RESUMEN
PURPOSE: Studies comparing the effect of aromatase inhibitor (AI) and tamoxifen use on cardiovascular disease (CVD) risk factors in hormone receptor-positive breast cancer (BC) survivors report conflicting results. We examined associations of endocrine therapy use with incident diabetes, dyslipidemia, and hypertension. METHODS: The Pathways Heart Study examines cancer treatment exposures with CVD-related outcomes in Kaiser Permanente Northern California members with BC. Electronic health records provided sociodemographic and health characteristics, BC treatment, and CVD risk factor data. Hazard ratios (HR) and 95% confidence intervals (CI) of incident diabetes, dyslipidemia, and hypertension in hormone receptor-positive BC survivors using AIs or tamoxifen compared with survivors not using endocrine therapy were estimated using Cox proportional hazards regression models adjusted for known confounders. RESULTS: In 8985 BC survivors, mean baseline age and follow-up time was 63.3 and 7.8 years, respectively; 83.6% were postmenopausal. By treatment, 77.0% used AIs, 19.6% used tamoxifen, and 16.0% used neither. Postmenopausal women who used tamoxifen had an increased rate (HR 1.43, 95% CI 1.06-1.92) of developing hypertension relative to those who did not use endocrine therapy. Tamoxifen use was not associated with incident diabetes, dyslipidemia, or hypertension in premenopausal BC survivors. Postmenopausal AI users had higher hazard rates of developing diabetes (HR 1.37, 95% CI 1.05-1.80), dyslipidemia (HR 1.58, 95% CI 1.29-1.92), and hypertension (HR 1.50, 95% CI 1.24-1.82) compared with non-endocrine therapy users. CONCLUSION: Hormone receptor-positive BC survivors treated with AIs may have higher rates of developing diabetes, dyslipidemia, and hypertension over an average 7.8 years post-diagnosis.
Asunto(s)
Neoplasias de la Mama , Hipertensión , Femenino , Humanos , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/epidemiología , Antineoplásicos Hormonales/efectos adversos , Factores de Riesgo Cardiometabólico , Tamoxifeno/efectos adversos , Hipertensión/epidemiología , Inhibidores de la Aromatasa/efectos adversos , Factores de RiesgoRESUMEN
PURPOSE: While clinical heart failure (HF) is recognized as an adverse effect from breast cancer (BC) treatment, sparse data exist on specific HF phenotypes in affected BC survivors. We examined risk of HF by left ventricular ejection fraction (LVEF) status in women with a history of BC. METHODS: 14,804 women diagnosed with all stages of invasive BC from 2005 to 2013 and with no history of HF were matched 1:5 to 74,034 women without BC on birth year, race, and ethnicity. LVEF values were extracted from echocardiography studies within 30 days before through 90 days after the HF clinical encounter. HF was stratified into HF with preserved ejection fraction (HFpEF, LVEF ≥ 45%) and HF with reduced ejection fraction (HFrEF, LVEF < 45%). Cumulative incidence rates (CIRs) were estimated with competing risk of overall death. Hazard ratios (HR) were calculated by multivariable Cox proportional hazards regression. RESULTS: Mean time to HF diagnosis was 5.31 years (range 0.03-13.03) in cases and 5.25 years (range 0.01-12.94) in controls. 10-year CIRs were 1.2% and 0.9% for overall HF, 0.8% and 0.7% for HFpEF, and 0.4% and 0.2% for HFrEF in cases and controls, respectively. In fully adjusted models, an overall significant increased risk of HF in cases versus controls was observed (HR: 1.31, 95% CI 1.14, 1.51). The increased risk was seen for both HFrEF (HR: 1.59, 95% CI 1.22, 2.08) and HFpEF (HR: 1.22; 95% CI 1.03, 1.45). CONCLUSION: BC survivors experienced higher risk of HF compared with women without BC, and the risk persisted across LVEF phenotypes. Systematic cardio-oncology surveillance should be considered to mitigate this risk in BC patients.
Asunto(s)
Neoplasias de la Mama , Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/epidemiología , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etiología , Humanos , Pronóstico , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
BACKGROUND: This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer. METHODS: This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta-Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH-NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS). RESULTS: Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16-negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85-0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84-0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90-1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75-0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78-0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86-1.08; P for interaction = .011). CONCLUSIONS: LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.
