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BACKGROUND: Gastric cancer (GC), gastroesophageal junction cancer (GEJC), and esophageal adenocarcinoma (EAC), together, are leading causes of cancer deaths worldwide. Patient health-related quality of life (HRQoL) and well-being has become increasingly important alongside traditional oncologic outcomes for both patients and clinicians and may aid treatment decisions. We conducted a survey to examine the clinical characteristics, humanistic burden, and the effects of first-line (1L) treatment in patients with GC/GEJC/EAC, across different geographic regions, to address the paucity of real-world data. METHODS: Clinicians treating patients with unresectable advanced or metastatic GC/GEJC/EAC in China, France, Germany, Japan, the United Kingdom, and the United States, during April-October 2019, were invited to provide data on their patients' demographics, clinical characteristics, treatment, and HRQoL via medical chart reviews, clinician surveys, and patient questionnaires. Data were analyzed using descriptive statistics, regression analyses comparing active treatment and best supportive care. Patients were also stratified into subgroups that were identified either as human epidermal growth factor receptor 2 (HER2) positive, HER2 negative (which has a higher prevalence but for whom there are limited treatment options), or unknown HER2 status. RESULTS: Survey data were analyzed for 995 patients, 87% of whom were on active treatment, most commonly dual or triple chemotherapy. Demographics and clinical characteristics were similar across countries with most patients having GC and the lowest incidence of GEJC and EAC in China. Overall, most patients had de novo disease with good response to 1L treatment, while their HRQoL and well-being was significantly worse than the general population. In 682 patients on active treatment with HER2 negative or unknown status, HRQoL also appeared to be worse in those with recurrent disease. Regression analysis identified several drivers of treatment decisions and factors impacting patients' HRQoL, including stage of disease and comorbidities. CONCLUSIONS: In patients with advanced GC/GEJC/EAC, screening and assessment of HER2 status as well as patient-reported HRQoL outcomes are invaluable in aiding treatment decisions. The introduction of appropriate therapy soon after diagnosis has the prospect of achieving improved HRQoL and survival in these patients.
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Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Estudos Retrospectivos , Qualidade de Vida , Receptor ErbB-2/metabolismo , Junção Esofagogástrica/patologiaRESUMO
BACKGROUND: Patients with cancer of the oesophagus or gastro-oesophageal junction have a high risk of recurrence after treatment with curative intent. The aim of this study was to analyse the site of recurrence, treatment, and survival in patients with recurrent disease. METHODS: Patients with non-metastatic oesophageal or junctional carcinoma treated with curative intent between January 2015 and December 2016 were selected from the Netherlands Cancer Registry. Data on recurrence were collected in the second half of 2019. Overall survival (OS) was assessed by Kaplan-Meier methods. RESULTS: In total, 862 of 1909 patients (45.2 per cent) for whom information on follow-up was available had disease recurrence, and 858 patients were included. Some 161 of 858 patients (18.8 per cent) had locoregional recurrence only, 415 (48.4 per cent) had distant recurrence only, and 282 (32.9 per cent) had combined locoregional and distant recurrence. In all, 518 of 858 patients (60.4 per cent) received best supportive care only and 315 (39.6 per cent) underwent tumour-directed therapy. Patients with locoregional recurrence alone more often received chemoradiotherapy than those with distant or combined locoregional and distant recurrence (19.3 per cent versus 0.7 and 2.8 per cent), and less often received systemic therapy (11.2 per cent versus 30.1 and 35.8 per cent). Median OS was 7.6, 4.2, and 3.3 months for patients with locoregional, distant, and combined locoregional and distant recurrence respectively (P < 0.001). CONCLUSION: Disease recurred after curative treatment in 45.2 per cent of patients. Locoregional recurrence developed in only 18.8 per cent. The vast majority of patients presented with distant or combined locoregional and distant recurrence, and received best supportive care.
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Neoplasias Esofágicas , Recidiva Local de Neoplasia , Humanos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/patologia , Esofagectomia/métodos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Resultado do Tratamento , Estudos RetrospectivosRESUMO
Aim: This study assessed the work productivity and financial impact of advanced gastroesophageal adenocarcinomas, comprising gastric, esophageal and gastroesophageal junction cancers, on patients of working age and their caregivers. Patients & methods: A multicenter medical chart review and surveys of patients with advanced gastroesophageal adenocarcinoma and their caregivers was conducted in France, Germany, the UK, China, Japan and the USA. Results: Across differing regions, the study highlighted the impact of cancer on patients' ability to work, to function normally and on their wellbeing, as well as the economic burden placed on patients and their caregivers. Conclusion: Advanced gastroesophageal adenocarcinomas have a significant impact on patients' and caregivers' well-being and are associated with reduced work productivity, and income loss.
