The proposed research will address the following overarching challenges defined by the Breast Cancer Research Program (BCRP): (1) identify what drives breast cancer growth; determine how to stop it; (2) identify why some breast cancers become metastatic; and (3) eliminate the mortality associated with metastatic breast cancer.

This proposal is focused on helping women with advanced breast cancer. When cancer spreads into the fluid spaces that surround the surface of the brain and spinal cord, it is called leptomeningeal disease (LMD). Although it was discovered nearly 150 years ago, LMD remains incurable with few treatment options. Although any malignancy can spread to the cerebrospinal fluid (CSF) space, breast cancer (particularly the Her2+ subtype) is the most common. Our proposal focuses on breast cancer LMD.

Significant progress has been made in developing breast cancer treatments that target systemic disease, but efficacy in the central nervous system (CNS) remains a challenge, with LMD typically developing while the systemic tumor burden is well managed. And the presence of nodular deposits is associated with the greatest suffering from headaches and intractable pain due to cranial and spinal nerve irritation. Our proposal investigates (using unprecedented surgically obtained tissue) the biology of why LMD is so aggressive. This clearer understanding of drives LMD, will guide our focused efforts on testing existing Food and Drug Administration (FDA)-approved therapies (for other cancers) to treat LMD. This will allow us to proceed to clinical trials at the end of the grant period and has the potential to fulfill the immediate goals of the BCRP.

Over the last 9 years, I have provided care to woman with breast cancer metastases to the CNS. During this time, the lack of progress with treatment of LMD has only taken on more urgency as other biological therapies have proven effective for systemic disease. Innovations and discovery from the work proposed in this grant will be streamlined to clinical trials, if appropriate.

We have launched several first-in-human clinical trials, and currently I am the lead surgeon for delivery of CAR-T cells into the CSF of patients with brain metastases from Her2+ breast cancers. We have the commitment, personal investment, and institutional environment to help improve both the length and quality of life for women with advanced breast cancer.