Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):E3119-27. doi: 10.1073/pnas.1216078109. Epub 2012 Oct 15.
Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.
脑转移是治疗人表皮生长因子受体 2（HER2）扩增型乳腺癌患者的严重障碍。尽管大多数患者使用 HER2 抑制剂控制了颅外疾病，但脑转移仍经常发生。由于这些脑转移对治疗没有反应，因此它们常常是治疗失败的原因。我们使用 BT474 细胞的原位异种移植建立了 HER2 扩增型乳腺癌脑转移的小鼠模型。与患者所见相同，HER2 抑制剂曲妥珠单抗和拉帕替尼控制了乳房中的肿瘤进展，但未能控制大脑中的肿瘤生长。我们观察到，HER2 抑制剂与抗血管内皮生长因子受体 2（VEGFR2）抗体的联合使用可显著减缓大脑中的肿瘤生长，从而带来显著的生存获益。这种获益主要归因于增强的抗血管生成作用：联合治疗降低了脑异种移植物中的总微血管密度和功能性微血管密度。此外，联合治疗导致脑病变的坏死明显增加。此外，我们观察到在将曲妥珠单抗和拉帕替尼与抗 VEGFR2 抗体联合使用后，抗肿瘤活性甚至更好。与对照组相比，这种三药联合方案将中位总生存期延长了五倍，与两种药物方案相比延长了两倍。这些发现支持了将这种三药方案用于治疗 HER2 扩增型乳腺癌脑转移的临床开发。
