Clinical Activity of Trastuzumab and Vinorelbine in Women With HER2-Overexpressing Metastatic Breast Cancer

Division of Adult Oncology and Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 06/2001; 19(10):2722-30.
Source: PubMed


To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer.
Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy.
Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity.
Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

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    • "Due to these studies, the combination of taxanes plus trastuzumab became the standard first-line therapy in HER2-positive breast cancer. However, the association of trastuzumab with vinorelbine also produced response rates over 60% [30] [31] [32]. Recently, the results of a randomized phase III trial (HERNATA), comparing vinorelbine plus trastuzumab versus docetaxel plus trastuzumab were published [33]. "
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    ABSTRACT: Breast carcinoma is a complex and heterogeneous disease and several different molecular alterations are involved in its pathogenesis and progression. Different growth factor receptor-driven signaling pathways sustain the growth and survival of breast cancer cells. Actually, three targeted agents are available for the treatment of breast cancer: trastuzumab, a monoclonal antibody directed against the human epidermal growth factor receptor-2 (HER2); lapatinib, an oral available dual tyrosine-kinase inhibitor of the human epidermal growth factor receptor-1 (HER1, EGFR) and HER2; bevacizumab, a monoclonal antibody directed against the vascular endothelial growth factor (VEGF). All these agents demonstrated to be synergistic with chemotherapy. In addition, recently concluded clinical trials suggest that signaling inhibitors can prevent or overcome resistance to endocrine therapy in estrogen receptor positive (ER+) breast cancer. Moreover, several other targeted drugs are under investigation in clinical trials. The aim of this review is to give a synthetic but complete picture of various target agents for breast cancer therapy that are under clinical trials or currently available in clinical practice.
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    • "Treatment with trastuzumab (Herceptin®), a humanized murine anti-HER2 monoclonal antibody [1], produced an objective response rate of 15% in extensively pretreated patients [2] and in 26% of previously untreated women with HER2-overexpressing metastatic breast cancer [3]. Trastuzumab in combination with chemotherapy was significantly more effective than chemotherapy alone in prolonging the time to disease progression, duration of response and overall survival [4], [5], [6], [7], resulting in its approval by the FDA in 1998. Trastuzumab provided one of the first deliberately targeted therapies for a human cancer and has now become the first-line treatment of choice for patients with primary or recurrent HER2-overexpressing breast cancer [8]. "
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    ABSTRACT: Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been investigated in depth, the effect of trastuzumab on microRNA (miRNA) has not been extensively studied. We have performed miRNA microarray profiling before and after trastuzumab treatment in SKBr3 and BT474 human breast cancer cells that overexpress HER2. We found that trastuzumab treatment of SKBr3 cells significantly decreased five miRNAs and increased three others, whereas treatment of BT474 cells significantly decreased two miRNAs and increased nine. The only change in miRNA expression observed in both cell lines following trastuzumab treatment was upregulation of miRNA-194 (miR-194) that was further validated in vitro and in vivo. Forced expression of miR-194 in breast cancer cells that overexpress HER2 produced no effect on apoptosis, modest inhibition of proliferation, significant inhibition of cell migration/invasion in vitro and significant inhibition of xenograft growth in vivo. Conversely, knockdown of miR-194 promoted cell migration. Increased miR-194 expression markedly reduced levels of the cytoskeletal protein talin2 and specifically inhibited luciferase reporter activity of a talin2 wild-type 3'-untranslated region, but not that of a mutant reporter, indicating that talin2 is a direct downstream target of miR-194. Trastuzumab treatment inhibited breast cancer cell migration and reduced talin2 expression in vitro and in vivo. Knockdown of talin2 inhibited cell migration/invasion. Knockdown of trastuzumab-induced miR-194 expression with a miR-194 inhibitor compromised trastuzumab-inhibited cell migration in HER2-overexpressing breast cancer cells. Consequently, trastuzumab treatment upregulates miR-194 expression and may exert its cell migration-inhibitory effect through miR-194-mediated downregulation of cytoskeleton protein talin2 in HER2-overexpressing human breast cancer cells.
    PLoS ONE 07/2012; 7(7-10.1371/journal.pone.0041170). DOI:10.1371/journal.pone.0041170 · 3.23 Impact Factor
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    • "Despite initial encouraging results, the response rate to trastuzumab is ≤40% as single agent in the first-line treatment of metastatic breast cancer, and the median duration of response is between 9 and 12 months [Baselga, 2001; Burstein et al. 2001; Vogel et al. 2002]. This suggests that de novo and acquired resistance to trastuzumab occur. "
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    ABSTRACT: In recent years, new strategies for the treatment of breast cancer have focused on extensive target identification and understanding the expression, regulation and function of critical signaling pathways involved in breast cancer initiation and progression. This has led to significant progress in developing and understanding human epidermal growth factor receptor 2 (HER2)-targeted therapies, which in turn, has translated into significant increases in median survival for patients with HER2-overexpressing breast cancer. It is becoming increasingly difficult to make specific recommendations for the optimal treatment of HER2-overexpressing breast cancer since the field is evolving so rapidly. However, despite the many randomized trials that have been undertaken showing improvement in survival, the current standard treatment for HER2-overexpressing breast cancer continues to revolve around the addition of chemotherapy to a HER2-targeted agent, which in turn, carries substantial toxicities. This article reviews agents that have recently been investigated to treat HER2-overexpressing breast cancers. The goal is ultimately to increase the magnitude and duration of response to trastuzumab-based treatment while minimizing toxicity. Studies addressing length of therapy duration, the superiority and side-effect profile of the different biological drug combinations, and determination of biomarkers of resistance to HER2 therapy will be instrumental in decreasing morbidity and mortality for patients with HER2-overexpressing breast cancer.
    rapeutic Advances in Medical Oncology, The 05/2012; 4(3):139-47. DOI:10.1177/1758834012440834 · 2.83 Impact Factor
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