Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer

Abstract

Background: Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer.

Methods: We randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo.

Results: In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%).

Conclusions: Pertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. (Funded by F. Hoffmann-La Roche/Genentech; APHINITY ClinicalTrials.gov number, NCT01358877 .).

Figure 1. Kaplan–Meier Plot of Invasive-Disease–free Survival

Invasive-disease–free survival was defined as the time from randomization until the date of the first occurrence of one of the following invasive-disease events: recurrence of ipsilateral invasive breast tumor, recurrence of ipsilateral locoregional invasive disease, a distant disease recurrence, con-tralateral invasive breast cancer, or death from any cause.

Figure 2. Forest Plot of Invasive-Disease–free Survival

Hormone-receptor status was based on the test results determined by a central laboratory, which repeated the testing that was performed locally at each participating center. For hormone-receptor status, negative denotes estrogen-receptor–negative and progesterone-receptor–negative; positive denotes estrogen-receptor–positive, progesterone-receptor–positive, or both. Under the original protocol (protocol A), patients with node-negative tumors were initially eligible for participation in the trial if at least one of the following high-risk features was present: histologic or nuclear grade 3, negativity for estrogen and progesterone receptors, or age younger than 35 years. Under protocol B, which included an amendment that was added after 3655 patients had undergone randomization, patients with node-negative disease were no longer eligible for enrollment. NA denotes not applicable.