerly anticipated interim results from three clinical trials of trastuzumab (Herceptin) showed that the use of the drug in the adjuvant setting cut the risk of relapse in half in early breast cancer patients. As the data continue to accumulate and mature, the benefi t appears consistent and real, according to work presented at the San Antonio Breast Cancer Symposium in December. However, questions remain about how best to use trastuzumab, how to manage the cardiotoxicity that comes with its use, and how to make up for the fact that all the trials have been halted early, ruling out the possibility of gathering long-term survival data from a randomized setting. Adding to the interim results from three other trials presented last year, Dennis Slamon , M.D., Ph.D., professor of hematology and oncology at the University of California Medical School in Los Angeles, presented the results from the fi rst planned interim analysis of the Breast Cancer International Research Group (BCIRG) 006 trial. The trial compared the effi cacy of an anthracyclinebased regimen both with and without trastuzumab. A third arm of the trial was designed to tease apart the cardiotoxicity often seen with both trastuzumab and anthracyclines such as doxorubicin. These women received docetaxel and carboplatin with concurrent trastuzumab. A total of 3,222 women with HER-2 – expressing node-positive or high-risk, node-negative operable breast cancer en rolled in the study. As in the other trials, women treated with chemotherapy plus trastuzumab did better than did those treated with chemotherapy alone. Specifi cally, after a median follow-up of 23 months, 147 (13.7%) of women treated with doxorubicin and cyclophosphamide followed by docetaxel suffered recurrence or death, compared with 77 (7.2%) of the patients who were treated with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab. In the non-anthracycline arm, 98 (9.1%) had a recurrence or died. Although both of the trastuzumab arms showed statistically signifi cant improvement relative to the control arm for disease-free survival, there was no statistical difference between the two trastuzumab arms, said Slamon. There was, however, a statistically signifi cant difference in the frequency of cardiac events between the two experimental arms. In the doxorubicin – trastuzumab arm, 17% of patients lost 10% or more of their left ventricular ejection frac tion (LVEF), compared with 9% in the doxorubicin control arm and 8% in the carboplatin – trastuzumab arm. “ This phenomenon is real and not short term, despite what we have been previously told, ” said Slamon. His team has not seen a complete recovery in all the patients who had a decrease in LVEF in the doxorubicin – trastuzumab arm, even after therapy has been completed and with the use of cardiac medication. The lingering drop in LVEF tended to be in the subclinical range, which could re fl ect variability in the test itself or could refl ect real changes in the women’s physiology. It is not clear whether these decreases will develop into something more serious over time. “ Is a subclinical decline important? No one knows but we are treating these women in the adjuvant setting and they could go on to live 30, 40, 50 years, ” said Slamon. Because the other trastuzumab trials included only paclitaxel-based combinations ( see News, Vol. 97, No. 12, p. 870 , “ Trastuzumab Trials Steal Show at ASCO Meeting ” ), the new results Trastuzumab Faces Trials, Clinical and Otherwise