Anne McTiernan

The Women's Health Initiative trial of combined estrogen plus progestin was stopped early when overall health risks, including invasive breast cancer, exceeded benefits. Outstanding issues not previously addressed include characteristics of breast cancers observed among women using hormones and whether diagnosis may be influenced by hormone effects on mammography.To determine the relationship among estrogen plus progestin use, breast cancer characteristics, and mammography recommendations.Following a comprehensive breast cancer risk assessment, 16 608 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive combined conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo from 1993 to 1998 at 40 clinical centers. Screening mammography and clinical breast examinations were performed at baseline and yearly thereafter.Breast cancer number and characteristics, and frequency of abnormal mammograms by estrogen plus progestin exposure.In intent-to-treat analyses, estrogen plus progestin increased total (245 vs 185 cases; hazard ratio [HR], 1.24; weighted P<.001) and invasive (199 vs 150 cases; HR, 1.24; weighted P =.003) breast cancers compared with placebo. The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P =.04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P =.04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001), a pattern which continued for the study duration.Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.

The purpose of this study was to describe the prevalence of and correlates for pelvic organ prolapse.This was a cross-sectional analysis of women who enrolled in the Women's Health Initiative Hormone Replacement Therapy Clinical Trial (n = 27,342 women). Baseline questionnaires ascertained demographics and personal habits. A baseline pelvic examination assessed uterine prolapse, cystocele, and rectocele. Descriptive statistics and logistic regression models were used to investigate factors that were associated with pelvic organ prolapse.In the 16,616 women with a uterus, the rate of uterine prolapse was 14.2%; the rate of cystocele was 34.3%; and the rate of rectocele was 18.6%. For the 10,727 women who had undergone hysterectomy, the prevalence of cystocele was 32.9% and of rectocele was 18.3%. After controlling for age, body mass index, and other health/physical variables, African American women demonstrated the lowest risk for prolapse. Hispanic women had the highest risk for uterine prolapse. Parity and obesity were strongly associated with increased risk for uterine prolapse, cystocele, and rectocele.Pelvic organ prolapse is a common condition in older women. The risk for prolapse differs between ethnic groups, which suggests that the approaches to risk-factor modification and prevention may also differ. These data will help address the gynecologic needs of diverse populations.

To examine the effects of aerobic exercise on cognition and other biomarkers associated with Alzheimer disease pathology for older adults with mild cognitive impairment, and assess the role of sex as a predictor of response.Six-month, randomized, controlled, clinical trial.Veterans Affairs Puget Sound Health Care System clinical research unit.Thirty-three adults (17 women) with amnestic mild cognitive impairment ranging in age from 55 to 85 years (mean age, 70 years). Intervention Participants were randomized either to a high-intensity aerobic exercise or stretching control group. The aerobic group exercised under the supervision of a fitness trainer at 75% to 85% of heart rate reserve for 45 to 60 min/d, 4 d/wk for 6 months. The control group carried out supervised stretching activities according to the same schedule but maintained their heart rate at or below 50% of their heart rate reserve. Before and after the study, glucometabolic and treadmill tests were performed and fat distribution was assessed using dual-energy x-ray absorptiometry. At baseline, month 3, and month 6, blood was collected for assay and cognitive tests were administered.Performance measures on Symbol-Digit Modalities, Verbal Fluency, Stroop, Trails B, Task Switching, Story Recall, and List Learning. Fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulinlike growth factor-I, and beta-amyloids 40 and 42.Six months of high-intensity aerobic exercise had sex-specific effects on cognition, glucose metabolism, and hypothalamic-pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction. For women, aerobic exercise improved performance on multiple tests of executive function, increased glucose disposal during the metabolic clamp, and reduced fasting plasma levels of insulin, cortisol, and brain-derived neurotrophic factor. For men, aerobic exercise increased plasma levels of insulinlike growth factor I and had a favorable effect only on Trails B performance.This study provides support, using rigorous controlled methodology, for a potent nonpharmacologic intervention that improves executive control processes for older women at high risk of cognitive decline. Moreover, our results suggest that a sex bias in cognitive response may relate to sex-based differences in glucometabolic and hypothalamic-pituitary-adrenal axis responses to aerobic exercise.

BackgroundPositive association between obesity and survival after breast cancer was demonstrated in previous meta-analyses of published data, but only the results for the comparison of obese versus non-obese was summarised.MethodsWe systematically searched in MEDLINE and EMBASE for follow-up studies of breast cancer survivors with body mass index (BMI) before and after diagnosis, and total and cause-specific mortality until June 2013, as part of the World Cancer Research Fund Continuous Update Project. Random-effects meta-analyses were conducted to explore the magnitude and the shape of the associations.ResultsEighty-two studies, including 213 075 breast cancer survivors with 41 477 deaths (23 182 from breast cancer) were identified. For BMI before diagnosis, compared with normal weight women, the summary relative risks (RRs) of total mortality were 1.41 [95% confidence interval (CI) 1.29–1.53] for obese (BMI >30.0), 1.07 (95 CI 1.02–1.12) for overweight (BMI 25.0–<30.0) and 1.10 (95% CI 0.92–1.31) for underweight (BMI <18.5) women. For obese women, the summary RRs were 1.75 (95% CI 1.26–2.41) for pre-menopausal and 1.34 (95% CI 1.18–1.53) for post-menopausal breast cancer. For each 5 kg/m2 increment of BMI before, <12 months after, and ≥12 months after diagnosis, increased risks of 17%, 11%, and 8% for total mortality, and 18%, 14%, and 29% for breast cancer mortality were observed, respectively.ConclusionsObesity is associated with poorer overall and breast cancer survival in pre- and post-menopausal breast cancer, regardless of when BMI is ascertained. Being overweight is also related to a higher risk of mortality. Randomised clinical trials are needed to test interventions for weight loss and maintenance on survival in women with breast cancer.

Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer.In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured.A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P=0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P=0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P=0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed.Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. (Funded by Pfizer and others; NCIC CTG MAP.3 ClinicalTrials.gov number, NCT00083174.).

