Brain metastases from breast cancer (BCBM) constitute the second most common cause of brain metastasis (BM), and the incidence of these frequently lethal lesions is currently increasing, following better systemic treatment. Patients with ER-negative and HER2-positive metastatic breast cancer (BC) are the most likely to develop BM, but if this diagnosis remains associated with a worse prognosis, long survival is now common for patients with HER2-positive BC. BCBM represents a therapeutic challenge that needs a coordinated treatment strategy along international guidelines. Surgery has always to be considered when feasible. It is now well established that stereotaxic radiosurgery allows for equivalent control and less-cognitive toxicities than whole-brain radiation therapy, which should be delayed as much as possible. Medical treatment for BCBM is currently a rapidly evolving field. It has been shown that the blood-brain barrier (BBB) is often impaired in macroscopic BM, and several chemotherapy regimens, antibody-drug conjugates and tyrosine-kinase inhibitors have been shown to be active on BCBM and can be part of the global treatment strategy. This paper provides an overview of the therapeutic option for BCBM that is currently available and outlines potential new approaches for tackling these deadly secondary tumours.

Treatment strategies for breast cancer brain metastases

Leptomeningeal carcinomatosis (LC) is defined as infiltration of the leptomeninges by metastatic carcinoma, a relatively uncommon but devastating complication of many malignancies. Although only 5% of patients with breast cancer develop leptomeningeal involvement, it remains the most common etiology of LC. It can occur as a late-stage complication of systemic progression or present as the first sign of metastatic disease, with or without parenchymal brain metastases. Lobular carcinomas have a higher propensity to metastasize into the meninges when compared to ductal carcinoma, especially the triple-negative subtype, which usually is associated with a shorter interval between metastatic breast cancer diagnosis and the development of LC. Prognosis remains poor, with median survival of 4 months for patients receiving state-of-the-art treatment. The main factors associated with survival are performance status at diagnosis, CSF protein level and triple-negative subtype. Headache is commonly the first clinical presentation of LC, and the diagnostic workup usually requires CSF-cytological analysis and or/MRI. The current management of LC consists of a combination of intra-CSF chemotherapy, systemic therapy, radiotherapy and/or best-supportive care. The standard intra-CSF chemotherapy regimen is methotrexate. Radiotherapy is used for relieving obstruction points on CSF-outflow channels due to ependymal nodules, tumor deposits or bulky disease. Objective responses have been reported with intrathecal administration of trastuzumab for HER2-positive disease, yet this strategy is still under investigation. Further prospective trials are needed to better address the impact of these treatment modalities on overall survival and quality of life.

Leptomeningeal carcinomatosis in patients with breast cancer.

BACKGROUND
DEPOSEIN (NCT01645839) was a randomized open-label phase III study to explore the role of intrathecal chemotherapy in patients with newly diagnosed leptomeningeal metastasis (LM), a common manifestation of breast cancer.
METHODS
Patients with newly diagnosed LM defined by tumor cells in the cerebrospinal fluid or combination of clinical and neuroimaging signs of LM were randomized to receive systemic therapy alone (control group) or systemic therapy plus intrathecal liposomal cytarabine (experimental group). Progression-free survival related to LM (LM-PFS) was the primary endpoint.
RESULTS
Thirty-seven and 36 patients were assigned to the control and the experimental groups. Median number of liposomal cytarabine injections in the experimental group was five (range 1-20). Focal radiotherapy was performed in six (16%) and three (8%) patients in the control and experimental groups. In the intent-to-treat population, median LM-PFS was 2.2 months (95% confidence interval (CI) 1.3-3.1) in the control versus 3.8 months (95% CI 2.3-6.8) in the experimental group (hazard ratio 0.61, 95% CI 0.38-0.98) (P=0.04). Seventy-one patients have died. Median overall survival was 4.0 months (95% CI 2.2-6.3) in the control versus 7.3 months (95% CI 3.9-9.6) in the experimental group (hazard ratio 0.85, 95% CI 0.53-1.36) (P=0.51). Serious adverse events were reported in 22 and 30 patients, respectively. Quality of life until progression did not differ between groups.
CONCLUSION
The addition of intrathecal liposomal cytarabine to systemic treatment improves LM-related PFS. Confirmatory trials with optimized patient selection criteria and more active drugs may be required to demonstrate a survival benefit from intrathecal pharmacotherapy.

Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer

Targeting brain metastases in breast cancer

Intrathecal administration of anti-HER2 treatment for the treatment of meningeal carcinomatosis in breast cancer: A metanalysis with meta-regression.

Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis.

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Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis.