Lay Summary: Role of Herceptin in adjuvant therapy of breast cancer.
Two large randomized controlled clinical trials sponsored by the National Cancer Institute involving more than 3300 patients with early-stage HER-2 positive invasive breast cancer found that those patients who received trastuzumab in combination with standard chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel) had a statistically significant 52% decrease in risk for breast cancer recurrence compared with patients who received chemotherapy alone 2. These studies included women with HER2 positive and node positive breast cancer with no distant metastatic disease. One study also included persons with high risk node negative breast cancer: tumor greater than 2 cm, estrogen/progestin receptor negative, nuclear grade 2-3 or age less than 35 years. In one study, Herceptin therapy was administered weekly for three months, then every 21 days for one year. In another study, This is the regimen used in this case.
Herceptin therapy was administered weekly for one year. Four years into the study, 85 percent of women with early-stage HER-2 positive breast cancer who received trastuzumab were free of recurrence, compared with 67 percent of women who did not receive the drug. The data monitoring committees overseeing the combined analysis of these trials recommended that the results of a combined interim analysis be made public because the studies had met their primary endpoints of increasing disease-free survival and overall survival in patients receiving trastuzumab in combination with chemotherapy. Most patients in these studies had lymph node-positive breast cancer, with only a minority having lymph node-negative disease. The limited information in the node-negative group did not allow for a separate analysis of this group. In these studies, the likelihood of congestive heart failure in women receiving standard combination chemotherapy and trastuzumab was increased by 3 percent to 4 percent. However, subsequent studies were more supportive 5.
An international, multicenter, randomized controlled clinical trial (Herceptin Adjuvant Trial (HERA)) found that one year treatment with trastuzumab after adjuvant chemotherapy significantly improved disease free survival among women with early stage HER-2 positive breast cancer 1. The study compared one or two years of trastuzumab given every three weeks with observation in women with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy (surgery with or without radiotherapy) and at least four cycles of neoadjuvant or adjuvant chemotherapy. Eligible subjects had node positive disease (regardless of tumor size) or node-negative disease (if tumor size was greater than 1 cm) and no distant metastases. Subjects in the HERA study were assigned to three groups: two years of treatment with trastuzumab, one year of trastuzumab, and observation. The study by Piccart-Gebhart reported results only of the groups assigned to one year of trastuzumab treatment and observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second non-breast malignant disease, or death) were observed; 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval 0.43 to 0.67), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percent. Overall survival in the two groups was not statistically significantly different (29 deaths with trastuzumab versus 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab.
In conclusion, both NCCN and NICE support this regimen for adjuvant use in early breast cancer.
1.National Comprehensive Cancer Network (NCCN). Breast cancer. Clinical Practice Guidelines in Oncology — v2.2005. Jenkintown, PA: NCCN; 2015.
2.Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672.
3.Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684.
4.Hortobagyi GN. Trastuzumab in the treatment of breast cancer. N Engl J Med. 2005;353(16):1734-1736.
5.NICE clinical guideline 80 (Breast cancer: early and locally advanced, published in February 2009)