Earlier planned joint analyses of outcomes in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and the North Central Cancer Treatment Group (NCCTG) N9831 trial showed that adding trastuzumab (Herceptin) to adjuvant chemotherapy improved disease-free survival and overall survival in women with early-stage HER2-positive breast cancer. In the definitive joint analysis of overall survival, reported in the Journal of Clinical Oncology by Edith A. Perez, MD, of the Mayo Clinic, Jacksonville, Florida, and colleagues, the addition of trastuzumab to chemotherapy was associated with a 37% reduction in mortality risk over long-term follow-up.¹

Study Details

In total, 4,046 patients with HER2-positive operable breast cancer were randomly assigned to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials combined. Stratification factors consisted of study, intended paclitaxel schedule (once every 3 weeks vs once per week), number of positive nodes (0–4, 4–9, ≥ 10), estrogen receptor and progesterone receptor status, and other patient and disease characteristics.

In an initial joint analysis after a median follow-up of 2 years, trastuzumab treatment was associated with a 52% reduction in disease-free survival events (P < .001) and a trend toward improved overall survival (P = .015). A second analysis at a median follow-up of 3.9 years showed that trastuzumab treatment continued to be associated with improved disease-free survival (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45–0.60) and improved overall survival (HR = 0.61, 95% CI = 0.50–0.75). The current definitive overall survival analysis was scheduled to be conducted when a total of 710 deaths had occurred.

Improved Survival

Median time on study was 8.4 years. Among the 2,028 women in the trastuzumab group and 2,018 in the control group, 4.0% vs 5.9% had locoregional recurrence, 11.2% vs 19.2% had distant recurrence, and 10.4% vs 16.9% died as a result of breast cancer. Death due to cardiac conditions occurred in 0.4% vs 0.1%, including congestive heart failure in 3 vs 2 patients, cardiac arrest in 3 vs 1, cardiomyopathy in 1 vs 0, myocardial infarction in 1 vs 0, and unspecified cardiac condition in 1 vs 0.

Ten-year overall survival was 84% in the trastuzumab group vs 75.2% in the control group, with a HR for death of 0.63 (P < .001). On analysis adjusting for stratification factors and age, tumor size, and extent of surgery, the adjusted HR was 0.61 (P < .001). Ten-year disease-free survival was 73.7% vs 62.2% (HR = 0.60, P < .001; adjusted HR = 0.58, P < .001).

Subgroup Analyses

Similar significant overall survival benefit of trastuzumab treatment was observed in patients with estrogen receptor– and progesterone receptor–negative disease (10-year overall survival = 81.6% vs 73.0%, HR = 0.65, 95% CI = 0.53–0.80) and in those with estrogen receptor– and progesterone receptor–positive disease (10-year overall survival = 86.0% vs 77.1%, HR = 0.61, 95% CI = 0.49–0.76).

Disease-free survival benefit was also similar in patients with estrogen receptor– and progesterone receptor–negative disease (10-year disease-free survival = 70.9% vs 58.6%, HR = 0.62, 95% CI = 0.52–0.73) and those with estrogen receptor– and progesterone receptor–positive disease (10-year disease-free survival = 76.1% vs 65.1%, HR = 0.61, 95% CI = 0.51–0.72).

Subgroup analyses also showed similar overall survival benefit of trastuzumab treatment according to age < 40 years (HR = 0.67, 95% CI = 0.46–0.99), 40 to 49 years (HR = 0.65, 95% CI = 0.49–0.86), 50 to 59 years (HR = 0.68, 95% CI = 0.52–0.90), and ≥ 60 years (HR = 0.51, 95% CI = 0.37–0.69) and according to tumor size 0.1 to 2 cm (HR = 0.51, 95% CI = 0.38–0.69), 2.1 to 5 cm (HR = 0.68, 95% CI = 0.56–0.82), and > 5 cm (HR = 0.58, 95% CI = 0.39–0.88). Significant disease-free survival benefits were also observed with trastuzumab treatment in all age categories (HRs = 0.50–0.64) and tumor size categories (HRs = 0.47–0.65).

According to nodal involvement, 10-year overall survival rates for the trastuzumab vs control groups were 89.0% vs 83.1% for 0 to 3 positive nodes, 79.2% vs 70.4% for 4 to 9 positive nodes, and 71.7% vs 52.6% for ≥ 10 positive nodes.

The investigators concluded: “The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence.” ■

Disclosure: The study was supported by grants from the National Institutes of Health, NSABP (now part of NRG), NCCTG (now part of Alliance), and Genentech. Dr. Perez reported no potential conflicts of interest. For full disclosures of all study authors, visit jco.ascopubs.org.

Reference

1. 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. October 20, 2014 (early release online).