Adjuvant trastuzumab in HER2-positive breast cancer

Abstract

Background: Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab.

Methods: We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety.

Results: At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study.

Conclusions: The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials.gov number, NCT00021255.).

Figure 1. Disease-free Survival among All Patients and According to TOP2A Status

Shown are the results of Kaplan–Meyer analyses of relative rates of disease-free survival among all study patients (Panel A), those without coamplification of the gene encoding topoisomerase II alpha (TOP2A) (Panel B), and those with coamplification of TOP2A (Panel C). AC-T denotes doxorubicin and cyclophosphamide followed by docetaxel, and TCH docetaxel, carboplatin, and trastuzumab.

Figure 2. Left Ventricular Ejection Fraction (LVEF) at 48 Months

Shown are the values for the mean left ventricular ejection fraction for 3086 of 3222 patients (96%) in the three study groups. At the time of this analysis, sufficient numbers of LVEF determinations were not yet available beyond 48 months. AC-T denotes doxorubicin and cyclophosphamide followed by docetaxel, and TCH docetaxel, carboplatin, and trastuzumab.