Blood Lipids, Lipoproteins, and Apolipoproteins With Risk of Coronary Heart Disease: A Prospective Study Among Racially Diverse Populations.

BACKGROUND: Comprehensive blood lipoprotein profiles and their association with incident coronary heart disease (CHD) among racially and geographically diverse populations remain understudied. METHODS AND RESULTS: We conducted nested case-control studies of CHD among 3438 individuals (1719 pairs), including 1084 White Americans (542 pairs), 1244 Black Americans (622 pairs), and 1110 Chinese adults (555 pairs). We examined 36 plasma lipids, lipoproteins, and apolipoproteins, measured by nuclear magnetic resonance spectroscopy, with incident CHD among all participants and subgroups by demographics, lifestyle, and metabolic health status using conditional or unconditional logistic regression adjusted for potential confounders. Conventionally measured blood lipids, that is, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol, were each associated with incident CHD, with odds ratios (ORs) being 1.33, 1.32, 1.24, and 0.79 per 1-SD increase among all participants. Seventeen lipoprotein biomarkers showed numerically stronger associations than conventional lipids, with ORs per 1-SD among all participants ranging from 1.35 to 1.57 and a negative OR of 0.78 (all false discovery rate <0.05), including apolipoprotein B100 to apolipoprotein A1 ratio (OR, 1.57 [95% CI, 1.45-1.7]), low-density lipoprotein-triglycerides (OR, 1.55 [95% CI, 1.43-1.69]), and apolipoprotein B (OR, 1.49 [95% CI, 1.37-1.62]). All these associations were significant and consistent across racial groups and other subgroups defined by age, sex, smoking, obesity, and metabolic health status, including individuals with normal levels of conventionally measured lipids. CONCLUSIONS: Our study highlighted several lipoprotein biomarkers, including apolipoprotein B/ apolipoprotein A1 ratio, apolipoprotein B, and low-density lipoprotein-triglycerides, strongly and consistently associated with incident CHD. Our results suggest that comprehensive lipoprotein measures may complement the standard lipid panel to inform CHD risk among diverse populations.

Hypertension and risk of endometrial cancer: a pooled analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer (EC) are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for EC. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of EC remains unclear. In this study we evaluated hypertension as an independent risk factor for EC and whether this association is modified by other established risk factors. METHODS: We included 15,631 EC cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between hypertension and EC and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of EC (OR=1.14, 95% CI:1.09-1.19). There was significant heterogeneity by study design (Phet<0.01), with a stronger magnitude of association observed among case-control vs. cohort studies. Stronger associations were also noted for pre-/peri-menopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with EC risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for EC.

Sodium Intake and Cause-Specific Mortality Among Predominantly Low-Income Black and White US Residents.

IMPORTANCE: Epidemiologic evidence regarding the outcomes of dietary sodium intake on mortality remains limited for low-income individuals, particularly Black people. OBJECTIVE: To investigate the associations of excessive dietary sodium with all-cause and cause-specific mortality among predominantly low-income Black and White Americans. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included participants aged 40 to 79 years from the Southern Community Cohort Study who were recruited at Community Health Centers in 12 southeastern states from 2002 to 2009. Analyses were conducted between March 2022 and June 2023. EXPOSURES: Dietary sodium intake was assessed using a validated food frequency questionnaire at baseline. MAIN OUTCOMES AND MEASURES: Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for mortality outcomes (all-cause, cardiovascular disease [CVD], coronary heart disease [CHD], stroke, heart failure, cancer, and other) associated with sodium intake. Nonlinear associations and population-attributable risk (PAR) of the mortality burden associated with excess sodium were further assessed. RESULTS: Among the 64 329 participants, 46 185 (71.8%) were Black, 18 144 (28.2%) were White, and 39 155 (60.9%) were female. The mean (SD) age at study enrollment was 51.3 (8.6) years for Black participants and 53.3 (9.3) years for White counterparts. Mean (SD) dietary sodium intake was 4512 (2632) mg/d in Black individuals and 4041 (2227) mg/d in White individuals; 37 482 Black individuals (81.2%) and 14 431 White individuals (79.5%) exceeded the current dietary recommendations of 2300 mg/d. During a median (IQR) follow-up of 13.8 (11.3-15.8) years, 17 811 deaths were documented, including 5701 from CVD. After adjustment for potential confounders, in Black individuals, HRs per 1000-mg increase in daily sodium intake were 1.07 (95% CI, 1.03-1.10) and 1.08 (95% CI, 1.02-1.14) for deaths from total CVD and CHD, respectively; while in White individuals, the corresponding HRs were 1.08 (95% CI, 1.02-1.14) and 1.13 (95% CI, 1.03-1.23). No significant associations were found for cancer mortality. PAR estimates suggest that sodium intake above the recommended threshold may account for 10% of total CVD, 13% of CHD, and 30% of heart failure deaths in this low-income southern population. CONCLUSIONS AND RELEVANCE: In this cohort study of 64 329 low-income Americans, nearly 80% of study participants consumed sodium exceeding the current recommended daily amount, which was associated with 10% to 30% of CVD mortality. Public health programs targeted to reduce sodium intake among this underserved population may be beneficial.

