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Importance: In 2020, some health insurance plans updated their medical policy to cover germline genetic testing for all patients diagnosed with colorectal cancer (CRC). Guidelines for universal tumor screening via microsatellite instability and/or immunohistochemistry (MSI/IHC) for mismatch repair protein expression for patients with CRC have been in place since 2009. Objectives: To examine whether uptake of MSI/IHC screening and germline genetic testing in patients with CRC has improved under these policies and to identify actionable findings and management implications for patients referred for germline genetic testing. Design, Setting, and Participants: The multicenter, retrospective cohort study comprised 2 analyses of patients 18 years or older who were diagnosed with CRC between January 1, 2017, and December 31, 2020. The first analysis used an insurance claims data set to examine use of MSI/IHC screening and germline genetic testing for patients diagnosed with CRC between 2017 and 2020 and treated with systemic therapy. The second comprised patients with CRC who had germline genetic testing performed in 2020 that was billed under a universal testing policy. Main Outcomes and Measures: Patient demographic characteristics, clinical information, and use of MSI/IHC screening and germline genetic testing were analyzed. Results: For 9066 patients with newly diagnosed CRC (mean [SD] age, 64.2 [12.7] years; 4964 [54.8%] male), administrative claims data indicated that MSI/IHC was performed in 6645 eligible patients (73.3%) during the study period, with 2288 (25.2%) not receiving MSI/IHC despite being eligible for coverage. Analysis of a second cohort of 55â¯595 patients with CRC diagnosed in 2020 and covered by insurance found that only 1675 (3.0%) received germline genetic testing. In a subset of patients for whom germline genetic testing results were available, 1 in 6 patients had pathogenic or likely pathogenic variants, with most of these patients having variants with established clinical actionability. Conclusions and Relevance: This nationwide cohort study found suboptimal rates of MSI/IHC screening and germline genetic testing uptake, resulting in clinically actionable genetic data being unavailable to patients diagnosed with CRC, despite universal eligibility. Effective strategies are required to address barriers to implementation of evidence-based universal testing policies that support precision treatment and optimal care management for patients with CRC.
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Neoplasias Colorretais Hereditárias sem Polipose , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Neoplasias Colorretais Hereditárias sem Polipose/genética , Estudos de Coortes , Estudos Retrospectivos , Instabilidade de Microssatélites , Testes Genéticos/métodos , Células Germinativas , PolíticasRESUMO
Aim: Healthcare utilization and costs were compared following 25-gene panel (panel) or single syndrome (SS) testing for hereditary breast and ovarian cancer. Materials & methods: Retrospective cohort study of patients unaffected by cancer with panel (n = 6359) or SS (n = 4681) testing for hereditary breast and ovarian cancer (01 January 2014 to 31 December 2016). Groups were determined by test type and result (positive, negative, variant of uncertain significance [VUS]). Results: There were no differences in total unadjusted healthcare costs between the panel (US$14,425) and SS (US$14,384) groups (p = 0.942). Among VUS patients in the panel and SS groups, mean all-cause costs were US$14,404 versus US$20,607 (p = 0.361) and mean risk-reduction/early detection-specific costs were US$718 versus US$679 (p = 0.890), respectively. Adjusted medical costs were not significantly different between panel and SS cohorts. Conclusion: Healthcare utilization and costs were comparable between the SS and panel tests overall and for patients with VUS.
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Neoplasias da Mama , Neoplasias Ovarianas , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Carcinoma Epitelial do Ovário , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Estudos RetrospectivosRESUMO
BACKGROUND/AIM: Limited published real-world data describe adverse events (AEs) among patients treated for mantle-cell lymphoma (MCL). The aim of this retrospective study was to describe treatment patterns, AEs, and associated healthcare costs. PATIENTS AND METHODS: Patients had two or more claims coded for MCL diagnosis, the first claim date (07/01/2012-05/31/2017) was the index date. Patients with pre-index MCL diagnosis or systemic treatment, or hematopoietic stem cell transplantation were excluded. Cohorts by regimen were followed for up to three lines of therapy. RESULTS: Patients (n=395; median age 72 years; 31% female) were observed over a total of 576 lines of therapy, the most common being bendamustine plus rituximab; rituximab monotherapy; R-CHOP; and ibrutinib. The most frequent AEs were hypertension (40.5%), anemia (37.7%), and infection (36.1%). However, hepatotoxicity ($19,645), stroke ($18,893), and renal failure ($9,037) were associated with the highest medical costs per patient per month. CONCLUSION: Among patients receiving common systemic treatments for MCL, AEs occurred frequently; some imposed substantial inpatient care costs.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/economia , Linfoma de Célula do Manto/tratamento farmacológico , Insuficiência Renal/economia , Acidente Vascular Cerebral/economia , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/economia , Adenina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/efeitos adversos , Cloridrato de Bendamustina/economia , Cloridrato de Bendamustina/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/economia , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/economia , Doxorrubicina/uso terapêutico , Feminino , Custos de Cuidados de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piperidinas/economia , Piperidinas/uso terapêutico , Prednisona/efeitos adversos , Prednisona/economia , Prednisona/uso terapêutico , Insuficiência Renal/induzido quimicamente , Estudos Retrospectivos , Rituximab/efeitos adversos , Rituximab/economia , Rituximab/uso terapêutico , Acidente Vascular Cerebral/induzido quimicamente , Vincristina/efeitos adversos , Vincristina/economia , Vincristina/uso terapêuticoRESUMO
BACKGROUND: Since treatment patterns in metastatic soft tissue sarcoma (mSTS) have not been studied subsequent to US approval of pazopanib in 2012, this study sought to examine mSTS treatment patterns by line of therapy, including regimen and duration of therapy. METHODS: This retrospective study employed administrative claims from a large US health plan from 1/2006-9/2015. Adult mSTS patients were required to have an NCCN-recommended therapy and be continuously enrolled in the health plan during the study period. The most frequent regimens for distinct lines of therapy (LOT) were assessed. Sensitivity analyses evaluated changes to study findings using two alternate medical and pharmacy claims diagnostic algorithms to define the STS study population. RESULTS: Among 555 patients with mSTS, mean age was 59 years and 54% were male. During the study period, 41% of patients initiated ≥ 2 LOTs; 16% had ≥ 3 LOTs and 5% had ≥ 4 LOTs. Docetaxel + gemcitabine was most common in LOT1, pazopanib in LOT2 and LOT3, and doxorubicin in LOT4. The five most common LOT1 regimens represented 53% of patients; among the remaining 47%, the most common regimen represented < 6% of patients. Among patients with pazopanib in LOT2 and LOT3, the most common prior regimen was docetaxel + gemcitabine (47% and 30% respectively). Kaplan-Meier estimation of median treatment duration overall for LOT1 was 3.5 months, while for LOT2 and LOT3, median treatment duration was 2.9 and 3.3 months, respectively. For both sensitivity analyses, patient demographic and clinical characteristics were similar to the original study population, and the five most frequently used regimens in LOT1 and LOT2 were similar among the three populations regardless of the population selection criteria employed. CONCLUSION: Choice of regimen by LOT among patients with mSTS is varied; < 65% of patients in any LOT received the five most common regimens. Pazopanib, the only approved targeted therapy, is primarily used in second and later lines of therapy and is mostly given post docetaxel + gemcitabine.
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BACKGROUND: Guidelines recommend that women with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) initiate hormonal therapy before chemotherapy. This study compared outcomes of women with mBC who received chemotherapy first vs hormonal therapy. METHODS: A retrospective cohort study of women with mBC was conducted using a large US commercial health plan database between January 1, 2008-April 30, 2013. Subjects had evidence of a HR+/HER2- tumor sub-type in a cancer registry and use of chemotherapy or hormonal therapy in claims. Subjects were continuously enrolled for ≥6 months after metastasis and assigned to cohorts for receiving chemotherapy only or hormonal therapy only during first-line (CT-1L vs HT-1L). Adjusted incidence rates of clinically significant events were compared using a negative binomial model, and adjusted healthcare costs were compared using a generalized linear model. RESULTS: Three hundred and twenty-four women with HR+/HER2- mBC met the selection criteria; 179 (55%) received CT-1L and 145 (45%) received HT-1L. Mortality rates did not differ between cohorts (unadjusted incidence rate ratio (IRR) = 1.67, 95% CI = 0.82-3.46; adjusted IRR = 0.64, 95% CI = 0.32-1.27). Adjusted average total all-cause healthcare costs were $11 090 for women with CT-1L and $6743 for women with HT-1L (cost ratio =1.64, 95% CI =1.36-1.99). CONCLUSIONS: Observed use of first-line chemotherapy (>50%) was higher than expected given the HR + molecular profile of the tumors. Chemotherapy use during first-line did not appear to be associated with a survival benefit, but was associated with significantly higher costs compared with the use of hormonal therapy during first-line; however, this comparison is limited by demographic and baseline characteristic differences between the two cohorts. This study contributes to understanding real-world treatment patterns and the associated clinical and economic outcomes of using chemotherapy vs hormonal therapy as a first-line treatment option for the HR+/HER2- mBC population.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Custos de Cuidados de Saúde , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Adulto , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos RetrospectivosRESUMO
BACKGROUND: In this study, we compare 2 treatment options and determine cost-effectiveness and cost-utility. METHODS: We carried out a decision analysis populated with data from patients with brain metastasis in a concurrent trial randomized to either stereotactic radiosurgery (SRS) and observation or SRS and whole brain radiation therapy. Outcomes included actual life years saved (LYS), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). Costs used were from the healthcare perspective and utilities were captured through a time-trade-off method, using 10-year, 5-year, and 1-year time horizons. One-way sensitivity analyses were carried out to determine robustness of the decision analysis model. RESULTS: Compared with SRS and whole brain radiation therapy, SRS and observation not only had a higher average cost ($74,000 vs $119,000, respectively) but also a higher average effectiveness (0.60 LYS vs 1.64 LYS, respectively) with an ICER of $44,231/LYS or $41,783/QALY (with utilities captured using a 10-year horizon). Slightly higher ICER estimates were achieved with utilities captured using the other time horizons ($43,280/QALY and $44,064/QALY, respectively). Sensitivity analysis showed that the following variables had the highest impact on the ICER: probability of no recurrence in recursive-partitioning analysis class 2 after SRS and observation; probability of being alive after SRS and observation in recursive-partitioning analysis class 2 and being treated for recurrence. CONCLUSIONS: Compared with other interventions in the $50,000 to $100,000/QALY cost-effectiveness range, the application of SRS and observation, with subsequent neurosurgical management of recurrences, is shown to be a reasonable treatment modality for brain metastases.
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Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Irradiação Craniana/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Radiocirurgia/economia , Adulto , Idoso , Neoplasias Encefálicas/economia , Neoplasias Encefálicas/secundário , Análise Custo-Benefício , Custos Diretos de Serviços/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , TexasRESUMO
OBJECTIVE: ⢠To investigate the effect of combining gemcitabine plus capecitabine (GX) with bevacizumab (A) in patients with metastatic RCC previously treated with cytokines and targeted agents. METHODS: ⢠The combination of GX + A was evaluated in patients with metastatic RCC using institutional databases. ⢠Data included demographics, previous therapies, number of metastatic sites, Memorial Sloan-Kettering Cancer Center risk stratification variables, and previous nephrectomy status. ⢠Descriptive statistics and survival analysis were employed for data analysis. RESULTS: ⢠Between January 2005 and October 2008, 28 patients were identified. Mean age was 55.7 years. Fifteen (53.57%) patients had been given tyrosine kinase inhibitor (TKI) previously. Nine (32.14%) patients had clear cell histology, 10 (35.71%) patients had sarcomatoid features on histopathology, and 19 