HER2-Positive Metastatic Breast Cancer and Brain Metastases: Survival Outcomes

Breast cancer is the most common cancer among women worldwide, with 2.3 million new cases each year, and brain involvement in metastatic disease is a major problem. In ERBB2-positive breast cancer, also known as HER2 or HER2/neu-positive disease, central nervous system (CNS) metastases remain an important cause of death because of limitations in treatment response.

A retrospective follow-up study conducted at Memorial Sloan Kettering Cancer Center and published on 31 January 2025 in JAMA Network Open investigated overall survival in patients with HER2-positive breast cancer and CNS metastases. It highlighted differences between patients with CNS metastases alone and those with additional extracranial metastases.

How Does Breast Cancer Metastasize to the Brain?

Breast cancer cells can spread through blood vessels to other parts of the body and other organs. This process involves cancer cells attaching to blood vessels, crossing the vessel wall (extravasation) and spreading to distant sites. Breast cancer cells use certain molecules and enzymes to attach to and cross blood vessel walls. These molecules help the cells adhere to the vessel wall and penetrate it. Because the brain has its own distinct blood vessels, cancer cells must cross the blood-brain barrier to reach it.

Image explanation: After spreading through the bloodstream, breast cancer cells leave the vessels and invade brain tissue. They then grow around vessels without requiring neoangiogenesis (new blood vessel formation), while the blood-brain barrier is still intact. To grow further, the new metastasis must stimulate angiogenesis. At this point, the blood-brain barrier may break down and a blood-tumor barrier begins to form.

Details of the JAMA Study

The study included 274 patients treated between 2010-2022. Most were women (99.3%), and the median age was 53,7. At diagnosis, 45.6% had metastatic disease. Among patients diagnosed with CNS metastases, 26.6% had disease confined to the CNS, while the remainder also had extracranial spread.

Survival Outcomes

The study found important associations between the pattern of disease spread, overall survival and the risk of CNS-related death.

• Patients with leptomeningeal (brain membrane) metastases had the shortest median overall survival: 1.24 years (95% CI = 0.89–2.08 years).
• Overall survival in patients with extracranial metastases: 2.16 years (95% CI = 1.87–2.58 years).
• Overall survival in patients with only parenchymal or dural CNS disease: 3.57 years (95% CI = 2.10–5.63 years) (P = 0.001).

During follow-up, 70.1% of all patients died, and 55.2% of these deaths were CNS-related. The most common cause of CNS-related death was neurological loss of function due to the progression of brain metastases.

Patients with CNS-confined disease continued to be at risk of CNS-related death.

• 3-year CNS-related mortality: 34.0% (95% CI = 22.8% - 45.4%)
• 3-year mortality from other causes: 6.1% (95% CI = 1.9% - 13.7%)

Treatment Strategies and Recommendations

The researchers emphasized the importance of aggressive local and systemic treatment to control progression of CNS metastases. Multivariable analyses showed a significantly higher risk of CNS-related death in patients with leptomeningeal disease (HR = 1.87; 95% CI = 1.19–2.93; P = 0.007). A higher risk of CNS-related death was also observed among those who received whole-brain radiotherapy (HR = 1.71; 95% CI = 1.13–2.58; P = 0.01).

Conclusion

A large proportion of patients with HER2-positive breast cancer and CNS metastases die because of CNS disease progression. Although patients with CNS-confined disease survive longer, their risk of CNS-related death remains high. There is a clear need for more effective CNS-penetrating systemic treatments. Patients with CNS disease should be included in clinical trials of emerging ERBB2-targeted treatments, and new trial designs should focus on CNS-related endpoints.