Two papers in the October 20, 2005, issue of the New England Journal of Medicine detail the results of three randomized trials demonstrating the effectiveness of adjuvant or neoadjuvant Herceptin (trastuzumab) in preventing relapses in women with localized breast cancer.[1][2] These data were previously presented at the 2005 meeting of the American Society of Clinical Oncology May 13-17, 2005, in Orlando, Florida. Herceptin is a monoclonal antibody targeted against the HER-2 receptor. It is currently approved by the U.S. Food and Drug Administration for use 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. Recent studies have focused on the role of Herceptin in the treatment of localized breast cancer.

European researchers presented an interim analysis of the Herceptin Adjuvant (HERA) study which randomly allocated 1694 women to receive two years of Herceptin and 1694 to one year of Herceptin. Herceptin was administered every three weeks. A total of 1693 women were not treated and served as the control group. One-third of women in the HERA trial were lymph node negative. Herceptin was begun after adjuvant or neoadjuvant chemotherapy of the physician’s choice. Almost all patients were treated with an anthracycline, but only approximately one-quarter received a taxane-containing regimen. The current analysis only compared patients receiving one year of Herceptin to those in the control group. Table 1 summarizes the main findings of this trial.

Table 1: HERA Trial comparing Herceptin after adjuvant therapy to control

The above results translate to a 50% reduction in the rate of distant relapses by the use of Herceptin.

Symptomatic congestive heart failure occurred in 1.7% of the Herceptin group and 0.06 of the control group. There were 6 fatal adverse events in the Herceptin group and 3 in the control group. There was one cardiac death in the control group but 9 patients in the Herceptin group had severe congestive heart failure.  These authors suggest that one year of Herceptin should be standard therapy for women with HER2-positive breast cancer following completion of adjuvant or neoadjuvant therapy.

The second study was 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 in over 3,000 women with HER2-positive early breast cancer. 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. Table 2 presents the main findings of these pooled data from two trials.

Table 2: NSABP B13 and NCCTG N9831

Herceptin improved disease-free survival, time to disease recurrence and time to distant recurrence by approximately 50%. Overall survival was improved by approximately 33% and the risk of contralateral breast cancer and deaths from breast cancer were reduced by approximately one third.

The cumulative incidence of grade II or IV congestive heart failure or death from heart failure was 0.8 in the control group and 4.1% in the Herceptin group. A detailed analysis of one of the two U.S. 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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