Asunto(s)
Neoplasias de Cabeza y Cuello/clasificación , Neoplasias de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/clasificación , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Adulto , Factores de Edad , Fraccionamiento de la Dosis de Radiación , Quimioterapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radioterapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Massively-parallel-sequencing, coupled with sample multiplexing, has made genetic tests broadly affordable. However, intractable index mis-assignments (commonly exceeds 1%) were repeatedly reported on some widely used sequencing platforms. RESULTS: Here, we investigated this quality issue on BGI sequencers using three library preparation methods: whole genome sequencing (WGS) with PCR, PCR-free WGS, and two-step targeted PCR. BGI's sequencers utilize a unique DNA nanoball (DNB) technology which uses rolling circle replication for DNA-nanoball preparation; this linear amplification is PCR free and can avoid error accumulation. We demonstrated that single index mis-assignment from free indexed oligos occurs at a rate of one in 36 million reads, suggesting virtually no index hopping during DNB creation and arraying. Furthermore, the DNB-based NGS libraries have achieved an unprecedentedly low sample-to-sample mis-assignment rate of 0.0001 to 0.0004% under recommended procedures. CONCLUSIONS: Single indexing with DNB technology provides a simple but effective method for sensitive genetic assays with large sample numbers.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Bacterias/genética , Humanos , Secuenciación Completa del Genoma , Flujo de TrabajoRESUMEN
BACKGROUND: It is difficult to predict whether a patient with head and neck cancer (HNC) is more likely to die of the cancer or another comorbidity. Competing event models can help to identify individual patients or groups of patients who may be undertreated or overtreated in clinical practice. METHODS: Patients with HNC (n = 884), aged 18 to 85 years and diagnosed from 2000 to 2015 with stage II to IVB disease according to the seventh edition of the American Joint Committee on Cancer system, were identified. With a generalized competing event (GCE) model that controlled for age, sex, tumor site, surgical treatment, and Charlson Comorbidity Index (CCI), the association between these factors and the relative hazard for cancer mortality was determined. Logistic regression models were used to estimate the odds of receiving platinum-based chemoradiotherapy or a less intensive therapy, with adjustments made for age, sex, tumor site, CCI, stage, smoking, and alcohol abuse history. RESULTS: Compared with men, women had an increased relative hazard ratio for death from HNC versus other causes, which was reported as an adjusted ω+ ratio comparing women with men (ω+ ratio, 1.95; 95% CI, 1.09-3.49), even though they were less likely to receive intensive chemoradiotherapy than men (adjusted odds ratio, 0.69; 95% CI, 0.48-0.99). CONCLUSIONS: These findings indicate that women in this cohort may be undertreated in clinical practice and potentially miss the opportunity for their HNC to be aggressively treated. This study supports the use of GCE models to identify patients who are potentially undertreated and may also help to guide future research in health disparities.
Asunto(s)
Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/terapia , Adulto , Anciano , Anciano de 80 o más Años , California/epidemiología , Quimioradioterapia , Comorbilidad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Background: Previous studies have found that overestimating treatment effects (i.e. 'optimism bias') leads to underpowered clinical trials. The prevalence of 'optimism bias' in contemporary National Clinical Trials Network (NCTN) cancer clinical trials is unknown. Methods: We conducted a systematic review of NCTN phase III randomized trials published from January 2007 to January 2017. We compared the hypothesized versus observed treatment effects in each trial, and examined whether trial-related factors were correlated with the study results. We also reviewed the methods of each protocol to assess whether a rationale for the hypothesized effect size was provided. Results: We identified 161 clinical trials, of which 130 were eligible for analysis. Original protocols could not be located for 8 trials (5.0%). Twenty-eight trials (21.5%) observed a statistically significant difference in the primary end point favoring the experimental treatment. The median ratio of observed-to-expected hazard ratios among trials that observed a statistically significant effect on the primary end point was 1.07 (range: 0.33-1.28) versus 1.32 (range: 0.86-2.02) for trials that did not, compared with 1.34 and 1.86, respectively, for National Cancer Institute (NCI) trials published between 1955 and 2006. An effect size at least as large as the one projected in the protocol trials was observed in 9.8% of trials, compared with 17% of NCI trials published from 1955 to 2006. Most trials (64.6%) provided no rationale to support the magnitude of the proposed treatment effect in the protocol. Conclusions: Despite a reduction in 'optimism bias' compared with previous eras, most contemporary NCTN phase III trials failed to establish statistically significant benefits of new cancer therapies. Better rationalization of proposed effect sizes in research protocols is needed.