Cancer survivors are often highly motivated to seek information about food choices, physical activity, and dietary supplement use to improve their treatment outcomes, quality of life, and survival. To address these concerns, the American Cancer Society (ACS) convened a group of experts in nutrition, physical activity, and cancer to evaluate the scientific evidence and best clinical practices related to optimal nutrition and physical activity after the diagnosis of cancer. This report summarizes their findings and is intended to present health care providers with the best possible information from which to help cancer survivors and their families make informed choices related to nutrition and physical activity. The report discusses nutrition and physical activity issues during the phases of cancer treatment and recovery, living after recovery from treatment, and living with advanced cancer; select nutrition and physical activity issues such as body weight, food choices, and food safety; issues related to select cancer sites; and common questions about diet, physical activity, and cancer survivorship.

BackgroundCancer survivors often seek information about how lifestyle factors, such as physical activity, may influence their prognosis. We systematically reviewed studies that examined relationships between physical activity and mortality (cancer-specific and all-cause) and/or cancer biomarkers.

The association of TEE with all-cause mortality is uncertain, as is the dependence of this association on age.To examine the association between TEE and all-cause mortality, and its age interaction, in a Women’s Health Initiative (WHI) cohort of postmenopausal United States women (1992–present).A cohort of 1131 WHI participants having DLW TEE assessment of ∼10.0 y (median) following WHI enrollment with ∼13.7 y (median) of subsequent follow-up, was used to study the EE associations with all-cause mortality. To enhance the comparability of TEE and total EI, key analyses excluded participants having >5% weight change between WHI enrollment and DLW assessment. The influence of participant age on mortality associations was examined, as was the ability of concurrent and earlier weight and height measurements to explain the results.There were 308 deaths following the TEE assessment through 2021. TEE was unrelated to overall mortality (P = 0.83) in this cohort of generally healthy, older (mean 71 y at TEE assessment) United States women. However, this potential association varied with age (P = 0.003). Higher TEE was associated with a higher mortality rate at the age of 60 y and a lower mortality rate at the age of 80 y. Within the weight-stable subset (532 participants, 129 deaths), TEE was weakly positively related to overall mortality (P = 0.08). This association also varied with age (P = 0.03), with mortality HRs (95% CIs) for a 20% increment in TEE of 2.33 (1.24, 4.36) at the age of 60 y, 1.49 (1.10, 2.02) at 70 y of age, and 0.96 (0.66, 1.38) at 80 y of age. This pattern remained, although was somewhat attenuated, following control for baseline weight and weight changes between WHI enrollment and TEE assessment.Higher EE is associated with higher all-cause mortality among younger postmenopausal women, only partially explained by weight and weight change.This study is registered with clinicaltrials.gov identifier: NCT00000611.

Purpose Chronic inflammation is believed to contribute to the development and progression of breast cancer. Systemic C-reactive protein (CRP) and serum amyloid A (SAA) are measures of low-grade chronic inflammation and potential predictors of cancer survival. Patients and Methods We evaluated the relationship between circulating markers of inflammation and breast cancer survival using data from the Health, Eating, Activity, and Lifestyle (HEAL) Study (a multiethnic prospective cohort study of women diagnosed with stage 0 to IIIA breast cancer). Circulating concentrations of CRP and SAA were measured approximately 31 months after diagnosis and tested for associations with disease-free survival (approximately 4.1 years of follow-up) and overall survival (approximately 6.9 years of follow-up) in 734 disease-free breast cancer survivors. Cox proportional hazards models were used with adjustment for potential confounding factors to generate hazard ratios (HRs) and 95% CIs. Results Elevated SAA and CRP were associated with reduced overall survival, regardless of adjustment for age, tumor stage, race, and body mass index (SAA P trend &lt; .0001; CRP P trend = .002). The HRs for SAA and CRP tertiles suggested a threshold effect on survival, rather than a dose-response relationship (highest v lowest tertile: SAA HR = 3.15; 95% CI, 1.73 to 5.65; CRP HR = 2.27; 95% CI, 1.27 to 4.08). Associations were similar and still significant after adjusting for self-reported history of cardiovascular events and censoring cardiovascular disease deaths. Elevated CRP and SAA were also associated with reduced disease-free survival, although these associations were of borderline significance (SAA P trend = .04; CRP P trend = .07). Conclusion Circulating SAA and CRP may be important prognostic markers for long-term survival in breast cancer patients, independent of race, tumor stage, and body mass index.

The lower breast cancer incidence in minority women and the higher breast cancer mortality in African American women than in white women are largely unexplained. The influence of breast cancer risk factors on these differences has received little attention.Racial/ethnic differences in breast cancer incidence and outcome were examined in 156,570 postmenopausal women participating in the Women's Health Initiative. Detailed information on breast cancer risk factors including mammography was collected, and participants were followed prospectively for breast cancer incidence, pathological breast cancer characteristics, and breast cancer mortality. Comparisons of breast cancer incidence and mortality across racial/ethnic groups were estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional hazard models. Tumor characteristics were compared as odds ratios (ORs) and 95% confidence intervals in logistic regression models.After median follow-up of 6.3 years, 3938 breast cancers were diagnosed. Age-adjusted incidences for all minority groups (i.e., African American, Hispanic, American Indian/Alaskan Native, and Asian/Pacific Islander) were lower than for white women, but adjustment for breast cancer risk factors accounted for the differences for all but African Americans (HR = 0.75, 95% CI = 0.61 to 0.92) corresponding to 29 cases and 44 cases per 10,000 person years for African American and white women, respectively. Breast cancers in African American women had unfavorable characteristics; 32% of those in African Americans but only 10% in whites were both high grade and estrogen receptor negative (adjusted OR = 4.70, 95% CI = 3.12 to 7.09). Moreover, after adjustment for prognostic factors, African American women had higher mortality after breast cancer than white women (HR = 1.79, 95% CI = 1.05 to 3.05) corresponding to nine and six deaths per 10 000 person-years from diagnosis in African American and white women, respectively.Differences in breast cancer incidence rates between most racial/ethnic groups were largely explained by risk factor distribution except in African Americans. However, breast cancers in African American women more commonly had characteristics of poor prognosis, which may contribute to their increased mortality after diagnosis.

