Trastuzumab combined with doublet or single-agent chemotherapy as first-line therapy for HER2-positive metastatic breast cancer.

PURPOSE: To investigate the efficacy and safety of doublet versus single-agent chemotherapy (CT) plus trastuzumab (H) as first-line therapy for human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer (MBC). METHODS: We searched for randomized clinical trials (RCTs) that evaluated the treatment effects of single-agent or doublet CT+H as first-line therapies for HER2-positive MBC. The main outcomes measured for this study included the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). A meta-analysis and trial sequential analysis (TSA) were performed, and the study quality was evaluated using the GRADE framework. The PROSPERO registry number of our analysis is CRD42016043766. RESULTS: The results from four RCTs including 1044 participants were pooled. Moderate-quality evidence indicated that compared with single-agent CT+H, doublet CT+H correlated better with prolonged PFS (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.63-0.75, P < 0.0001) and OS (HR = 0.90, 95% CI 0.88-0.92, P < 0.0001). However, moderate-quality evidence revealed no significant difference between the two regimens regarding the ORR (relative risk [RR] = 1.07, 95% CI 0.98-1.17, P = 0.157), which was confirmed by TSA, indicating that the cumulative Z-curve entered the futility area. Moderate-quality evidence indicated that treatment-related grade 3 or 4 toxicities of thrombocytopenia (RR = 4.08, P = 0.000), nausea/vomiting (RR = 4.26, P = 0.002), diarrhea (RR = 2.81, P = 0.002), and stomatitis (RR = 5.02, P = 0.003) were observed more frequently with doublet CT+H than with single-agent CT+H. CONCLUSIONS: Compared with single-agent CT, the combination of doublet CT with trastuzumab as first-line therapy for HER2-positive MBC is associated with longer PFS and OS, but more treatment-related grade 3 or 4 toxicities. Therefore, doublet CT appears to be an appropriate regimen for HER2-positive MBC with a good performance status.

Long noncoding RNA ROR1­AS1 overexpression predicts poor prognosis and promotes metastasis by activating Wnt/ß-catenin/EMT signaling cascade in cervical cancer.

OBJECTIVE: Several long noncoding RNAs (lncRNAs) display functional effects in the tumorigenesis and progression of cervical cancer (CC). We aimed to investigate the roles of lncRNA tyrosine protein kinase transmembrane receptor 1 antisense RNA 1 (ROR1­AS1) in the development of CC patients. PATIENTS AND METHODS: Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was performed for the determination of ROR1­AS1 levels in both CC tissues and cell lines. The clinical value of ROR1­AS1 expression in CC patients was statistically analyzed. After transfection with si-ROR1­AS1 in SiHa and HeLa cells, cellular growth and apoptosis were examined by Cell Counting Kit (CCK-8) assay, cell colony formation, and flow cytometry. Then, wound-healing assays and transwell assays were performed to evaluate cell migration and invasion, respectively. The related proteins of epithelial-mesenchymal transition (EMT) markers and Wnt/ß-catenin signaling pathway was assessed using Western blot assays. RESULTS: We found that that the expressions of ROR1­AS1 were distinctly increased in CC tissues and cell lines. Clinical study revealed that high ROR1­AS1 expression was associated with distant metastasis, FIGO stage, and shorter five-year survival. Functional assays by performing in vitro assays revealed that inhibition of ROR1­AS1 distinctly suppressed CC cell proliferation, colony formation, migration and invasion, and promoted apoptosis. Based on results of Western blot, we showed that the downregulation of ROR1­AS1 inhibited the levels of N-cadherin and vimentin. In addition, the distinctly decreased levels of c-myc, ß-catenin, and cyclin D1 were observed in CC cells transfected with si-ROR1­AS1. CONCLUSIONS: Our results suggest that ROR1­AS1 is likely to serve as an efficient therapeutic approach in respect of CC treatment. Our results suggest that KLF5 may be a potential therapeutic target in laryngeal carcinoma.

Selective enrichment of hepatocellular cancer stem cells by chemotherapy.

This study investigated the enrichment of cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) by chemotherapy. SMMC-7721 cells were inoculated into mice treated with 0, 2, 5 or 10 mg/kg cyclophosphamide (CTX). Tissue from the resulting tumours was re-inoculated into CTX-treated mice two more times, thus producing three generations of tumour cells for each dose of CTX. Chromosome and fluorescence-activated cell sorting analyses were performed to determine the purity of the enriched cells. Sphere culture, colony formation and proliferation assays demonstrated that the self-renewal potential, proliferative activity and clonogenicity of the enriched cells in vitro increased with increasing chemotherapy dose and generation. The ability of the enriched cells to produce xenograft tumours in mice was also dependent on chemotherapy dose and generation. In conclusion, subjecting HCC cells to chemotherapy in vivo enriched the samples for HCC CSCs in a dose- and generation-dependent manner.