Is adding ribociclib to fulvestrant cost-effective in treating postmenopausal women with HR+/HER2- advanced or metastatic breast cancer? A US payer perspective cost utility analysis.

BACKGROUND: Breast cancer is the most prevalent type of cancer in women in the United States. Ribociclib plus fulvestrant combination therapy gained US Food and Drug Administration approval to treat postmenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or metastatic breast cancer in 2018. OBJECTIVE: To determine the cost-effectiveness of ribociclib plus fulvestrant vs placebo plus fulvestrant therapy in the target population from a US payer perspective. METHODS: A partitioned survival analysis model composed of 3 health states (progression free, progressed disease, and death) was constructed to evaluate the cost-effectiveness of ribociclib plus fulvestrant vs placebo plus fulvestrant. The progression-free survival and the overall survival data points were extracted from published Kaplan-Meier curves in the MONALEESA-3 study and fitted to parametric curves. The safety and efficacy of the treatment was referenced from the MONALEESA-3 trial. Costs were obtained from standard sources including the Red Book for medication costs, Medicare Clinical Laboratory/Physician Fee Schedule for clinical utilization, and the literature for costs of managing adverse events, subsequent therapy, and end-of-life care. Utility and disutility values were obtained from literature to calculate quality-adjusted life-years (QALYs). One-way and probabilistic sensitivity analyses were conducted to test the model robustness. Several scenario analyses were also investigated. RESULTS: In the base case, the ribociclib plus fulvestrant arm was associated with $522,844 and 3.25 QALYs compared with $50,395 and 2.14 QALYs in the placebo plus fulvestrant arm, leading to an incremental cost-effectiveness ratio of $425,951/QALY. The cost of ribociclib had the biggest impact on the model and constituted 84% of the total cost for the ribociclib plus fulvestrant arm. The probabilistic sensitivity analysis projected that the ribociclib plus fulvestrant treatment would have a net benefit over the placebo plus fulvestrant therapy at a willingness-to-pay (WTP) threshold of $405,600/QALY. CONCLUSIONS: At a WTP threshold of $150,000/QALY, the addition of ribociclib to fulvestrant is not considered to be cost-effective in postmenopausal women with HR+/HER2- advanced or metastatic breast cancer. The findings send a strong price signal to the manufacturer and can be used to facilitate payers with price negotiation in making coverage decisions.

Exendin-4 Pretreatment Attenuates Kainic Acid-Induced Hippocampal Neuronal Death.

Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist that protects against brain injury. However, little is known about the effect of Ex-4 on kainic acid (KA)-induced seizures and hippocampal cell death. Therefore, this study evaluated the neuroprotective effects of Ex-4 pretreatment in a mouse model of KA-induced seizures. Three days before KA treatment, mice were intraperitoneally injected with Ex-4. We found that Ex-4 pretreatment reversed KA-induced reduction of GLP-1R expression in the hippocampus and attenuated KA-induced seizure score, hippocampal neuronal death, and neuroinflammation. Ex-4 pretreatment also dramatically reduced hippocampal lipocalin-2 protein in KA-treated mice. Furthermore, immunohistochemical studies showed that Ex-4 pretreatment significantly alleviated blood-brain barrier leakage. Finally, Ex-4 pretreatment stimulated hippocampal expression of phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB), a known target of GLP-1/GLP-1R signaling. These findings indicate that Ex-4 pretreatment may protect against KA-induced neuronal damage by regulating GLP-1R/CREB-mediated signaling pathways.

Cost-Effectiveness of Adding Ribociclib to Endocrine Therapy for Patients With HR-Positive, HER2-Negative Advanced Breast Cancer Among Premenopausal or Perimenopausal Women.

PURPOSE: To evaluate the cost-effectiveness of adding ribociclib to endocrine therapy for pre/perimenopausal women with hormone receptor-positive (HR+), human epidermal receptor 2-negative (HER2-) advanced breast cancer from the US payer perspective. METHODS: A partitioned survival analysis model with three health states (progression-free, progressed disease, and death) was developed to compare the cost and effectiveness of ribociclib in combination with endocrine therapy versus endocrine therapy alone based on clinical data from the MONALEESA-7 phase 3 randomized clinical trials. Life years (LYs), quality-adjusted life-years (QALYs), and total costs were estimated and used to calculate incremental cost-effectiveness ratio (ICER) over a lifetime. Deterministic and probabilistic sensitivity analyses were conducted to test the uncertainties of model inputs. Additional scenario analyses were performed. RESULTS: In the base-case, ribociclib plus endocrine therapy was more effective than endocrine therapy with an additional 1.39 QALYs but also more costly with an ICER of $282,996/QALY. One-way deterministic sensitivity analysis showed that overall survival associated with the treatments and the cost of ribociclib had the greatest impact on the ICER. The probabilistic sensitivity analysis showed that only beyond a willingness-to-pay (WTP) threshold of $272,867, ribociclib plus endocrine therapy would surpass endocrine therapy alone as a cost-effective option. CONCLUSIONS: From the US payer perspective, ribociclib plus endocrine therapy for pre/perimenopausal patients with HR+/HER2- advanced breast cancer is not cost-effective at a WTP threshold of $100,000 or $150,000 per QALY in comparison of endocrine therapy alone.

Mono-(2-Ethylhexyl)phthalate Regulates Cholesterol Efflux via MicroRNAs Regulated m6A RNA Methylation.

Mono-(2-ethylhexyl)phthalate (MEHP) is a major bioactive metabolite which occurs from the widely used industrial plasticizer di(2-ethylhexyl)phthalate, which has been found to be toxic to several human physiological systems, including the cardiometabolic system. Recently, RNA methylation has been shown to be involved in cardio-metabolic regulation. Despite the importance of m6A mRNA methylation in physiological processes, studies of RNA methylation associated with endocrine disrupting chemicals are lacking. Here, we investigated the effects of MEHP in a cholesterol efflux pathway and the roles of m6A methylation using murine macrophage Raw 264.7 cells. MEHP exposure significantly reduced (P < 0.01 for 50 µM) m6A mRNA methylation with decreases in both mRNA (P < 0.01 for 5 and 50 µM) and protein (P < 0.05 for 0.5 µM; P < 0.01 for 5 µM; and P < 0.001 for 50 µM) expression levels of METTL14, a component of the methyltransferase complex. However, m5C RNA methylation remained unchanged. MEHP significantly reduced the expression of Scavenger Receptor B type 1 (SR-B1) (P < 0.01 for 5 µM and P < 0.05 for 50 µM). Additionally, we demonstrated that silencing METTL14 with MEHP decreased SR-B1 gene expression compared to the MEHP treatment (P < 0.01) or silencing METTL14 alone (P < 0.05). Furthermore, MEHP significantly promoted the m6A modification in SR-B1 (P < 0.001) and activated miRNAs which are predicted to regulate METTL14, such as miR16-1-3p (P < 0.05 for 50 µM MEHP), miR101a-3p (P < 0.05 for 5 and 50 µM MEHP), miR362-3-5p (P < 0.05 for 50 µM MEHP), miR501-5p (P < 0.01 for 50 µM MEHP), miR532-3p (P < 0.05 for 50 µM MEHP), and miR542-3p (P < 0.05 for 50 µM MEHP). Together, these results reveal for the first time that MEHP can modulate RNA methylation to regulate SR-B1 in a cholesterol efflux pathway.

PTK7+ Mononuclear Cells Express VEGFR2 and Contribute to Vascular Stabilization by Upregulating Angiopoietin-1.

OBJECTIVE: In angiogenesis, circulating mononuclear cells are recruited to vascular lesions; however, the underlying mechanisms are poorly understood. APPROACH AND RESULTS: Here, we characterize the functional role of protein tyrosine kinase 7 (PTK7)-expressing CD11b(+) mononuclear cells in vitro and in vivo using a mouse model of angiogenesis. Although the frequencies of PTK7(+)CD11b(+) cells in the bone marrow remained similar after vascular endothelial growth factor-A-induced neovascularization, we observed an 11-fold increase in the cornea. Importantly, vascular endothelial growth factor-A-induced chemotaxis of PTK7(+) cells was mediated by vascular endothelial growth factor receptor 2. In a coculture with endothelial cells, PTK7(+)CD11b(+) cells stabilized the vascular network for 2 weeks by expressing high levels of angiopoietin-1. The enhanced vascular stability was abolished by knockdown of angiopoietin-1 in PTK7(+)CD11b(+) cells and could be restored by angiopoietin-1 treatment. CONCLUSIONS: We conclude that PTK7 expression in perivascular mononuclear cells induces vascular endothelial growth factor receptor 2 and angiopoietin-1 expression and thus contributes to vascular stabilization in angiogenesis.

Neutralization of ocular surface TNF-α reduces ocular surface and lacrimal gland inflammation induced by in vivo dry eye.

PURPOSE: The purpose of this study was to investigate the effectiveness of tumor necrosis factor (TNF)-α blocker for treatment of dry eye (DE)-induced inflammation and determine a more effective method to suppress lacrimal gland inflammation. Efficacy of topical versus systemic administration of TNF-α blockers was determined using a murine dry eye (DE) model. METHODS: The TNF-α blocker HL036 was developed by modification of the TNF receptor I. Protein purity, binding affinity, and clearance of TNF-α was compared with etanercept. Using DE-induced C57BL/6 mice, corneal erosion and goblet cell counts were measured after subcutaneous or topical treatment with etanercept or HL036. Inflammatory cytokines in cornea and lacrimal glands were determined by quantitative RT-PCR and ELISA. RESULTS: HL036 showed TNF-α binding affinity comparable to etanercept, as measured by surface plasmon resonance. HL036 concentration was significantly higher in cornea and anterior segment than etanercept and effectively eliminated TNF-α on ocular surfaces. Etanercept was preferentially concentrated in the posterior segment. Corneal erosion and goblet cell counts were improved only with topically applied etanercept and HL036. Ocular surface IFN-γ, IL-6, and IL-21 were significantly decreased by topical HL036. DE-induced lacrimal gland IFN-γ and IL-6 expression was effectively suppressed by topical etanercept and HL036. CONCLUSIONS: Topical TNF-α blockers effectively suppressed lacrimal gland and corneal inflammation by suppressing IFN-γ, IL-21, and IL-6. Differences in TNF-α affinity, clearance, and local concentration of blockers may account for the anti-inflammatory effects in different ocular regions.

Molecular mechanisms of MHC class I-antigen processing: redox considerations.

Major histocompatibility complex (MHC) class I molecules present antigenic peptides to the cell surface for screening by CD8(+) T cells. A number of ER-resident chaperones assist the assembly of peptides onto MHC class I molecules, a process that can be divided into several steps. Early folding of the MHC class I heavy chain is followed by its association with beta(2)-microglobulin (beta(2)m). The MHC class I heavy chain-beta(2)m heterodimer is incorporated into the peptide-loading complex, leading to peptide loading, release of the peptide-filled MHC class I molecules from the peptide-loading complex, and exit of the complete MHC class I complex from the ER. Because proper antigen presentation is vital for normal immune responses, the assembly of MHC class I molecules requires tight regulation. Emerging evidence indicates that thiol-based redox regulation plays critical roles in MHC class I-restricted antigen processing and presentation, establishing an unexpected link between redox biology and antigen processing. We review the influences of redox regulation on antigen processing and presentation. Because redox signaling pathways are a rich source of validated drug targets, newly discovered redox biology-mediated mechanisms of antigen processing may facilitate the development of more selective and therapeutic drugs or vaccines against immune diseases.