Supplemental B-Vitamins and Risk of Upper Gastrointestinal Cancers in the Women's Health Initiative.

B-vitamins contribute to DNA synthesis, maintenance, and regulation. Few studies have examined associations of supplemental sources of B-vitamins with the incidence of upper gastrointestinal (GI) cancers [including gastric (GCA) and esophageal (ECA) cancers]; the only prior study to comprehensively examine such intakes reported potential elevated risks of ECA. We examined 159,401 postmenopausal women, ages 50-79 years at baseline, including 302 incident GCA and 183 incident ECA cases, over 19 years of follow-up within the Women's Health Initiative observational study and clinic trials. Adjusted Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations of supplemental B-vitamins [riboflavin (B2), pyridoxine (B6), folic acid (B9), or cobalamin (B12)] with GCA and ECA risk, respectively. Although HRs were generally below 1.0, we observed no statistically significant associations between supplemental intakes of any of the evaluated B-vitamins with the risk of GCA or ECA. As the first prospective study to comprehensively assess these associations, our findings do not corroborate prior research indicating potential harm from supplemental B-vitamin intake for upper GI cancer risk. This study adds evidence that supplemental intakes of B-vitamins may be used by postmenopausal women without regard to their relationship with upper GI cancer risk.

The association of prediagnostic circulating levels of cardiometabolic markers, testosterone and sex hormone-binding globulin with risk of breast cancer among normal weight postmenopausal women in the UK Biobank.

Emerging evidence suggests that normal weight postmenopausal women with a relative excess of body fat are at increased breast cancer risk. However, little is known about the associations between obesity-related blood markers and risk of breast cancer among these individuals. In this prospective study comprising 58 629 normal weight postmenopausal women (body mass index between 18.5 kg/m2 and 24.9 kg/m2 ) who were enrolled in the UK Biobank cohort between 2006 and 2010, we examined the associations of glycated hemoglobin, triglycerides, high-density lipoprotein cholesterol, C-reactive protein (CRP), testosterone and sex hormone-binding globulin (SHBG) with risk of breast cancer. A total of 1268 postmenopausal breast cancer cases were ascertained during a median follow-up period of 7 years. Women with CRP, total testosterone and free testosterone (FT) levels in the highest quintile had increased risk of breast cancer compared to those in the lowest quintile (HRQ5 vs Q1 : 1.35, 95% confidence interval [CI]: 1.12-1.63, HR Q5 vs Q1 : 1.47, 95% CI: 1.20-1.80 and HR Q5 vs Q1 : 1.53, 95% CI: 1.23-1.90, respectively), whereas those with SHBG in the highest quintile had reduced risk (HR Q5 vs Q1 : 0.70, 95% CI: 0.56-0.88). These associations were attenuated but persisted after additional adjustment for BMI, fat mass index (whole body fat mass [kg]/height [m2 ]) or waist circumference and after mutual adjustment for testosterone, CRP and/or SHBG. Our study suggests that the risk of postmenopausal breast cancer among normal weight women is increased in association with relatively high levels of CRP and testosterone and with relatively low levels of SHBG.

The association of body fat composition with risk of breast, endometrial, ovarian and colorectal cancers among normal weight participants in the UK Biobank.

BACKGROUND: The association between body fat composition and risk of cancer in normal weight individuals (body mass index (BMI) 18.5-24.9 kg/m2) is unclear. METHODS: We examined the association of measures of adiposity with risk of incident cancers of the breast (postmenopausal), endometrium, ovary and colon/rectum among 149,928 normal weight individuals (40-70 years) who were enrolled in the UK Biobank cohort between 2006 and 2010. RESULTS: All of the body fat measures were positively associated with invasive postmenopausal breast cancer risk (hazard ratios (HR) for the uppermost quintile (Q5) versus the lowest quintile (Q1) ranged from 1.32 (95% CI: 1.09-1.60) for waist circumference (WC) to 1.56 (1.28-1.90) for BMI). Trunk fat mass index (HRQ5 vs Q1: 1.72, 95% CI: 1.02-2.89) and WC (HRQ5 vs Q1: 1.65, 95% CI: 1.01-2.70)) were positively associated with risk of endometrial cancer. Among males, trunk fat:trunk fat free mass ratio, trunk fat:leg fat mass ratio and (HRQ5 vs Q1: 1.63, 95% CI: 1.02-2.60; 1.92, 1.20-3.07 and 1.68, 1.05-2.66, respectively) were positively associated with colon cancer risk. None of the body fat measures was associated with risk of ovarian cancer or colorectal cancer in women. CONCLUSION: The findings of this study suggest that the current normal weight category based on BMI includes individuals who are at increased risk of some obesity-related cancers.