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Adenocarcinoma/psicologia , Cuidadores/psicologia , Efeitos Psicossociais da Doença , Neoplasias Esofágicas/psicologia , Fatores Socioeconômicos , Neoplasias Gástricas/psicologia , Absenteísmo , Adenocarcinoma/tratamento farmacológico , Eficiência , Emprego , Neoplasias Esofágicas/tratamento farmacológico , Feminino , Humanos , Renda , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Treatment effect waning (TEW) refers to the attenuation of treatment effects over time. Assumptions of a sustained immuno-oncologic treatment effect have been a source of contention in health technology assessment (HTA). We review how TEW has been addressed in HTA and in the wider scientific literature. We analysed company submissions to English language HTA agencies and summarised methods and assumptions used. We subsequently reviewed TEW-related work in the ISPOR Scientific Presentations Database and conducted a targeted literature review (TLR) for evidence of the maintenance of immuno-oncology (IO) treatment effects post-treatment discontinuation. We found no standardised approach adopted by companies in submissions to HTA agencies, with immediate TEW most used in scenario analyses. Independently fitted survival models do however suggest TEW may often be implicitly modelled. Materials in the ISPOR scientific database suggest gradual TEW is more plausible than immediate TEW. The TLR uncovered evidence of durable survival in patients treated with IOs but no evidence that directly addresses the presence or absence of TEW. Our HTA review shows the need for a consistent and appropriate implementation of TEW in oncology appraisals. However, the TLR highlights the absence of direct evidence on TEW in literature, as TEW is defined in terms of relative treatment effects-not absolute survival. We propose a sequence of steps for analysts to use when assessing whether a TEW scenario is necessary and appropriate to present in appraisals of IOs.
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Background: Treatment of advanced or metastatic esophageal adenocarcinoma (EAC) follows the guidelines for gastroesophageal junction adenocarcinoma (GEJC) and gastric adenocarcinoma (GAC), but patients with EAC are often excluded from clinical studies of GEJC/GAC. Objectives: Here we describe treatment and survival of patients with advanced EAC, GEJC, and GAC to provide population-based evidence on distinctions and similarities between these populations. Design: Retrospective cohort study of patients with unresectable advanced (cT4b) or metastatic (cM1) EAC, GEJC, or GAC (2015-2020) were selected from the Netherlands Cancer Registry. Methods: Overall survival (OS) was assessed using Kaplan-Meier methods, log-rank tests, and multivariable Cox regression. Results: In all, 7391 patients were included (EAC: n = 3346, GEJC: n = 1246, and GAC: n = 2798). Patients with EAC were more often males and more often had ⩾2 metastatic locations. First-line systemic therapy was received by 42%, 47%, and 36% of patients with EAC, GEJC, and GAC, respectively. Median OS was 5.0, 5.1, and 4.0 months for all patients with EAC, GEJC, and GAC, respectively (p < 0.001). Median OS from start of first-line therapy of patients with human epidermal growth factor receptor 2 (HER2)-negative adenocarcinomas was 7.6, 7.8, and 7.5 months (p = 0.12) and of patients with HER2-positive carcinoma receiving first-line trastuzumab-containing therapy was 11.0, 13.3, and 9.5 months (p = 0.37) in EAC, GEJC, and GAC, respectively. After multivariable adjustment, no difference in OS for patients with EAC, GEJC, and GAC was observed. Conclusion: Despite differences in clinical characteristics and treatment strategies, survival between patients with advanced EAC, GEJC, and GAC was similar. We advocate that EAC patients should not be excluded from clinical trials for patients with molecularly similar GEJC/GAC.
