Researchers from Europehave reported that women with HER2-positive localized breast cancer who have received adjuvant or neoadjuvant chemotherapy benefit from the administration of Herceptin (trastuzumab). The results of this randomized trial were presented at the 2005 meeting of the American Society of Clinical Oncology May 13-17 2005 in Orlando, Florida.[1]

Herceptin is a monoclonal antibody targeted against the HER-2 receptor. It is currently approved as a single agent in the treatment of HER2-positive metastatic breast cancer in patients who have received prior therapy, and as initial therapy to be used in combination with Taxol® (paclitaxel) in HER2-positive metastatic breast cancer. It is estimated that approximately 30% of breast cancers over express HER2. The major toxicity of Herceptin is cardiac dysfunction especially when combined with anthracyclines.

Results presented at this year’s ASCO meeting included a joint analysis of the two large U.S. phase III randomized clinical trials (NSABP B13 and NCCTG N9831), both of which evaluated Herceptin in the adjuvant setting of over 3,000 women with HER2-positive early breast cancer.[2] The two trials compared doxorubicin and cyclophosphamide (AC) followed by Taxol® with or without Herceptin. One arm of the joint analysis included patients treated with AC +T sequentially followed with Herceptin, while another arm consisted of patients treated with AC+T treated with concurrent Herceptin. Herceptin therapy was continued for a total of one year. Patients in these trials were node-positive or high-risk node-negative patients, and had received no prior anthracycline or taxane therapy. Overall, at 4 years, disease-free survival was 85% for patients treated with Herceptin, compared to 67% in those treated with chemotherapy only. This study also suggested that concurrent administration of Herceptin was superior to sequential administration. Differences in congestive heart failure or cardiac deaths were less than 4% in the Herceptin versus chemotherapy-only arms.

In the European study (HERA) patients were randomized to receive observation, one year of Herceptin therapy or two years of Herceptin therapy after adjuvant or neoadjuvant chemotherapy of the physician’s choice.1 Almost all patients were treated with an anthracycline but only approximately one-quarter received a taxane-containing regimen. One-third of women in the HERA trial were lymph node negative. At a median follow up of 1.5 years, the two-year DFS was 85.8% for Herceptin treated patients compared to 77.4% in the control arm for a hazard ratio of 0.54, P<0.0001. The two-year DDFS was markedly improved with a hazard ratio of 0.51 and the two-year overall survival hazard ratio was 0.76, not yet reaching a statistical significance but certainly encouraging at this early follow up. Symptomatic congestive heart failure occurred in 0.5% of patients receiving Herceptin vs. 0% in the observation arm.

A detailed analysis of one of the two US trials (N-9831) showed that 7% of women had a drop in ejection fraction to the lower limit of normal or more than 15 points from baseline or both and, therefore, did not receive Herceptin on protocol.[3] In the chemo plus Herceptin arm, 21% of women had a nadir LVEF which was <lower limit of normal or >15 points drop from baseline. No clinical cardiac events occurred in the control arm at the interim analysis compared to 3.3% patients developing CHF or a drop below the pre-specified LVEF boundary prompting an interruption in study drug. Therefore, adding Herceptin to chemotherapy causes a predictable increase in cardiac events but acceptable based on the large clinical benefit. The relatively high incidence of changes in LVEF strongly documents the need to monitor patients carefully during Herceptin therapy.

Comments: The combined U.S. and European data suggest the addition of Herceptin should be the standard of care in the adjuvant and possibly the neoadjuvant treatment of HER2-positive breast cancer, as survival is improved with acceptable toxicity. Further analyses of optimal scheduling of Herceptin and cardiac monitoring schedules need to be performed. Thus, Herceptin can now be considered standard therapy for early HER2 positive breast cancer.

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