Madhusudan Srinivasan, Foster Martin, Muthuramalingam Sethupathi R, Braybrooke Jeremy P, Wilner Susan, Kaur Kulwinder, Han Cheng, Hoare Susan, Balkwill Frances, Talbot Denis C, Ganesan Trivadi S, Harris Adrian L
Cancer Research United Kingdom Medical Oncology Unit, University of Oxford, The Churchill, Oxford Radcliffe Hospitals, Headington, Oxford, United Kingdom.
Clin Cancer Res. 2004 Oct 1;10(19):6528-34. doi: 10.1158/1078-0432.CCR-04-0730.
Tumor necrosis factor (TNF) alpha is a key player in the tumor microenvironment and is involved in the pathogenesis of breast cancer. Etanercept is a recombinant human soluble p75 TNF receptor that binds to TNF-alpha and renders it biologically unavailable. In the current study, we sought to determine the toxicity, biological activity, and therapeutic efficacy of Etanercept in metastatic breast cancer.
We initiated a Phase II, nonrandomized, open-labeled study in patients with progressive metastatic breast cancer refractory to conventional therapy (Phase I toxicity data were available in patients with rheumatoid arthritis). Etanercept was administered subcutaneously at a dose of 25 mg twice weekly until disease progression.
Sixteen patients were recruited [median age 53 years (range, 34 to 74)]. A total of 141.6 weeks of therapy was administered (median of 8.1 weeks). Seven patients received > or =12 weeks of therapy. The most common side effects were injection site reactions (6), fatigue (5), loss of appetite (2), nausea (1), headache (1), and dizziness (1). Brief period of disease stabilization was seen in 1 patient lasting for 16.4 weeks. Immunoreactive TNF-alpha was elevated within 24 hours of therapy and persisted until the end of treatment (days 7, 28, 56, and 84). Phytohemagglutinin stimulates the production of interleukin-6 and CCL2 in peripheral blood cells, and the ability of Etanercept to modulate this response was assessed in a cytokine release assay. A consistent decrease in interleukin-6 and CCL2 level was seen compared with pretreatment values in serial blood samples (days 1, 7, 28, 56, and 84).
Our study shows the safety and biological activity of Etanercept in breast cancer and provides data to assess pharmacodynamic endpoints of different schedules of Etanercept and combinations with chemotherapy or other biological therapies.
肿瘤坏死因子（TNF）α是肿瘤微环境中的关键因子，参与乳腺癌的发病机制。依那西普是一种重组人可溶性p75 TNF受体，可与TNF-α结合并使其失去生物学活性。在本研究中，我们旨在确定依那西普在转移性乳腺癌中的毒性、生物学活性和治疗效果。
我们对传统治疗难治的进展期转移性乳腺癌患者开展了一项II期、非随机、开放标签研究（类风湿关节炎患者有I期毒性数据）。依那西普以25 mg的剂量皮下注射，每周两次，直至疾病进展。
招募了16名患者[中位年龄53岁（范围34至74岁）]。共进行了141.6周的治疗（中位8.1周）。7名患者接受了≥12周的治疗。最常见的副作用为注射部位反应（6例）、疲劳（5例）、食欲减退（2例）、恶心（1例）、头痛（1例）和头晕（1例）。1例患者出现了为期16.4周的疾病短暂稳定期。免疫反应性TNF-α在治疗后24小时内升高，并持续至治疗结束（第7、28、56和84天）。植物血凝素刺激外周血细胞产生白细胞介素-6和CCL2，并在细胞因子释放试验中评估依那西普调节这种反应的能力。与系列血样（第1、7、28、56和84天）的预处理值相比，白细胞介素-6和CCL2水平持续下降。
我们的研究显示了依那西普在乳腺癌中的安全性和生物学活性，并提供了数据以评估依那西普不同给药方案以及与化疗或其他生物疗法联合使用时的药效学终点。