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Background: Real-world data on treatment and outcomes in patients with synchronous metastatic disease compared with patients with metachronous metastatic disease in esophagogastric cancer have not been published before. The aim of our study was to explore treatment, overall survival (OS), and time to treatment fialure (TTF) in patients with synchronous and metachronous metastatic esophagogastric adenocarcinoma. Methods: Patients with synchronous metastatic disease (2015-2017) and patients with metachronous metastatic disease initially treated with curative intent for nonmetastatic disease (2015-2016) were selected from the Netherlands Cancer Registry. OS and TTF were assessed from metastatic diagnosis for patients with synchronous, early metachronous (⩽6 months) or late metachronous (>6 months) metastatic disease using Kaplan-Meier curves with two-sided log-rank test. Results: Median OS was 4.2, 2.1, and 4.4 months in patients with synchronous, early metachronous, and late metachronous metastatic disease, respectively (p < 0.001). The proportion of patients receiving systemic treatment was 41.3%, 21.5%, and 32.5% for synchronous, early metachronous, and late metachronous metastatic disease, respectively (p = 0.001). Among patients receiving systemic treatment, median OS was 8.8, 4.5, and 9.1 months (p < 0.001) and median TTF was 6.1, 3.8, and 5.7 months (p < 0.001) in synchronous, early metachronous, and late metachronous metastatic disease, respectively. Conclusion: Patients with early metachronous metastatic disease have a worse survival compared with patients with synchronous or late metachronous metastatic disease. These patients less often receive systemic treatment, and even when treated, survival is worse compared with patients with synchronous or late metachronous metastatic disease, suggesting a more aggressive tumor behavior.
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INTRODUCTION: Management of locally advanced, unresectable, or metastatic (adv/met) esophageal adenocarcinoma (EAC) follows clinical guidance for gastric cancer (GC) and gastroesophageal junction cancer (GEJC). However, evidence for these guidelines is based largely on patients with adv/met GC/GEJC, and generally excludes patients with EAC. It is currently unclear whether patients with adv/met GC/GEJC and adv/met EAC have similar demographics and clinical outcomes in real-world practice. METHODS: Adult patients diagnosed with adv/met GC/GEJC and adv/met EAC between January 1, 2011 and November 30, 2018 were identified (Flatiron Health database); patients with confirmed human epidermal growth factor receptor 2 (HER2)-positive tumors were excluded, and index was date of adv/met diagnosis. Median overall survival (OS) from start of first-line therapy until death/censoring was estimated by the Kaplan-Meier method. Multivariable analysis (Cox proportional hazards) was conducted to identify factors associated with OS. RESULTS: In total, 3052 patients were identified (adv/met GC/GEJC, n = 2083; adv/met EAC, n = 969). Patients with EAC were more likely to be male, have a history of smoking, have a higher body weight and body mass index, and were less likely to be Hispanic/Latino or Medicaid enrollees than patients with GC/GEJC. A similar proportion of patients with adv/met GC/GEJC (75%; n = 2326) and adv/met EAC (77%; n = 1573) received first-line therapy. Fluoropyrimidine plus platinum combinations were the most frequent first-line regimen in both groups (36%). Median OS was similar for patients with adv/met GC/GEJC and adv/met EAC (9.7 vs. 9.1 months, respectively; hazard ratio [95% confidence interval] 0.96 [0.87-1.06]; p = 0.4320). CONCLUSION: Despite minor differences in baseline demographics, clinical outcomes for patients with adv/met GC/GEJC and EAC are similar. This supports the inclusion of patients with adv/met EAC in clinical trials assessing adv/med GC/GEJC.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/epidemiologia , Adulto , Neoplasias Esofágicas/tratamento farmacológico , Junção Esofagogástrica , Feminino , Humanos , Masculino , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/epidemiologiaRESUMO
BACKGROUND: Standard first-line treatments for advanced soft tissue sarcoma (STS) have changed little for 40 years, and outcomes have been poor. Recently, the United States (US) Food and Drug Administration conditionally approved olaratumab in combination with doxorubicin (Olara + Dox) based on a randomized phase II trial that reported a significant 11.8-month improvement in median survival versus single-agent doxorubicin (Dox). The present study investigated the cost-effectiveness of Olara + Dox compared with Dox and five other standard-of-care regimens from the US payer perspective. METHODS: An economic model was constructed to estimate costs and outcomes over patients' lifetimes from start of therapy. Progression-free and overall survival were based on survival analysis of patient-level data and a meta-analysis. Adverse-event rates were based on trials. Costs were from published sources. RESULTS: Olara + Dox resulted in an estimated additional 1.27 life-years (LYs) compared with Dox, with an increase in total expected lifetime costs of $133,653. The incremental cost-effectiveness ratio (ICER) was estimated at $105,408 per LY gained; in a fully incremental analysis, all other regimens were dominated (higher costs and lower LYs or a higher ICER). CONCLUSION: Olara + Dox is cost-effective for STS treatment compared with Dox and other standard-of-care regimens at willingness-to-pay thresholds of $150,000 per LY and above.