Asunto(s)
Ensayos Clínicos Fase III como Asunto/normas , Investigación Empírica , Diseño de Investigaciones Epidemiológicas , Neoplasias/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Humanos , Pronóstico , Sesgo de PublicaciónRESUMEN
The purpose of this study is to conduct validity and reliability testing of a new instrument, the Preferences and Self-Efficacy of Diet and Physical Activity Behaviors Questionnaire for Latina Women (PSEDPALW), which is for women who identify as Latina and are breast cancer survivors. PSEDPALW measures preferences and self-efficacy for four behaviors: physical activity (PA), fruit and vegetable (FV) intake, dietary fat (DF) intake, and added sugar (AS) intake (eight scales in total). Validity testing was conducted through an expert panel review and a cognitive interviewing focus group (n = 4). Reliability was tested via internal consistency reliability (n = 118) and test-retest reliability (n = 30). Validity testing was used to refine PSEDPALW. Reliability testing was conducted on three versions with 104, 47, and 41 items. PA scales had acceptable Cronbach's α (>0.70) but low ICC (NS). FV and DF scales had acceptable Cronbach's α (>0.70), with preferences for the shorter (47- and 41-item) versions (Cronbach's α < 0.70), and all scales had moderate ICC (p < 0.05, except the FV scale on the 104-item version (p = 0.07)). The AS preferences scale had Cronbach's α < 0.70, with self-efficacy > 0.70 for all versions and ICC moderate for all versions (p ≤ 0.01). PSEDPALW may be useful to assess diet and physical activity preferences and self-efficacy in theory-based diet and physical activity interventions in women who identify as Latina and are breast cancer survivors.
Asunto(s)
Neoplasias de la Mama , Supervivientes de Cáncer , Femenino , Humanos , Autoeficacia , Reproducibilidad de los Resultados , Dieta , Ejercicio Físico , Hispánicos o Latinos , Encuestas y CuestionariosRESUMEN
PURPOSE: Studies comparing the effect of aromatase inhibitor (AI) and tamoxifen use on cardiovascular disease (CVD) risk factors in hormone-receptor positive breast cancer (BC) survivors report conflicting results. We examined associations of endocrine therapy use with incident diabetes, dyslipidemia, and hypertension. METHODS: The Pathways Heart Study examines cancer treatment exposures with CVD-related outcomes in Kaiser Permanente Northern California members with BC. Electronic health records provided sociodemographic and health characteristics, BC treatment, and CVD risk factor data. Hazard ratios (HR) and 95% confidence intervals (CI) of incident diabetes, dyslipidemia, and hypertension in hormone-receptor positive BC survivors using AIs or tamoxifen compared with survivors not using endocrine therapy were estimated using Cox proportional hazards regression models adjusted for known confounders. RESULTS: In 8,985 BC survivors, mean baseline age and follow-up time was 63.3 and 7.8 years, respectively; 83.6% were postmenopausal. By treatment, 77.0% used AIs, 19.6% used tamoxifen, and 16.0% used neither. Postmenopausal women who used tamoxifen had an increased rate (HR: 1.43, 95% CI: 1.06-1.92) of developing hypertension relative to those who did not use endocrine therapy. Tamoxifen use was not associated with incident diabetes, dyslipidemia, or hypertension in premenopausal BC survivors. Postmenopausal AI users had higher hazard rates of developing diabetes (HR: 1.37, 95% CI: 1.05-1.80), dyslipidemia (HR: 1.58, 95% CI: 1.29-1.92) and hypertension (HR: 1.50, 95% CI: 1.24-1.82) compared with non-endocrine therapy users. CONCLUSION: Hormone-receptor positive BC survivors treated with AIs may have higher rates of developing diabetes, dyslipidemia, and hypertension over an average 7.8 years post-diagnosis.
RESUMEN
We examined the effect of waist-to-hip ratio, body mass index (BMI), diet, and physical activity on cognitive functioning among Hispanic/Latina breast cancer survivors in a cross-sectional design study. Participants were 54 Hispanic/Latina breast cancer survivors and completed the NIH Toolbox Cognition Battery. Linear Regression Models tested if statistically significant correlations held with covariates. After controlling for covariates, moderate and hard physical activity were not associated with cognition. However, very hard physical activity was positively associated with faster processing speed (ß = 0.56, p < 0.001) and composite cognition score (ß = 0.36, p < 0.05). Total time (minutes) of moderate to very hard physical activity was positively associated with cognitive flexibility (ß = 0.52, p < 0.001). Total caloric intake was positively associated with episodic memory (ß = 0.35 p < 0.05). BMI and WHR were not associated with cognition. These findings showed positive association with engagement in more MVPA and harder intensity physical activity to better cognitive functioning among Hispanic/Latina breast cancer survivors.ClinicalTrials.gov NCT02780271.
