Goldenberg M M
Mount Sinai NYU Health, New York, New York 10029, USA.
Clin Ther. 1999 Feb;21(2):309-18. doi: 10.1016/S0149-2918(00)88288-0.
Amplification of the human epidermal growth factor receptor 2 protein (HER2) in primary breast carcinomas has been shown to correlate with poor clinical prognosis for certain patients. Trastuzumab (Herceptin, Genentech, Inc., South San Francisco, California) is a highly purified recombinant DNA-derived humanized monoclonal immunoglobulin G1 kappa antibody that binds with high affinity and specificity to the extracellular domain of the HER2 receptor. In vitro and in vivo preclinical studies have shown that administration of trastuzumab alone or in combination with paclitaxel or carboplatin significantly inhibits the growth of breast tumor-derived cell lines that overexpress the HER2 gene product. At therapeutic doses in breast cancer patients, the mean half-life of trastuzumab is 5.8 days. Trastuzumab serum concentrations reach steady state with mean trough and peak concentrations of 79 microg/mL and 123 microg/mL, respectively. In a 222-patient, single-arm clinical study, treatment with a loading dose of trastuzumab 4 mg/kg administered IV followed by weekly IV doses of 2 mg/kg produced an overall response rate of 14% (2% complete remission and 12% partial remission). The beneficial effects were greatest in patients with the greatest degree (3+) of HER2 protein overexpression. In another clinical study, 469 women with metastatic breast carcinoma were randomized to a paclitaxel or anthracycline-plus-cyclophosphamide regimen with or without trastuzumab. The overall response rate was significantly greater in the trastuzumab-plus-chemotherapy group than in the chemotherapy-alone cohort. The magnitude of observed effects was greatest with pacli taxel plus trastuzumab. The most common adverse effects attributed to trastuzumab in clinical studies were fever and chills, pain, asthenia, nausea, vomiting, increased cough, diarrhea, headache, dyspnea, infection, rhinitis, and insomnia. Trastuzumab in combination with chemotherapy can lead to cardiotoxicity, leukopenia, anemia, diarrhea, abdominal pain, and infection. Trastuzumab has been approved by the US Food and Drug Administration as a single agent for the treatment of patients who have metastatic breast cancer involving overexpression of the HER2 protein and who have received 1 or more chemotherapy regimens; in combination with paclitaxel, it has been approved for the treatment of such patients who have not received chemotherapy.
原发性乳腺癌中人类表皮生长因子受体2蛋白（HER2）的扩增已被证明与某些患者的不良临床预后相关。曲妥珠单抗（赫赛汀，基因泰克公司，加利福尼亚州南旧金山）是一种高度纯化的重组DNA衍生的人源化单克隆免疫球蛋白G1κ抗体，它以高亲和力和特异性与HER2受体的细胞外结构域结合。体外和体内临床前研究表明，单独给予曲妥珠单抗或与紫杉醇或卡铂联合使用，可显著抑制过表达HER2基因产物的乳腺肿瘤衍生细胞系的生长。在乳腺癌患者的治疗剂量下，曲妥珠单抗的平均半衰期为5.8天。曲妥珠单抗血清浓度达到稳态时，平均谷浓度和峰浓度分别为79μg/mL和123μg/mL。在一项222例患者的单臂临床研究中，静脉注射4mg/kg的曲妥珠单抗负荷剂量，随后每周静脉注射2mg/kg，总缓解率为14%（2%完全缓解和12%部分缓解）。HER2蛋白过表达程度最高（3+）的患者受益最大。在另一项临床研究中，469名转移性乳腺癌女性被随机分为接受紫杉醇或蒽环类药物加环磷酰胺方案，同时或不同时使用曲妥珠单抗。曲妥珠单抗加化疗组的总缓解率显著高于单纯化疗组。观察到的效果在紫杉醇加曲妥珠单抗组最为显著。临床研究中归因于曲妥珠单抗的最常见不良反应是发热和寒战、疼痛、乏力、恶心、呕吐、咳嗽加重、腹泻、头痛、呼吸困难、感染、鼻炎和失眠。曲妥珠单抗与化疗联合使用可导致心脏毒性、白细胞减少、贫血、腹泻、腹痛和感染。曲妥珠单抗已被美国食品药品监督管理局批准作为单一药物，用于治疗HER2蛋白过表达的转移性乳腺癌患者，且这些患者已接受过1种或更多种化疗方案；与紫杉醇联合使用时，已被批准用于治疗未接受过化疗的此类患者。