Metformin's role in lowering colorectal cancer risk among individuals with diabetes from the Southern Community Cohort Study.

BACKGROUND: Metformin, utilized to manage hyperglycemia, has been linked to a reduced risk of colorectal cancer (CRC) among individuals with diabetes. However, evidence is lacking for non-Hispanic Black individuals and those with lower socioeconomic status (SES), who face elevated risk for both diabetes and CRC. In this study, we investigated the association between metformin use and incident CRC risk within the Southern Community Cohort Study (SCCS), a racially- and SES-diverse prospective cohort. METHODS: Participants reported their diabetes diagnosis and medications, including metformin, upon enrollment (2002-2009) and during follow-up surveys approximately every five years. Incident cases of CRC were identified through state cancer registries and the National Death Index. Proportional hazards models were employed to explore the relationship between metformin use and CRC risk, adjusted for cancer risk factors. RESULTS: A total of 25,992 participants with diabetes were included in the analysis, among whom 10,095 were taking metformin. Of these participants, 76% identified as non-Hispanic Black, and 60% reported household incomes <$15,000/year. Metformin use was associated with a significantly lower CRC risk (HR [95% CI]: 0.71 [0.55-0.93]), with consistent results for both colon (0.80 [0.59-1.07]) and rectal cancers (0.49 [0.28-0.86]). The protective association appeared to be stronger among non-Hispanic White individuals (0.51 [0.31-0.85]) compared to non-Hispanic Black participants (0.80 [0.59-1.08], p-interaction =.13). Additionally, a protective association was observed among obese individuals (BMI ≥30 kg/m2, 0.59 [0.43-0.82] but not among non-obese participants (0.99 [0.65-1.51], p-interaction =.05) CONCLUSION: Our findings indicate that metformin use is associated with a reduced risk of CRC in individuals with diabetes, including among those from predominantly low SES backgrounds. These results support previous epidemiological findings, and demonstrate that the protective association for metformin in relation to incident CRC likely generalizes to populations with higher underlying risk.

Interaction between Continuous Pack-Years Smoked and Polygenic Risk Score on Lung Cancer Risk: Prospective Results from the Framingham Heart Study.

BACKGROUND: Lung cancer risk attributable to smoking is dose dependent, yet few studies examining a polygenic risk score (PRS) by smoking interaction have included comprehensive lifetime pack-years smoked. METHODS: We analyzed data from participants of European ancestry in the Framingham Heart Study Original (n = 454) and Offspring (n = 2,470) cohorts enrolled in 1954 and 1971, respectively, and followed through 2018. We built a PRS for lung cancer using participant genotyping data and genome-wide association study summary statistics from a recent study in the OncoArray Consortium. We used Cox proportional hazards regression models to assess risk and the interaction between pack-years smoked and genetic risk for lung cancer adjusting for European ancestry, age, sex, and education. RESULTS: We observed a significant submultiplicative interaction between pack-years and PRS on lung cancer risk (P = 0.09). Thus, the relative risk associated with each additional 10 pack-years smoked decreased with increasing genetic risk (HR = 1.56 at one SD below mean PRS, HR = 1.48 at mean PRS, and HR = 1.40 at one SD above mean PRS). Similarly, lung cancer risk per SD increase in the PRS was highest among those who had never smoked (HR = 1.55) and decreased with heavier smoking (HR = 1.32 at 30 pack-years). CONCLUSIONS: These results suggest the presence of a submultiplicative interaction between pack-years and genetics on lung cancer risk, consistent with recent findings. Both smoking and genetics were significantly associated with lung cancer risk. IMPACT: These results underscore the contributions of genetics and smoking on lung cancer risk and highlight the negative impact of continued smoking regardless of genetic risk.

