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BACKGROUND: Copy number alterations (CNA) are acquired during the evolution of cancers from their early stage to metastatic stage. This study aims at analysing the clinical value of the identified metastasis-associated CNAs both in metastatic breast cancers (mBCs) and early breast cancers (eBCs). METHODS: Single-nucleotide polymorphism (SNP)-array was performed on 926 biopsies from mBC patients, enrolled in SAFIR02-BREAST prospective trial. CNA profiles of eBCs from The Cancer Genome Atlas Breast Invasive Carcinoma (n = 770), Molecular Taxonomy of Breast Cancer International Consortium (n = 1620) and PACS04 trial (n = 243) cohorts were used as references for comparing mBCs and eBCs CNA profiles. Overall survival was the considered survival endpoint. RESULTS: Among the twenty-one genes frequently altered in ER + /HER2- mBCs: focal amplification of TERT was associated with poor outcome in the ER + /HER2- mBC population. Among the ER + /HER2- mBCs patients for whom CDK4/6 inhibitors information before biopsies collection was available: we identified seven genes on post-treatment biopsies, including the cyclin-dependent kinase 4 (CDK4), which was amplified in 9.8% of the ER + /HER2- mBCs pretreated population, as compared to 1.5% in the ER + /HER2- mBCs unpretreated population (P = 2.82E-04) as well as the 3 eBC populations. CDK4 amplification was associated with poor outcome in the ER + /HER2- eBCs. CONCLUSIONS: This study provides insights into the biology of mBCs and identifies clinically useful genomic features for future improvement of breast cancer patient management.
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Linfócitos do Interstício Tumoral , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Prognóstico , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. Exposure: TIL abundance in breast tissue from resected primary tumors. Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.
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Linfócitos do Interstício Tumoral , Neoplasias de Mama Triplo Negativas , Adulto , Humanos , Pessoa de Meia-Idade , Adjuvantes Imunológicos , Colúmbia Britânica , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
BACKGROUND: Darolutamide and enzalutamide are second-generation androgen receptor inhibitors with activity in men with castrate-resistant prostate cancer (CRPC) and different toxicity profiles. OBJECTIVE: ODENZA is a prospective, randomized, multicenter, cross-over, phase 2 trial designed to assess preference between darolutamide and enzalutamide in men with asymptomatic or mildly symptomatic metastatic CRPC (mCRPC). DESIGN, SETTING, AND PARTICIPANTS: Patients were randomized 1:1 to receive either darolutamide 1200 mg/d for 12 wk followed by enzalutamide 160 mg/d for 12 wk or enzalutamide followed by darolutamide. In both arms, the second treatment was given in absence of cancer progression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was patient preference between the two drugs, as assessed by a preference questionnaire (p value calculated with the Prescott test). After week 24, patients entered an extension period during which they received their preferred treatment until progression or toxicity. The main secondary objectives included reasons for patient preference, response at week 12, tolerance of each drug, and measurement compared with baseline of cognitive outcomes assessed using tablet questionnaires. RESULTS AND LIMITATIONS: Overall, 249 patients, with a median age of 72 yr, were randomized. Among the 200 patients who fulfilled the preplanned criteria for the evaluation of the primary endpoint of preference, 97 (49% [41; 56]), 80 (40% [33; 47]), and 23 (12% [7; 16]) chose darolutamide, chose enzalutamide, and had no preference, respectively (p = 0.92). Reduced fatigue, easier administration, and better quality of life were the main criteria that influenced patient choice. A moderate benefit in episodic memory from darolutamide was observed for the acquisition of new information (least square [LS] means difference = 2.2, effect size = 0.5) and for the recall of that information after a brief delay (LS means difference = 0.7, effect size = 0.3). Using the Brief Fatigue Inventory questionnaire, patients reported greater fatigue with enzalutamide (3.3 [3.0; 3.6]) than with darolutamide (2.7 [2.4; 3.0]). There was no difference in terms of depression, seizures, and falls. CONCLUSIONS: The study did not show a difference in preference between the two treatments. In men with mCRPC, darolutamide was associated with a clinically meaningful benefit in episodic memory and less fatigue compared with enzalutamide. PATIENT SUMMARY: Preference between darolutamide and enzalutamide was well balanced in men with castrate-resistant prostate cancer. Darolutamide was associated with a significant benefit in verbal learning and less fatigue compared with enzalutamide.
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Benzamidas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração , Pirazóis , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Preferência do Paciente , Qualidade de Vida , Estudos Prospectivos , Nitrilas/uso terapêutico , Cognição , FadigaRESUMO
Several tests have been recently implemented in the nonparametric comparison of current status survival data. However, they are not suited for the situation of crossing hazards. In this setting, we propose a new test specifically designed for crossing hazards alternatives. The proposed test is compared to classical implemented tests through simulations mimicking crossing hazards situations with various schemes of censoring. The results show that the proposed test has a correct type I error and generally outperforms the existing methods. The application of the proposed test on a real dataset on immunogenicity of interferon-ß among multiple sclerosis patients highlights the interest of the proposed test.
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Terapia Biológica/mortalidade , Modelos de Riscos Proporcionais , Análise de Sobrevida , Terapia Biológica/métodos , Interpretação Estatística de Dados , Humanos , Interferon beta/imunologia , Interferon beta/uso terapêutico , Modelos Estatísticos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologiaRESUMO
OBJECTIVES: In cross-sectional studies of time-to-event data collected by patient examinations at a single random point in time, a fraction of them will not experience the event regardless of the length of the follow-up time. This is the case in clinical immunology studies that include a mixed population, with both immune-reactive and immune-tolerant (or non-susceptible) patients. In these cases, classical tests of current status data may perform poorly. New methods for testing these data are needed. METHODS: In the two-sample comparison setting, we propose a score test for testing the null hypothesis that survival does not differ in either the non-susceptible fraction or the time-to-event distribution among the susceptible fraction. RESULTS: In a wide range of scenarios, simulation results show interesting improvements in power for the proposed score test compared to the logrank-type test in most of the configurations we investigated. In a cross-sectional study of drug immunogenicity among treated multiple sclerosis patients, the proposed score test reveals that gender is associated with the immunogenicity of interferon.
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Esclerose Múltipla/imunologia , Análise de Sobrevida , Estudos Transversais , Feminino , Humanos , Masculino , Modelos Teóricos , Esclerose Múltipla/patologiaRESUMO
Gaussian mixture analysis is frequently used to model the age-at-onset (AAO) in bipolar I disorder and identify homogeneous subsets of patients. This study aimed to examine whether, using admixture analysis of AAO, cross-sectional designs (which cause right truncation), unreliable diagnosis for individuals younger than 10 years old (which causes left truncation) and the selection criterion used for admixture analysis impact the number of identified subsets. A simulation study was performed. Different criteria - the likelihood ratio test (LRT), the Akaike information criterion (AIC), and the Bayesian information criterion (BIC) - were compared using no, left and/or right truncation simulated data. The error rate of each criterion (percentage of erroneous number of detected subsets) was estimated. An application to two real databases, including 2,876 and 1,393 patients, is provided. Without data truncation and regardless of the distribution of AAO, the LRT and the AIC had much higher error rates (12% and 33%, respectively) than the BIC (1%). For a homogeneous population, the error rate increased with the introduction of left truncation. This study shows that the number of subsets identified using admixture analysis may depend on the sample size, the selection criterion, and the study design.