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1.
Int J Gynecol Cancer ; 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451560

RESUMO

PURPOSE: Weight cycling, defined as intentional weight loss followed by unintentional weight regain, may attenuate the benefit of intentional weight loss on endometrial cancer risk. We summarized the literature on intentional weight loss, weight cycling after intentional weight loss, bariatric surgery, and endometrial cancer risk. METHODS: A systematic search was conducted using MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases published between January 2000 and November 2018. We followed Preferred Reporting Items of Systematic Reviews and Meta-analysis (PRISMA) guidelines. We qualitatively summarized studies related to intentional weight loss and weight cycling due to the inconsistent definition, and quantitatively summarized studies when bariatric surgery was the mechanism of intentional weight loss. RESULTS: A total of 127 full-text articles were reviewed, and 13 were included (bariatric surgery n=7, self-reported intentional weight loss n=2, self-reported weight cycling n=4). Qualitative synthesis suggested that, compared with stable weight, self-reported intentional weight loss was associated with lower endometrial cancer risk (RR range 0.61-0.96), whereas self-reported weight cycling was associated with higher endometrial cancer risk (OR range 1.07-2.33). The meta-analysis yielded a 59% lower risk of endometrial cancer following bariatric surgery (OR 0.41, 95% CI 0.22 to 0.74). CONCLUSIONS: Our findings support the notion that intentional weight loss and maintenance of a stable, healthy weight can lower endometrial cancer risk. Strategies to improve awareness and maintenance of weight loss among women with obesity are needed to reduce endometrial cancer risk.

2.
J Clin Oncol ; 37(28): 2528-2536, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369302

RESUMO

PURPOSE: Cardiovascular disease (CVD) is a major source of morbidity and mortality among breast cancer survivors. Although body mass index (BMI) is associated with CVD risk, adipose tissue distribution may better identify patients with a high risk of CVD after breast cancer. METHODS: Among 2,943 patients with nonmetastatic breast cancer without prior CVD, we used International Classification of Diseases (9th and 10th revisions) codes to identify incidence of nonfatal stroke, myocardial infarction, heart failure, or CVD death. From clinically acquired computed tomography scans obtained near diagnosis, we measured visceral adiposity (centimeters squared), subcutaneous adiposity (centimeters squared), and intramuscular adiposity (fatty infiltration into muscle [Hounsfield Units, scored inversely]). We estimated hazard ratios (HRs) and 95% CIs per SD increase in adiposity accounting for competing risks and adjusting for demographics, smoking, cancer treatment, and pre-existing CVD risk factors. RESULTS: Mean (SD) age was 56 (12) years. Over a median follow-up of 6 years, 328 CVD events occurred. Each SD increase in visceral or intramuscular adiposity was associated with an increase in CVD risk (HR, 1.15 [95% CI, 1.03 to 1.29] and HR, 1.21 [95% CI, 1.06 to 1.37]), respectively). Excess visceral and intramuscular adiposity occurred across all BMI categories. Among normal-weight patients, each SD greater visceral adiposity increased CVD risk by 70% (HR, 1.70 [95% CI, 1.10 to 2.62]). CONCLUSION: Visceral and intramuscular adiposity were associated with increased CVD incidence after breast cancer diagnosis, independent of pre-existing CVD risk factors and cancer treatments. The increased CVD incidence among normal-weight patients with greater visceral adiposity would go undetected with BMI alone. Measures of adipose tissue distribution may help identify high-risk patients and tailor CVD prevention strategies.