Increased body weight at the time patients are diagnosed with breast carcinoma has been associated with an increased risk of recurrence and reduced survival. Weight gain also is common after diagnosis. Increasing physical activity (PA) after diagnosis may minimize these adverse outcomes. In this population-based study, the authors investigated whether PA levels after diagnosis declined from prediagnosis levels and whether any changes in PA varied by disease stage, adjuvant treatment, patient age, or body mass index (BMI) in 812 patients with incident breast carcinoma (from in situ to Stage IIIa).Types of sports and household activities and their frequency and duration for the year prior to diagnosis and for the month prior to the interview (i.e., 4-12 months postdiagnosis) were assessed during a baseline interview.Patients decreased their total PA by an estimated 2.0 hours per week from prediagnosis to postdiagnosis, an 11% decrease (P < 0.05). Greater decreases in sports PA were observed among women who were treated with radiation and chemotherapy (50% decrease) compared with women who underwent surgery only (24% decrease) or who were treated with radiation only (23%; (P < 0.05). Greater decreases in sports PA were observed among obese patients (41% decrease) compared with patients of normal weight (24% decrease; P < 0.05).PA levels were reduced significantly after patients were diagnosed with breast carcinoma. Greater decreases in PA observed among heavier patients implied a potential for greater weight gain among women who already were overweight. Randomized, controlled trials are needed to evaluate how PA may improve the prognosis for patients with breast carcinoma.

Women who are physically active have a decreased risk for breast cancer, but the types, amounts, and timing of activity needed are unknown.To prospectively examine the association between current and past recreational physical activity and incidence of breast cancer in postmenopausal women.Prospective cohort study in 74 171 women aged 50 to 79 years who were recruited by 40 US clinical centers from 1993 through 1998.Incident invasive and in situ breast cancer.We documented 1780 newly diagnosed cases of breast cancer over a mean follow-up of 4.7 years. Compared with less active women, women who engaged in regular strenuous physical activity at age 35 years had a 14% decreased risk of breast cancer (relative risk [RR], 0.86; 95% confidence interval [CI], 0.78-0.95). Similar but attenuated findings were observed for strenuous physical activity at ages 18 years and 50 years. An increasing total current physical activity score was associated with a reduced risk for breast cancer (P =.03 for trend). Women who engaged in the equivalent of 1.25 to 2.5 hours per week of brisk walking had an 18% decreased risk of breast cancer (RR, 0.82; 95% CI, 0.68-0.97) compared with inactive women. Slightly greater reduction in risk was observed for women who engaged in the equivalent of 10 hours or more per week of brisk walking. The effect of exercise was most pronounced in women in the lowest tertile of body mass index (BMI) (<24.1), but also was observed for women in the middle tertile of BMI (24.1-28.4).These data suggest that increased physical activity is associated with reduced risk for breast cancer in postmenopausal women, longer duration provides most benefit, and that such activity need not be strenuous.

This article reviews and updates the evidence on the associations between physical activity and risk for cancer, and for mortality in persons with cancer, as presented in the 2018 Physical Activity Guidelines Advisory Committee Scientific Report.Systematic reviews of meta-analyses, systematic reviews, and pooled analyses were conducted through December 2016. An updated systematic review of such reports plus original research through February 2018 was conducted. This article also identifies future research needs.In reviewing 45 reports comprising hundreds of epidemiologic studies with several million study participants, the report found strong evidence for an association between highest versus lowest physical activity levels and reduced risks of bladder, breast, colon, endometrial, esophageal adenocarcinoma, renal, and gastric cancers. Relative risk reductions ranged from approximately 10% to 20%. Based on 18 systematic reviews and meta-analyses, the report also found moderate or limited associations between greater amounts of physical activity and decreased all-cause and cancer-specific mortality in individuals with a diagnosis of breast, colorectal, or prostate cancer, with relative risk reductions ranging almost up to 40% to 50%. The updated search, with five meta-analyses and 25 source articles reviewed, confirmed these findings.Levels of physical activity recommended in the 2018 Guidelines are associated with reduced risk and improved survival for several cancers. More research is needed to determine the associations between physical activity and incidence for less common cancers and associations with survival for other cancers. Future studies of cancer incidence and mortality should consider these associations for population subgroups, to determine dose-response relationships between physical activity and cancer risk and prognosis, and to establish mechanisms to explain these associations.

The increasing prevalence of obesity is a major public health concern. Physical activity may promote weight and body fat loss.To examine the effects of exercise on total and intra-abdominal body fat overall and by level of exercise.Randomized controlled trial conducted from 1997 to 2001.A total of 173 sedentary, overweight (body mass index > or =24.0 and >33% body fat), postmenopausal women aged 50 to 75 years who were living in the Seattle, Wash, area.Participants were randomly assigned to an intervention consisting of exercise facility and home-based moderate-intensity exercise (n = 87) or a stretching control group (n = 86).Changes in body weight and waist and hip circumferences at 3 and 12 months; total body, intra-abdominal, and subcutaneous abdominal fat at 12 months.Twelve-month data were available for 168 women. Women in the exercise group participated in moderate-intensity sports/recreational activity for a mean (SD) of 3.5 (1.2) d/wk for 176 (91) min/wk. Walking was the most frequently reported activity. Exercisers showed statistically significant differences from controls in baseline to 12-month changes in body weight (-1.4 kg; 95% confidence interval [CI], -2.5 to -0.3 kg), total body fat (-1.0%; 95% CI, -1.6% to -0.4%), intra-abdominal fat (-8.6 g/cm2; 95% CI, -17.8 to 0.9 g/cm2), and subcutaneous abdominal fat (-28.8 g/cm2); 95% CI, -47.5 to -10.0 g/cm2). A significant dose response for greater body fat loss was observed with increasing duration of exercise.Regular exercise such as brisk walking results in reduced body weight and body fat among overweight and obese postmenopausal women.