Type 2 Diabetes and Colorectal Cancer Risk.

Importance: Type 2 diabetes and colorectal cancer (CRC) disproportionately burden indviduals of low socioeconomic status and African American race. Although diabetes is an emerging CRC risk factor, associations between diabetes and CRC in these populations are understudied. Objective: To determine if diabetes is associated with CRC risk in a cohort representing understudied populations. Design, Setting, and Participants: This cohort study uses data from the prospective Southern Community Cohort Study in the US, which recruited from 2002 to 2009 and completed 3 follow-up surveys by 2018. Of about 85 000 participants, 86% enrolled at community health centers, while 14% were enrolled via mail or telephone from the same 12 recruitment states. Participants with less than 2 years of follow-up, previous cancer diagnosis (excluding nonmelanoma skin cancer) at enrollment, missing enrollment diabetes status, diabetes diagnosis before age 30, and without diabetes at enrollment with no follow-up participation were excluded. Data were analyzed from January to September 2023. Exposures: Physician-diagnosed diabetes and age at diabetes diagnosis were self-reported via survey at enrollment and 3 follow-ups. Main Outcomes and Measures: Diabetes diagnosis was hypothesized to be positively associated with CRC risk before analysis. Incident CRC was assessed via state cancer registry and National Death Index linkage. Hazard ratios and 95% CIs were obtained via Cox proportional hazard models, using time-varying diabetes exposure. Results: Among 54 597 participants, the median (IQR) enrollment age was 51 (46-58) years, 34 786 (64%) were female, 36 170 (66%) were African American, and 28 792 (53%) had income less than $15 000 per year. In total, 289 of 25 992 participants with diabetes developed CRC, vs 197 of 28 605 participants without diabetes. Diabetes was associated with increased CRC risk (hazard ratio [HR], 1.47; 95% CI, 1.21-1.79). Greater associations were observed among participants without colonoscopy screening (HR, 2.07; 95% CI, 1.16-3.67) and with smoking history (HR, 1.62; 95% CI, 1.14-2.31), potentially due to cancer screening differences. Greater associations were also observed for participants with recent diabetes diagnoses (diabetes duration <5 years compared with 5-10 years; HR, 2.55; 95% CI, 1.77-3.67), possibly due to recent screening. Conclusions and Relevance: In this study where the majority of participants were African American with low socioeconomic status, diabetes was associated with elevated CRC risk, suggesting that diabetes prevention and control may reduce CRC disparities. The association was attenuated for those who completed colonoscopies, highlighting how adverse effects of diabetes-related metabolic dysregulation may be disrupted by preventative screening.

Night shift work, sleep duration and endometrial cancer risk: A pooled analysis from the Epidemiology of Endometrial Cancer Consortium (E2C2).

Data on the role of circadian related factors in the etiology of endometrial cancer are scarce. We collected individual data on night shift work or daily sleep duration from 7,207 cases and 22,027 controls participating in 11 studies from the Epidemiology of Endometrial Cancer Consortium (E2C2). Main analyses were performed among postmenopausal women: 6,335 endometrial cancer cases and 18,453 controls. Using individual data, study-specific odd ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated with logistic regression and pooled analyses were conducted using random-effects meta-analyses. A non-significant inverse association was observed between endometrial cancer and night shift work (OR=0.89, 95%CI=0.72-1.09; I2=0.0%, Pheterogeneity=0.676). Associations did not vary by shift type (permanent or rotating), or duration of night work. Categorizations of short (<7h) or long (≥9h) sleep duration were not associated with endometrial cancer risk (ORshort=1.02, 95%CI=0.95-1.10; I2=55.3%, Pheterogeneity=0.022; ORlong=0.93, 95%CI=0.81-1.06; I2=11.5%, Pheterogeneity=0.339). No associations were observed per 1-h increment of sleep (OR=0.98, 95%CI=0.95-1.01; I2=46.1%, Pheterogeneity=0.063), but an inverse association was identified among obese women (OR=0.93, 95%CI=0.89-0.98 per 1-h increment; I2=12.7%, Pheterogeneity=0.329). Overall, these pooled analyses provide evidence that night shift work and sleep duration are not strong risk factors for endometrial cancer in postmenopausal women.

