RESUMEN
OBJECTIVES: This study aims to explore the cost-effectiveness of atezolizumab plus bevacizumab against sorafenib for first-line treatment of locally advanced or metastatic hepatocellular carcinoma (HCC) in Singapore. METHODS: A partitioned survival model was developed from a healthcare system perspective, with a 10-year lifetime horizon. Clinical inputs and utilities were obtained from the IMbrave150 trial. Healthcare resource use costs were obtained from published local sources; drug costs reflected the most recent public hospital selling prices. Outcomes included life years, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). Deterministic and probabilistic sensitivity analyses were performed to assess the model's robustness. RESULTS: Atezolizumab plus bevacizumab offered an additional 1.42 life years and 1.09 QALYs, with an additional cost of S$111,847; the ICER was S$102,988/QALY. The World Health Organization considers interventions with ICERs <1 gross domestic product (GDP)/capita to be highly cost-effective. At a willingness-to-pay (WTP) threshold of S$114,165/QALY (Singapore's 2022 GDP/capita), atezolizumab plus bevacizumab is cost-effective compared with sorafenib. The ICER was most sensitive to variations in utilities, but all parameter variations had no significant impact on the model outcomes. CONCLUSION: At a WTP threshold of Singapore's GDP/capita, atezolizumab plus bevacizumab is cost-effective compared with sorafenib.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Carcinoma Hepatocelular , Análisis Costo-Beneficio , Neoplasias Hepáticas , Años de Vida Ajustados por Calidad de Vida , Sorafenib , Humanos , Bevacizumab/administración & dosificación , Bevacizumab/economía , Sorafenib/administración & dosificación , Sorafenib/economía , Singapur , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/economía , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/economía , Carcinoma Hepatocelular/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/economía , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Costos de los Medicamentos , Análisis de Costo-EfectividadRESUMEN
OBJECTIVES: The Asian PEONY trial showed that add-on pertuzumab to trastuzumab and chemotherapy significantly improved pathological complete response in the neoadjuvant treatment of patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC). This study evaluated the cost-effectiveness of pertuzumab as an add-on therapy to trastuzumab and chemotherapy for neoadjuvant treatment of patients with HER2+ EBC in Singapore. METHODS: A six-state Markov model was developed from the Singapore healthcare system perspective, with a lifetime time horizon. Model outputs were: costs; life-years (LYs); quality-adjusted LYs (QALYs); incremental cost-effectiveness ratios (ICERs). Sensitivity/scenario analyses explored model uncertainties. RESULTS: The base case projected the addition of pertuzumab to be associated with improved outcomes by 0.277 LYs and 0.271 QALYs, increased costs by S$1,387, and an ICER of S$5,121/QALY. The ICER was most sensitive to the pCR rate, and the probabilistic sensitivity analysis showed that add-on pertuzumab had an 81.3% probability of being cost-effective at a willingness-to-pay threshold of S$45,000/QALY gained. CONCLUSIONS: This model demonstrated that the long-term clinical impact of early pertuzumab use, particularly the avoidance of metastatic disease and thus avoidance of higher costs and mortality rates, make neoadjuvant pertuzumab a cost-effective option in the management of patients with HER2+ breast cancer in Singapore.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Biosimilares Farmacéuticos , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Terapia Neoadyuvante , Análisis de Costo-Efectividad , Singapur , Receptor ErbB-2/metabolismo , Análisis Costo-Beneficio , Protocolos de Quimioterapia Combinada Antineoplásica , TrastuzumabRESUMEN
We have recently reported that PML-RAR-induced misfolding of the N-CoR protein could be reversed by retinoic acid (RA), a therapeutic agent that promotes differentiation of acute promyelocytic leukemia (APL) cells. This finding suggests a role of misfolded N-CoR in the differentiation arrest of APL cells and highlights its significance as a potential molecular target in protein conformation-based therapy for APL. Based on this hypothesis, we investigated the therapeutic potential of several protein conformation modifiers on APL-derived cell lines NB4 and NB4-R1. Through a small-scale screening of these selected compounds, we identified genistein as a potent inhibitor of growth of both RA-sensitive and RA-resistant APL cells. Genistein inhibited the growth of NB4 cells through its collective regulatory effects on cell cycle progression, differentiation, and apoptosis. Genistein-induced apoptosis of NB4 cells was mediated by activation of caspase-9 and caspase-3 and was associated with a decrease in mitochondrial transmembrane potential and cytosolic release of cytochrome c. Genistein promoted differentiation of both RA-sensitive and RA-resistant NB4 cells and induced cell cycle arrest by blocking the G(2)-M transition. Genistein up-regulated the expression of PML and N-CoR proteins, promoted degradation of PML-RAR, and reorganized the microspeckled distribution of PML oncogenic domains to a normal dot-like pattern in NB4 cells. Moreover, genistein significantly reversed the PML-RAR-induced misfolding of N-CoR protein by possibly inhibiting the selective phosphorylation-dependent binding of N-CoR to PML-RAR. These findings identify genistein as a potent modifier of N-CoR protein conformation and highlights its therapeutic potential in both RA-sensitive and RA-resistant APL cells.
Asunto(s)
Antineoplásicos/farmacología , Genisteína/farmacología , Leucemia Promielocítica Aguda/metabolismo , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Pliegue de Proteína , Proteínas Represoras/química , Proteínas Represoras/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Ciclo Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Línea Celular , Regulación hacia Abajo/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Leucemia Promielocítica Aguda/enzimología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteínas de Neoplasias/química , Co-Represor 1 de Receptor Nuclear , Péptido Hidrolasas/genética , Fosfoserina/metabolismo , Fosfotirosina/metabolismo , Proteína de la Leucemia Promielocítica , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Receptores de Ácido Retinoico/metabolismo , Factores de Transcripción/química , Tretinoina/farmacología , Proteínas Supresoras de Tumor/químicaRESUMEN
We have recently reported that accumulation of misfolded nuclear hormone receptor corepressor (N-CoR) as insoluble protein aggregates in acute promyelocytic leukemia (APL) cells induces endoplasmic reticulum (ER) stress and activates unfolded protein response (UPR). Although accumulation of misfolded proteins is known to trigger UPR-induced cytotoxic cell death in several neurodegenerative disorders, APL cells are notably resistant to UPR-induced apoptosis. The molecular basis for the paradoxical response of APL cells to UPR is not known. Here, we report that a glycoprotease, selectively expressed in APL cells, regulates the response of APL cells to UPR-induced apoptosis through processing of misfolded N-CoR protein. Results show that misfolded N-CoR is cleaved selectively in APL cells, and cellular extracts of APL cells and human primary APL cells contain activity that cleaves N-CoR protein. Purification and spectrometric analysis of N-CoR cleaving activity from an APL cell line reveals that it is a glycoprotein endopeptidase known as OSGEP. Furthermore, the cleavage of N-CoR in APL cells could be blocked by the broad-spectrum protease inhibitor AEBSF and by RNA interference-mediated down-regulation of OSGEP expression. AEBSF selectively inhibits growth and promotes apoptosis of APL cells possibly through a mechanism involving AEBSF-induced accumulation of insoluble N-CoR protein and by triggering ER stress. Taken together, these findings suggest that selective induction of protease activity in APL cells may represent a novel cytoprotective component of UPR, which could be exploited by tumor cells to survive the toxic insult of misfolded protein(s).