Ying Wang

Up-regulation of miR-21 Mediates Resistance to Trastuzumab Therapy for Breast Cancer

Trastuzumab resistance emerges to be a major issue in anti-human epidermal growth factor receptor 2 (HER2) therapy for breast cancers. Here, we demonstrated that miR-21 expression was up-regulated and its function was elevated in HER2+ BT474, SKBR3, and MDA-MB-453 breast cancer cells that are induced to acquire trastuzumab resistance by long-term exposure to the antibody, whereas protein expression of the PTEN gene, a miR-21 target, was reduced. Blocking the action of miR-21 with antisense oligonucleotides re-sensitized the resistant cells to the therapeutic activities of trastuzumab by inducing growth arrest, proliferation inhibition, and G1-S cell cycle checking in the presence of the antibody. Ectopic expression of miR-21 in HER2+ breast cancer cells confers resistance to trastuzumab. Rescuing PTEN expression with a p3XFLAG-PTEN-mut construct with deleted miR-21 targeting sequence at its 3′ UTR restored the growth inhibition of trastuzumab in the resistant cells by inducing PTEN activation and AKT inhibition. In vivo, administering miR-21 antisense oligonucleotides restored trastuzumab sensitivity in the resistant breast cancer xenografts by inducing PTEN expression, whereas injection of miR-21 mimics conferred trastuzumab resistant in the sensitive breast tumors via PTEN silence. Up-regulatin of miR-21 in tumor biopsies obtained from patients receiving pre-operative trastuzumab therapy was associated with poor trastuzumab response. Therefore, miR-21 overexpression contributes to trastuzumab resistance in HER2+ breast cancers and antagonizing miR-21 demonstrates therapeutic potential by sensitizing the malignancy to anti-HER2 treatment.

MicroRNA 34c Gene Down-regulation via DNA Methylation Promotes Self-renewal and Epithelial-Mesenchymal Transition in Breast Tumor-initiating Cells

Background: The mechanisms for miRNA dysregulation in BT-ICs remain obscure. Results: Single hypermethylated CpG site in the promoter region of miR-34c gene repressed miR-34c expression by reducing DNA binding activities of Sp1 and promoted self-renewal and EMT of BT-ICs. Conclusion: Single hypermethylated CpG site in the promoter region contributes to the reduction of microRNA in BT-ICs. Significance: Methylation regulates the expression of microRNA in BT-ICs. Tumor-initiating cells (T-ICs), a subpopulation of cancer cells with stem cell-like properties, are related to tumor relapse and metastasis. Our previous studies identified a distinct profile of microRNA (miRNA) expression in breast T-ICs (BT-ICs), and the dysregulated miRNAs contribute to the self-renewal and tumorigenesis of these cells. However, the underlying mechanisms for miRNA dysregulation in BT-ICs remain obscure. In the present study, we demonstrated that the expression and function of miR-34c were reduced in the BT-ICs of MCF-7 and SK-3rd cells, a breast cancer cell line enriched for BT-ICs. Ectopic expression of miR-34c reduced the self-renewal of BT-ICs, inhibited epithelial-mesenchymal transition, and suppressed migration of the tumor cells via silencing target gene Notch4. Furthermore, we identified a single hypermethylated CpG site in the promoter region of miR-34c gene that contributed to transcriptional repression of miR-34c in BT-ICs by reducing DNA binding activities of Sp1. Therefore, miR-34c reduction in BT-ICs induced by a single hypermethylated CpG site in the promoter region promotes self-renewal and epithelial-mesenchymal transition of BT-ICs.

What lies behind chemotherapy-induced amenorrhea for breast cancer patients: a meta-analysis.

AbstractnTo evaluate the incidence of chemotherapy-induced amenorrhea (CIA) and its therapeutic impact in premenopausal breast cancer patients. A systematic search was performed to identify clinical studies that compared the incidence of CIA with different chemotherapy regimens and oncological outcomes with and without CIA. The fixed-effects and random-effects models were used to assess the pooled estimates. Heterogeneity and sensitivity analyses were performed to explore heterogeneity among studies and to assess the effects of study quality. A total of 15,916 premenopausal breast cancer patients from 46 studies were included. The cyclophosphamide-based regimens, taxane-based regimens, and anthracycline/epirubicin-based regimens all increased the incidence of CIA with pooled odds ratios of 2.25 (95xa0% CI 1.26–4.03, Pxa0=xa00.006), 1.26 (95xa0% CI 1.11–1.43, Pxa0=xa00.0003) and 1.39 (95xa0% CI 1.15–1.70, Pxa0=xa00.0008), respectively. The three-drug combination regimens of cyclophosphamide,anthracycline/epirubicin, and taxanes (CAT/CET) caused the highest rate of CIA compared with the other three drug combinations (OR 1.41, 95xa0% CI 1.16–1.73, Pxa0=xa00.0008). Tamoxifen therapy was also correlated with a higher incidence of CIA, with an OR of 1.48. Patients with CIA were found to exhibit better disease-freexa0survival (DFS) and overall survival (OS) compared with patients without CIA. With respect to molecular subtype, this DFS advantage remained significant in hormone-sensitive patients (HR 0.61, 95xa0% CI 0.52–0.72, Pxa0<xa00.00001). The current meta-analysis has demonstrated that anthracycline/epirubicin, taxanes, cyclophosphamide, and tamoxifen all contributed to elevated rates of CIA, and CIA was not merely a side effect of chemotherapy but was a better prognostic marker, particularly for ER-positive premenopausal early-stage breast cancer patients. However, this topic merits further randomized control studies to detect the associations between CIA and patient prognosis after adjusting for age, ER status, and other influential factors.

