Abstract:

Breast cancer has been the second most common solid tumor that metastasizes to the central nervous system after lung cancer. Triple-negative breast cancer (TNBC) has an earlier occurrence and high incidence of brain metastasis with its associated poor prognosis and limited treatment options due to the presence of the blood-brain barrier and lack of targeted drugs. Local treatment, including surgery and radiation therapy, are still the main therapy for brain metastasis. Surgical resection can not only relieve neurologic impairment of brain metastasis patients, but also can clarify the pathological type. Moreover, surgical resection combined with radiotherapy can improve the prognosis of brain metastasis patients compared to surgery or radiotherapy alone. By now, whole-brain radiation therapy (WBRT) is still considered the gold standard for multiple brain metastases, and meningeal metastases, but it will lead to neurocognitive decline, so hippocampal avoidance is essential. For selected patients with oligometastases, stereotactic radiotherapy has replaced WBRT to reduce cognitive toxicity. However, local treatment of TNBC brain metastasis cannot control the progress of brain metastasis and has significant side effects, so systemic therapy is needed. Chemotherapy drugs such as capecitabine and cisplatin can penetrate the blood-brain barrier, but their efficacy is limited. Therefore, the research and development of new targeted drugs and the exploration of new targets are necessary for TNBC brain metastasis. Research has found that patients carrying germline BRCA1/2 mutations have a higher risk of brain metastasis. Currently, the poly adenosine diphosphate ribose polymerase (PARP) inhibitor demonstrated antitumor activity in patients with advanced breast cancer and a germline BRCA1/2 mutation, and it can penetrate the blood-brain barrier. The phase Ⅲ trial EMBRACA reported that the PARP inhibitor talazoparib can prolong the progression-free survival of TNBC patients with brain metastasis. In addition, antibody drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) can also penetrate the blood-brain barrier. Studies such as DEBBRAH have shown that T-DXd has significant therapeutic effects in HER2 positive brain metastasis patients, while research on HER2 low expression patients has not yet reached the endpoint, and its role in TNBC brain metastasis is worth looking forward to. Sacituzumab govitecan (SG) is also an ADC composed of an antibody targeting the human trophoblast cell-surface antigen 2. The phase Ⅲ ASCENT study showed that in the full population (including 61 patients with brain metastasis), SG could significantly prolong the progression-free survival of advanced TNBC patients compared to the patients who received chemotherapy. ANG1005, a novel taxane derivative, can cross the blood-brain barrier as well. A multicenter, open-label phase Ⅱ study revealed that ANG1005 could prolong overall survival of patients with brain metastasis. In addition, phosphoinositide3-kinase, (PI3K)/protein kinase (AKT)/mammalian target of rapamycin (mTOR) pathway inhibitors, fatty acid synthase inhibitors, and the drugs with new delivery systems have become potential treatment options for TNBC brain metastasis patients. Although the Impassion 130 reported that no benefit trend for immunotherapy in TNBC brain metastasis, basic research has shown that radiotherapy combined with immunotherapy has a synergistic effect. Currently, multiple clinical trials (NCT03483012, NCT03449238, etc.) are exploring the efficacy of radiotherapy combined with immunotherapy in brain metastasis, and the results are promising. This article reviewed the research progress of TNBC brain metastasis treatment.

Key words: Triple-negative breast cancer, Brain metastasis, Local therapy, Chemotherapy, Targeted therapy, Immunotherapy