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The Arf tumor suppressor inhibits cell cycle progression through both p53-dependent and p53-independent mechanisms, including interference with rRNA processing. Using tandem-affinity-tagged p19(Arf), we purified Arf-associated proteins from mouse NIH 3T3 fibroblasts undergoing cell cycle arrest. Tagged p19(Arf) associated with nucleolar and ribosomal proteins, including nucleophosmin/B23 (NPM), a protein thought to foster the maturation of preribosomal particles. NPM is an abundant protein, only a minor fraction of which binds to p19(Arf); however, a significant proportion of p19(Arf) associates with NPM. The interaction between p19(Arf) and NPM requires amino acid sequences at the Arf amino terminus, which are also required for Mdm2 binding, as well as the central acidic domain of NPM and an adjacent segment that regulates NPM oligomerization. The interaction between p19(Arf) and NPM occurs in primary mouse embryonic fibroblasts, including those lacking both Mdm2 and p53. In an NIH 3T3 derivative cell line (MT-Arf) engineered to conditionally express an Arf transgene, induced p19(Arf) associates with NPM and colocalizes with it in high-molecular-weight complexes (2 to 5 MDa). An NPM mutant lacking its carboxyl-terminal nucleic acid-binding domain oligomerizes with endogenous NPM, inhibits p19(Arf) from entering into 2- to 5-MDa particles, and overrides the ability of p19(Arf) to retard rRNA processing.
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Proteínas Nucleares/metabolismo , Proteína Supressora de Tumor p14ARF/metabolismo , Animais , Inibidor p16 de Quinase Dependente de Ciclina , Genes Reporter , Camundongos , Mutação , Células NIH 3T3 , Proteínas Nucleares/genética , Nucleofosmina , Ligação Proteica , RNA Ribossômico/metabolismo , Ribossomos/metabolismo , TransfecçãoRESUMO
Carriers of mutations in the BRCA2 gene are at a highly elevated risk of breast and other cancers. The BRCA2 gene encodes a very large protein thought to play a role in DNA repair. To examine the effect of mutation of BRCA2 on sensitivity to ionizing radiation, we used a previously described mouse model system (Brca2(Tr)) in which the Brca2 open reading frame is truncated. Mouse embryo fibroblasts carrying this mutation have a proliferative defect, which we show here can be substantially rescued by genetic ablation of p53. Proliferating Brca2(Tr/Tr)/p53(-/-) cells, like Brca2(Tr/Tr) cells, show genomic instability. We used the clonogenic survival assay, which depends on the ability of cells to proliferate, to examine the cell cycle dependence of radiation sensitivity of Brca2(Tr/Tr)/p53(-/-) compared to p53(-/-) and wild-type cells. This showed that the Brca2 mutation had little effect on cells irradiated in quiescence but sensitized proliferating cells to ionizing radiation on a p53(-/-) background. These results suggest that the major role of Brca2 in mediating cell survival after irradiation is in the S and G(2) phases of the cell cycle.
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Ciclo Celular , Genes BRCA2 , Mutação , Tolerância a Radiação/genética , Animais , Neoplasias da Mama/radioterapia , Ciclo Celular/genética , Ciclo Celular/efeitos da radiação , Linhagem Celular , Centrossomo/efeitos da radiação , Feminino , Humanos , Técnicas In Vitro , Camundongos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Lymphomagenesis in Emu-Myc mice is opposed by the Arf tumor suppressor, whose inactivation compromises p53 function and accelerates disease. Finding nascent Emu-Myc-induced tumors in which p19Arf causes cell-cycle arrest or apoptosis is problematic, since such cells will be eliminated until Arf or p53 function is lost. Knock-in mice expressing a green fluorescent protein (GFP) in lieu of Arf coding sequences allow analysis of Arfpromoter regulation uncoupled from p19Arf action. Prior to frank lymphoma development, unexpectedly low levels of Emu-Myc-induced p19Arf or GFP were expressed. However, as lymphomas arose in Arf+/GFP heterozygotes, additional oncogenic events synergized with Emu-Myc to further induce the functionally null Arf-Gfp allele. Concomitant up-regulation of p19Arf was not observed; instead, the wild-type allele was inactivated. We infer that very low levels of Arf are tumor suppressive, and that further induction provides the selective pressure for the emergence of tumors that have inactivated the gene.