3.
J Natl Cancer Inst ; 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31355882

RESUMO

BACKGROUND: The quantity and distribution of adipose tissue may be prognostic measures of mortality in colorectal cancer patients and such associations may vary by patient sex. METHODS: This cohort included 3,262 stage I-III colorectal cancer patients. Visceral and subcutaneous adipose tissues were quantified using computed tomography. The primary endpoint was all-cause mortality. Restricted cubic splines estimated statistical associations with two-sided P values. RESULTS: Visceral adipose tissue was prognostic of mortality in a reverse L-shaped pattern (nonlinear P=0.02); risk flat to a threshold (≈260 cm2), then increased linearly. Subcutaneous adipose tissue was prognostic of mortality in a J-shaped pattern (nonlinear P<0.001); risk was higher at extreme (<50 cm2) but lower at intermediate values (>50 to ≤ 560 cm2). Patient sex modified the prognostic associations between visceral adipose tissue (Pinteraction=0.049) and subcutaneous adipose tissue (Pinteraction=0.04) with mortality. Among men, visceral adiposity was associated with mortality in a J-shaped pattern (nonlinear P=0.003), whereas among women, visceral adiposity was associated with mortality in a linear pattern (linear P=0.008). Among men, subcutaneous adiposity was associated with mortality in an L-shaped pattern (nonlinear P=0.01), whereas among women, subcutaneous adiposity was associated with mortality in a J-shaped pattern (nonlinear P<0.001). CONCLUSIONS: Visceral and subcutaneous adipose tissue were prognostic of mortality in patients with colorectal cancer; the shape of these associations were often nonlinear and varied by patient sex. These results offer insight into the potential biological mechanisms that link obesity with clinical outcomes in patients with cancer, suggesting that the dysregulated deposition of excess adiposity is prognostic of mortality.

4.
JAMA Netw Open ; 2(7): e197337, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31339542

RESUMO

Importance: Current public health guidelines for obesity prevention and control focus on promoting a normal body mass index (BMI), rarely addressing central obesity, which is reflected by high waist circumference (WC) and common in the general population. Studies of the association of normal-weight central obesity with long-term health outcomes are sparse. Objective: To examine associations of normal-weight central obesity with all-cause and cause-specific mortality in postmenopausal women in the United States. Design, Setting, and Participants: A nationwide prospective cohort study of 156 624 postmenopausal women enrolled in the Women's Health Initiative at 40 clinical centers in the United States between 1993 and 1998. These women were observed through February 2017. Data analysis was performed from September 15, 2017, to March 13, 2019. Exposures: Different combinations of BMI (calculated as weight in kilograms divided by height in meters squared; normal weight: BMI, 18.5-24.9; overweight: BMI, 25.0-29.9; and obesity: BMI, ≥30) and WC (normal: WC, ≤88 cm and high: WC, >88 cm). Main Outcomes and Measures: Mortality from all causes, cardiovascular disease, and cancer. Results: Of the 156 624 women (mean [SD] age, 63.2 [7.2] years), during 2 811 187 person-years of follow-up, 43 838 deaths occurred, including 12 965 deaths from cardiovascular disease (29.6%) and 11 828 deaths from cancer (27.0%). Compared with women with normal weight and no central obesity and adjusted for demographic characteristics, socioeconomic status, lifestyle factors, and hormone use, the hazard ratio for all-cause mortality was 1.31 (95% CI, 1.20-1.42) among women with normal weight and central obesity, 0.91 (95% CI, 0.89-0.94) among women with overweight and no central obesity, 1.16 (95% CI, 1.13-1.20) for women with overweight and central obesity, 0.93 (95% CI, 0.89-0.94) for women with obesity and no central obesity, and 1.30 (95% CI, 1.27-1.34) for women with obesity and central obesity. Compared with normal weight without central obesity, normal-weight central obesity was associated with higher risk of cardiovascular disease mortality (hazard ratio, 1.25; 95% CI, 1.05-1.46) and cancer mortality (hazard ratio, 1.20; 95% CI, 1.01-1.43). Conclusions and Relevance: Normal-weight central obesity in women was associated with excess risk of mortality, similar to that of women with BMI-defined obesity with central obesity. These findings underscore the need for future public health guidelines to include the prevention and control of central obesity, even in individuals with normal BMI.