Associations of life course obesity with endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: Adult obesity is a strong risk factor for endometrial cancer (EC); however, associations of early life obesity with EC are inconclusive. We evaluated associations of young adulthood (18-21 years) and adulthood (at enrolment) body mass index (BMI) and weight change with EC risk in the Epidemiology of Endometrial Cancer Consortium (E2C2). METHODS: We pooled data from nine case-control and 11 cohort studies in E2C2. We performed multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for BMI (kg/m2) in young adulthood and adulthood, with adjustment for BMI in adulthood and young adulthood, respectively. We evaluated categorical changes in weight (5-kg increments) and BMI from young adulthood to adulthood, and stratified analyses by histology, menopausal status, race and ethnicity, hormone replacement therapy (HRT) use and diabetes. RESULTS: We included 14 859 cases and 40 859 controls. Obesity in adulthood (OR = 2.85, 95% CI = 2.47-3.29) and young adulthood (OR = 1.26, 95% CI = 1.06-1.50) were positively associated with EC risk. Weight gain and BMI gain were positively associated with EC; weight loss was inversely associated with EC. Young adulthood obesity was more strongly associated with EC among cases diagnosed with endometrioid histology, those who were pre/perimenopausal, non-Hispanic White and non-Hispanic Black, among never HRT users and non-diabetics. CONCLUSIONS: Young adulthood obesity is associated with EC risk, even after accounting for BMI in adulthood. Weight gain is also associated with EC risk, whereas weight loss is inversely associated. Achieving and maintaining a healthy weight over the life course is important for EC prevention efforts.

Dietary omega-3 fatty acids and endometrial cancer risk in the Epidemiology of Endometrial Cancer Consortium: An individual-participant meta-analysis.

BACKGROUND: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology. MATERIALS AND METHODS: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk. RESULTS: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade. CONCLUSION: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.

Genetic Variants Associated With Systolic Blood Pressure in Children and Adolescents.

Background Genetics, along with lifestyle and behavioral characteristics, play an important role in hypertension in adults. Our aim was to identify genetic variants associated with blood pressure in childhood and adolescence. Methods and Results We conducted a candidate single-nucleotide polymorphism (SNP) analysis and genome-wide association study among 9778 participants aged <18 years in BioVU, the Vanderbilt University Medical Center biobank. The outcome was childhood blood pressure percentile from age 0 to 18 years. For the candidate SNP analysis, a total of 457 previously identified SNPs were examined. Linear regression was used to test the association between genetic variants and median systolic blood pressure (SBP) percentile. Adjusted models included median age, self-reported sex, race, the first 4 principal components of ancestry, and median body mass index Z score. Analyses were conducted in the overall cohort and stratified by age group. A polygenic risk score was calculated for each participant, and the association between polygenic risk score and median SBP percentile in childhood was examined using linear regression. In the overall candidate SNP analysis, 2 SNPs reached significance: rs1018148 (FBN1; P=1.0×10-4) and rs11105354 (ATP2B1; P=1.4×10-4). In the postpuberty age group, 1 SNP reached significance: rs1018148 (FBN1; P=2.2×10-5). In the genome-wide association study of all participants, no SNPs reached genome-wide significance. Higher polygenic risk score was associated with higher SBP percentile (ß, 0.35 [95% CI, 0.10-0.60)], and there was a significant interaction with age (P for interaction<0.01). Conclusions These findings suggest that genetic variants play an important role in SBP in childhood and adolescence and provide evidence for age-specific genetic associations with SBP.

Physical activity in association with mortality among Black women diagnosed with breast cancer in the Southern Community Cohort Study.

PURPOSE: Physical activity (PA) is associated with many health benefits. While PA has been associated with reduced mortality after breast cancer diagnosis in many studies, few studies have examined the role of PA in breast cancer survival among underserved and minority populations, including Black women. We investigated PA in association with mortality among Black predominantly low-income breast cancer survivors in the Southern Community Cohort Study (SCCS). METHODS: Study participants were women diagnosed with incident breast cancer (n = 949) in the SCCS, which is a prospective cohort study of predominantly low-income adults aged 40-79 years recruited from 12 Southeastern states between 2002 and 2009. Participants completed a detailed baseline questionnaire, with annual follow-up for mortality via registry linkages. Cox regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of pre-diagnosis PA (measured via a validated questionnaire) with all-cause and breast cancer-specific mortality. RESULTS: Breast cancer survivors had a mean age of 61.1 years and most (79.3%) had a household income of < $25,000. In adjusted models, higher levels of total PA (MET-hours/day) were inversely associated with all-cause mortality with HRs (95% CIs): 0.79 (0.59-1.06), 0.66 (0.49-0.90), and 0.60 (0.43-0.84), for Q2, Q3, and Q4 (reference: Q1), respectively, ptrend ≤ 0.01. A similar inverse association was found for breast cancer-specific mortality. CONCLUSION: Higher levels of pre-diagnosis PA were associated with improved survival among low-income Black breast cancer survivors. Resources to reduce barriers to PA participation and increase support for education and intervention efforts to promote PA among Black women are needed.