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Inibidor p16 de Quinase Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Linfoma/genética , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Progressão da Doença , Genes Reporter , Linfoma/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
We have established that the Arf tumor suppressor gene regulates mural cell biology in the hyaloid vascular system (HVS) of the developing eye. In the absence of Arf, perivascular cells accumulate within the HVS and prevent its involution. We now demonstrate that mural cell accumulation evident at embryonic day (E) 13.5 in Arf(-/-) mice was driven by excess proliferation at E12.5, when Arf expression was detectable in vitreous pericyte-like cells. Their expression of Arf overlapped with Pdgf receptor beta (Pdgfrbeta), which is essential for pericyte accumulation in the mouse. In cultured cells, p19Arf decreased Pdgfrbeta and blocked Pdgf-B-driven proliferation independently of Mdm2 and p53. The presence of a normal Arf allele correlated with decreased Pdgfrbeta in the embryonic vitreous. Pdgfrbeta was required for vitreous cell accumulation in the absence of Arf. Our findings demonstrate a novel, p53- and Mdm2-independent function for p19Arf. Instead of solely sensing excessive mitogenic stimuli, developmental cues induce Arf to block Pdgfrbeta-dependent signals and prevent the accumulation of perivascular cells selectively in a vascular bed destined to regress.
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Olho/citologia , Olho/embriologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/fisiologia , Transdução de Sinais/fisiologia , Proteína Supressora de Tumor p14ARF/metabolismo , Animais , Proliferação de Células , Inibidor p16 de Quinase Dependente de Ciclina , Camundongos , Camundongos Knockout , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2 , Proteínas Proto-Oncogênicas c-sis/metabolismo , Proteína Supressora de Tumor p14ARF/deficiência , Proteína Supressora de Tumor p14ARF/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Unknown mechanisms govern degradation of the p19Arf tumor suppressor, an activator of p53 and inhibitor of ribosomal RNA processing. Kinetic metabolic labeling of cells with [3H]-leucine indicated that p19Arf is a relatively stable protein (half-life approximately 6 h) whose degradation depends upon the ubiquitin-proteasome pathway. Although p19Arf binds to the Mdm2 E3 ubiquitin protein ligase to activate p53, neither of these molecules regulates p19Arf turnover. In contrast, the nucleolar protein nucleophosmin/B23, which binds to p19Arf with high stoichiometry, retards its turnover, and Arf mutants that do not efficiently associate with nucleophosmin/B23 are unstable and functionally impaired. Mouse p19Arf, although highly basic (22% arginine content), contains only a single lysine residue absent from human p14ARF, and substitution of arginine for lysine in mouse p19Arf had no effect on its rate of degradation. Mouse p19Arf (either wild-type or lacking lysine) and human p14ARF undergo N-terminal polyubiquitination, a process that has not as yet been documented in naturally occurring lysine-less proteins. Re-engineering of the p19Arf N terminus to provide consensus sequences for N-acetylation limited Arf ubiquitination and decelerated its turnover.
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Cisteína Endopeptidases/metabolismo , Complexos Multienzimáticos/metabolismo , Proteína Supressora de Tumor p14ARF/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Acetilação , Sequência de Aminoácidos , Animais , Inibidor p16 de Quinase Dependente de Ciclina , Genes Supressores de Tumor/fisiologia , Genes p16/fisiologia , Humanos , Leucina/metabolismo , Camundongos , Dados de Sequência Molecular , Mutação/genética , Células NIH 3T3 , Proteínas Nucleares/metabolismo , Nucleofosmina , Complexo de Endopeptidases do Proteassoma , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2 , Proteína Supressora de Tumor p53/metabolismoRESUMO
The Arf tumor suppressor protein inhibits cell proliferation through both p53-dependent and -independent mechanisms. Two rat monoclonal antibodies raised against a peptide corresponding to amino acids 54-75 of the mouse p19(Arf) protein reacted with the native protein expressed in mammalian cells. Neither antibody detected human or golden hamster Arf proteins. The two antibodies, both of IgG2b isotype, are directed to adjacent epitopes contained within residues 54-62 and 62-75, respectively, of the mouse p19(Arf) protein, and both were highly efficient in detecting p19(Arf) by immunoprecipitation, immunoblotting, and immunofluorescence. One antibody proved useful for immunohistochemical staining of p19(Arf) in fixed sections of mouse testes, revealing low levels of protein expression within the nucleoli of spermatogonia. This indicates that these antibodies should be useful in detecting the endogenous p(19Arf) protein at specific stages of mouse development and during early stages of tumorigenesis.