Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials

Abstract

Background: Breast cancer is the most common cancer in women in the U.S. and Western Europe. Amplification of the her-2/neu gene occurs in approximately 25% of invasive ductal carcinomas of the breast. The first HER-2/neu-targeted approach to reach the clinic was trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER-2/neu protein. Trastuzumab therapy prolongs the survival of patients with metastático HER-2/neu-overexpressing breast cancer when combined with chemotherapy and has recently been demonstrated to lead to dramatic improvements in disease-free survival when used in the adjuvant therapy setting in combination with or following chemotherapy. Here, we performed a meta-analysis of completed clinical trials of adjuvant trastuzumab in the adjuvant setting. Survival, recurrence, brain metastases, cardiotoxicity and directions for future research are discussed.

Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

“…Paradoxically, the targeted anti-HER2 therapy applied to the HER2-positive BC patients may be associated with an increased risk of BM development: four studies dedicated to the meta-analyses of large adjuvant trastuzumab trials found 1.3-to 1.8-fold increased risk of BM as the first metastatic site [58][59][60][61]. On the other side, the retrospective analysis showed no significant difference in BM development as the first site of recurrence amongst HER2-positive BC patients receiving 1-yearlong adjuvant trastuzumab against placebo (2 vs. 2%, respectively, P = 0.55) [62].…”

Pegylated liposomal doxorubicin and trastuzumab as 1st and 2nd line therapy in her2/neu positive metastatic breast cancer: a multicenter phase II trial

“…However, even in the adjuvant setting up to 14% of patients discontinued trastuzumab treatment due to asymptomatic but protocol sufficient decreases in LVEF. In a recent metanalysis pooled results from five randomized adjuvant trials of adjuvant trastuzumab revealed an increased likelihood of cardiac toxicity (HR 2.45, 1.89-3.16 95% CI, P = 0.001) in the trastuzumab treated patients [18]. In the neoadjuvant setting, preliminary results of the NOAH trial, presented at the 2007 ASCO Breast Cancer Symposium, revealed drops in LVEF of 15.7% for the trastuzumab regimen versus 11.5% for the non-trastuzumab arm in patients with locally advanced breast cancer receiving concomitantly 3 cycles of doxorubicin-paclitaxel (60 mg/m 2 , 150 mg/m 2 q3w), 4 cycles of Paclitaxel (175 mg/m 2 q3w) and 3 cycles of cyclophosphamide/methotrexate/5-fluorouracil (C 600 mg/m 2 , M 40 mg/m 2 , F 600 mg/m 2 ) [19].…”

“…It manifests in several forms, ranging from acute arrhythmias and nonspecific electrocardiogram changes to decreases in LVEF. Beside age, hypertension, diabetes and coronary heart disease, trastuzumab treatment represents a significant risk factor for the development of anthracycline related cardiotoxicity [12,18]. The most severe complication is cardiomyopathy leading potentially to a permanent cardiac damage [20].…”

Recommendations for research priorities in breast cancer by the Coalition of Cancer Cooperative Groups Scientific Leadership Council: systemic therapy and therapeutic individualization

“…Tamoxifen Tamoxifen was the first widely studied and approved endocrine therapy for HR-positive BC that is effective for the treatment of metastatic disease [47], reduces the risk of recurrence by about 50% when used as adjuvant therapy [5,6] and reduces the risk of BC by about 50% when used as preventive therapy in healthy women at high risk [16][17][18][19][20][21]. Ovarian suppression Chemotherapy-induced amenorrhea is a common complication of adjuvant chemotherapy, which is usually but not always indicative of menopause [63].…”

“…Randomized clinical trials have demonstrated that local excision resulted in comparable cure rates as mastectomy [4], and that adjuvant chemotherapy, endocrine therapy, and trastuzumab reduced local and systemic recurrence [5,6]. In order to bring about additional therapeutic advances, large, randomized clinical trials (CTs) remain critical.…”