To investigate the association between pre- and postdiagnosis physical activity (as well as change in prediagnosis to postdiagnosis physical activity) and mortality among women with breast cancer.This was a prospective observational study of 933 women enrolled onto the Health, Eating, Activity, and Lifestyle Study who were diagnosed with local or regional breast cancer between 1995 and 1998 and observed until death or September 2004, whichever came first. The primary outcomes measured were total deaths and breast cancer deaths. The primary exposures were physical activity in the year before and 2 years after diagnosis and the pre- to postdiagnosis change in physical activity.Compared with inactive women, the multivariable hazard ratios (HRs) for total deaths for women expending at least 9 metabolic equivalent hours per week (approximately 2 to 3 h/wk of brisk walking) were 0.69 (95% CI, 0.45 to 1.06; P = .045) for those active in the year before diagnosis and 0.33 (95% CI, 0.15 to 0.73; P = .046) for those active 2 years after diagnosis. Compared with women who were inactive both before and after diagnosis, women who increased physical activity after diagnosis had a 45% lower risk of death (HR = 0.55; 95% CI, 0.22 to 1.38), and women who decreased physical activity after diagnosis had a four-fold greater risk of death (HR = 3.95; 95% CI, 1.45 to 10.50).Moderate-intensity physical activity after a diagnosis of breast cancer may improve prognosis.

To systematically review and summarize evidence relevant to obesity and breast cancer clinical outcome, potential hormonal mediating mechanisms, and the current status of weight loss interventions for chronic disease management.A comprehensive, formal literature review was conducted to identify 5,687 citations with key information from 159 references summarized in text and tables. This process included a search for all breast cancer studies exploring associations among survival or recurrence and obesity at diagnosis or weight gain after diagnosis using prospective criteria.On the basis of observational studies, women with breast cancer who are overweight or gain weight after diagnosis are found to be at greater risk for breast cancer recurrence and death compared with lighter women. Obesity is also associated with hormonal profiles likely to stimulate breast cancer growth. Recently, use of weight loss algorithms proven successful in other clinical settings that incorporate dietary therapy, physical activity, and ongoing behavior therapy have been endorsed by the National Institutes of Health and other health agencies.Although definitive weight loss intervention trials in breast cancer patients remain to be conducted, the current evidence relating increased body weight to adverse breast cancer outcome and the documented favorable effects of weight loss on clinical outcome in other comorbid conditions support consideration of programs for weight loss in breast cancer patients. Recommendations for the clinical care of overweight or obese breast cancer patients are offered.

<h3>Objective.</h3> —To provide recommendations for cancer surveillance and risk reduction for individuals carrying mutations associated with hereditary nonpolyposis colon cancer (HNPCC). <h3>Participants.</h3> —A task force with expertise in medical genetics, oncology, primary care, gastroenterology, and epidemiology convened by the Cancer Genetics Studies Consortium (CGSC), organized by the National Human Genome Research Institute (previously the National Center for Human Genome Research). <h3>Evidence.</h3> —Studies evaluating cancer risk, surveillance, and risk reduction in individuals genetically susceptible to colon cancer were identified using MEDLINE and bibliographies of articles thus identified. Indexing terms used were "genetics" in combination with "colon cancer," and "screening" in combination with "cancer family" and "HNPCC." For studies evaluating specific interventions, quality of evidence was assessed using criteria of the US Preventive Services Task Force. <h3>Consensus Process.</h3> —The task force developed recommendations through discussions over a 14-month period. <h3>Conclusions.</h3> —Efficacy of cancer surveillance or other measures to reduce risk in individuals who carry cancer-predisposing mutations is unknown. Based on observational studies, colonoscopy every 1 to 3 years starting at age 25 years is recommended for individuals known to have HNPCC-associated mutations. Endometrial cancer screening is also recommended, based on expert opinion concerning presumptive benefit. No recommendation is made for or against prophylactic surgery (ie, colectomy, hysterectomy); these surgeries are an option for mutation carriers, but evidence of benefit is lacking. It is recommended that individuals considering genetic testing be counseled regarding the unknown efficacy of measures to reduce risk and that care for individuals with cancer-predisposing mutations be provided whenever possible within the context of research protocols designed to evaluate clinical outcomes.

Folic acid (FA) supplements and food fortification are used to prevent neural tube defects and to lower plasma homocysteine. Through exposure to food fortification and vitamin supplement use, large populations in the United States and elsewhere have an unprecedented high FA intake. We evaluated dietary and supplemental intakes of folate and FA in relation to an index of immune function, natural killer cell (NK) cytotoxicity, among 105 healthy, postmenopausal women. Among women with a diet low in folate (<233 microg/d), those who used FA-containing supplements had significantly greater NK cytotoxicity (P = 0.01). However, those who consumed a folate-rich diet and in addition used FA supplements > 400 microg/d had reduced NK cytotoxicity compared with those consuming a low-folate diet and no supplements (P = 0.02). Prompted by this observation, we assessed the presence of unmetabolized FA in plasma as a biochemical marker of excess FA. Unmetabolized folic acid was detected in 78% of plasma samples from fasting participants. We found an inverse relation between the presence of unmetabolized FA in plasma and NK cytotoxicity. NK cytotoxicity was approximately 23% lower among women with detectable folic acid (P = 0.04). This inverse relation was stronger among women >or= 60 y old and more pronounced with increasing unmetabolized FA concentrations (P-trend = 0.002). Because of the increased intake of FA in many countries, our findings highlight the need for further studies on the effect of long-term high FA intake on immune function and health.

