Nancy U. Lin, MD

Advancing new strategies to prevent and treat breast cancer metastasis to the brain and central nervous system.

Impact

Brain metastases (cancer that has spread to the brain) remains a major problem in breast cancer. Nearly half of HER2-positive metastatic breast cancers (MBCs), 25 to 45 percent of triple-negative MBCs, and 15 percent of ER-positive MBCs spread to the brain during the course of the disease. Dr. Lin is focused on developing effective strategies to prevent and treat metastases to the central nervous system (CNS), either to the brain or to the spinal fluid and lining of the brain (leptomeningeal disease, LMD), which will help extend survival of patients and improve their quality of life.

Progress Thus Far

Therapies targeting the HER2 protein are generally effective in patients with HER2-positive MBC. However, these therapies lose their effectiveness in patients whose cancer has spread to the CNS, either because they are ineffective in the brain, or the cancer evades the treatments by other means. Dr. Lin has successfully led clinical trials testing the drugs lapatinib, neratinib and tucatinib for the treatment of HER2-positive MBC patients—this has led to FDA approval of these treatments. Most clinical trials exclude patients with brain metastases or LMD and clinical trials led by Dr. Lin are among the first to include them.

Dr. Lin and her team are characterizing the genomic alterations that predispose patients to develop brain metastases. They are analyzing data from over 2,000 patients with MBC and have observed that brain metastases are genomically distinct from primary tumors and other sites of metastases. They have also identified specific mutations that are associated with the development of brain metastases. The team has also generated preliminary data that an antibody-drug conjugate (trastuzumab deruxtecan, T-DXd), may be effective in the CNS. T-DXd (Enhertu®) is FDA approved for treatment of HER2-low MBC but has not been tested in patients with CNS disease.

What’s next

In the coming year, they will be conducting a multicenter national clinical study within the Translational Breast Cancer Research Consortium (TBCRC) evaluating the effects of T-DXd in patients with breast cancer brain metastasis. In addition, Dr. Lin and her team will launch a multicenter phase II clinical trial testing another antibody-drug conjugate, datopotamab deruxtecan, in patients with HER2-negative and triple-negative breast cancer brain metastasis or LMD.

Lastly, the team will develop and launch a multicenter registry study designed to collect and pool demographic, clinical and pathologic data, as well as research biospecimens including blood, cerebrospinal fluid, and tumor tissue in patients with MBC and LMD. The primary goal of this registry is to describe the outcomes with a variety of therapies in patients with LMD. The research team will use imaging to assess tumor response, neurological exams, and patient-reported outcomes to rapidly report on real world activity of diverse therapeutics outside of clinical trials. It will provide a practical platform to aggregate information on treatment outcomes to inform patient care.