Metabolic syndrome and risk of endometrial cancer in postmenopausal women: a prospective study.

BACKGROUND: Obesity is a strong risk factor for endometrial cancer, but it is unclear whether metabolic syndrome (MetS) contributes to endometrial cancer risk over and above the contribution of obesity. METHODS: We examined the association of MetS and its components with risk of endometrial cancer in a sub-cohort of 24,210 women enrolled in the Women's Health Initiative cohort study. Two variants of the National Cholesterol Education Program Adult Treatment Panel III definition of the MetS were used: one including and one excluding waist circumference (WC). Cox proportional hazards models were used to estimate the association of the study exposures with disease risk. RESULTS: When WC was included in the definition, MetS showed an approximately two-fold increase in endometrial cancer risk (HR 2.20; 95% CI 1.61-3.02); however, when WC was excluded, MetS was no longer associated with risk. We also observed that women with hyperglycemia, dyslipidemia and hypertension, in combination, had almost a twofold increased risk of endometrial cancer, independent of WC (HR 1.94; 95% CI 1.09, 3.46). Glucose, and, in particular, WC and body mass index were also positively associated with risk. CONCLUSIONS: Our findings suggest that MetS may predict risk of endometrial cancer independent of obesity among women with the remaining four Mets components.

Dietary B-Vitamin Intake and Risk of Breast, Endometrial, Ovarian and Colorectal Cancer among Canadians.

Few studies have explored the associations of thiamin, niacin and riboflavin with risk of cancer despite their role in potentially cancer-associated one-carbon metabolism. Using multivariable Cox proportional hazards regression models modified for the case-cohort design, we examined the associations of dietary intake of the above-mentioned B vitamins, as well as folate, and vitamins B6 and B12, with risk of the breast (n = 922), endometrial (n = 180), ovarian (n = 104) and colorectal (n = 266) cancers among age-stratified subcohorts of 3,185 women who were randomly selected from a cohort of 73,909 participants. None of the B-vitamins were associated with risk of breast or colorectal cancers. However, relatively high dietary intake of folate intake was inversely associated with risk of endometrial (HRq4 vs q1: 0.52; 95% CI: 0.29-0.93) and ovarian (HRq3 vs q1: 0.39; 95% CI: 0.19-0.80) cancers while relatively high dietary intake of vitamin B6 was inversely associated with ovarian cancer risk (HRq3 vs q1: 0.49; 95% CI: 0.24-0.98). These findings suggest that dietary intake of folate may reduce risk of endometrial and ovarian cancers and dietary intake of vitamin B6 may reduce risk of ovarian cancer.

The association of the healthy eating index with risk of colorectal cancers (overall and by subsite) among Canadians.