Lifestyle interventions for weight loss are the cornerstone of obesity therapy, yet their optimal design is debated. This is particularly true for postmenopausal women; a population with a high prevalence of obesity yet toward whom fewer studies are targeted. We conducted a year-long, 4-arm randomized trial among 439 overweight-to-obese postmenopausal sedentary women to determine the effects of a calorie-reduced, low-fat diet (D), a moderate-intensity, facility-based aerobic exercise program (E), or the combination of both interventions (D+E), vs. a no-lifestyle-change control (C) on change in body weight and composition. The group-based dietary intervention had a weight-reduction goal of ≥10%, and the exercise intervention consisted of a gradual escalation to 45-min aerobic exercise 5 day/week. Participants were predominantly non-Hispanic whites (85%) with a mean age of 58.0 ± 5.0 years, a mean BMI of 30.9 ± 4.0 kg/m(2) and an average of 47.8 ± 4.4% body fat. Baseline and 12-month weight and adiposity measures were obtained by staff blinded to participants' intervention assignment. Three hundred and ninety nine women completed the trial (91% retention). Using an intention-to-treat analysis, average weight loss at 12 months was -8.5% for the D group (P < 0.0001 vs. C), -2.4% for the E group (P = 0.03 vs. C), and -10.8% for the D+E group (P < 0.0001 vs. C), whereas the C group experienced a nonsignificant -0.8% decrease. BMI, waist circumference, and % body fat were also similarly reduced. Among postmenopausal women, lifestyle-change involving diet, exercise, or both combined over 1 year improves body weight and adiposity, with the greatest change arising from the combined intervention.

Purpose Obese women and women who gain weight after a breast cancer diagnosis are at a greater risk for breast cancer recurrence and death compared with lean women and women who do not gain weight after diagnosis. In this population-based study, we assessed weight and body fat changes from during the first year of diagnosis to during the third year after diagnosis, and whether any changes in weight and body fat varied by demographic, prognostic, and lifestyle factors in 514 women with incident Stage 0-IIIA breast cancer. Methods Patients were participants in the Health, Eating, Activity, and Lifestyle (HEAL) study. Weight and body fat (via dual-energy x-ray absorptiometry scans) were measured during the baseline visit and 2 years later at a follow-up visit. Analysis of covariance methods were used to obtain mean weight and body fat changes adjusted for potential cofounders. Results Women increased their weight and percent body fat by 1.7 ± 4.7 kg and 2.1% ± 3.9%, respectively, from during their first year of diagnosis to during their third year of diagnosis. A total of 68% and 74% of patients gained weight and body fat, respectively. Greater increases in weight were observed among women diagnosed with a higher disease stage, younger age, being postmenopausal, and women who decreased their physical activity from diagnosis to up to 3 years after diagnosis (P for trend &lt; .05). Conclusion Weight and body fat increased in the postdiagnosis period. Future research should focus on the effect of physical activity on weight and fat loss and breast cancer prognosis.

Obesity has been proposed as a risk factor for pancreatic cancer.Pooled data were analyzed from the National Cancer Institute Pancreatic Cancer Cohort Consortium (PanScan) to study the association between prediagnostic anthropometric measures and risk of pancreatic cancer. PanScan applied a nested case-control study design and included 2170 cases and 2209 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression for cohort-specific quartiles of body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), weight, height, waist circumference, and waist to hip ratio as well as conventional BMI categories (underweight, <18.5; normal weight, 18.5-24.9; overweight, 25.0-29.9; obese, 30.0-34.9; and severely obese, > or = 35.0). Models were adjusted for potential confounders.In all of the participants, a positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs lowest BMI quartile, 1.33; 95% CI, 1.12-1.58; P(trend) < .001). In men, the adjusted OR for pancreatic cancer for the highest vs lowest quartile of BMI was 1.33 (95% CI, 1.04-1.69; P(trend) < .03), and in women it was 1.34 (95% CI, 1.05-1.70; P(trend) = .01). Increased waist to hip ratio was associated with increased risk of pancreatic cancer in women (adjusted OR for the highest vs lowest quartile, 1.87; 95% CI, 1.31-2.69; P(trend) = .003) but less so in men.These findings provide strong support for a positive association between BMI and pancreatic cancer risk. In addition, centralized fat distribution may increase pancreatic cancer risk, especially in women.

Abstract Elevated circulating estrogens and a sedentary lifestyle increase risk for breast cancer. The effect of exercise on circulating estrogens in sedentary postmenopausal women is unknown. The objective of this study was to examine the effects of a 12-month moderate-intensity exercise intervention on serum estrogens. We randomly assigned 173 sedentary, overweight (body mass index &amp;gt; 24.0 kg/m2, body fat &amp;gt; 33%), postmenopausal women, ages 50–75 years, not using hormone therapy, living in the Seattle, Washington, area for the next year, and willing to be randomly assigned to an exercise intervention or stretching control group. The exercise intervention included facility and home-based exercise (45 min, 5 days/week moderate intensity sports/recreational exercise). A total of 170 (98.3%) women completed the study with exercisers averaging 171 min/week of exercise. After 3 months, exercisers experienced declines in estrone, estradiol, and free estradiol of 3.8, 7.7, and 8.2%, respectively, versus no change or increased concentrations in controls (P = 0.03, 0.07, and 0.02, respectively). At 12 months, the direction of effect remained the same, although the differences were no longer statistically significant. The effect was limited to women who lost body fat: women whose percentage of body fat [by dual energy x-ray absortiometry (DEXA)] decreased by ≥2% had statistically significant (comparing exercisers versus controls) decreases at 12 months of 11.9, 13.7, and 16.7% for serum estrone, estradiol, and free estradiol, respectively. We concluded that a 12-month moderate-intensity exercise intervention in postmenopausal women resulted in significant decreases in serum estrogens. The association between increased physical activity and reduced risk for postmenopausal breast cancer may be partly explained by effects on serum estrogens.