Metabolomic Analysis of Renal Cell Carcinoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

Background: In the US in 2021, 76,080 kidney cancers are expected and >80% are renal cell carcinomas (RCCs). Along with excess fat, metabolic dysfunction is implicated in RCC etiology. To identify RCC-associated metabolites, we conducted a 1:1 matched case−control study nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Methods: We measured 522 serum metabolites in 267 cases/control pairs. Cases were followed for a median 7.1 years from blood draw to diagnosis. Using conditional logistic regression, we computed adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing risk between 90th and 10th percentiles of log metabolite intensity, with the significance threshold at a false discovery rate <0.20. Results: Four metabolites were inversely associated with risk of RCC during follow-up­C38:4 PI, C34:0 PC, C14:0 SM, and C16:1 SM (ORs ranging from 0.33−0.44). Two were positively associated with RCC risk­C3-DC-CH3 carnitine and C5 carnitine (ORs = 2.84 and 2.83, respectively). These results were robust when further adjusted for metabolic risk factors (body mass index (BMI), physical activity, diabetes/hypertension history). Metabolites associated with RCC had weak correlations (|r| < 0.2) with risk factors of BMI, physical activity, smoking, alcohol, and diabetes/hypertension history. In mutually adjusted models, three metabolites (C38:4 PI, C14:0 SM, and C3-DC-CH3 carnitine) were independently associated with RCC risk. Conclusions: Serum concentrations of six metabolites were associated with RCC risk, and three of these had independent associations from the mutually adjusted model. These metabolites may point toward new biological pathways of relevance to this malignancy.

Association of Healthy Lifestyles With Risk of Alzheimer Disease and Related Dementias in Low-Income Black and White Americans.

BACKGROUND AND OBJECTIVES: Although the importance of healthy lifestyles for preventing Alzheimer disease and related dementias (ADRD) has been recognized, epidemiologic evidence remains limited for non-White or low-income individuals who bear disproportionate burdens of ADRD. This population-based cohort study aims to investigate associations of lifestyle factors, individually and together, with the risk of ADRD among socioeconomically disadvantaged Americans. METHODS: In the Southern Community Cohort Study, comprising two-thirds self-reported Black and primarily low-income Americans, we identified incident ADRD using claims data among participants enrolled in Medicare for at least 12 consecutive months after age 65 years. Five lifestyle factors-tobacco smoking, alcohol consumption, leisure-time physical activity (LTPA), sleep hours, and diet quality-were each scored 0 (unhealthy), 1 (intermediate), or 2 (healthy) based on the health guidelines. A composite lifestyle score was created by summing all scores. Cox regression was used to estimate hazard ratios (HRs, 95% CIs) for incident ADRD, treating death as a competing risk. RESULTS: We identified 1,694 patients with newly diagnosed ADRD among 17,209 participants during a median follow-up of 4.0 years in claims data; the mean age at ADRD diagnosis was 74.0 years. Healthy lifestyles were individually associated with an 11%-25% reduced risk of ADRD: multivariable-adjusted HR (95% CI) was 0.87 (0.76-0.99) for never vs current smoking, 0.81 (0.72-0.92) for low-to-moderate vs no alcohol consumption, 0.89 (0.77-1.03) for ≥150 minutes of moderate or ≥75 minutes of vigorous LTPA each week vs none, 0.75 (0.64-0.87) for 7-9 hours vs >9 hours of sleep, and 0.85 (0.75-0.96) for the highest vs lowest tertiles of the Healthy Eating Index. The composite lifestyle score showed a dose-response association with up to 36% reduced risk of ADRD: multivariable-adjusted HRs (95% CIs) across quartiles were 1 (ref), 0.88 (0.77-0.99), 0.79 (0.70-0.90), and 0.64 (0.55-0.74); p trend <0.001. The beneficial associations were observed regardless of participants' sociodemographics (e.g., race, education, and income) and health conditions (e.g., history of cardiometabolic diseases and depression). DISCUSSION: Our findings support significant benefits of healthy lifestyles for ADRD prevention among socioeconomically disadvantaged Americans, suggesting that promoting healthy lifestyles and reducing barriers to lifestyle changes are crucial to tackling the growing burden and disparities posed by ADRD.