Asunto(s)
Neoplasias de la Mama , Supervivientes de Cáncer , Neoplasias de la Mama/psicología , Supervivientes de Cáncer/psicología , Cognición , Estudios Transversales , Femenino , Hispánicos o Latinos , HumanosRESUMEN
BACKGROUND: The design of a randomized pilot trial evaluating the feasibility of two doses of a digital health intervention promoting changes in nutrition and physical activity in breast cancer (BC) survivors is described. METHODS: Eligible women were adults with history of early-stage breast cancer and > 60 days post-treatment, consumed <5 servings/day of fruits/vegetables and/or engaged in <150 min/week of aerobic moderate-to-vigorous physical activity, and had internet access. Participants were randomized to 6 months of either a "low" (1 session) or "high" (12 sessions) dose digital health intervention. Zoom-delivered sessions focused on improving diet and physical activity through didactic and experiential classes delivered by a registered dietitian, chef, exercise physiologist, and culinary educator. All study participants received weekly motivational texts, a Fitbit, and study website access. Diet, accelerometry, anthropometric, psychosocial, and biospecimen data were collected remotely at baseline and six months. Primary outcome was feasibility measured via accrual rate, adherence, retention, and acceptability. RESULTS: Recruitment began in December 2019, was suspended in March 2020 due to the COVID-19 pandemic, resumed September 2020, and concluded in January 2021. Women were identified from the local BC registry and flyers posted in the oncology clinic. Of 929 women recruited, 321 completed the screening assessment, and of these, 138 were eligible. A total of 74 women were enrolled and randomized to the study. CONCLUSION: BC survivors were successfully enrolled in a digital health nutrition and physical activity intervention. If feasible, this intervention will be tested in larger and more diverse populations of cancer survivors. TRIAL REGISTRATION: ClinicalTrials.govNCT04200482.
Asunto(s)
Neoplasias de la Mama , COVID-19 , Supervivientes de Cáncer , Adulto , Femenino , Humanos , Supervivientes de Cáncer/psicología , Neoplasias de la Mama/terapia , Neoplasias de la Mama/psicología , Estudios de Factibilidad , Pandemias , Sobrevivientes , Ejercicio Físico , Proyectos PilotoRESUMEN
BACKGROUND: Among Latinos, greater acculturation to the United States (US) is associated with risk of obesity and obesity-related comorbidities. Less is known about the associations between acculturation and obesity-related modifiable risk factors, such as diet quality and physical activity (PA) among Latina breast cancer survivors. OBJECTIVE: The aim of this study was to explore associations between acculturation and weight status, diet quality, and PA among Latina breast cancer survivors. DESIGN: This is a cross-sectional secondary analysis of baseline data on demographic and clinical characteristics, acculturation, anthropometric measures, diet quality, and PA collected from Latina breast cancer survivors enrolled in the ¡Mi Vida Saludable! (My Healthy Life) behavioral diet and PA intervention trial. PARTICIPANTS/SETTING: Participants were Latina women (n = 167) residing in New York City, with a medical history of stage 0 to III breast cancer, no evidence of recurrent or metastatic disease, and at least 90 days post cancer treatment who participated in the ¡Mi Vida Saludable! randomized controlled trial between July 2016 and October 2018. MAIN OUTCOME MEASURES: Acculturation status was measured by the Short Acculturation Scale for Hispanics score, language preference, place of birth, and duration of US residence. Weight, height, and waist and hip circumferences were measured at an in-person clinic visit. Diet information was collected via 3 telephone-based 24-hour dietary recalls and PA information was collected via staff administered 7-day recalls. STATISTICAL ANALYSES PERFORMED: Linear regression models examined associations between acculturation and weight status, diet quality, and PA. RESULTS: Based on the Short Acculturation Scale for Hispanics acculturation score, more acculturated compared with less acculturated Latinas were younger in age, more educated, and had higher annual household incomes (all, P < .05). Compared with Spanish-speaking Latinas, English-speaking Latinas had larger waist circumference (103 vs 96.1 cm; P = .01) and poorer-quality diets (Healthy Eating Index 2015 scores, 57.3 vs 71.5; P < .001). Greater levels of acculturation were also associated with higher levels of leisure walking at a moderate-to-vigorous intensity (265.8 vs 179.0 min/wk; P =.04). CONCLUSIONS: Greater levels of acculturation were associated with higher central obesity and poorer-quality diets. Future lifestyle modification trials tailored to the unique role of acculturation on adopting behavior change recommendations is a promising next step in this line of research.
