Brain Metastases in Breast Cancer: Features, Symptoms and Treatment

After lung cancer, breast cancer is the second most common cancer to metastasize to the brain. Brain metastases are becoming more common as survival improves. Risk is higher in advanced breast cancer, affecting 10-16% of women with advanced disease compared with only 3% of women with early-stage disease.

What Are the Symptoms of Brain Metastases?

Symptoms depend on the number, size and location of metastases. Common examples include:

• Headache
• Nausea and vomiting
• Loss of appetite
• Weakness
• Fatigue
• Depression
• Behavioral changes
• Memory loss or impairment
• Walking difficulties
• Speech difficulties
• Visual disturbances
• Hearing loss or impairment
• Dizziness or loss of balance

Risk Factors for Brain Metastases in Breast Cancer

Risk varies by breast cancer subtype. Women with triple-negative breast cancer or HER2-positive disease have greater risk than those with other subtypes. Patients carrying a BRCA1 or BRCA2 mutation may also have a higher risk.

Treatment is complex and may involve radiotherapy, systemic therapy or a combined plan, depending on general health, disease progression and other factors.

How Are Brain Metastases Diagnosed?

Symptoms can resemble those of other conditions, so brain imaging is generally used. The most useful radiological examination is MRI (magnetic resonance imaging). It can detect the presence and size of metastases, assess treatment response and provide post-treatment surveillance.

How Does Breast Cancer Spread to the Brain?

Breast cancer cells can spread through blood vessels to other organs. They attach to vessel walls, cross them through extravasation and disseminate to distant sites, using molecules and enzymes that help them adhere to and penetrate vessel walls. The brain differs from other regions in having its own blood vessels, so cancer cells must cross the blood-brain barrier to reach it.

Treatment of Brain Metastases

Treatment aims to improve quality of life and prolong survival. However, complete cure of brain metastases is not possible.

Management in breast cancer is complex and individualized, but early diagnosis and treatment can improve quality of life and prolong survival.

Local/Regional Treatment

For patients with a favorable prognosis, choices among surgery, whole-brain radiotherapy and stereotactic radiosurgery also consider patient preferences. Systemic treatment is recommended for patients with HER2-positive metastatic disease and limited, asymptomatic brain metastases. For those with a poor prognosis, whole-brain radiotherapy or best supportive care is recommended.

Decisions for treatment-resistant brain metastases should be made by a multidisciplinary oncology team. They consider prior brain radiotherapy (RT), symptoms, metastasis size and location, extracranial burden and patient preferences. Symptom control includes edema management, venous thromboembolic disease management and seizure prevention. However, routine preventive antiseizure treatment is not recommended in patients with breast cancer who have never had a seizure.

Treating Edema Caused by Brain Metastases

Metastases can expand among normal brain tissue and increase pressure, disrupting fluid balance and causing cerebral edema. This involves fluid accumulation and swelling as fluid leaks from brain vessels into the surrounding tissue.

Mannitol and Dekort are used to reduce symptoms caused by brain metastases. Mannitol reduces edema or raised intracranial pressure, while Dekort reduces inflammation. Since metastases often cause edema and pressure, these drugs can help relieve symptoms. However, adverse effects and resistance limit initial use to a short period (3 days). Mannitol is stopped after 3 days, while corticosteroids such as Dekort may continue longer at a lower dose.

Systemic Treatment

Systemic treatment is generally planned after local treatment, surgery and/or radiotherapy (RT). In hormone receptor-positive disease, endocrine therapy is individualized according to prior treatments and patient preferences. For HER2-positive disease, trastuzumab alone or trastuzumab/pertuzumab is recommended. Treatment duration should be individualized because predictive data are unavailable.

Direct systemic treatment is considered when local therapy is not possible.

Existing systemic therapy may continue if extracranial disease is responsive or stable, particularly when well tolerated and a reasonable local option exists for brain metastases. If it is poorly tolerated, the next systemic option is used.

• For HER2-negative breast cancer, single-agent chemotherapy is most commonly used.
• Hormonal therapy can act against brain metastases in hormone receptor-positive disease. However, endocrine therapy alone is unsuitable, and local treatment is required. After local therapy, subsequent systemic treatment depends on previous therapies and the tumor's PIK3CA-mutation status .
• Options in HER2-positive disease include tucatinib-capecitabine-trastuzumab, fam-trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1). If unavailable, neratinib with capecitabine or lapatinib plus capecitabine are alternatives.
• Current trial data suggest longer survival with tucatinib-capecitabine-trastuzumab and T-DXd than other treatments in HER2-positive breast cancer with brain metastases. Effectiveness nevertheless varies with patient and disease characteristics. The chart below shows median results with tucatinib-capecitabine-trastuzumab, fam-trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1) in HER2-positive brain metastases for progression-free survival (PFS) :

• • Median overall survival was 22 months with tucatinib-capecitabine-trastuzumab versus 13 months with capecitabine-trastuzumab alone.
  • Median overall survival data for trastuzumab deruxtecan (T-DXd) have not yet matured.
  • Median overall survival with trastuzumab emtansine (T-DM1) is 18.9 months.
• For patients with triple-negative breast cancer, immunotherapies, PARP inhibitors and sacituzumab govitecan are newer drugs to consider after local treatment of brain metastases. Selection should be based on previous medicines, inherited breast cancer susceptibility mutation status (germline genetic testing), and tumor PD-L1 expression .

Prognosis in Breast Cancer with Brain Metastases

Before newer drugs, median overall survival with whole-brain radiotherapy was less than six months. A more recent retrospective analysis of 112 patients diagnosed with brain metastases between 1997 and 2007 found median survival of 14.4 months overall and 23.1 months in HER2-positive disease, reflecting the impact of newer targeted drugs for metastatic HER2-positive breast cancer. Outcomes remain poorer in patients with triple-negative disease and brain metastases.

Leptomeningeal metastasis involves cancer spreading through the central nervous system membranes or cerebrospinal fluid, generally after metastasis elsewhere. Symptoms can include headache, nausea, vomiting, weakness, numbness, tingling and even loss of consciousness, reflecting effects on brain and spinal cord function. Treatment generally combines approaches such as systemic chemotherapy, radiotherapy and intrathecal chemotherapy, depending on cancer type, extent and general health.

Leptomeningeal metastases are treated with medicines and radiation, although intrathecal treatment, delivered into cerebrospinal fluid, is rarely used. Prognosis has not improved markedly over the past decade and remains poor.

Summary

• Brain metastases from breast cancer are becoming more common as survival improves.
• New brain metastases should initially be managed with local approaches such as surgery and radiotherapy.
• In hormone receptor-negative, HER2-negative disease, systemic treatment is selected according to prior therapy, receptor status and other tumor molecular features.
• Several agents are active against brain metastases in hormone receptor-positive and HER2-positive disease. T-DXd or tucatinib-capecitabine-trastuzumab may be more suitable than other systemic agents. T-DM1 may be preferred if extracranial disease progresses after brain metastases have been treated.
• Prognosis is improving as advances in systemic therapy provide better extracranial disease control. Options for leptomeningeal disease remain limited.