6.
Int J Cancer ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209889

RESUMO

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

7.
Comput Med Imaging Graph ; 75: 47-55, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31132616

RESUMO

In diseases such as cancer, patients suffer from degenerative loss of skeletal muscle (cachexia). Muscle wasting and loss of muscle function/performance (sarcopenia) can also occur during advanced aging. Assessing skeletal muscle mass in sarcopenia and cachexia is therefore of clinical interest for risk stratification. In comparison with fat, body fluids and bone, quantifying the skeletal muscle mass is more challenging. Computed tomography (CT) is one of the gold standard techniques for cancer diagnostics and analysis of progression, and therefore a valuable source of imaging for in vivo quantification of skeletal muscle mass. In this paper, we design a novel deep neural network-based algorithm for the automated segmentation of skeletal muscle in axial CT images at the third lumbar (L3) and the fourth thoracic (T4) levels. A two-branch network with two training steps is investigated. The network's performance is evaluated for three trained models on separate datasets. These datasets were generated by different CT devices and data acquisition settings. To ensure the model's robustness, each trained model was tested on all three available test sets. Errors and the effect of labeling protocol in these cases were analyzed and reported. The best performance of the proposed algorithm was achieved on 1327 L3 test samples with an overlap Jaccard score of 98% and sensitivity and specificity greater than 99%.

8.
Int J Cancer ; 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31037736

RESUMO

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

9.
JAMA Oncol ; 5(7): 967-972, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31095251

RESUMO

Importance: Patients with colorectal cancer (CRC) are up to 4-fold more likely than individuals without a history of cancer to develop cardiovascular disease. Clinical care guidelines recommend that physicians counsel patients with CRC regarding the association between obesity (defined using body mass index [BMI] calculated as weight in kilograms divided by height in meters squared) and cardiovascular disease risk; however, this recommendation is based on expert opinion. Objective: To determine which measures of body composition are associated with major adverse cardiovascular events (MACEs) in patients with CRC. Design, Setting, and Participants: Population-based retrospective cohort study of 2839 patients with stage I to III CRC diagnosed between January 2006 and December 2011 at an integrated health care system in North America. Exposures: The primary exposures were BMI and computed tomography-derived body composition measurements (eg, adipose tissue compartments and muscle characteristics) obtained at the diagnosis of CRC. Main Outcomes and Measures: The primary outcome was time to the first occurrence of MACE after diagnosis of CRC, including myocardial infarction, stroke, and cardiovascular death. Results: In this population-based cohort study of 2839 participants with CRC (1384 men and 1455 women), the average age (SD) was 61.9 (11.5) years (range, 19-80 years). A substantial number of patients were former (1127; 40%) or current smokers (340; 12%), with hypertension (1150; 55%), hyperlipidemia (1389; 49%), and type 2 diabetes (573; 20%). The cumulative incidence of MACE 10 years after diagnosis of CRC was 19.1%. Body mass index was positively correlated with some computed tomography-derived measures of body composition. However, BMI was not associated with MACE; contrasting BMI categories of greater than or equal to 35 vs 18.5 to 24.9, the hazard ratio (HR) was 1.23 (95% CI, 0.85-1.77; P = .50 for trend). Visceral adipose tissue area was associated with MACE; contrasting the highest vs lowest quintile, the HR was 1.54 (95% CI, 1.02-2.31; P = .04 for trend). Subcutaneous adipose tissue area was not associated with MACE; contrasting the highest vs lowest quintile, the HR was 1.15 (95% CI, 0.78-1.69; P = .65 for trend). Muscle mass was not associated with MACE; contrasting the highest vs lowest quintile, the HR was 0.96 (95% CI, 0.57-1.61; P = .92 for trend). Muscle radiodensity was associated with MACE; contrasting the highest (ie, less lipid stored in the muscle) vs lowest quintile, the HR was 0.67 (95% CI, 0.44-1.03; P = .02 for trend). Conclusions and Relevance: Visceral adiposity and muscle radiodensity appear to be risk factors for MACE. Body mass index may have limited use for determining cardiovascular risk in this patient population.