BACKGROUND: Healthy dietary patterns characterized by high intake of fruits and vegetables, grains/cereals, and lean meat/fish, and low intake of red/processed meats and refined carbohydrates, have been shown to be associated with reduced risk of colorectal cancer, but evidence regarding their association with colorectal cancer subsites is limited. Hence, this study was conducted to assess the association of a healthy dietary pattern, as reflected in the Healthy Eating Index (HEI) (a composite score based on consumption of various food groups), with risk of colorectal cancer, overall and by subsite. METHODS: We conducted a case-cohort study in the Canadian Study of Diet, Lifestyle and Health (CSDLH). The study included all cases of incident colorectal cancer in the entire cohort, and an age-stratified subcohort of 3185 women and 2622 men. Cox regression models were used to estimate hazard ratios (HR) for the association between the HEI and the risk of colorectal cancer, overall and by subsite. We also assessed the association by sex and by selected metabolic factors. RESULTS: For both sexes combined, the highest quintile of the HEI score was inversely associated with risk of colorectal cancer, colon cancer and proximal colon cancer (HR: 0.65; 95% CI: 0. 49-0.85, HR: 0.60, 95% CI: 0.44-0.83 and HR: 0.54, 95% CI: 0.35-0.85, respectively). However, these associations were mostly observed among men (HR: 0.56; 95% CI: 0.38-0.81, HR: 0.44, 95% CI: 0.28-0.69 and HR: 0.26; 95% CI: 0.12-0.56, for colorectal cancer, colon cancer and proximal colon cancer, respectively; p-interactions=0.029, 0.032 and 0.063, respectively). An inverse association was also observed between the HEI and risk of colorectal cancer among normal weight participants, overweight/obese participants, non-smokers, non-alcohol drinkers and participants who were physically inactive. CONCLUSION: A healthy dietary pattern may reduce risk of colorectal cancer, particularly among men.

New-Onset Diabetes after an Obesity-Related Cancer Diagnosis and Survival Outcomes in the Women's Health Initiative.

BACKGROUND: Individuals diagnosed with an obesity-related cancer (ORC survivors) are at an elevated risk of incident diabetes compared with cancer-free individuals, but whether this confers survival disadvantage is unknown. METHODS: We assessed the rate of incident diabetes in ORC survivors and evaluated the association of incident diabetes with all-cause and cancer-specific mortality among females with ORC in the Women's Health Initiative cohort (N = 14,651). Cox proportional hazards regression models stratified by exposure-risk periods (0-1, >1-3, >3-5, >5-7, and >7-10 years) from ORC diagnosis and time-varying exposure (diabetes) analyses were performed. RESULTS: Among the ORC survivors, a total of 1.3% developed diabetes within ≤1 year of follow-up and 2.5%, 2.3%, 2.3%, and 3.6% at 1-3, 3-5, 5-7, and 7-10 years of follow-up, respectively, after an ORC diagnosis. The median survival for those diagnosed with diabetes within 1-year of cancer diagnosis and those with no diabetes diagnosis in that time frame was 8.8 [95% confidence interval (CI), 7.0-14.5) years and 16.6 (95% CI, 16.1-17.0) years, respectively. New-onset compared with no diabetes as a time-varying exposure was associated with higher risk of all-cause (HR, 1.27; 95% CI, 1.16-1.40) and cancer-specific (HR, 1.17; 95% CI, 0.99-1.38) mortality. When stratified by exposure-risk periods, incident diabetes in ≤1 year of follow-up was associated with higher all-cause (HR, 1.76; 95% CI, 1.40-2.20) and cancer-specific (HR0-1, 1.82; 95% CI, 1.28-2.57) mortality, compared with no diabetes diagnosis. CONCLUSIONS: Incident diabetes was associated with worse cancer-specific and all-cause survival, particularly in the year after cancer diagnosis. IMPACT: These findings draw attention to the importance of diabetes prevention efforts among cancer survivors to improve survival outcomes.

Association of a Healthy Lifestyle Index with Risk of Breast Cancer among Women with Normal Body Mass Index in the UK Biobank.

BACKGROUND: A high healthy lifestyle index (HLI), a composite score based on good diet quality, low alcohol consumption, no smoking, moderate to high physical activity, and waist circumference <80 cm, has been consistently associated with a reduced risk of breast cancer. Recently, high levels of body fat were found to be associated with an elevated risk of breast cancer in postmenopausal women with a normal body mass index (BMI; 18.5-<25 kg/m2). Whether the HLI is associated with breast cancer risk in women with normal BMI is unknown. METHODS: We studied 102,572 women aged 40 to 69 years with a normal BMI at enrollment into the UK Biobank cohort study. The HLI was created by assigning to each component higher scores for healthier behaviors and then summing the scores. The HLI was categorized by tertiles and age- and multivariable-adjusted HRs for the association of the HLI with breast cancer risk by menopausal status were estimated using Cox proportional hazards models. RESULTS: In postmenopausal women, compared with a low HLI, higher scores were associated with a reduced risk of breast cancer [HRHLI-3rd tertile = 0.76; 95% confidence interval (CI), 0.64-0.91]. Findings were similar for premenopausal women, although they did not reach statistical significance, except when smoking status was excluded from the HLI score (HLIwithout smoking: HR3rd tertile = 0.71; 95% CI, 0.56-0.90). CONCLUSIONS: In normal BMI postmenopausal women, a high HLI score was associated with a reduced risk of breast cancer. IMPACT: Following a healthy lifestyle may reduce the risk of breast cancer among normal weight postmenopausal women.