Sociocultural Factors, Access to Healthcare, and Lifestyle: Multifactorial Indicators in Association with Colorectal Cancer Risk.

Black Americans of low socioeconomic status (SES) have higher colorectal cancer incidence than other groups in the United States. However, much of the research that identifies colorectal cancer risk factors is conducted in cohorts of high SES and non-Hispanic White participants. Adult participants of the Southern Community Cohort Study (N = 75,182) were followed for a median of 12.25 years where 742 incident colorectal cancers were identified. The majority of the cohort are non-Hispanic White or Black and have low household income. Cox models were used to estimate HRs for colorectal cancer incidence associated with sociocultural factors, access to and use of healthcare, and healthy lifestyle scores to represent healthy eating, alcohol intake, smoking, and physical activity. The association between Black race and colorectal cancer was consistent and not diminished by accounting for SES, access to healthcare, or healthy lifestyle [HR = 1.34; 95% confidence interval (CI),1.10-1.63]. Colorectal cancer screening was a strong, risk reduction factor for colorectal cancer (HR = 0.65; 95% CI, 0.55-0.78), and among colorectal cancer-screened, Black race was not associated with risk. Participants with high school education were at lower colorectal cancer risk (HR = 0.81; 95% CI, 0.67-0.98). Income and neighborhood-level SES were not strongly associated with colorectal cancer risk. Whereas individual health behaviors were not associated with risk, participants that reported adhering to ≥3 health behaviors had a 19% (95% CI, 1-34) decreased colorectal cancer risk compared with participants that reported ≤1 behaviors. The association was consistent in fully-adjusted models, although HRs were no longer significant. Colorectal cancer screening, education, and a lifestyle that includes healthy behaviors lowers colorectal cancer risk. Racial disparities in colorectal cancer risk may be diminished by colorectal cancer screening. PREVENTION RELEVANCE: Colorectal cancer risk may be reduced through screening, higher educational attainment and performing more health behaviors. Importantly, our data show that colorectal cancer screening is an important colorectal cancer prevention strategy to eliminate the racial disparity in colorectal cancer risk. See related Spotlight, p. 561.

Evaluating breast cancer predisposition genes in women of African ancestry.

PURPOSE: Studies conducted primarily among European ancestry women reported 12 breast cancer predisposition genes. However, etiologic roles of these genes in breast cancer among African ancestry women have been less well-investigated. METHODS: We conducted a case-control study in African American women, which included 1117 breast cancer cases and 2169 cancer-free controls, and a pooled analysis, which included 7096 cases and 8040 controls of African descent. Odds ratios of associations with breast cancer risk were estimated. RESULTS: Using sequence data, we identified 61 pathogenic variants in 12 breast cancer predisposition genes, including 11 pathogenic variants not yet reported in previous studies. Pooled analysis showed statistically significant associations of breast cancer risk with pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, TP53, NF1, RAD51C, and RAD51D (all P < .05). The associations with BRCA1, PALB2, and RAD51D were stronger for estrogen receptor (ER)-negative than for ER-positive breast cancer (P heterogeneity < .05), whereas the association with CHEK2 was stronger for ER-positive than for ER-negative breast cancer. CONCLUSION: Our study confirmed previously identified associations of breast cancer risk with BRCA1, BRCA2, PALB2, ATM, TP53, NF1, and CHEK2 and provided new evidence to extend the associations of breast cancer risk with RAD51C and RAD51D, which was identified previously in European ancestry populations, to African ancestry women.

Distinct Genomic Landscapes in Early-Onset and Late-Onset Endometrial Cancer.