Asunto(s)
Neoplasias de la Mama , Supervivientes de Cáncer , Aculturación , Estudios Transversales , Dieta , Ejercicio Físico , Femenino , Hispánicos o Latinos , Humanos , Obesidad/terapia , Estados UnidosRESUMEN
PURPOSE: The incidence of cardiometabolic risk factors in breast cancer (BC) survivors has not been well described. Thus, we compared risk of hypertension, diabetes, and dyslipidemia in women with and without BC. METHODS: Women with invasive BC diagnosed from 2005 to 2013 at Kaiser Permanente Northern California (KPNC) were identified and matched 1:5 to noncancer controls on birth year, race, and ethnicity. Cumulative incidence rates of hypertension, diabetes, and dyslipidemia were estimated with competing risk of overall death. Subdistribution hazard ratios (sHRs) were estimated by Fine and Gray regression, adjusted for cardiovascular disease-related risk factors, and stratified by treatment and body mass index (BMI). RESULTS: A total of 14,942 BC cases and 74,702 matched controls were identified with mean age 61.2 years and 65% non-Hispanic White. Compared with controls, BC cases had higher cumulative incidence rates of hypertension (10.9% v 8.9%) and diabetes (2.1% v 1.7%) after 2 years, with higher diabetes incidence persisting after 10 years (9.3% v 8.8%). In multivariable models, cases had higher risk of diabetes (sHR, 1.16; 95% CI, 1.07 to 1.26) versus controls. Cases treated with chemotherapy (sHR, 1.23; 95% CI, 1.11 to 1.38), left-sided radiation (sHR, 1.29; 95% CI, 1.13 to 1.48), or endocrine therapy (sHR, 1.23; 95% CI, 1.12 to 1.34) continued to have higher diabetes risk. Hypertension risk was higher for cases receiving left-sided radiation (sHR, 1.11; 95% CI, 1.02 to 1.21) or endocrine therapy (sHR, 1.10; 95% CI, 1.03 to 1.16). Normal-weight (BMI < 24.9 kg/m2) cases had higher risks overall and within treatment subgroups versus controls. CONCLUSION: BC survivors at KPNC experienced elevated risks of diabetes and hypertension compared with women without BC depending on treatments received and BMI. Future studies should examine strategies for cardiometabolic risk factor prevention in BC survivors.
Asunto(s)
Neoplasias de la Mama , Diabetes Mellitus , Hipertensión , Neoplasias de la Mama/epidemiología , Factores de Riesgo Cardiometabólico , Diabetes Mellitus/epidemiología , Femenino , Humanos , Hipertensión/epidemiología , Incidencia , Persona de Mediana Edad , Factores de Riesgo , SobrevivientesRESUMEN
PURPOSE: To examine cardiovascular disease (CVD) and mortality risk in women with breast cancer (BC) by cancer therapy received relative to women without BC. METHODS: The study population comprised Kaiser Permanente Northern California members. Cases with invasive BC diagnosed from 2005 to 2013 were matched 1:5 to controls without BC on birth year and race/ethnicity. Cancer treatment, CVD outcomes, and covariate data were from electronic health records. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs of CVD incidence and mortality by receipt of chemotherapy treatment combinations, radiation therapy, and endocrine therapy. RESULTS: A total of 13,642 women with BC were matched to 68,202 controls without BC. Over a 7-year average follow-up (range < 1-14 years), women who received anthracyclines and/or trastuzumab had high risk of heart failure/cardiomyopathy relative to controls, with the highest risk seen in women who received both anthracyclines and trastuzumab (HR, 3.68; 95% CI, 1.79 to 7.59). High risk of heart failure and/or cardiomyopathy was also observed in women with BC with a history of radiation therapy (HR, 1.38; 95% CI, 1.13 to 1.69) and aromatase inhibitor use (HR, 1.31; 95% CI, 1.07 to 1.60), relative to their controls. Elevated risks for stroke, arrhythmia, cardiac arrest, venous thromboembolic disease, CVD-related death, and death from any cause were also observed in women with BC on the basis of cancer treatment received. CONCLUSION: Women with BC had increased incidence of CVD events, CVD-related mortality, and all-cause mortality compared with women without BC, and risks varied according to the history of cancer treatment received. Studies are needed to determine how women who received BC treatment should be cared for to improve cardiovascular outcomes.
