What protects the brain in metastatic breast cancer with HER2 positivity?

From the Guidelines

The combination of tucatinib, capecitabine, and trastuzumab is the most effective treatment for protecting the brain in metastatic breast cancer with HER2 positivity, particularly in patients with brain metastases without symptomatic mass effect and whose disease has progressed on at least one previous treatment. For HER2-positive metastatic breast cancer with brain metastases, the standard treatments typically include:

• Targeted therapies: Trastuzumab (Herceptin) combined with pertuzumab (Perjeta) and chemotherapy
• Tyrosine kinase inhibitors: Tucatinib (Tukysa) or neratinib (Nerlynx)
• Antibody-drug conjugates: Trastuzumab emtansine (Kadcyla) or trastuzumab deruxtecan (Enhertu)
• Local treatments: Stereotactic radiosurgery or whole brain radiation therapy These treatments are designed to target HER2-positive cancer cells and cross the blood-brain barrier to reach brain metastases, as supported by the ASCO guideline update 1 and the HER2CLIMB trial 1. When dealing with brain metastases in HER2-positive breast cancer, it's crucial to work closely with a multidisciplinary team including oncologists, radiation oncologists, and neurosurgeons to determine the best treatment approach based on the number, size, and location of brain metastases, as well as the patient's overall health and disease status. Additionally, recent studies have shown that trastuzumab deruxtecan (T-DXd) may become an additional standard of care for patients with HER2-positive metastatic breast cancer, including those with brain metastases, due to its efficacy in patients with active brain metastases 1. However, the most recent and highest quality study, the 2025 expert recommendations on treatment sequencing and challenging clinical scenarios in HER2-positive metastatic breast cancer, suggests that the combination of tucatinib, trastuzumab, and capecitabine may be the preferred treatment option for patients with brain metastases 1.

From the FDA Drug Label

TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

The combination of tucatinib, trastuzumab, and capecitabine protects the brain in metastatic breast cancer with HER2 positivity by treating the brain metastases.

• Tucatinib is a tyrosine kinase inhibitor that targets HER2.
• Trastuzumab is a monoclonal antibody that targets HER2.
• Capecitabine is a chemotherapeutic agent that is converted to 5-fluorouracil in the body. This combination has been shown to be effective in treating HER2-positive metastatic breast cancer, including patients with brain metastases 2.

From the Research

Protection of the Brain in Metastatic Breast Cancer with HER2 Positivity

• The administration of anti-HER2 monoclonal antibodies, such as trastuzumab and pertuzumab, can delay the onset of symptomatic brain disease in patients with HER2-positive breast cancer 3.
• However, the limited penetration of these compounds into the central nervous system (CNS) hinders their efficacy in preventing brain metastases 3, 4.
• Small-molecule tyrosine kinase inhibitors, such as lapatinib, neratinib, afatinib, and tucatinib, have shown promise in preventing and treating brain metastases in HER2-positive breast cancer patients due to their ability to penetrate the blood-brain barrier more efficiently 3, 5.
• Combination therapies, such as trastuzumab and pyrotinib, have also shown favorable responses in patients with HER2-positive metastatic breast cancer with brain metastases 6.
• Pertuzumab, when added to trastuzumab and taxane, has been shown to significantly delay the occurrence of brain metastases in the first-line metastatic setting 5.
• Neratinib and tucatinib have also demonstrated benefits in delaying brain metastases progression and improving overall survival in patients with HER2-positive metastatic breast cancer 5.

Current Treatment Approaches

• Current treatment approaches for brain metastasis in HER2-positive breast cancer include traditional treatment, targeted treatment, immunotherapy, and other treatment modalities 7.
• Targeted therapies, such as tyrosine kinase inhibitors, have shown promise in improving patient survival rates and preventing brain metastases 3, 5.
• Identifying potential targets and understanding the molecular and cellular mechanisms of brain metastasis are crucial for improving treatment outcomes in patients with HER2-positive breast cancer 7.