Management of breast cancer brain metastases: Focus on human epidermal growth factor receptor 2-positive breast cancer

After the introduction of trastuzumab, a monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2), the overall survival (OS) among patients with HER2-positive breast cancer has been substantially improved. However, among these patients, the incidence of brain metastases (BM) has been increasing and an increased proportion of them have died of intracranial progression, which makes HER2-positive breast cancer brain metastases (BCBM) a critical issue of concern. For local control of limited BM, stereotactic radiosurgery (SRS) and surgical resection are available modalities with different clinical indications. Postoperative or preoperative radiation is usually delivered in conjunction with surgical resection to boost local control. Adjuvant whole-brain radiotherapy (WBRT) should be deferred for limited BM because of its impairment of neurocognitive function while having no benefit for OS. Although WBRT is still the standard treatment for local control of diffuse BM, SRS is a promising treatment for diffuse BM as the technique continues to improve. Although large molecules have difficulty crossing the blood brain barrier, trastuzumab-containing regimens are critical for treating HER2-positive BCBM patients because they significantly prolong OS. Tyrosine kinase inhibitors are more capable of crossing into the brain and they have been shown to be beneficial for treating BM in HER2-positive patients, especially lapatinib combined with capecitabine. The antiangiogenic agent, bevacizumab, can be applied in the HER2-positive BCBM scenario as well. In this review, we also discuss several strategies for delivering drugs into the central nervous system and several microRNAs that have the potential to become biomarkers of BCBM.

Nanomaterials with dual immunomodulatory functions for synergistic therapy of breast cancer brain metastases

A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases.Immunotherapy has made progress in the treatment of tumors,but limited by the non-immunogenicity of tumors and strong immunosuppressive environment,patients with TNBC brain metastases have not yet benefited from immunotherapy.Dual immunoregulatory strategies with enhanced immune activation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients.Here,we propose a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and construct reduction-sensitive immune microenvironment regulation nanomaterials(SIL@T).SIL@T modified with targeting peptide penetrates the BBB and is subsequently internalized into metastatic breast cancer cells,releasing silybin and oxaliplatin responsively in the cells.SIL@T preferentially accumulates at the metastatic site and can significantly prolong the survival period of model animals.Mechanistic studies have shown that SIL@T can effectively induce immunogenic cell death of metastatic cells,activate immune responses and increase infiltration of CD8+T cells.Meanwhile,the activation of STAT3 in the metastatic foci is attenuated and the immunosuppressive microenvironment is reversed.This study demonstrates that SIL@T with dual immunomodulatory functions provides a promising immune synergistic therapy strategy for breast cancer brain metastases.

Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment

Breast cancer brain metastases(BCBMs)are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth.Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable bloodbrain barrier(BBB).Accumulation studies prove that low density lipoprotein receptor-related protein 1(LRP1)is promising target for BBB transcytosis.However,as the primary clearance receptor for amyloid beta and tissue plasminogen activator,LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics.Matrix metalloproteinase-1(MMP1)is highly enriched in metastatic niche to promote growth of BCBMs.Herein,it is reported that nanoparticles(NPs-K-s-A)tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2(A),can surmount the BBB and escape LRP1-mediated clearance in metastatic niche.NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice,while comparable brain accumulation in normal mice.The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs.Due to the efficient BBB penetration,special and remarkable clearance escape,and facilitated therapeutic outcome,the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.