The Association of Predicted Resting Energy Expenditure with Risk of Breast Cancer among Postmenopausal Women in the Women's Health Initiative Cohort.

Obesity and obesity-related metabolic disorders, such as diabetes and chronic inflammation, have been positively associated both with postmenopausal breast cancer and with resting energy expenditure (REE). However, there is limited epidemiologic evidence on the associations between REE and risk of postmenopausal breast cancer. We used multivariable Cox proportional hazards models to examine the association between predicted REE (calculated using the Ikeda, Livingston, and Mifflin equations) and risk of postmenopausal breast cancer overall and by subtypes, and by level of body fat) among 137,283 postmenopausal women in the Women's Health Initiative (WHI). All predicted REEs were positively associated with risk of invasive breast cancer [HRq5 vs. q1 = 1.69; 95% confidence interval (CI), 1.57-1.81; HR = 1.69; 95% CI, 1.57-1.82; and HR = 1.68; 95% CI, 1.56-1.80 for Ikeda, Livingston, and Mifflin, respectively]. These positive associations were observed irrespective of the hormone receptor subtype, grade, and stage of the tumors, but were most pronounced for estrogen receptor-positive/progesterone receptor-positive tumors. After additional adjustment for body mass index (BMI), the associations were mostly attenuated and remained statistically significant for most of the outcomes. We also observed an interaction between the predicted REEs and BMI, with the associations being somewhat stronger among normal weight and overweight women than among obese women (Pinteractions < 0.05). Our findings indicate that relatively high REE is associated with increased risk of invasive breast cancer among postmenopausal women (particularly for the obesity-related tumor subtypes), irrespective of the equation used. Further studies using more objective measures of REE are, however, needed to confirm our findings. PREVENTION RELEVANCE: This study showed that higher resting energy expenditure (REE) was associated with higher postmenopausal breast cancer risk. REE provides energy to support cancer-associated disorders such as obesity and inflammation. Thus, studies on its association with breast cancer can help to improve our understanding of the pathophysiology of breast cancer.

Sugar-containing beverages and their association with risk of breast, endometrial, ovarian and colorectal cancers among Canadian women.

BACKGROUND: The association of sugar containing beverages (SCBs) with risk of breast, endometrial, ovarian and colorectal cancers is unclear. Therefore, we investigated these associations in the Canadian Study of Diet, Lifestyle, and Health. METHODS: The study population comprised an age-stratified subcohort of 3185 women and 848, 161, 91 and 243 breast, endometrial, ovarian and colorectal cancer cases, respectively. We used Cox proportional hazards regression models modified for the case-cohort design to assess the associations of SCBs with risk of the aforementioned cancers. RESULTS: Compared to SCB intake in the lowest tertile, SCB intake in the highest tertile was positively associated with endometrial cancer risk (HRT3 vs T1 = 1.58, 95 % CI = 1.08-2.33 and 1.78, 95 % CI = 1.12-2.81 for overall and Type 1 endometrial cancer, respectively) and ovarian cancer (HRT3 vs T1 = 1.76, 95 % CI: 1.09-2.83). Fruit juice intake was also positively associated with risk of Type 1endometrial (HRT3 vs T1 = 1.63, 95 % CI = 1.03-2.60). After excluding women with diabetes or cardiovascular diseases, we also observed sugar-sweetened beverages (SSBs) intake in the highest tertile was associated with higher risk of Type 1 endometrial cancer (HR T3 vs T1 = 1.65; 95 % CI: 1.03-2.64). None of the beverages was associated with risk of breast or colorectal cancer. CONCLUSION: We conclude that, in this cohort, relatively high SCB intake was associated with higher risk of endometrial and ovarian cancers, but not of breast or colorectal cancers. Our findings also suggest that relatively high SSB and fruit juice intake are associated with higher risk of Type 1 endometrial cancer.