10.
Obesity (Silver Spring) ; 27(6): 997-1004, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31021535

RESUMO

OBJECTIVE: Previous studies of breast cancer survival have not considered specific depots of adipose tissue such as subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). METHODS: This study assessed these relationships among 3,235 women with stage II and III breast cancer diagnosed between 2005 and 2013 at Kaiser Permanente Northern California and between 2000 and 2012 at Dana Farber Cancer Institute. SAT and VAT areas (in centimeters squared) were calculated from routine computed tomography scans within 6 (median: 1.2) months of diagnosis, covariates were collected from electronic health records, and vital status was assessed by death records. Hazard ratios (HRs) and 95% CIs were estimated using Cox regression. RESULTS: SAT and VAT ranged from 19.0 to 891 cm2 and from 0.484 to 454 cm2 , respectively. SAT was related to increased risk of death (127-cm2 increase; HR [95% CI]: 1.13 [1.02-1.26]), but no relationship was found with VAT (78.18-cm2 increase; HR [95% CI]: 1.02 [0.91-1.14]). An association with VAT was noted among women with stage II cancer (stage II: HR: 1.17 [95% CI: 0.99-1.39]; stage III: HR: 0.90 [95% CI: 0.76-1.07]; P interaction < 0.01). Joint increases in SAT and VAT were associated with mortality above either alone (simultaneous 1-SD increase: HR 1.19 [95% CI: 1.05-1.34]). CONCLUSIONS: SAT may be an underappreciated risk factor for breast cancer-related death.

11.
Am J Clin Nutr ; 109(3): 615-625, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30850836

RESUMO

BACKGROUND: Sarcopenia and low skeletal muscle radiodensity (SMD) have been associated with adverse outcomes in patients with colorectal cancer (CRC); however, factors contributing to these 2 muscle abnormalities are unclear. OBJECTIVES: The aim of this study was to investigate the association of medical and demographic characteristics with muscle abnormalities among patients with nonmetastatic CRC. METHODS: Patients with stage I-III invasive CRC (2006-11) who had diagnostic computed tomography (CT) available from Kaiser Permanente Northern California electronic medical records were included. CT-assessed sarcopenia and low SMD were defined according to optimal stratification. Logistic regressions including age, stage, site, total adipose tissue (TAT), race/ethnicity, neutrophil-lymphocyte ratio, smoking history, alcohol use, and Charlson Comorbidity Score were performed to identify characteristics associated with muscle abnormalities. RESULTS: The study included 3262 patients (49.9% females) with a mean ± SD age of 62.6 ± 11.4 y. Sarcopenia and low SMD were highly prevalent (42.4% and 29.6%, respectively). Age and sex interactions were noted for muscle mass, but not SMD. Age was associated with higher odds of muscle abnormalities in a dose-response manner. Compared with those aged ≤50 y, patients aged 70-80 y had considerably higher odds (OR: 6.19; 95% CI: 4.72, 8.11) of sarcopenia, and low SMD (OR: 17.81; 95% CI: 11.73, 27.03). High TAT was related to a higher odds of low SMD (OR: 9.62; 95% CI: 7.37, 12.56), but lower odds of sarcopenia (OR: 0.59; 95% CI: 0.48, 0.71). Compared with Caucasians, African Americans had lower odds of sarcopenia and low SMD. Patients with a higher neutrophil-lymphocyte ratio had higher odds of having both muscle abnormalities. Patients who were smokers or had any comorbidity had higher odds of low SMD, but not sarcopenia. CONCLUSIONS: Muscle abnormalities were common in patients with nonmetastatic CRC, with great variability in muscle mass and SMD across age, TAT, and race/ethnicity. Factors associated with muscle abnormalities may be used to facilitate risk stratification and the guidance of targeted strategies to counteract these abnormalities.

