Annals of oncology : official journal of the European Society for Medical Oncology
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One of the major expectations from the use of humanized monoclonal antibodies in cancer therapy has been that of exploiting the specificity and sensitivity of the immune system to achieve selective therapeutic effects devoid of the often severe toxicity caused by chemotherapy. The tolerability of trastuzumab (Herceptin) as it emerged from the trials where the drug was used as a single agent or in combination with chemotherapy largely confirmed that expectation. ⋯ However, the occurrence of cardiac toxicity that was unexpectedly high, especially in patients previously or concomitantly treated with anthracyclines, could not be predicted on the basis of the putative mechanism of action of the antibody. The safety profile of trastuzumab is discussed here with a particular focus on cardiotoxicity and the issues relating to patient management during trastuzumab therapy.
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Randomized Controlled Trial Multicenter Study Clinical Trial
Trastuzumab combined with chemotherapy for the treatment of HER2-positive metastatic breast cancer: pivotal trial data.
A pivotal, randomized, multicenter, phase III trial was conducted to compare chemotherapy in combination with trastuzumab (Herceptin) vs. chemotherapy (anthracycline plus cyclophosphamide [AC] or paclitaxel) alone as first-line treatment for HER2-positive metastatic breast cancer. Results from a total of 469 patients, randomized to receive either chemotherapy alone or chemotherapy plus trastuzumab, revealed that the addition of trastuzumab improved time to disease progression significantly (7.6 vs. 4.6 months. P = 0.0001) compared with chemotherapy alone. ⋯ Patients receiving combination therapy also had a greater overall response rate (49% vs. 32%, P = 0.0002) and a longer median response duration (9.3 vs. 5.9 months, P = 0.0001) than those who received chemotherapy alone. Most importantly, median follow-up of 29 months revealed a significantly increased median survival in patients receiving trastuzumab plus chemotherapy (25.4 vs. 20.3 months, P < 0.025) compared with those receiving chemotherapy alone. Trastuzumab plus chemotherapy was well tolerated; adverse events were typically mild-to-moderate chills and fever and occurred in approximately 40% of patients, primarily following the first administration only.
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Current evidence shows that adjuvant cytotoxic or hormonal therapy increases the disease-free and overall survival of patients. The analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed that anthracycline/cyclophosphamide (AC)-containing regimens are more effective than those without AC, providing an 11% greater reduction in the risk of death compared with non-AC-containing regimens. In addition, paclitaxel and docetaxel have significant anti-tumor activity in previously treated patients and sequential treatment with paclitaxel may further reduce the risk of recurrence and improve survival. ⋯ AC --> paclitaxel + trastuzumab vs. AC --> paclitaxel --> trastuzumab). Results from these trials will determine whether this novel therapy has a survival benefit in early breast cancer.
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Following the pivotal clinical trials of trastuzumab (Herceptin), further phase II and III studies have been initiated. Preliminary results from a phase II, dose-response study of single-agent trastuzumab in 113 HER2-positive metastatic breast cancer patients without prior chemotherapy for stage IV disease have shown that the overall response rate was 23% (six complete responses and 20 partial responses), with similar results using both standard- and high-dose regimens of trastuzumab. Another phase II study of trastuzumab plus paclitaxel, both given weekly, in 63 HER2-positive and -negative patients with metastatic breast cancer produced an overall response rate of 62% in HER2-positive and 44% in HER2-negative patients. ⋯ These include docetaxel +/- trastuzumab, aromatase inhibitor +/- trastuzumab, CMF (cyclophosphamide, methotrexate, 5-fluorouracil) +/- trastuzumab, vinorelbine + trastuzumab, all in HER2-positive patients, and epirubicin-cyclophosphamide (EC) + trastuzumab in HER2-positive patients vs. EC alone in HER2-negative patients. The results from these trials should be available over the next one to two years.
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Human epidermal growth factor receptors (HER/erbB) constitute a family of four cell surface receptors involved in transmission of signals controlling normal cell growth and differentiation. A range of growth factors serve as ligands, but none is specific for the HER2 receptor. HER receptors exist as both monomers and dimers, either homo- or heterodimers. ⋯ This explains why HER2 overexpression is an indicator of poor prognosis in breast tumors and may be predictive of response to treatment. HER2 is a highly specific and promising target for new breast cancer treatments. The recombinant human anti-HER2 monoclonal antibody (rhuMAb-HER2, trastuzumab, Herceptin) induces rapid removal of HER2 from the cell surface, thereby reducing its availability to heterodimers and reducing oncogenicity.