Asunto(s)
Neoplasias de la Mama , Enfermedades Cardiovasculares , Insuficiencia Cardíaca , Antraciclinas/uso terapéutico , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/terapia , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Femenino , Insuficiencia Cardíaca/epidemiología , Humanos , Modelos de Riesgos Proporcionales , Factores de Riesgo , Trastuzumab/uso terapéuticoRESUMEN
PURPOSE: Previous studies have found that patients with head and neck cancer (HNC) with a higher relative hazard for recurrence versus competing mortality (ω+ ratio) are more likely to benefit from intensive therapy. Nomograms to predict this ratio (ω scores) can be useful to guide clinical management; however, comorbidity and other risk factors are frequently lacking from trial samples. METHODS AND MATERIALS: In this study of 7117 US veterans, we evaluated the ability of a ω score nomogram developed from clinical trial data to stratify patients with HNC treated with radiation therapy by their relative risk of cancer progression versus competing mortality. We then fit generalized competing event models to determine the effect of comorbidity and other covariates on the ω+ ratio. RESULTS: The ω score was effective in stratifying patients with HNC according to their risk for cancer recurrence relative to competing mortality, especially among patients aged >70 years. Patients with ω score ≥0.80 were more likely to receive intensive therapy compared with patients with a ω score <0.80 (66 vs. 54%; P < .001). On multivariable generalized competing event regression, T2-4 category (relative hazard ratio [RHR], 1.08; 95% confidence interval [CI], 1.01-1.16), N2-3 category (RHR, 1.07; 95% CI, 1.01-1.15), and being employed (RHR, 1.11; 95% CI, 1.03-1.20) were associated with increased ω+ ratio, and increasing age (RHR, 0.83; 95% CI, 0.78-0.89), Charlson comorbidity index ≥2 (RHR, 0.85; 95% CI, 0.79-0.91), being a current smoker (RHR, 0.90; 95% CI, 0.84-0.96), and lower body mass index (RHR, 0.89; 95% CI, 0.84-0.95) were associated with a decreased ω+ ratio. CONCLUSIONS: The ω scores are effective in stratifying patients with HNC and are correlated with the intensity of treatment given. The ω scores incorporating comorbidity and other risk factors could help identify patients with HNC most likely to benefit from intensive therapy.
Asunto(s)
Neoplasias de Cabeza y Cuello/radioterapia , Recurrencia Local de Neoplasia , Nomogramas , Selección de Paciente , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Factores de Edad , Anciano , Comorbilidad , Intervalos de Confianza , Progresión de la Enfermedad , Empleo , Femenino , Neoplasias de Cabeza y Cuello/clasificación , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Radioterapia de Intensidad Modulada , Análisis de Regresión , Factores de Riesgo , Fumadores , Carcinoma de Células Escamosas de Cabeza y Cuello/clasificación , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Delgadez/complicaciones , Veteranos/estadística & datos numéricosRESUMEN
Nucleic acid ligases are crucial enzymes that repair breaks in DNA or RNA during synthesis, repair and recombination. Various genomic tools have been developed using the diverse activities of DNA/RNA ligases. Herein, we demonstrate a non-conventional ability of T4 DNA ligase to insert 5' phosphorylated blunt-end double-stranded DNA to DNA breaks at 3'-recessive ends, gaps, or nicks to form a Y-shaped 3'-branch structure. Therefore, this base pairing-independent ligation is termed 3'-branch ligation (3'BL). In an extensive study of optimal ligation conditions, the presence of 10% PEG-8000 in the ligation buffer significantly increased ligation efficiency to more than 80%. Ligation efficiency was slightly varied between different donor and acceptor sequences. More interestingly, we discovered that T4 DNA ligase efficiently ligated DNA to the 3'-recessed end of RNA, not to that of DNA, in a DNA/RNA hybrid, suggesting a ternary complex formation preference of T4 DNA ligase. These novel properties of T4 DNA ligase can be utilized as a broad molecular technique in many important genomic applications, such as 3'-end labelling by adding a universal sequence; directional tagmentation for NGS library construction that achieve theoretical 100% template usage; and targeted RNA NGS libraries with mitigated structure-based bias and adapter dimer problems.
