Preclinical Efficacy of Ado-trastuzumab Emtansine in the Brain Microenvironment
Preclinical Efficacy of Ado-trastuzumab Emtansine in the Brain Microenvironment
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DOI：
10.1093/jnci/djv313
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发表时间：
2016-02-01
影响因子：
10.3
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
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作者：
Askoxylakis, Vasileios;Ferraro, Gino B.;Jain, Rakesh K.
背景资料：中枢神经系统（CNS）转移是治疗人表皮生长因子受体2（HER 2）阳性乳腺癌的主要问题，因为HER 2靶向治疗对脑病变的疗效令人失望。抗体-药物偶联物ado-曲妥珠单抗-美坦新偶联物（T-DM 1）已在曲妥珠单抗耐药的系统性乳腺癌中显示出疗效。在这里，我们测试的假设，T-DM 1可以克服曲妥珠单抗耐药的小鼠模型的脑metabolis.Methods：我们治疗雌性裸鼠轴承BT474或MDA-MB-361脑转移瘤（n = 9-11每组）或生长在器官型脑切片培养的癌细胞与曲妥珠单抗或T-DM 1在等效或等效剂量。使用活体成像，分子技术和组织学分析，我们确定了肿瘤生长，小鼠生存，癌细胞凋亡和增殖，肿瘤药物分布和HER 2信号。数据采用单因素方差分析（ANOVA）、Kaplan-Meier分析和决定系数进行分析。所有的统计检验都是双侧的。结果：与曲妥珠单抗相比，T-DM 1延迟了HER 2阳性乳腺癌脑转移瘤的生长。这些发现在HER 2驱动和PI 3 K驱动的肿瘤之间是一致的。T-DM 1的活性导致生存益处（BT474肿瘤的中位生存期：曲妥珠单抗为28天，T-DM 1为112天，风险比= 6.2，95%置信区间= 6.1至85.84，P < .001）。两组之间的药物分布或HER 2信号传导没有差异。然而，T-DM 1导致肿瘤细胞凋亡的统计学显著增加（ApopTag的单因素方差分析，P < .001），这与有丝分裂灾难有关。结论：由于DM 1组分的细胞毒性，T-DM 1可以克服HER 2驱动或PI 3 K驱动的乳腺癌脑病变中对曲妥珠单抗治疗的抗性。T-DM 1用于HER 2阳性乳腺癌CNS转移患者的临床研究是必要的。
Background: Central nervous system (CNS) metastases represent a major problem in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer because of the disappointing efficacy of HER2-targeted therapies against brain lesions. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in murine models of brain metastases.Methods: We treated female nude mice bearing BT474 or MDA-MB-361 brain metastases (n = 9-11 per group) or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. Data were analyzed with one-way analysis of variance (ANOVA), Kaplan-Meier analysis, and Coefficient of Determination. All statistical tests were two-sided.Results: T-DM1 delayed the growth of HER2-positive breast cancer brain metastases compared with trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a survival benefit (median survival for BT474 tumors: 28 days for trastuzumab vs 112 days for T-DM1, hazard ratio = 6.2, 95% confidence interval = 6.1 to 85.84, P < .001). No difference in drug distribution or HER2-signaling was revealed between the two groups. However, T-DM1 led to a statistically significant increase in tumor cell apoptosis (one-way ANOVA for ApopTag, P < .001), which was associated with mitotic catastrophe.Conclusions: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven or PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted.