Grant: Project Grant - PA: Cancer Research - Breast Cancer

Breast cancer is the second most common cancer globally. Approximately 20% of breast cancers are Her2+, and amenable to targeted therapies like trastuzumab, an anti-Her2 receptor antibody. However, trastuzumab has poor penetration past the blood-brain barrier (BBB) due to its large size and poor activity against brain metastasis. Current treatments for breast cancer brain metastases include surgery and radiation therapy, both of which pose additional upfront risk and are limited in their repeatability. Therefore, there is an urgent need to develop new, less toxic treatment for patients with brain metastases, including enhancing the delivery of trastuzumab across the BBB, so it can be as effective in the brain as it is in the body. Transcranial MR-guided focused ultrasound (MRgFUS) is an emerging technology that can temporarily open the BBB in a non-invasive, spatially-precise, and temporary manner. We have previously shown MRgFUS is well tolerated in patients with primary brain tumors and neurodegenerative diseases. In animal studies, the procedure can enhance the brain delivery of trastuzumab several fold. We propose to leverage the promising preclinical data to conduct a phase I trial combining MRgFUS with trastuzumab-based therapy in patients with Her2+ breast cancer brain metastases. Our objectives are to evaluate the safety, feasibility, and potential efficacy. We are also investigating the use of radiolabelled 111In-BzDTPA-NLS-trastuzumab, to more accurately determine the impact of MRgFUS on the pharmacokinetics of trastuzumab, and to, for the first time, provide direct evidence of target engagement of Herceptin within tumour. Exploratory outcomes will include measuring success of BBB opening, the impact of BBB opening on tumour volumes, progression and recurrence of disease, and plasma biomarkers to quantify and describe the safety of MRgFUS. Positive results will mark a significant step in developing this novel treatment approach in the next five years.