12.
Hum Genet ; 138(4): 307-326, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30820706

RESUMO

Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
13.
Nat Genet ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510241

RESUMO

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30443695

RESUMO

PURPOSE: Liver diseases including non-alcoholic fatty liver disease (NAFLD) and ensuing alterations to the micro-environment may affect development of liver metastasis. Mirroring the rise in obesity rates, prevalence of NAFLD is increasing globally. Our objective was to examine the association between NAFLD and mortality in colorectal cancer patients. METHODS: Colorectal Cancer-Sarcopenia and Near-term Survival (C-SCANS) is a retrospective cohort study which included 3,262 stage I-III patients, aged 18-80 years, and diagnosed between 2006 and 2011 at Kaiser Permanente Northern California. Cox proportional hazards regression was used to calculate multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: After up to 10 years of follow-up, 879 deaths, including 451 from CRC were identified. Cases diagnosed with NAFLD before and within 1 month after CRC diagnosis (pre-existing NAFLD; n = 83) had a HR of 1.64 (95% CI 1.06-2.54) for overall and a HR of 1.85 (95% CI 1.03-3.30) for CRC-specific mortality compared to those without NAFLD. Findings did not differ significantly by sex, stage, tumor location, and smoking status, and were also similar when restricted to obese patients only. CONCLUSIONS: Independent of body mass index and prognostic indicators, CRC patients with pre-existing NAFLD had a worse prognosis than those without NAFLD.

16.
Cancer ; 2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30311638

RESUMO

BACKGROUND: Although the proportion of triple-negative breast cancers (TNBCs) diagnosed among older women is low, the number of TNBC cases is substantial because of the high incidence of breast cancer after the age of 65 years. The molecular features of TNBC in this age group have not been well described. METHODS: This study examined a population-based cohort of women with stage I to III TNBC diagnosed between the ages of 25 and 91 years with the PAM50 gene expression subtyping assay. The concordance between the TNBC classification by immunohistochemistry and the gene expression classification by PAM50, the expression of individual genes, and 5-year recurrence and breast cancer mortality in older women (≥65 years old) and younger women (<50 years old) was assessed. RESULTS: The molecular subtype distribution in TNBC was significantly different according to the age at diagnosis. TNBC was more likely to be classified as basal-like in women younger than 50 years (sensitivity, 0.91; 95% confidence interval, 0.77-0.97) than women 65 years old or older (sensitivity, 0.72; 95% confidence interval, 0.48-0.87); 35% of clinical TNBC cases in the latter group were the human epidermal growth factor receptor 2 (HER2)-enriched subtype by molecular classification. Older women with TNBC also had significantly higher expression of ERBB2 and lower expression of all 10 proliferation-associated genes tested (P < .01). The risk of breast cancer death within 5 years was significantly higher in women with TNBC in comparison with women with hormone receptor-positive cancers in all age groups. CONCLUSIONS: This study revealed differences in molecular subtypes among clinical TNBC cases based on patient age. A potentially targetable HER2-enriched group raises the possible need for intrinsic subtyping in older women with TNBC.

17.
J Cachexia Sarcopenia Muscle ; 9(5): 898-908, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30066490

RESUMO

BACKGROUND: Low skeletal muscle quantified using computed tomography (CT) scans is associated with morbidity and mortality among cancer patients. However, existing methods to assess skeletal muscle from CT are time-consuming, expensive, and require training. Clinic-friendly tools to screen for low skeletal muscle in cancer patients are urgently needed. METHODS: We included 807 scans from non-metastatic colorectal cancer patients. With the digital ruler available in most radiological software, we implemented an abbreviated method to assess skeletal muscle area at the third lumbar vertebra (L3), which consisted of assessing the height and width of the psoas and paraspinal muscles and computing their combined 'linear area' in centimetres squared (cm2 ). A subset of CT scans was assessed twice by two analysts to compute intra-rater and inter-rater reliability. We derived cut-points for 'low' linear area using optimal stratification and then calculated the sensitivity and specificity of these cut-points relative to standard methods (total L3 cross-sectional area assessed with Slice-O-Matic research software). We further evaluated the association of low linear area with death from any cause after colorectal cancer diagnosis in Cox proportional hazards models adjusting for demographics, smoking, body mass index category, and tumour characteristics. RESULTS: The linear area was highly correlated with total cross-sectional area assessed using standard methods [r = 0.92; 95% confidence interval (CI): 0.91, 0.93] overall and within subgroups defined by age, sex, and body mass index group. Intra-rater and inter-rater reliability were equally high (both intra-class correlations = 0.98). Cut-points for low linear area were sensitive (0.75; 95% CI: 0.70, 0.80) and specific (0.77; 95% CI: 0.73, 0.80) for identifying low skeletal muscle relative to the standard of total L3 cross-sectional area. The hazard ratio and 95% CI for death associated with a low linear area were hazard ratio = 1.66; 95% CI: 1.22, 2.25. CONCLUSIONS: Clinic-friendly methods that assess linear area from CT scans are an accurate screening tool to identify low skeletal muscle among non-metastatic colorectal cancer patients. These linear measures are associated with mortality after colorectal cancer, suggesting they could be clinically useful both to improve prognostication and to provide a practical screening tool to identify cancer patients who require nutrition or exercise intervention.

