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Published on: February 8, 2017
Preclinical Efficacy of Ado-trastuzumab Emtansine in the Brain Microenvironment
Vasileios Askoxylakis1, Gino B Ferraro1, David P Kodack1
1: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
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.
Insights
Ado-trastuzumab emtansine (T-DM1) effectively treats HER2-positive breast cancer brain metastases, overcoming trastuzumab resistance by inducing cancer cell death. This antibody-drug conjugate offers a promising therapeutic strategy for patients with CNS involvement.
Area of Science:
- Oncology
- Pharmacology
- Neuroscience
Background:
- Central nervous system (CNS) metastases are a significant challenge in HER2-positive breast cancer treatment.
- HER2-targeted therapies show limited efficacy against brain lesions.
- Ado-trastuzumab emtansine (T-DM1) has demonstrated success in systemic HER2-positive breast cancer resistant to trastuzumab.
Purpose of the Study:
- To evaluate the efficacy of T-DM1 in overcoming trastuzumab resistance in murine models of HER2-positive breast cancer brain metastases.
- To investigate the mechanisms underlying T-DM1's activity against CNS lesions.
Main Methods:
- Female nude mice with BT474 or MDA-MB-361 brain metastases were treated with trastuzumab or T-DM1.
- Intravital imaging, molecular techniques, and histological analysis were employed.
- Tumor growth, survival, apoptosis, proliferation, drug distribution, and HER2 signaling were assessed.
Main Results:
- T-DM1 significantly delayed brain metastases growth and improved survival compared to trastuzumab.
- T-DM1 induced a significant increase in tumor cell apoptosis via mitotic catastrophe.
- No significant differences in drug distribution or HER2 signaling were observed between treatments.
Conclusions:
- T-DM1 overcomes trastuzumab resistance in HER2- or PI3K-driven breast cancer brain lesions.
- The DM1 component's cytotoxicity is key to T-DM1's efficacy.
- Clinical investigation of T-DM1 for CNS metastases in HER2-positive breast cancer is recommended.