Asunto(s)
ADN Ligasas/metabolismo , ADN/metabolismo , Ingeniería Genética/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , ARN/metabolismo , HumanosRESUMEN
PURPOSE: Previous studies indicate that the benefit of therapy depends on patients' risk for cancer recurrence relative to noncancer mortality (ω ratio). We sought to test the hypothesis that patients with head and neck cancer (HNC) with a higher ω ratio selectively benefit from intensive therapy. EXPERIMENTAL DESIGN: We analyzed 2,688 patients with stage III-IVB HNC undergoing primary radiotherapy (RT) with or without systemic therapy on three phase III trials (RTOG 9003, RTOG 0129, and RTOG 0522). We used generalized competing event regression to stratify patients according to ω ratio and compared the effectiveness of intensive therapy as a function of predicted ω ratio (i.e., ω score). Intensive therapy was defined as treatment on an experimental arm with altered fractionation and/or multiagent concurrent systemic therapy. A nomogram was developed to predict patients' ω score on the basis of tumor, demographic, and health factors. Analysis was by intention to treat. RESULTS: Decreasing age, improved performance status, higher body mass index, node-positive status, P16-negative status, and oral cavity primary predicted a higher ω ratio. Patients with ω score ≥0.80 were more likely to benefit from intensive treatment [5-year overall survival (OS), 70.0% vs. 56.6%; HR of 0.73, 95% confidence interval (CI): 0.57-0.94; P = 0.016] than those with ω score <0.80 (5-year OS, 46.7% vs. 45.3%; HR of 1.02, 95% CI: 0.92-1.14; P = 0.69; P = 0.019 for interaction). In contrast, the effectiveness of intensive therapy did not depend on risk of progression. CONCLUSIONS: Patients with HNC with a higher ω score selectively benefit from intensive treatment. A nomogram was developed to help select patients for intensive therapy.
Asunto(s)
Quimioradioterapia/mortalidad , Neoplasias de Cabeza y Cuello/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Nomogramas , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/terapia , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Tasa de SupervivenciaRESUMEN
The diversity of disease presentations warrants one single assay for detection and delineation of various genomic disorders. Herein, we describe a gel-free and biotin-capture-free mate-pair method through coupling Controlled Polymerizations by Adapter-Ligation (CP-AL). We first demonstrated the feasibility and ease-of-use in monitoring DNA nick translation and primer extension by limiting the nucleotide input. By coupling these two controlled polymerizations by a reported non-conventional adapter-ligation reaction 3' branch ligation, we evidenced that CP-AL significantly increased DNA circularization efficiency (by 4-fold) and was applicable for different sequencing methods but at a faction of current cost. Its advantages were further demonstrated by fully elimination of small-insert-contaminated (by 39.3-fold) with a â¼50% increment of physical coverage, and producing uniform genome/exome coverage and the lowest chimeric rate. It achieved single-nucleotide variants detection with sensitivity and specificity up to 97.3 and 99.7%, respectively, compared with data from small-insert libraries. In addition, this method can provide a comprehensive delineation of structural rearrangements, evidenced by a potential diagnosis in a patient with oligo-atheno-terato-spermia. Moreover, it enables accurate mutation identification by integration of genomic variants from different aberration types. Overall, it provides a potential single-integrated solution for detecting various genomic variants, facilitating a genetic diagnosis in human diseases.
Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Técnicas de Genotipaje/métodos , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodos , Predisposición Genética a la Enfermedad , Humanos , Infertilidad Masculina/genética , MasculinoRESUMEN
Purpose: Treatments for locoregionally advanced head and neck cancer (LAHNC) negatively impact swallowing function, but the long-term incidence of severe toxicity requiring esophageal dilation is not well-documented in the population. The aim of this study was to compare the incidence of long-term esophageal dilation across varying treatments for LAHNC. Methods and Materials: We identified 5,223 patients with LAHNC diagnosed from 2000 to 2009 in the SEER-Medicare database. We compared the incidence of esophageal dilation for surgery alone vs. surgery plus adjuvant radiotherapy (RT) and chemoradiotherapy (CRT) vs. definitive RT or CRT. Results: The cumulative incidence of esophageal dilation for all sites at 10 years, according to treatment group were as follows: CRT, 14% (95% confidence interval (CI), 12-17%); definitive RT, 13% (95% CI, 10-16%); surgery alone, 5% (95% CI, 3-7%); surgery and CRT, 15% (95% CI, 11-19%); surgery and adjuvant RT: 10% (95% CI, 8-13%). There was no significant difference in the incidence of esophageal dilation between surgery plus adjuvant RT/CRT or definitive RT/CRT (p = 0.37), but the incidence was significantly increased in both groups compared to surgery alone (p = 0.003). On multivariable analysis, chemotherapy was associated with significantly increased incidence of esophageal dilation (HR 2.9, 95% CI 1.5-5.5, p < 0.001) in oropharyngeal cancers. Conclusions: The incidence of esophageal dilation is similar in LAHNC patients undergoing RT with or without surgery. Chemoradiotherapy increases the long-term risk of esophageal dilation events over surgery alone.
