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.)

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

“…In the BCIRG006 trial, docetaxel administered with carboplatin and trastuzumab showed similar efficacy to an anthracycline‐based regimen, while having significantly less cardiac adverse events (0.4% symptomatic HF) 45. Similar rates of cardiac adverse events were reported in a recent single‐arm study of paclitaxel plus trastuzumab for small, node‐negative, HER2‐positive breast cancer (0.5% symptomatic HF) 46…”

“…However, not all cases of cardiotoxicity associated with the use of the trastuzumab are reversible. In the BCIRG006, of 194 patients randomized to doxorubicin+cyclophosphamide+docetaxel+trastuzumab who had a decline of at least 10% in LVEF, the decrease persisted for at least 4 years in 33% 45. Even in the absence of anthracycline use, persistent declines in LVEF following trastuzumab administration have been reported 46.…”

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

“…Several studies have shown that in HER2-overexpressing or amplifi ed breast cancers, the anti-HER2 humanized recombinant monoclonal antibody trastuzumab, in combination with chemotherapy, was signifi cantly more effective than chemotherapy alone, both in the metastatic and the adjuvant settings ( 36,37 ). In spite of the effectiveness of this treatment, only one third of patients who are eligible for the treatment respond; moreover, most of the patients who initially respond show disease progression within 1 year of treatment.…”

High expression of integrin β6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers

“…Tumors with overexpression of HER2 tend to have a poor prognosis in general 10. In most populations, approximately 20% of the breast cancer patients meet the diagnostic thresholds set for positive expression of HER2 protein 11, 12.…”