RESUMO
PURPOSE: In metastatic triple-negative breast cancer (mTNBC), consistent biomarkers of immune checkpoint inhibitor (ICI) therapy benefit remain elusive. We evaluated the immune, genomic, and transcriptomic landscape of mTNBC in patients treated with ICIs. METHODS: We identified 29 patients with mTNBC treated with pembrolizumab or atezolizumab, either alone (n = 9) or in combination with chemotherapy (n = 14) or targeted therapy (n = 6), who had tumor tissue and/or blood available before ICI therapy for whole-exome sequencing. RNA sequencing and CIBERSORTx-inferred immune population analyses were performed (n = 20). Immune cell populations and programmed death-ligand 1 expression were assessed using multiplexed immunofluorescence (n = 18). Clonal trajectories were evaluated via serial tumor/circulating tumor DNA whole-exome sequencing (n = 4). Association of biomarkers with progression-free survival and overall survival (OS) was assessed. RESULTS: Progression-free survival and OS were longer in patients with high programmed death-ligand 1 expression and tumor mutational burden. Patients with longer survival also had a higher relative inferred fraction of CD8+ T cells, activated CD4+ memory T cells, M1 macrophages, and follicular helper T cells and enrichment of inflammatory gene expression pathways. A mutational signature of defective repair of DNA damage by homologous recombination was enriched in patients with both shorter OS and primary resistance. Exploratory analysis of clonal evolution among four patients treated with programmed cell death protein 1 blockade and a tyrosine kinase inhibitor suggested that clonal stability post-treatment was associated with short time to progression. CONCLUSION: This study identified potential biomarkers of response to ICIs among patients with mTNBC: high tumor mutational burden; presence of CD8+, CD4 memory T cells, follicular helper T cells, and M1 macrophages; and inflammatory gene expression pathways. Pretreatment deficiencies in the homologous recombination DNA damage repair pathway and the absence of or minimal clonal evolution post-treatment may be associated with worse outcomes.
Assuntos
Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/genética , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Mutação , Intervalo Livre de Progressão , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Physical activity and cardiorespiratory fitness are associated with improved cardiovascular health and reduced all-cause mortality. The relation between self-reported physical activity, objective physical fitness, and the association of each with cardiometabolic risk has not been fully described. We studied 2,800 healthy Brazilian subjects referred for an employer-sponsored health screening. Physical activity level was determined as "low," "moderate," or "high" with the International Physical Activity Questionnaire: Short Form (IPAQ-SF). Fitness was measured as METs achieved on a maximal, symptom-limited, treadmill stress test. Using multivariate linear regression analysis, we calculated age, gender, and smoking-adjusted correlation coefficients among IPAQ-SF, fitness, and cardiometabolic risk factors. Mean age of study participants was 43 ± 9 years; 81% were men, and 43% were highly active. Mean METs achieved was 12 ± 2. IPAQ-SF category and fitness were moderately correlated (r = 0.377). Compared with IPAQ-SF category, fitness was better correlated with cardiometabolic risk factors including anthropomorphic measurements, blood pressure, fasting blood glucose, dyslipidemia, high-sensitivity C-reactive protein, and hepatic steatosis (all p <0.01). Among these, anthropomorphic measurements, blood pressure, high-sensitivity C-reactive protein, and hepatic steatosis had the largest discrepancies in correlation, whereas lipid factors had the least discrepant correlation. When IPAQ-SF and fitness were discordant, poor fitness drove associations with elevated cardiometabolic risk. In conclusion, self-reported physical activity level and directly measured fitness are moderately correlated, and the latter is more strongly associated with a protective cardiovascular risk profile.
Assuntos
Fenômenos Fisiológicos Cardiovasculares , Exercício Físico/fisiologia , Aptidão Física/fisiologia , Adulto , Idoso , Brasil , Doenças Cardiovasculares/fisiopatologia , Metabolismo Energético , Teste de Esforço , Feminino , Humanos , Modelos Lineares , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Autorrelato , Inquéritos e Questionários , Adulto JovemRESUMO
Hepatic steatosis is closely associated with the metabolic syndrome. We assessed for an independent association between hepatic steatosis and atherogenic dyslipidemia after adjustment for obesity, physical activity, hyperglycemia, and systemic inflammation. We studied 6,333 asymptomatic subjects without clinical cardiovascular disease undergoing a health screen in Brazil from November 2008 to July 2010. Hepatic steatosis was diagnosed by ultrasound. Atherogenic dyslipidemia was defined using 2 definitions: criteria for (1) metabolic syndrome or (2) insulin resistance (triglyceride/high-density-lipoprotein cholesterol ratio of ≥2.5 in women and ≥3.5 in men). In hierarchical multivariate regression models, we evaluated for an independent association of hepatic steatosis with atherogenic dyslipidemia. Hepatic steatosis was detected in 36% of participants (average age 43.5 years, 79% men, average body mass index 26.3 kg/m(2)). Subjects with hepatic steatosis had similar levels of low-density-lipoprotein cholesterol, with significantly lower level of high-density-lipoprotein cholesterol and higher level of triglyceride compared with those without steatosis. Hepatic steatosis remained significantly independently associated with atherogenic dyslipidemia of both definitions (metabolic syndrome [odds ratio 2.47, 95% confidence interval 2.03 to 3.02] and insulin resistance [odds ratio 2.50, 95% confidence interval 2.13 to 2.91]) after multivariate adjustment. Stratified analyses showed a persistent independent association in nonobese subjects, those without metabolic syndrome, those with normal high-sensitivity C-reactive protein, nonalcohol abusers, and those with normal liver enzymes. Hepatic steatosis was significantly associated with atherogenic dyslipidemia independent of obesity, physical activity, hyperglycemia, and systemic inflammation after multivariate adjustment. In conclusion, this adds to the growing body of evidence that hepatic steatosis may play a direct metabolic role in conferring increased cardiovascular risk.
Assuntos
Aterosclerose/etiologia , Dislipidemias/etiologia , Fígado Gorduroso/complicações , Lipídeos/sangue , Adulto , Aterosclerose/sangue , Aterosclerose/epidemiologia , Índice de Massa Corporal , Brasil/epidemiologia , Dislipidemias/sangue , Dislipidemias/epidemiologia , Fígado Gorduroso/sangue , Fígado Gorduroso/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos , Fatores de RiscoRESUMO
Obesity demonstrates a direct relation with cardiovascular risk and all-cause mortality, while cardiorespiratory fitness demonstrates an inverse relation. In clinical practice, several cardiometabolic (CM) risk factors are commonly measured to gauge cardiovascular risk, but the interaction between fitness and obesity with regard to CM risk has not been fully explored. In this study, 2,634 Brazilian adults referred for employer-sponsored heath exams were assessed. Obesity was defined as body mass index >30 kg/m(2) or waist circumference >102 cm in men or >88 cm in women when body mass index was 25 to 30 kg/m(2). Fitness was quantified by stage achieved on an Ellestad treadmill stress test, with those completing stage 4 considered fit. Hepatic steatosis was determined by ultrasound. CM risk factors were compared after stratifying patients into 4 groups: fit and normal weight, fit and obese, unfit and normal weight, and unfit and obese. Approximately 22% of patients were obese; 12% were unfit. Fitness and obesity were moderately correlated (ρ = 0.38 to 0.50). The sample included 6.5% unfit and normal-weight subjects and 16% fit and obese subjects. In overweight and obese patients, fitness was negatively associated with CM risk (p <0.01 for all values). In fit patients, increasing body mass index was positively associated with CM risk (p <0.01 for all values). In instances of discordance between fitness and obesity, obesity was the stronger determinant of CM risk. In conclusion, fitness and obesity are independently associated with CM risk. The effects of fitness and obesity are additive, but obesity is more strongly associated with CM risk when fitness and obesity are discordant. These findings underscore the need for weight loss in obese patients and suggest an unmeasured benefit of fitness.