Levels of estrogen, androgen, and prolactin have been related to risk of postmenopausal breast cancer. However, the determinants of these hormone concentrations are not established. The purpose of this study was to examine correlates of endogenous sex hormones.Associations among adiposity, physical activity, and diet and concentrations of estradiol, free estradiol, estrone, testosterone, free testosterone, sex hormone-binding globulin (SHBG), androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and prolactin were evaluated in 267 postmenopausal women randomly selected from the Women's Health Initiative Dietary Modification Trial.In multiple regression analyses on log-transformed hormones, BMI was positively associated with estrone (beta = 0.031, p < 0.001), estradiol (beta = 0.048, p < 0.001), free estradiol (beta = 0.062, p < 0.001), free testosterone (beta = 0.017, p = 0.02), and prolactin (beta = 0.012, p = 0.02) and negatively associated with SHBG (beta = -0.02, p = 0.001). Total physical activity (metabolic equivalent tasks per week) was negatively associated with concentrations of estrone, estradiol, and androstenedione (beta = -0.006, -0.007, and -0.005, respectively, all p < or = 0.05). Using a composite variable of BMI and physical activity dichotomized by median values, women with high BMI/low physical activity had a mean estrone concentration of 28.8 pg/mL, compared with 24.1, 19.9, and 18.4 pg/mL for women with high BMI/high physical activity, low BMI/low physical activity, and low BMI/high physical activity, respectively (p trend < 0.001). Similar trends were observed for estradiol and free estradiol and, in inverse, for SHBG.These associations may, in part, explain the positive associations between overweight/obesity and a sedentary lifestyle on breast cancer risk.

Obesity and components of energy imbalance, that is, excessive energy intake and suboptimal levels of physical activity, are established risk factors for cancer incidence. Accumulating evidence suggests that these factors also may be important after the diagnosis of cancer and influence the course of disease, as well as overall health, well-being, and survival. Lifestyle and medical interventions that effectively modify these factors could potentially be harnessed as a means of cancer control. However, for such interventions to be maximally effective and sustainable, broad sweeping scientific discoveries ranging from molecular and cellular advances, to developments in delivering interventions on both individual and societal levels are needed. This review summarizes key discussion topics that were addressed in a recent Institute of Medicine Workshop entitled, "The Role of Obesity in Cancer Survival and Recurrence"; discussions included (i) mechanisms associated with obesity and energy balance that influence cancer progression; (ii) complexities of studying and interpreting energy balance in relation to cancer recurrence and survival; (iii) associations between obesity and cancer risk, recurrence, and mortality; (iv) interventions that promote weight loss, increased physical activity, and negative energy balance as a means of cancer control; and (v) future directions.

Overweight or obese breast cancer patients have a worse prognosis compared with normal-weight patients. This may be attributed to hyperinsulinemia and dysregulation of adipokine levels associated with overweight and obesity. Here, we evaluate whether low levels of adiponectin and a greater level of insulin resistance are associated with breast cancer mortality and all-cause mortality.We measured glucose, insulin, and adiponectin levels in fasting serum samples from 527 women enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between adiponectin and insulin and glucose levels (expressed as the Homeostatic Model Assessment [HOMA] score) represented as continuous measures and median split categories, along with breast cancer mortality and all-cause mortality, using Cox proportional hazards models.Increasing HOMA scores were associated with reduced breast cancer survival (hazard ratio [HR], 1.12; 95% CI, 1.05 to 1.20) and reduced all-cause survival (HR, 1.09; 95% CI, 1.02 to 1.15) after adjustment for possible confounders. Higher levels of adiponectin (above the median: 15.5 μg/mL) were associated with longer breast cancer survival (HR, 0.39; 95% CI, 0.15 to 0.95) after adjustment for covariates. A continuous measure of adiponectin was not associated with either breast cancer-specific or all-cause mortality.Elevated HOMA scores and low levels of adiponectin, both associated with obesity, were associated with increased breast cancer mortality. To the best of our knowledge, this is the first demonstration of the association between low levels of adiponectin and increased breast cancer mortality in breast cancer survivors.

Although studies have shown that physically active breast cancer survivors have lower all-cause mortality, the association between change in physical activity from before to after diagnosis and mortality is not clear. We examined associations among pre- and postdiagnosis physical activity, change in pre- to postdiagnosis physical activity, and all-cause and breast cancer-specific mortality in postmenopausal women. A longitudinal study of 4,643 women diagnosed with invasive breast cancer after entry into the Women's Health Initiative study of postmenopausal women. Physical activity from recreation and walking was determined at baseline (prediagnosis) and after diagnosis (assessed at the 3 or 6 years post-baseline visit). Women participating in 9 MET-h/wk or more (∼ 3 h/wk of fast walking) of physical activity before diagnosis had a lower all-cause mortality (HR = 0.61; 95% CI, 0.44-0.87; P = 0.01) compared with inactive women in multivariable adjusted analyses. Women participating in ≥ 9 or more MET-h/wk of physical activity after diagnosis had lower breast cancer mortality (HR = 0.61; 95% CI, 0.35-0.99; P = 0.049) and lower all-cause mortality (HR = 0.54; 95% CI, 0.38-0.79; P < 0.01). Women who increased or maintained physical activity of 9 or more MET-h/wk after diagnosis had lower all-cause mortality (HR = 0.67; 95% CI, 0.46-0.96) even if they were inactive before diagnosis. High levels of physical activity may improve survival in postmenopausal women with breast cancer, even among those reporting low physical activity prior to diagnosis. Women diagnosed with breast cancer should be encouraged to initiate and maintain a program of physical activity.

