Trastuzumab plus paclitaxel following doxorubicin and cyclophosphamide improves survival in patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer, according to planned definitive overall survival results from a joint analysis of a report published in the Journal of Clinical Oncology.1
For the joint-analysis of NCCTG N9831 and NSABP B-31, researchers enrolled 2,101 women with primary, operable, node-positive or high-risk node-negative HER2-positive invasive breast cancer and 2,101 women with primary, operable, node-positive HER-2 positive invasive breast cancer, respectively.
Of those in N9831, 971 were randomly assigned to receive doxorubicin 60 mg/m2 IV plus cyclophosphamide 600 mg/m2 IV once every 3 weeks for 4 cycles, followed by paclitaxel 80 mg/m2 IV weekly for 12 weeks (Arm A), and 973 were randomly assigned to receive the same regimen plus trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly for 1 year after doxorubicin and cyclophosphamide (Arm C).
Of those in B-31, 1,047 patients were randomly assigned to receive doxorubicin plus cyclophosphamide every 3 weeks, followed by paclitaxel 80 mg/m2 IV weekly for 12 weeks or 175 mg/m2 once every 3 weeks for 4 weeks (Arm 1), and 1,055 patients were assigned to receive the same regimen plus trastuzumab (Arm 2). Some patients also received hormonal therapy and radiotherapy.1
Results showed that patients who received trastuzumab had significantly improved overall survival compared with those in the control arms (adjusted hazard ratio [HR]=0.61; 95% CI: 0.52,0.71; P<0.001). Further analyses demonstrated that all subgroups of patients experienced statistically significant benefit with the addition of trastuzumab to adjuvant chemotherapy.
Particularly, those with estrogen receptor-negative and progesterone receptor-negative tumors had a HR of 0.65 (95% CI: 0.53,0.80) and those with estrogen receptor-positive and/or progesterone receptor-positive tumors had a HR of 0.61 (95% CI: 0.49,0.76). At 10 years since randomization, the overall survival was 84% for the trastuzumab group compared to 75.2% for the control group.1
In addition, patients that received trastuzumab had significantly improved disease-free survival compared to those who did not receive trastuzumab in addition to adjuvant chemotherapy (adjusted HR=0.58; 95% CI: 0.52,0.66; P<0.001). All subgroups demonstrated similar benefit in regard to disease-free survival from the addition of trastuzumab.
Of note, the HRs were 0.62 (95% CI: 0.52,0.73) and 0.61 (95% CI: 0.51,0.72) for those with estrogen receptor-negative and progesterone receptor-negative tumors and those with estrogen receptor-positive and/or progesterone receptor-positive tumors, respectively. The 10-year disease-free survival rate was 73.7% and 62.2% for the trastuzumab and control groups, respectively.1
“The most important findings are that we demonstrated the long-term efficacy of this adjuvant treatment for patients with early-stage HER2-positive breast cancer,” Edith A. Perez, MD, Deputy Director at Large for Mayo Clinic Cancer Center in Jacksonville, FL, and lead author of the study said.
“Our data are very important because when we give preventive therapy or adjuvant therapy to patients, those therapies may only work for 2 years, it’s very important for patients and physicians to understand that although these therapies are given for a maximum of 1 year, the benefit of trastuzumab extends to the 10-year point. The importance of this is that we solidified the clear improvement in overall survival by the addition of trastuzumab, which is the anti-HER2 monoclonal antibody, for patients’ management.”
Furthermore, trastuzumab has been associated with cardiotoxicity, but this analysis shows that the cumulative incidence of cardiac events between both regimens was 3.0% at 3 years and 2.7% at 7 years, and 0.2% and 0.1% of patients died as a result of cardiac issues in trastuzumab and control groups, respectively. The authors suggest that the difference in incidence of cardiac-related death does not outweigh the benefit of the trastuzumab-containing regimen compared with the chemotherapy only regimen.
“There is a small risk [of cardiotoxicity], but when we looked at short-term data and certainly long-term data, although we understand that a few percentage of patients may develop congestive heart failure, the majority of these patients actually recover their cardiac function. Specifically, when we look at 10-year survival data, which includes everything, the survival benefit of adding trastuzumab is very clear. There is no doubt about it,” Dr. Perez said.
Although the positive results showed that anti-HER2 therapy improved survival when added to adjuvant chemotherapy during the 8.4-year median follow-up period, trastuzumab has been approved by the U.S. Food and Drug Administration for the treatment of HER2 overexpressing breast cancer since 1998 and the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of invasive breast cancer already recommend adjuvant endocrine therapy plus adjuvant chemotherapy with trastuzumab for the treatment of patients with hormone receptor-positive, node-positive, HER2-positive invasive breast cancer and adjuvant chemotherapy with trastuzumab for hormone receptor-negative, node-positive, HER2- positive disease.2,3
“[The study] may have clinical implications here in the United States,” noted Dr. Perez, “but for patients in many other parts of the world where there has been continued restriction to the use of adjuvant traztuzumab it will be particularly reassuring that we are improving survival without serious side effects,” she continued. Another outcome of the research, according to Dr. Perez is the fact that the work served as a model to conduct correlative work to identify proteins and genes that may be associated with benefit to trastuzumab.
“By conducting this important clinical trial, we have not only changed standards of care in the United States and globally, but we have obtained appropriate biospecimens to try to better understand the patients that will be most likely to respond to specific therapies,” she said.
“Our study has helped set the standard of care, and now we understand that there are long-term benefits to patients with essentially minimal risk of side effects,” Dr. Perez concluded.
- Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744-3752.
- Herceptin® (trastuzumab) [package insert]. Genentech, Inc. South San Francisco, CA. http://www.gene.com/download/pdf/herceptin_prescribing.pdf.
- NCCN Clinical Practice Guidelines in Oncology™. Breast Cancer. V 3.2014. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed December 18, 2014.