patients (67.86%) had a prior nephrectomy. ⢠Initial treatment consisted of G (mean dose 786.07 mg/m²) every 2 weeks, X (mean dose 2.73 g/day), and A (mean dose 10 mg/kg) every 2 weeks. Median progression-free survival (PFS) was 5.9 months and the median overall survival (OS) was 10.4 months. ⢠In patients with previous TKI therapy, median PFS was 6.2 months and median OS was 11.7 months. ⢠In patients with sarcomatoid features, median PFS was 3.9 months and OS was 9.0 months. ⢠Three patients discontinued one or more of the drugs because of adverse reactions. CONCLUSIONS: ⢠The combination of GX + A shows potential efficacy and acceptable tolerability in patients with intermediate and poor prognosis metastatic RCC. ⢠Based on these observations, a phase II trial is now underway assessing this combination in patients with sarcomatoid RCC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Bevacizumab , Institutos de Câncer , Capecitabina , Carcinoma de Células Renais/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Esquema de Medicação , Métodos Epidemiológicos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do Tratamento , GencitabinaRESUMO
Smads2 and 3 transduce signals of TGF-beta from the cell surface to the nucleus. We used mice with a targeted deletion of Smad3 to study the specific contributions of this signaling pathway to pathogenic effects of TGF-beta. Focusing on models involving epithelial-to-mesenchymal transition (EMT), including injury to the lens and retina of the eye and to the kidney, we have found that loss of Smad3 blocks EMT and attenuates development of fibrotic sequelae. Smad3 also plays a critical role in both the tumor suppressor and pro-metastatic effects of TGF-beta in carcinogenesis. These observations suggest that development of small molecule inhibitors of Smad3 might have clinical application in treatment of fibrotic diseases as well as late stage cancers.
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Células Epiteliais/metabolismo , Mesoderma/citologia , Metástase Neoplásica/patologia , Neoplasias/prevenção & controle , Proteína Smad3/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Diferenciação Celular/fisiologia , Membrana Celular/imunologia , Membrana Celular/metabolismo , Núcleo Celular/imunologia , Núcleo Celular/metabolismo , Fibrose/metabolismo , Humanos , Mesoderma/metabolismo , Neoplasias/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/genéticaRESUMO
The role of transforming growth factor beta (TGF-beta) in carcinogenesis is complex, with tumor suppressor and pro-oncogenic activities depending on the particular tumor cell and its stage in malignant progression. We previously have demonstrated in breast cancer cell lines that Smad2/3 signaling played a dominant role in mediating tumor suppressor effects on well-differentiated breast cancer cell lines grown as xenografts and prometastatic effects on a more invasive, metastatic cell line. Our present data based on selective interference with activation of endogenous Smad2 and Smad3 by stable expression of a mutant form of the TGF-beta type I receptor (RImL45) unable to bind Smad2/3 but with a functional kinase again show that reduction in Smad2/3 signaling by expression of RImL45 enhanced the malignancy of xenografted tumors of the well-differentiated MCF10A-derived tumor cell line MCF10CA1h, resulting in formation of larger tumors with a higher proliferative index and more malignant histologic features. In contrast, expression of RImL45 in the more aggressive MCF10CA1a cell line strongly suppressed formation of lung metastases following tail vein injection. These results suggest a causal, dominant role for the endogenous Smad2/3 signaling pathway in the tumor suppressor and prometastatic activities of TGF-beta in these cells. Using an in vitro assay, we further show that non-Smad signaling pathways, including p38 and c-Jun NH(2)-terminal kinase, cooperate with TGF-beta/Smads in enhancing migration of metastatic MCF10CA1a cells, but that, although necessary for migration, these other pathways are not sufficient for metastasis.
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Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/genética , Transativadores/metabolismo , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Humanos , Camundongos , Camundongos Nus , Mutação , Metástase Neoplásica , Fosforilação , Proteínas Serina-Treonina Quinases , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/biossíntese , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteína Smad2 , Proteína Smad3 , Transativadores/genética , Ativação Transcricional , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/fisiologiaRESUMO
TGF-beta elicits context-dependent and cell-specific effects that often appear conflicting, such as stimulation or inhibition of growth, apoptosis or differentiation. It is puzzling how such a diverse array of responses can result from binding of TGF-beta to a single receptor complex that activates a seemingly straightforward signal-transduction scheme dependent on shuttling of Smad transducer proteins from the receptor to the nucleus. Here, we discuss a novel paradigm for TGF-beta signaling in endothelial cells in which the same ligand can induce opposing effects mediated by activation of two different classes of Smads through a chimeric receptor complex.