Cancer Risk in Normal Weight Individuals with Metabolic Obesity: A Narrative Review.

Obesity represents one of the most significant public health challenges worldwide. Current clinical practice relies on body mass index (BMI) to define the obesity status of an individual, even though the index has long been recognized for its limitations as a measure of body fat. In normal BMI individuals, increased central adiposity has been associated with worse health outcomes, including increased risks of cardiovascular disease and metabolic disorders. The condition leading to these outcomes has been described as metabolic obesity in the normal weight (MONW). More recent evidence suggests that MONW is associated with increased risk of several obesity-related malignancies, including postmenopausal breast, endometrial, colorectal, and liver cancers. In MONW patients, the false reassurance of a normal range BMI can lead to lost opportunities for implementing preventive interventions that may benefit a substantial number of people. A growing body of literature has documented the increased risk profile of MONW individuals and demonstrated practical uses for body composition and biochemical analyses to identify this at-risk population. In this review, we survey the current literature on MONW and cancer, summarize pathophysiology and oncogenic mechanisms, highlight potential strategies for diagnosis and treatment, and suggest directions for future research.

Associations of Dairy Intake with Circulating Biomarkers of Inflammation, Insulin Response, and Dyslipidemia among Postmenopausal Women.

BACKGROUND: Cardiometabolic diseases are prevalent in aging Americans. Although some studies have implicated greater intake of dairy products, it is not clear how dairy intake is related to biomarkers of cardiometabolic health. OBJECTIVE: Our aim was to test the hypothesis that associations of dairy foods with biomarkers of lipid metabolism, insulin-like growth factor signaling, and chronic inflammation may provide clues to understanding how dairy can influence cardiometabolic health. DESIGN: This was a cross-sectional study in the Women's Health Initiative using baseline food frequency questionnaire data to calculate dairy intake. PARTICIPANTS/SETTING: Participants were 35,352 postmenopausal women aged 50 to 79 years at 40 clinical centers in the United States. MAIN OUTCOME MEASURES: Baseline (1993-1998) concentrations of 20 circulating biomarkers were measured. STATISTICAL ANALYSES: Multivariable-adjusted linear regression was used to estimate percent difference in biomarker concentrations per serving of total dairy and individual foods (milk, cheese, yogurt, butter, and low-fat varieties). RESULTS: Lower triglyceride concentrations were associated with greater intake of total dairy (-0.8% [95% CI -1.2% to -0.3%]), mainly driven by full-fat varieties. Individual dairy foods had specific associations with circulating lipid components. For example, greater total milk intake was associated with lower concentrations of total cholesterol (-0.4% [95% CI -0.7% to -0.2%]) and high-density lipoprotein cholesterol (-0.5% [95% CI -0.9% to -0.1%]), whereas greater butter intake was associated with higher total cholesterol (0.6% [95% CI 0.2% to 1.0%]) and high-density lipoprotein cholesterol (1.6% [95% CI 1.1% to 2.0%]) concentrations. In contrast, higher total yogurt intake was associated with lower total cholesterol (-1.1% [95% CI -2.0% to -0.2%]) and higher high-density lipoprotein cholesterol (1.8% [95% CI 0.5% to 3.1%]). Greater total dairy intake (regardless of fat content), total cheese, full-fat cheese, and yogurt were consistently associated with lower concentrations of glucose, insulin, and C-reactive protein. However, milk and butter were not associated with these biomarkers. CONCLUSIONS: Higher dairy intake, except butter, was associated with a favorable profile of lipids, insulin response, and inflammatory biomarkers, regardless of fat content. Yet, specific dairy foods might influence these markers uniquely. Findings do not support a putative role of dairy in cardiometabolic diseases observed in some previous studies.