Prognostic immune-related gene models for breast cancer: a pooled analysis

Breast cancer, the most common cancer among women, is a clinically and biologically heterogeneous disease. Numerous prognostic tools have been proposed, including gene signatures. Unlike proliferation-related prognostic gene signatures, many immune-related gene signatures have emerged as principal biology-driven predictors of breast cancer. Diverse statistical methods and data sets were used for building these immune-related prognostic models, making it difficult to compare or use them in clinically meaningful ways. This study evaluated successfully published immune-related prognostic gene signatures through systematic validations of publicly available data sets. Eight prognostic models that were built upon immune-related gene signatures were evaluated. The performances of these models were compared and ranked in ten publicly available data sets, comprising a total of 2,449 breast cancer cases. Predictive accuracies were measured as concordance indices (C-indices). All tests of statistical significance were two-sided. Immune-related gene models performed better in estrogen receptor-negative (ER−) and lymph node-positive (LN+) breast cancer subtypes. The three top-ranked ER− breast cancer models achieved overall C-indices of 0.62–0.63. Two models predicted better than chance for ER+ breast cancer, with C-indices of 0.53 and 0.59, respectively. For LN+ breast cancer, four models showed predictive advantage, with C-indices between 0.56 and 0.61. Predicted prognostic values were positively correlated with ER status when evaluated using univariate analyses in most of the models under investigation. Multivariate analyses indicated that prognostic values of the three models were independent of known clinical prognostic factors. Collectively, these analyses provided a comprehensive evaluation of immune-related prognostic gene signatures. By synthesizing C-indices in multiple independent data sets, immune-related gene signatures were ranked for ER+, ER−, LN+, and LN− breast cancer subtypes. Taken together, these data showed that immune-related gene signatures have good prognostic values in breast cancer, especially for ER− and LN+ tumors.

Comparison of the Therapeutic Efficacy of the Early and the Delayed Use of Vinorelbine-Based Regimens for Patients with Advanced Breast Cancer.

Background: The aim of this study was to evaluate the efficacy of vinorelbine-based regimens as first-, second- and more-line therapies in advanced breast cancer (ABC) and to analyze the best timing of vinorelbine treatment. Methods: A total of 71 ABC patients were retrospectively reviewed. Of these, 35 patients were treated with vinorelbine-based regimens as first-line chemotherapy, and 36 patients were treated with vinorelbine-based regimens as second-line or more-line therapy. The primary end point of the study was progression-free survival (PFS). Results: No difference was found in baseline characteristics between the two groups (p > 0.1 for all comparisons). There was a significant difference in the objective response rate (ORR; p = 0.006) and clinical benefit rate (CBR; p = 0.013) between the first-line group and the second- or more-line groups. In the vinorelbine first-line group, the ORR was 68.6% (24 patients), and in the second-line or more-line groups the ORR was 36.1% (13 patients). A significant difference in PFS between the first-line group and the second-line or more-line groups was also observed (p = 0.030). The median PFS in the overall population was 6.3 ± 1.32 months (95% CI 3.69-8.90). The median PFS was 11.1 ± 3.76 months (95% CI 3.73-18.47) in the first-line group compared with 5.2 ± 1.35 months (95% CI 2.54-7.85) in the second-line or more-line groups. In patients treated with vinorelbine-trastuzumab combination as the first-line therapy, a complete response was observed in 1 patient (12.5%) and partial response in 5 patients (62.5%), giving an ORR of 75.0%. Progressive disease was observed in 1 patient (12.5%), and stable disease in 1 patient (12.5%), leading to a CBR of 87.5%. The median PFS was 13.8 ± 2.75 months (95% CI 8.42-19.18), and median OS was 37.0 ± 11.6 months (95% CI 14.18-59.82). No significant difference was found in overall survival (OS) between the groups (p = 0.612). Conclusion: For ABC patients, no significant difference in median OS was found between the early use and delayed use of vinorelbine-based regimens, but the short-term efficacy and PFS of vinorelbine-based regimens were significantly better in the early use group than in the delayed use group.

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

PurposeTo 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).MethodsWe 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 PROSPEROxa0registry number of our analysis is CRD42016043766.ResultsThe 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, Pxa0<xa00.0001) and OS (HRxa0=xa00.90, 95% CI 0.88–0.92, Pxa0<xa00.0001). However, moderate-quality evidence revealed no significant difference between the two regimens regarding the ORR (relative risk [RR]xa0=xa01.07, 95% CI 0.98–1.17, Pxa0=xa00.157), 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 (RRxa0=xa04.08, Pxa0=xa00.000), nausea/vomiting (RRxa0=xa04.26, Pxa0=xa00.002), diarrhea (RRxa0=xa02.81, Pxa0=xa00.002), and stomatitis (RRxa0=xa05.02, Pxa0=xa00.003) were observed more frequently with doublet CT+H than with single-agent CT+H.ConclusionsCompared 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.