This systematic umbrella review examines and updates the evidence on the relationship between physical activity (PA) and blood pressure (BP) presented in the 2008 Physical Activity Guidelines Advisory Committee Scientific Report.We performed a systematic review to identify systematic reviews and meta-analyses involving adults with normal BP, prehypertension, and hypertension published from 2006 to February 2018.In total, 17 meta-analyses and one systematic review with 594,129 adults ≥18 yr qualified. Strong evidence demonstrates: 1) an inverse dose-response relationship between PA and incident hypertension among adults with normal BP; 2) PA reduces the risk of cardiovascular disease (CVD) progression among adults with hypertension; 3) PA reduces BP among adults with normal BP, prehypertension, and hypertension; and 4) the magnitude of the BP response to PA varies by resting BP, with greater benefits among adults with prehypertension than normal BP. Moderate evidence indicates the relationship between resting BP and the magnitude of benefit does not vary by PA type among adults with normal BP, prehypertension, and hypertension. Limited evidence suggests the magnitude of the BP response to PA varies by resting BP among adults with hypertension. Insufficient evidence is available to determine if factors such as sex, age, race/ethnicity, socioeconomic status, and weight status or the frequency, intensity, time, and duration of PA influence the associations between PA and BP.Future research is needed that adheres to standard BP measurement protocols and classification schemes to better understand the influence of PA on the risk of comorbid conditions, health-related quality of life, and CVD progression and mortality; the interactive effects between PA and antihypertensive medication use; and the immediate BP-lowering benefits of PA.

Impaired glucose regulation is a defining characteristic of type 2 diabetes mellitus (T2DM) pathology and has been linked to increased risk of cognitive impairment and dementia. Although the benefits of aerobic exercise for physical health are well-documented, exercise effects on cognition have not been examined for older adults with poor glucose regulation associated with prediabetes and early T2DM. Using a randomized controlled design, twenty-eight adults (57-83 y old) meeting 2-h tolerance test criteria for glucose intolerance completed 6 months of aerobic exercise or stretching, which served as the control. The primary cognitive outcomes included measures of executive function (Trails B, Task Switching, Stroop, Self-ordered Pointing Test, and Verbal Fluency). Other outcomes included memory performance (Story Recall, List Learning), measures of cardiorespiratory fitness obtained via maximal-graded exercise treadmill test, glucose disposal during hyperinsulinemic-euglycemic clamp, body fat, and fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulin-like growth factor-1, amyloid-β (Aβ40 and Aβ42). Six months of aerobic exercise improved executive function (MANCOVA, p=0.04), cardiorespiratory fitness (MANOVA, p=0.03), and insulin sensitivity (p=0.05). Across all subjects, 6-month changes in cardiorespiratory fitness and insulin sensitivity were positively correlated (p=0.01). For Aβ42, plasma levels tended to decrease for the aerobic group relative to controls (p=0.07). The results of our study using rigorous controlled methodology suggest a cognition-enhancing effect of aerobic exercise for older glucose intolerant adults. Although replication in a larger sample is needed, our findings potentially have important therapeutic implications for a growing number of adults at increased risk of cognitive decline.

The 2018 Physical Activity Guidelines Advisory Committee Scientific Report provides the evidence base for the Physical Activity Guidelines for Americans, 2nd Edition.The 2018 Physical Activity Guidelines Advisory Committee addressed 38 questions and 104 subquestions selected for their public health relevance, potential to inform public policies and programs, maturity of the relevant science, and applicability to the general US population. Rigorous systematic literature searches and literature reviews were performed using standardized methods.Newly described benefits of physical activity include reduced risk of excessive weight gain in children and adults, incidence of 6 types of cancer, and fall-related injuries in older people. Physical activity is associated with enhanced cognitive function and mental health across the life span, plus improved mental health and physical function. There is no threshold that must be exceeded before benefits begin to accrue; the accrual is most rapid for the least active individuals. Sedentary time is directly associated with elevated risk of all-cause and cardiovascular mortality, incident cardiovascular disease and type 2 diabetes, and selected cancer sites. A wide range of intervention strategies have demonstrated success in increasing physical activity.The 2018 Physical Activity Guidelines Advisory Committee Scientific Report provides compelling new evidence to inform physical activity recommendations, practice, and policy.

This study aimed to determine the prevalence of sarcopenia and examine whether sarcopenia was associated with overall and breast-cancer-specific mortality in a cohort of women diagnosed with breast cancer (stages I–IIIA). A total of 471 breast cancer patients from western Washington State and New Mexico who participated in the prospective Health, Eating, Activity, and Lifestyle Study were included in this study. Appendicular lean mass was measured using dual X-ray absorptiometry scans at study inception, on average, 12 months after diagnosis. Sarcopenia was defined as two standard deviations below the young healthy adult female mean of appendicular lean mass divided by height squared (<5.45 kg/m2). Total and breast-cancer-specific mortality data were obtained from Surveillance Epidemiology and End Results registries. Multivariable Cox proportional hazard models assessed the associations between sarcopenia and mortality. Median follow-up was 9.2 years; 75 women were classified as sarcopenic, and among 92 deaths, 46 were attributed to breast cancer. In multivariable models that included age, race-ethnicity/study site, treatment type, comorbidities, waist circumference, and total body fat percentage, sarcopenia was independently associated with overall mortality (hazard ratio (HR) = 2.86; 95 % CI, 1.67–4.89). Sarcopenic women had increased risk of breast-cancer-specific mortality, although the association was not statistically significant (HR = 1.95, 95 % CI, 0.87–4.35). Sarcopenia is associated with an increased risk of overall mortality in breast cancer survivors and may be associated with breast-cancer-specific mortality. The development of effective interventions to maintain and/or increase skeletal muscle mass to improve prognosis in breast cancer survivors warrants further study. Such interventions may help breast cancer patients live longer.