PURPOSE: The spectrum of somatic mutations among women with endometrial cancer (EC) younger than 50 years (early-onset EC) remains unknown. We investigated distinct somatic mutation patterns among early-onset and late-onset (age ≥ 50 years) EC patients. METHODS: This cohort study included individuals age 18+ years diagnosed with pathologically confirmed EC in the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE, v9.1) consortium. We explored tumor mutational burden (TMB) and genomic patterns of EC by age at clinical sequencing using multivariable regression models adjusted for race, ethnicity, histology, sequencing assay, sample type, and TMB. RESULTS: Among 2,425 women with EC, 176 (7.3%) had early-onset EC and 1,923 (79.3%) had nonhypermutated (< 17.78 mutations/Mb) tumors. TMB significantly differed across age and histology groups. Among nonhypermutated ECs, early-onset patients had significantly lower odds of presenting with nonsilent FGFR2 and PIK3R1 somatic mutations compared with late-onset EC patients in adjusted models (FGFR2: odds ratio [OR] = 0.18, 95% CI, 0.04 to 0.76; PIK3R1: OR = 0.54, 95% CI, 0.31 to 0.92). By contrast, early-onset EC patients had increased odds of presenting with nonsilent CTNNB1 and BRCA2 mutations compared with late-onset patients (CTNNB1: OR = 3.32, 95% CI, 2.14 to 5.16; BRCA2: OR = 4.01, 95% CI, 1.55 to 10.38). Subsequent analyses stratified by race, ethnicity, and tumor histology identified distinct patterns of APC, KMT2D, KMT2C, and KRAS by race, ethnicity, and PTEN and APC patterns by histologic subtypes. CONCLUSION: Early-onset EC harbors a unique genomic landscape compared with late-onset disease. A distinct molecular phenotype of early-onset EC provides novel insights into a unique etiology and may yield clinical implications for developing targeted treatment modalities for younger patients.

Oncotype DX Risk Recurrence Score and Total Mortality for Early-Stage Breast Cancer by Race/Ethnicity.

BACKGROUND: Oncotype DX recurrence score (ODX RS) is a prognostic biomarker for early-stage, node-negative, estrogen receptor-positive (ER+) breast cancer. Whether test uptake, associated factors, and the test's prognostic values differ by race/ethnicity is unknown. METHODS: From the National Cancer Database, 2010-2014, we identified 227,259 early-stage ER+, node-negative breast cancer cases. Logistic regression was used to examine ODX RS uptake and associated factors among non-Hispanic White (White), non-Hispanic Black (Black), Hispanic, and Asian American patients. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall mortality with ODX RS by race/ethnicity. RESULTS: White patients were more likely to receive an ODX RS test compared with Black, Hispanic, and Asian American patients (36.7%, 32.8%, 31.6%, and 35.5%, respectively; P < 0.001). Disparities persisted after adjustments for demographics, clinical characteristics, and access-to-care, with rate ratios of 0.87 (95% CI, 0.85-0.88), 0.82 (95% CI, 0.80-0.85), and 0.89 (95% CI, 0.87-0.92), respectively, for Black, Hispanic, and Asian American compared with White patients. Black patients had higher proportions of high-risk scores (≥26) compared with White, Hispanic, and Asian American patients (19.1%, 14.0%, 14.2%, and 15.6%, respectively; P < 0.0001). ODX RS was predictive for total mortality across all races/ethnicities, particularly younger patients (<50). No significant race/ethnicity interactions were observed. CONCLUSIONS: Although ODX RS uptake and risk distribution varied by race/ethnicity, ODX RS was prognostic for mortality across groups. IMPACT: These findings emphasize the importance of developing strategies to increase ODX RS uptake among racial/ethnic minorities and call for more investigations on potential racial/ethnic differences in breast cancer biology. See related commentary by Wang et al., p. 704.

A pooled case-only analysis of obesity and breast cancer subtype among Black women in the southeastern United States.

PURPOSE: To evaluate the association between obesity and the relative prevalence of tumor subtypes among Black women with breast cancer (BC). METHODS: We conducted a pooled case-only analysis of 1,793 Black women with invasive BC recruited through three existing studies in the southeastern US. Multivariable case-only polytomous logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between obesity, measured by pre-diagnostic body mass index (BMI), and human epidermal growth factor receptor 2 + (HER2 +) and triple negative BC (TNBC) subtype relative to hormone receptor (HR) + /HER2- status (referent). RESULTS: Among 359 premenopausal women, 55.4% of cases were HR + /HER2 -, 20.1% were HER2 + , and 24.5% were TNBC; corresponding percentages among 1,434 postmenopausal women were 59.3%, 17.0%, and 23.6%. Approximately, 50-60% of both pre- and postmenopausal women were obese (BMI > 30 kg/m2), regardless of BC subtype. We did not observe a significant association between obesity and BC subtype. Among postmenopausal women, class I obesity (BMI 35 + kg/m2) was not associated with the development of HER2 + BC (OR 0.69; 95% CI 0.42-1.14) or TNBC (OR 0.93; 95% CI 0.60-1.45) relative to HR + /HER2- tumors. Corresponding estimates among premenopausal women were 1.03 (95% CI 0.43-2.48) and 1.13 (95% CI 0.48-2.64). CONCLUSION: In this large study of Black women with BC, there was no evidence of heterogeneity of BMI by BC subtype.

