Phase II study of weekly intravenous Trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer

Department of Medicine, Services of Breast and Gynecological Cancer Medicine and Clinical Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Seminars in Oncology (Impact Factor: 3.9). 09/1999; 26(4 Suppl 12):78-83.
Source: PubMed


The HER2/neu proto-oncogene is overexpressed in 25% to 30% of patients with breast cancer. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a recombinant humanized monoclonal antibody with high affinity for the HER2 protein, inhibits the growth of breast cancer cells overexpressing HER2. In this phase II study the efficacy and toxicity of weekly administration of trastuzumab was evaluated in 46 patients with metastatic breast cancer whose tumors overexpressed HER2. A loading dose of 250 mg trastuzumab was administered intravenously, which was followed by 10 weekly doses of 100 mg each. Upon completion of this treatment period, patients with no disease progression could receive a weekly maintenance dose of 100 mg. Patients in this trial had extensive metastatic disease, and most had received prior anticancer therapy. Ninety percent of patients achieved adequate serum levels of trastuzumab. Toxicity was minimal, and no antibodies against trastuzumab could be detected. Objective responses were observed in 5 of the 43 evaluable patients, which included 1 complete remission and 4 partial remissions, for an overall response rate of 11.6%. Responses were seen in mediastinum, lymph nodes, liver, and chest wall lesions. Minor responses (seen in 2 patients) and stable disease (14 patients) lasted for a median of 5.1 months. These results demonstrate that trastuzumab is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers who have received extensive prior therapy. The regression of human cancer through the targeting of putative growth factor receptors such as HER2 warrants further evaluation of trastuzumab in the treatment of breast cancer.

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    • "Trastuzumab (Herceptin), a humanized IgG1 that binds to HER2 ectodomain, is the first approved therapy for treating HER2-overexpressing breast cancers [54, 55]. It has been shown to induce tumor regressions in 12–35% of heavily pretreated metastatic breast cancers with HER2 overexpression [56-58]. In patients with HER2-positive early stage breast cancer, addition of trastuzumab to adjuvant chemotherapy has been associated with significant benefits in survival and locoregional/distant recurrence, but a worse outcome in central nervous system (CNS) recurrence [59]. "
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    ABSTRACT: The discovery of microRNAs (miRNAs) has opened up new avenues for studying cancer at the molecular level, featuring a post-genomic era of biomedical research. These non-coding regulatory RNA molecules of ~22 nucleotides have emerged as important cancer biomarkers, effectors, and targets. In this review, we focus on the dysregulated biogenesis and function of miRNAs in cancers with an overexpression of the proto-oncogene HER2. Many of the studies reviewed here were carried out in breast cancer, where HER2 overexpression has been extensively studied and HER2-targeted therapy practiced for more than a decade. MiRNA signatures that can be used to classify tumors with different HER2 status have been reported but little consensus can be established among various studies, emphasizing the needs for additional well-controlled profiling approaches and meta-analyses in large and well-balanced patient cohorts. We further discuss three aspects of microRNA dysregulation in or contribution to HER2-associated malignancies or therapies: (a) miRNAs that are up- or down-regulated by HER2 and mediate the downstream signaling of HER2; (b) miRNAs that suppress the expression of HER2 or a factor in HER2 receptor complexes, such as HER3; and (c) miRNAs that affect responses to anti-HER2 therapies. The regulatory mechanisms are elaborated using mainly examples of miR- 205, miR-125, and miR-21. Understanding the regulation and function of miRNAs in HER2-overexpressing tumors shall shed new light on the pathogenic mechanisms of microRNAs and the HER2 proto-oncogene in cancer, as well as on individualized or combinatorial anti-HER2 therapies.
    09/2013; 2(2):137-47. DOI:10.2174/22115366113029990011
    • "In addition, HER-2/neu-positivity is thought to predict the likelihood of resistance or sensitivity to some conventional hormonal therapies like tamoxifen. Herceptin (trastuzumab), a recombinant humanised anti-HER-2/neu monoclonal antibody has been shown to improve outcomes for women with metastatic breast cancer, either alone or in combination with chemotherapy.13 "
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    ABSTRACT: This is a literature review on the aetiology and pathogenesis of breast cancer, which is the most common cancer worldwide, and the second leading cause of cancer death, especially in Western countries. Several aetiological factors have been implicated in its pathogenesis, and include age, genetics, family history, diet, alcohol, obesity, lifestyle, physical inactivity, as well as endocrine factors. These factors act separately or together in the causation of breast cancer. More recently, triple negative breast cancer has been described in certain categories of patients and is associated with poorer prognosis and earlier recurrence compared with the conventional breast cancer. Therefore, adequate knowledge of these factors is important in identifying high risk groups and individuals, which will help in screening, early detection and follow-up. This will help to decrease the morbidity and mortality from this life-threatening disease.
    Journal of the Nigeria Medical Association 03/2013; 54(6):371-375. DOI:10.4103/0300-1652.126284
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    • "It was thus hypothesized that HER2 inhibition could be an effective therapeutic strategy for the treatment of HER2 overexpressing tumors. This led to the development of trastuzumab, a specific anti-HER2 humanized recombinant monoclonal antibody (mAb), which showed considerable clinical utility in patients with HER2-overexpressing breast tumors in both metastatic [6]–[10] and adjuvant [11]–[13] settings. "
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    ABSTRACT: Following the development of targeted therapies against EGFR and HER2, two members of the human epidermal receptor (HER) family of receptor tyrosine kinases, much interest has been focused on their expression in tumors. However, knowing the expression levels of individual receptors may not be sufficient to predict drug response. Here, we describe the development of antibody-based time-resolved Förster resonance energy transfer (TR-FRET) assays for the comprehensive analysis not only of EGFR and HER2 expression in tumor cryosections, but also of their activation through quantification of HER homo- or heterodimers. First, EGFR and HER2 expression levels were quantified in 18 breast tumors and the results were compared with those obtained by using reference methods. The EGFR number per cell determined by TR-FRET was significantly correlated with EGFR mRNA copy number (P<0.0001). Moreover, our method detected HER2 overexpression with 100% specificity and sensibility, as confirmed by the standard IHC, FISH and qPCR analyses. EGFR and HER2 dimerization was then assessed, using as controls xenograft tumors from cell lines with known dimer expression profiles. Our results show that quantification of HER dimerization provides information about receptor activation that cannot be obtained by quantification of single receptors. Quantifying HER expression and dimerization by TR-FRET assays might help identifying novel clinical markers for optimizing patients' treatment in oncology.
    PLoS ONE 07/2012; 7(7):e37065. DOI:10.1371/journal.pone.0037065 · 3.23 Impact Factor
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