Jun Cao

BACKGROUND: Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). This study was conducted to assess the efficacy and safety of apatinib in patients with non-triple-negative metastatic breast cancer who had received prior chemotherapy for their metastatic disease. METHODS: This multicenter, open-label, single arm study enrolled patients with non-triple-negative breast cancer, pretreated with anthracycline, taxanes and capecitabine, and who failed in the metastatic setting at least 1 and at most 4 prior chemotherapy regimens and at least one endocrine drug for hormone receptor-positive patients as well as at least one anti-Her2 drug for Her2-positive patients. The primary end point of this study was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Apatinib was administered as 500 mg daily on days 1 through 28 of each 4-week cycle. RESULTS: 38 patients were enrolled with a median age of 49 years (range, 35 to 62 years) and received apatinib for a median of 4 cycles (range from 0 to 10 cycles). 18 (47.4%) patients experienced dose reduction during treatment. The median relative dose intensity (relative to assigned dose for each cycle) was 82% (range, 45.0% to 100.0%). Median follow-up time was 10.1 months. Median PFS of all 38 patients was 4.0 months (95% confidence interval (CI), 2.8 m - 5.2 m). 36 patients were eligible for efficacy analysis. ORR was 16.7% (6/36). DCR was 66.7% (24/36). Median OS was 10.3 months (95% CI, 9.1 m - 11.6 m). The most common grade 3/4 treatment-related AEs were hypertension (20.5%), hand-foot syndrome (10.3%), and proteinuria (5.1%). Of three possibly drug-related SAEs recorded in the study, 2 (3.4%) deaths occurred within 28 days of last treatment and were both considered to be the result of disease progression. The other one was grade 2 diarrhea needing hospitalization. CONCLUSIONS: Apatinib exhibited objective efficacy in heavily pretreated, metastatic non-triple-negative breast cancer with manageable toxicity, and it might be better to be tested in breast cancer with high angiogenesis dependency. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01653561.

BACKGROUND: Reprogrammed energy metabolism as an emerging hallmark of cancer has recently drawn special attention since it facilitate cell growth and proliferation. Recently, long noncoding RNAs (lncRNAs) have been served as key regulators implicated in tumor development and progression by promoting proliferation, invasion and metastasis. However, the associations of lncRNAs with cellular energy metabolism in lung cancer (LC) need to be clarified. METHODS: Here, we conducted bioinformatics analysis and found insulin-like growth factor binding protein 4-1 (IGFBP4-1) as a new candidate lncRNA located in the upstream region of IGFBP4 gene. The expression levels of lnc-IGFBP4-1, mRNA levels of IGFBP4 in 159 paired lung cancer samples and adjacent, histological normal tissues by qRT-PCR. Over-expression and RNA interference (RNAi) approaches were adopted to investigate the biological functions of lnc-IGFBP4-1. The intracellular ATP level was measured using the Cell Titer-Glo Luminescent Cell Viability Assay kit, and changes in metabolic enzymes were examined in cancer cells and normal pulmonary epithelial cells with qRT-PCR. RESULTS: Our results showed that lnc-IGFBP4-1 was significantly up-regulated in LC tissues compared with corresponding non-tumor tissues (P < 0.01), and its expression level was significantly correlated with TNM stage (P < 0.01) and lymph node metastasis (P < 0.05). Further investigation showed that overexpression of lnc-IGFBP4-1 significantly promoted LC cell proliferation in vitro and in vivo, while downregulation of endogenous lnc-IGFBP4-1 could inhibited cell proliferation and induce apoptosis. Moreover, we found lnc-IGFBP4-1 could influences ATP production levels and expression of enzymes including HK2, PDK1 and LDHA, in addition, decline in both ATP production and these enzymes in response to 2-DG and 2-DG-combined Rho123, respectively, was observed in lnc-IGFBP4-1-overespressing LC cells, indicative of an enhanced aerobic glycolysis rate. Finally, lnc-IGFBP4-1 was observed to negatively correlate with gene IGFBP4, and lower expression level of IGFPB4 was found after lnc-IGFBP4-1-overexpression was transfected into PC9 cells, higher expression level of IGFPB4 was also found after lnc-IGFBP4-1-downregulation was transfected into GLC-82 cells, which indicates that IGFBP4 may exert its targeting function regulated by lnc-IGFBP4-1. CONCLUSIONS: Taken together, these findings provide the first evidence that lnc-IGFBP4-1 is significantly up-regulated in LC tissues and plays a positive role in cell proliferation and metastasis through possible mechanism of reprogramming tumor cell energy metabolism, which suggests that lnc-IGFBP4-1 may be a promising biomarker in LC development and progression and as a potential therapeutic target for LC intervention.

BACKGROUND: To identify the incidence, recurrence pattern and prognosis of brain metastases (BM) among women with metastatic triple negative breast cancer (mTNBC) treated consecutively at a single institution during a 7-year period. METHODS: Patients with histologically confirmed mTNBC were retrospectively identified. The incidence of BM as first site of recurrence and the cumulative BM incidence were computed. We used the Cox proportional hazards model to identify the univariate and multivariate factors associated with survival. RESULTS: Four hundred thirty three patients were included with a median overall survival (OS) of 21.6 months after median follow-up for 48.1 months. BM was found in 29% (127/433) of the patients and about a quarter (32/127) of BM was first recurrence. The cumulative incidence of BM at 1 and 2 years was 17 and 25%, respectively. The median time from the diagnosis of extracranial metastases to BM was 10 months. Median OS following a diagnosis of BM was 7.3 months. The longer median OS from time of first recurrent BM was noted compared with those of subsequent recurrent (17.3 vs 6.3 months, p = 0.008). However, patients with first recurrent BM were associated with shorter OS compared with those without BM (17.3 vs 22.1 months, p = 0.006). The independent factors that increased BM death risk were > 3 brain lesions, no BM-directed treatment, subsequent recurrent BM, symptomatic BM and uncontrolled extracranial metastasis. CONCLUSIONS: Patients with mTNBC have a high incidence of early BM with subsequent poor survival. The findings lend support to consideration of screening imaging of the brain for mTNBC patients.

Breast cancer is the most common malignant tumor in females worldwide. Chemotherapy is the standard breast cancer treatment; however, chemoresistance is often seen in patients with metastatic breast cancer. Owing to high heterogeneity, the mechanisms of breast cancer chemoresistance and metastasis have not been fully investigated. The possible molecular mechanisms of chemoresistance in breast cancer include efflux transporters, signaling pathways, non-coding RNAs, and cancer stem cells. However, to overcome this hurdle, the use of novel clinical strategies such as drug carriers, immunotherapy, and autophagy regulation, are being investigated. The goal of this review is to summarize the current data about the molecular mechanisms of breast cancer chemoresistance and the novel clinical strategies; thus, providing a useful clinical tool to explore optimal treatment for breast cancer.