Inclusion of Smoking Data in Cardiovascular Disease Risk Estimation.

Importance: Former heavy smokers (ie, those with ≥20 pack-years of smoking) may have higher atherosclerotic cardiovascular disease (ASCVD) risk than never smokers for up to 16 years after smoking cessation. However, the 2013 pooled cohort equations (PCE) do not account for pack-years of smoking and only consider current vs noncurrent smoking status without distinguishing former smokers from never smokers. Objective: To assess the predictive utility of smoking history when added to the PCE using data from 18 400 person examinations among Framingham offspring participants. Design, Setting, and Participants: This is a retrospective analysis of prospectively collected data from the Framingham Heart Study, a community-based cohort. Framingham Heart Study offspring cohort participants attending their first examination (1971-1975) who were followed-up through December 2016 were included. Exposures: Self-reported current/former/never smoking status, pack-years smoked, and years since quitting. Main Outcomes and Measures: Incident ASCVD (myocardial infarction, fatal/nonfatal ischemic stroke, coronary heart disease death). Results: Of 3908 patients, there were 358 and 197 events among 1895 men and 2013 women, respectively, with a mean (SD) age of 55 (9.5) years. Ever smoking prevalence was high (6474 men [77%] and 7760 women [78%]), as were median pack-years (men: 39; women: 32 overall person examinations). Four sex-specific ASCVD risk prediction models were built using pooled-repeated Cox proportional hazards regression. The PCEs were was fit in this sample with continuous predictors on their natural scale (ie, not logarithmically transformed) as well as polynomials accounting for nonlinearity and then cumulatively adjusted for former smoking, pack-years, and years since quitting. Models were compared via change in C statistic, continuous net reclassification improvement (NRI[>0]), and relative integrated discrimination improvement (rIDI). Including former smoking status, pack-years, and years since quitting had significant but modest NRI(>0) and rIDI values compared with the PCE with continuous variables on their natural scale in both sexes (men: NRI[>0] = 0.23; rIDI = 0.19; women: NRI[>0] = 0.34, rIDI = 0.11; change in C statistic = 0.01 for both). Conclusions and Relevance: Former smoking, pack-years, and years since quitting significantly improved ASCVD risk prediction in this sample. The Framingham Heart Study offspring cohort is largely composed of non-Hispanic White participants of European ancestry. If results are validated in cohorts of race and ethnicity groups other than White, these variables could be considered for inclusion in future ASCVD risk prediction models.

Racial Differences in Hepatocellular Carcinoma Incidence and Risk Factors among a Low Socioeconomic Population.

The purpose of this study was to examine differences in risk factors associated with hepatocellular carcinoma (HCC) among White and African Americans from low socioeconomic backgrounds in the Southern Community Cohort Study (SCCS). The SCCS is a prospective cohort study with participants from the southeastern US. HCC incidence rates were calculated. Multivariable Cox regression was used to calculate HCC-adjusted hazard ratios (aHR) associated with known baseline HCC risk factors for White and African Americans, separately. There were 294 incident HCC. The incidence rate ratio for HCC was higher (IRR = 1.4, 95%CI: 1.1-1.9) in African Americans compared to White Americans. White Americans saw a stronger association between self-reported hepatitis C virus (aHR = 19.24, 95%CI: 10.58-35.00) and diabetes (aHR = 3.55, 95%CI: 1.96-6.43) for the development of HCC compared to African Americans (aHR = 7.73, 95%CI: 5.71-10.47 and aHR = 1.48, 95%CI: 1.06-2.06, respectively) even though the prevalence of these risk factors was similar between races. Smoking (aHR = 2.91, 95%CI: 1.87-4.52) and heavy alcohol consumption (aHR = 1.59, 95%CI: 1.19-2.11) were significantly associated with HCC risk among African Americans only. In this large prospective cohort, we observed racial differences in HCC incidence and risk factors associated with HCC among White and African Americans.