Graphical abstract

Objective: Anlotinib is a novel tyrosine kinase inhibitor blocking angiogenesis. This study was performed to assess the efficacy and safety of anlotinib in patients with metastatic breast cancer. Methods: Patients with HER2-negative breast cancer, who were pre-treated with anthracycline or taxanes in a neoadjuvant, adjuvant, or metastatic setting, and had treatment failure after at least one prior chemotherapy regimen in the metastatic setting were enrolled. Anlotinib was administered at 12 mg daily for 14 days in a 21-day cycle until disease progression or unacceptable toxicity occurred. Simultaneously, 5-10 mL of venous blood was collected to perform circulating tumor DNA (ctDNA) testing every 2 treatment cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival, safety, and biomarkers. Results: Twenty-six eligible patients were enrolled, with a median age of 56 (30-75) years. The median follow-up time was 10.5 months. The ORR was 15.4%, the DCR was 80.8%, and the median PFS was 5.22 months (95% confidence interval 2.86-6.24). Fourteen (53.8%) patients survived for more than 10 months. The changes in the detectable ctDNA variant allele frequency were consistent with the tumor response. The most common treatment-related adverse events were hypertension (57.7%), thyroidstimulating hormone elevation (34.6%), and hand-foot syndrome (23.1%). Conclusion:Anlotinib showed objective efficacy with tolerable toxicity in heavily pre-treated, metastatic HER2-negative breast cancer. The dynamic changes in the ctDNA variant allele fraction may be predictive of the tumor response.

Purpose Immunologically quiescent of breast cancer cells has been recognized as the key impediment for the breast cancer immunotherapy. In this study, we aimed to investigate the role of nanoparticle-mediated sonodynamic therapy (SDT) in promoting anti-tumor immune of breast cancer cells and its potential immune mechanisms. Materials and Methods The phase-transformation nanoparticles (LIP-PFH nanoparticles) were in-house prepared and its physiochemical characters were detected. The CCK-8 assay, apoptosis analysis and Balb/c tumor model establishment were used to explore the anti-tumor effect of LIP-PFH nanoparticles triggered by low-intensity focused ultrasound (LIFU) both in vitro and in vivo. Flow cytometry and immunohistochemistry of CD4 + T, CD8 + T, CD8 + PD-1 + T in blood, spleen and tumor tissue were performed to represent the change of immune response. Detection of immunogenic cell death (ICD) markers was examined to study the potential mechanisms. Results LIP-PFH nanoparticles triggered by LIFU could inhibit the proliferation and promote the apoptosis of 4T1 cells both in vitro and in vivo. CD4 + T and CD8 + T cell subsets were significantly increased in blood, spleen and tumor tissue, meanwhile CD8 + PD-1 + T cells were reduced, indicating enhancement of anti-tumor immune response of breast cancer cells in the nanoparticle-mediated SDT group. Detection of ICD markers (ATP, high-mobility group box B1, and calreticulin) and flow cytometric analysis of dendritic cell (DC) maturity further showed that the nanoparticle-mediated SDT can promote DC maturation to increase the proportion of cytotoxic T cells by inducing ICD of breast cancer cells. Conclusion The therapy of nanoparticles-mediated SDT can effectively enhance anti-tumor immune response of 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.

BackgroundHER2-low expression breast cancer (BC) accounts for approximately 45%-55% of all BC cases. The purpose of this study was to investigate the prognostic difference between patients with HER2-low expression and HER2-zero BC.MethodsAn electronic search of Pubmed, Embase, Cochrane Library, and Web of Science databases was performed to screen studies that included prognostic comparisons between HER2-zero and HER2-low expression groups. A total of 14 studies involving 52106 patients were included.ResultsOur results indicated that HER2-low expression was associated with a significant benefit in OS among all patients with early BC (HR, 0.83; 95% CI, 0.78–0.88), patients with hormone-receptor positive BC (HR, 0.83; 95% CI, 0.77–0.89), and patients with TNBC (HR, 0.78; 95% CI, 0.70–0.87). HER2-low expression was associated with a significant benefit in DFS among all patients (HR, 0.81; 95% CI, 0.71–0.93), patients with hormone receptor-positive BC (HR, 0.81; 95% CI, 0.72–0.90), but no significant difference in DFS was found in patients with TNBC (HR, 0.87; 95% CI, 0.65–1.17). HER2-low expression was associated with a significant benefit in RFS among all patients (HR, 0.90; 95% CI, 0.85–0.95), patients with hormone receptor-positive BC (HR, 0.90; 95% CI, 0.84–0.96), but no significant difference in RFS was found in patients with TNBC (HR, 0.80; 95% CI, 0.55–1.16).ConclusionsAmong patients with early-stage BC, patients with HER2-low expression BC had better OS in the overall population, hormone receptor-positive and TNBC subgroups. Besides, favorable DFS and RFS were observed in both the overall population and hormone receptor-positive subgroup.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier (CRD 42022349458).