Sex hormones, SHBG and risk of colon and rectal cancer among men and women in the UK Biobank.

BACKGROUND: Experimental studies have suggested a role for sex hormones in the etiology of colorectal cancer (CRC) but epidemiological data are inconclusive. METHODS: We examined the associations of testosterone, estradiol, and sex hormone binding globulin (SHBG), with risk of CRC (n = 3,247) in 206,508 men and 219,106 women enrolled in the UK Biobank. Participants were followed for a median of 7.1 years. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for CRC risk. RESULTS: In men, in multivariable adjusted models testosterone and SHBG were not associated with CRC. Among men in the highest tertile of physical activity, SHBG was inversely associated with risk (HRq5vs. q1 0.75, 0.56-0.99,). In women, testosterone and SHBG were not associated with CRC risk. There were no differences in the associations between testosterone, SHBG and CRC risk in the analyses stratified by menopausal status. We did not observe an association between estradiol and CRC risk; however, given the limited number of individuals with detectable values of estradiol (13.2 % of the total sample) we are unable to draw a firm conclusions regarding this association. CONCLUSION: The results of this study did not provide support for associations of sex hormones and SHBG with CRC risk.

Prediagnostic Circulating Levels of Sex Steroid Hormones and SHBG in Relation to Risk of Ductal Carcinoma In Situ of the Breast among UK Women.

BACKGROUND: Sex steroid hormones and sex hormone-binding globulin (SHBG) have been implicated in the etiology of invasive breast cancer, but their associations with risk of the precursor lesion, ductal carcinoma in situ (DCIS) of the breast, remain unclear. METHODS: We used Cox proportional hazards regression models to estimate the associations of serum levels of estradiol (premenopausal women only), testosterone, and/or SHBG with DCIS risk among 182,935 women. After a median follow-up of 7.1 years, 186 and 531 DCIS cases were ascertained in premenopausal and postmenopausal women, respectively. RESULTS: Total and free estradiol were positively associated with risk of DCIS among premenopausal women. The HRs for the highest versus the lowest tertiles were 1.54 (1.06-2.23) and 1.72 [95% confidence interval (CI), 1.15-2.57], respectively. Among postmenopausal women, elevated levels of free testosterone (FT), and to a lesser extent, total testosterone, were positively associated with DCIS risk. The HRs for the highest versus the lowest quartiles were 1.42 (95% CI, 1.09-1.85) and 1.16 (95% CI, 0.91-1.48), respectively. Serum SHBG levels were inversely associated with risk of DCIS among postmenopausal women (HRq4 vs. q1: 0.75; 95% CI, 0.56-0.99). CONCLUSIONS: This study suggests that elevated levels of estradiol are associated with increased risk of DCIS among premenopausal women, and that among postmenopausal women, elevated levels of testosterone, and particularly those of FT, are associated with increased DCIS risk, while elevated levels of SHBG are associated with reduced risk. IMPACT: These findings may be helpful in developing prevention strategies aimed at reducing breast cancer risk among premenopausal and postmenopausal women.

Association of Sex Hormones with Risk of Cancers of the Pancreas, Kidney, and Brain in the UK Biobank Cohort Study.

BACKGROUND: There is some evidence to suggest that endogenous levels of sex hormones might influence the etiology of cancers of the pancreas, kidney, and brain, but epidemiologic data are lacking. METHODS: We evaluated the association of circulating levels of total and free testosterone, and of sex hormone-binding globulin (SHBG), with the risk of cancers of the pancreas, kidney, and brain, and of total and free estradiol with the risk of kidney cancer, in the UK Biobank cohort study (n = 425,793; 225 pancreatic cancers, 749 kidney cancers, 467 brain cancers). Multivariable Cox proportional hazards models were used to estimate HRs and 95% confidence intervals for the associations. RESULTS: Testosterone and SHBG levels were not associated with risk of pancreatic cancer. Most of the associations for the other two anatomic sites were null. There were inverse associations between total testosterone and brain cancer in men and between SHBG and risk of kidney cancer in the total sample and in women. Estradiol was not associated with the risk of kidney cancer. CONCLUSIONS: The results of this study provide little support for associations between sex hormones/SHBG and risk of cancers of the pancreas, kidney, and brain. Larger studies are warranted. IMPACT: Although these results provide little support for roles for sex hormones and SHBG in the etiology of cancers of the pancreas, kidney, and brain, there is a need for studies with larger numbers of cases.