18.
J Natl Cancer Inst ; 2018 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-29917119

RESUMO

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

19.
J Acad Nutr Diet ; 118(10): 1855-1863.e6, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29859758

RESUMO

BACKGROUND: Lifestyle factors are important for cancer survival. However, empirical evidence regarding the effects of dietary changes on mortality in breast cancer survivors is sparse. OBJECTIVE: The objective was to examine the associations of changes in overall diet quality, indicated by the Healthy Eating Index (HEI)-2010 score, with mortality in breast cancer survivors. DESIGN: This was a prospective cohort study from September 1993 through September 30, 2015. PARTICIPANTS/SETTING: This study included 2,295 postmenopausal women who were diagnosed with invasive breast cancer and completed a food frequency questionnaire both before and after the diagnosis of breast cancer in the Women's Health Initiative. MAIN OUTCOME MEASURES: The HEI-2010 score (maximum score of 100) was calculated based on consumption of 12 dietary components. The outcomes were mortality from all causes, breast cancer, and causes other than breast cancer. STATISTICAL ANALYSES PERFORMED: Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios of mortality from all causes, breast cancer, and other causes. RESULTS: Over 12 years of follow-up, 763 deaths occurred. Compared with women with relatively stable diet quality (±14.9% change in HEI-2010 score), women who decreased diet quality (≥15% decrease in HEI-2010 score) had a higher risk of death from breast cancer (adjusted hazard ratio 1.66, 95% CI 1.09 to 2.52). Increased diet quality (≥15% increase in HEI-2010 score) was not significantly associated with lower risk of death. These associations persisted after additional adjustment for change in body mass index. CONCLUSIONS: Among women with breast cancer, decreased diet quality after breast cancer diagnosis was associated with higher risk of death from breast cancer.

20.
Epidemiology ; 29(5): 604-613, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29864084

RESUMO

BACKGROUND: There is widespread concern about the use of body mass index (BMI) to define obesity status in postmenopausal women because it may not accurately represent an individual's true obesity status. The objective of the present study is to examine and adjust for exposure misclassification bias from using an indirect measure of obesity (BMI) compared with a direct measure of obesity (percent body fat). METHODS: We used data from postmenopausal non-Hispanic black and non-Hispanic white women in the Women's Health Initiative (n=126,459). Within the Women's Health Initiative, a sample of 11,018 women were invited to participate in a sub-study involving dual-energy x-ray absorptiometry scans. We examined indices of validity comparing BMI-defined obesity (≥30 kg/m), with obesity defined by percent body fat. We then used probabilistic bias analysis models stratified by age and race to explore the effect of exposure misclassification on the obesity-mortality relationship. RESULTS: Validation analyses highlight that using a BMI cutpoint of 30 kg/m to define obesity in postmenopausal women is associated with poor validity. There were notable differences in sensitivity by age and race. Results from the stratified bias analysis demonstrated that failing to adjust for exposure misclassification bias results in attenuated estimates of the obesity-mortality relationship. For example, in non-Hispanic white women 50-59 years of age, the conventional risk difference was 0.017 (95% confidence interval = 0.01, 0.023) and the bias-adjusted risk difference was 0.035 (95% simulation interval = 0.028, 0.043). CONCLUSIONS: These results demonstrate the importance of using quantitative bias analysis techniques to account for nondifferential exposure misclassification of BMI-defined obesity. See video abstract at, http://links.lww.com/EDE/B385.

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