RESUMEN
PURPOSE: Generalized competing event (GCE) models improve stratification of patients according to their risk of cancer events relative to competing causes of mortality. The potential impact of such methods on clinical trial power and cost, however, is uncertain. We sought to test the hypothesis that GCE models can reduce estimated clinical trial cost in elderly patients with cancer. METHODS: Patients with nonmetastatic head and neck (n = 9,677), breast (n = 22,929), or prostate cancer (n = 51,713) were sampled from the SEER-Medicare database. Using multivariable Cox proportional hazards models, we compared risk scores for all-cause mortality (ACM) and cancer-specific mortality (CSM) with GCE-based risk scores for each disease. We applied a cost function to estimate the cost and duration of clinical trials with a primary end point of overall survival in each population and in high-risk subpopulations. We conducted sensitivity analyses to examine model uncertainty. RESULTS: For the purpose of enriching subpopulations, GCE models reduced estimated clinical trial cost compared with Cox models of ACM and CSM in all disease sites. The relative cost reductions with GCE models compared with ACM and CSM models, respectively, were -68.4% and -14.4% in prostate cancer, -38.8% and -18.3% in breast cancer, and -17.1% and -4.1% in head and neck cancer. Cost savings in breast and prostate cancers were on the order of millions of dollars. The GCE model also reduced relative clinical trial duration compared with CSM and ACM models for all disease sites. The optimal risk score cutoff for clinical trial enrollment occurred near the top tertile for all disease sites. CONCLUSION: GCE models have significant potential to improve clinical trial efficiency and reduce cost, with a potentially large impact in prostate and breast cancers.
Asunto(s)
Neoplasias de la Mama , Ensayos Clínicos como Asunto/economía , Neoplasias de Cabeza y Cuello , Modelos Teóricos , Neoplasias de la Próstata , Anciano , Neoplasias de la Mama/economía , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Costos y Análisis de Costo , Femenino , Neoplasias de Cabeza y Cuello/economía , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/terapia , Humanos , Masculino , Neoplasias de la Próstata/economía , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/terapia , RiesgoRESUMEN
PURPOSE: Comorbidity is an independent predictor of mortality and treatment tolerance in head and neck cancer and should be considered with regard to treatment intensification. Multiple previously validated models can be used to evaluate comorbidity and propensity to benefit from intensive treatment, but they have not been directly compared. MATERIALS AND METHODS: An online tool was developed and used to calculate the Charlson Comorbidity Index (CCI), Adult Comorbidity Evaluation-27 (ACE-27), Cumulative Illness Rating Scale for Geriatrics (CIRS-G), Geriatric 8 (G8), Cancer and Aging Research Group (CARG), and Generalized Competing Event (GCE) scores. To assess interrater variability, five evaluators independently calculated scores on a retrospective cohort of 20 patients. Correlation between models as well as age and performance status were calculated from a cohort of 40 patients. RESULTS: The GCE and G8 models had an excellent (intraclass correlation coefficient and Fleiss' kappa ≥ 0.75) degree of interrater agreement. The CCI, ACE-27, CIRS-G, and CARG had a good (intraclass correlation coefficient and Fleiss' kappa 0.6-0.74) degree of interrater agreement. There was statistically significant correlation between models, especially with the CCI, ACE-27, and CIRS-G indices. Increased age was correlated with an increased CCI score and having moderate to severe comorbidity was correlated with the ACE-27 model. Except for the G8 model, the comorbidity indices were not associated with Eastern Cooperative Oncology Group performance status. CONCLUSION: We developed an online tool to calculate indices of comorbidity in patients with head and neck cancer with a high degree of reproducibility. Comorbidity is not strongly correlated with performance status and should be independently evaluated in patients.