Genetic Factors, Adherence to Healthy Lifestyle Behavior, and Risk of Invasive Breast Cancer Among Women in the UK Biobank.

BACKGROUND: Breast cancer is considered to result from a combination of genetic and lifestyle-related factors, but the degree to which an overall healthy lifestyle may attenuate the impact of multiple genetic variants on invasive breast cancer risk remains equivocal. METHODS: Using Cox proportional hazards regression models, we examined the association of a modified healthy lifestyle index (HLI) with risk of invasive breast cancer by genetic risk group among 146 326 women from the UK Biobank. We generated an HLI score based on a combination of diet, physical activity, smoking, alcohol consumption and anthropometry, and a polygenic risk score (PRS) using 304 breast cancer-associated genetic loci. RESULTS: Among premenopausal and postmenopausal women, a favorable lifestyle (highest tertile) was associated with 22% and 31% reductions in invasive breast cancer risk, respectively (hazard ratio [HR]high vs low = 0.78, 95% confidence interval [CI] = 0.64 to 0.94; HRhigh vs low = 0.69, 95% CI = 0.63 to 0.77, respectively), whereas a high PRS (highest tertile) was associated with more than a doubling in the risk in both groups. For premenopausal women, the greatest risk reduction in association with the HLI was seen among those with a high PRS (HRhigh vs low = 0.73, 95% CI = 0.75 to 0.95). In postmenopausal women, those with a favorable lifestyle had 30%, 29%, and 32% reductions in risk of invasive breast cancer in the low, intermediate, and high PRS groups, respectively (HRhigh vs low = 0.70, 95% CI = 0.56 to 0.88; HRhigh vs low = 0.71, 95% CI = 0.59 to 0.84; and HRhigh vs low = 0.68, 95% CI = 0.59 to 0.78, respectively). There was an additive but not multiplicative interaction between the HLI score and PRS for postmenopausal and, to a lesser extent, premenopausal women. CONCLUSION: Our findings support the view that an overall healthy lifestyle may attenuate the impact of genetic factors on invasive breast cancer risk among women of European ancestry.

The association between DXA-derived body fat measures and breast cancer risk among postmenopausal women in the Women's Health Initiative.

BACKGROUND: Most studies demonstrating an association between excess adiposity and postmenopausal breast cancer have used anthropometric measures, particularly body mass index (BMI). However, more direct body fat measures may more accurately determine the relationship between body fat distribution and breast cancer risk. METHODS: Cox proportional hazards regression models were created to examine the associations of dual-energy x-ray absorptiometry (DXA) body fat measures (at baseline and during follow-up) with breast cancer risk among 10 931 postmenopausal women from the Women's Health Initiative cohort. A total of 639 incident invasive breast cancer cases (including 484 estrogen receptor positive (ER+) cases) were ascertained after a median follow-up of 15.0 years. RESULTS: Excess whole body fat mass and trunk fat mass were positively associated with risk invasive breast cancer risk. These associations persisted even after additional adjustment for standard anthropometric measures. In time-dependent analyses, we observed that both whole body fat mass and trunk fat mass, in the highest versus lowest category, were associated with a doubling of risk of invasive breast cancer overall (HR: 2.17; 95% CI: 1.54-3.05 and 2.20; 1.55-3.14, respectively) and of ER+ breast cancer (2.05; 1.37-3.05 and 2.03; 1.34-3.07, respectively). The remaining DXA measures were also positively associated with breast cancer risk in baseline and time-dependent analyses. CONCLUSION: These findings suggest that DXA-derived body fat measures are positively associated with breast cancer risk after adjustment for BMI and other conventional breast cancer risk factors.