Abstract Obese and sedentary persons have increased risk for cancer; inflammation is a hypothesized mechanism. We examined the effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in 439 women. Overweight and obese postmenopausal women were randomized to 1-year: caloric restriction diet (goal of 10% weight loss, N = 118), aerobic exercise (225 min/wk of moderate-to-vigorous activity, N = 117), combined diet + exercise (N = 117), or control (N = 87). Baseline and 1-year high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA), interleukin-6 (IL-6), leukocyte, and neutrophil levels were measured by investigators blind to group. Inflammatory biomarker changes were compared using generalized estimating equations. Models were adjusted for baseline body mass index (BMI), race/ethnicity, and age. Four hundred and thirty-eight (N = 1 in diet + exercise group was excluded) were analyzed. Relative to controls, hs-CRP decreased by geometric mean (95% confidence interval, P value): 0.92 mg/L (0.53–1.31, P &amp;lt; 0.001) in the diet and 0.87 mg/L (0.51–1.23, P &amp;lt; 0.0001) in the diet + exercise groups. IL-6 decreased by 0.34 pg/mL (0.13–0.55, P = 0.001) in the diet and 0.32 pg/mL (0.15–0.49, P &amp;lt; 0.001) in the diet + exercise groups. Neutrophil counts decreased by 0.31 × 109/L (0.09–0.54, P = 0.006) in the diet and 0.30 × 109/L (0.09–0.50, P = 0.005) in the diet + exercise groups. Diet and diet + exercise participants with 5% or more weight loss reduced inflammatory biomarkers (hs-CRP, SAA, and IL-6) compared with controls. The diet and diet + exercise groups reduced hs-CRP in all subgroups of baseline BMI, waist circumference, CRP level, and fasting glucose. Our findings indicate that a caloric restriction weight loss diet with or without exercise reduces biomarkers of inflammation in postmenopausal women, with potential clinical significance for cancer risk reduction. Cancer Res; 72(9); 2314–26. ©2012 AACR.

Primary malignant bone sarcomas (MBS) are rare and there are few studies examining their incidence and outcome. Here, the incidence and survival of all subtypes of MBS registered in England between 1979 and 2007 were analysed from patient registry data held by the National Cancer Intelligence Network (NCIN). Over 11,002 new cases of MBS were registered, an average of 379 per year. There was no change in incidence demonstrated over the study period (p = 0.08). Although a peak incidence is observed in adolescence, approximately half of MBS are diagnosed in patients over 50 years. An improvement in outcome of MBS was observed between those patients registered from 1979 to 1983 and 1983 to 1987 (p < 0.0001), but there has been no improvement since. In the most recent period studied (patients diagnosed 1998-2002) 5-year survival was 55% in Ewing sarcoma, 70% in chondrosarcoma, 56% in chordoma and 43% in osteosarcoma. Patients diagnosed with osteosarcoma over the age of 40 years or with a non-extremity tumour have a significantly inferior outcome; 22% 5-year survival >40 years compared with 53% <40 years (p < 0.0001) and 16% non-extremity tumour compared to 48% extremity tumour (p < 0.0001). This population-based study has allowed us to confidently define the English incidence and survival rates of both the commoner bone tumours such as osteosarcoma, and rarer entities such as chordoma as well as groups with inferior outcome. The lack of significant improvement over recent decades for these diseases is cause for concern and further research.

C-reactive protein (CRP) and Serum amyloid A protein (SAA) increases with systemic inflammation and are related to worse survival for breast cancer survivors. This study examines the association between percent body fat and SAA and CRP and the potential interaction with NSAID use and weight change.Participants included 134 non-Hispanic white and Hispanic breast cancer survivors from the Health, Eating, Activity, and Lifestyle Study. Body fat percentage, measured with Dual Energy X-ray Absorptiometer (DEXA), and circulating levels of CRP and SAA were obtained 30 months after breast cancer diagnosis.Circulating concentrations of CRP and SAA were associated with increased adiposity as measured by DEXA after adjustment for age at 24-months, race/ethnicity, dietary energy intake, weight change, and NSAID use. Survivors with higher body fat ≥35% had significantly higher concentrations of CRP (2.01 mg/l vs. 0.85 mg/l) and SAA (6.21 mg/l vs. 4.21 mg/l) compared to non-obese (body fat < 35%). Women who had gained more than 5% of their body weight since breast cancer diagnosis had non-statistically significant higher geometric mean levels of CRP and SAA. Mean levels of CRP and SAA were higher among obese women who were non-users of NSAIDs compared to current users; the association with SAA reached statistical significance (Mean SAA = 7.24, 95%CI 6.13-8.56 for non-NSAID; vs. 4.87; 95%CI 3.95-6.0 for NSAID users respectively).Breast cancer survivors with higher body fat had higher mean concentrations of CRP and SAA than women with lower body fat. Further assessment of NSAID use and weight control in reducing circulating inflammatory markers among survivors may be worthwhile to investigate in randomized intervention trials as higher inflammatory markers are associated with worse survival.

Triple-negative (ie, estrogen receptor [ER], progesterone receptor, and HER2 negative) breast cancer occurs disproportionately among African American women compared with white women and is associated with a worse prognosis than ER-positive (ER+) breast cancer. Hormonally mediated risk factors may be differentially related to risk of triple-negative and ER+ breast cancers.Using data from 155,723 women enrolled in the Women's Health Initiative, we assessed associations between reproductive and menstrual history, breastfeeding, oral contraceptive use, and subtype-specific breast cancer risk. We used Cox regression to evaluate associations with triple-negative (N = 307) and ER+ (N = 2610) breast cancers and used partial likelihood methods to test for differences in subtype-specific hazard ratios (HRs).Reproductive history was differentially associated with risk of triple-negative and ER+ breast cancers. Nulliparity was associated with decreased risk of triple-negative breast cancer (HR = 0.61, 95% confidence interval [CI] = 0.37 to 0.97) but increased risk of ER+ breast cancer (HR = 1.35, 95% CI = 1.20 to 1.52). Age-adjusted absolute rates of triple-negative breast cancer were 2.71 and 1.54 per 10,000 person-years in parous and nulliparous women, respectively; by comparison, rates of ER+ breast cancer were 21.10 and 28.16 per 10,000 person-years in the same two groups. Among parous women, the number of births was positively associated with risk of triple-negative disease (HR for three births or more vs one birth = 1.46, 95% CI = 0.82 to 2.63) and inversely associated with risk of ER+ disease (HR = 0.88, 95% CI = 0.74 to 1.04). Ages at menarche and menopause were modestly associated with risk of ER+ but not triple-negative breast cancer; breastfeeding and oral contraceptive use were not associated with either subtype.The association between parity and breast cancer risk differs appreciably for ER+ and triple-negative breast cancers. These findings require further confirmation because the biological mechanisms underlying these differences are uncertain.

Purpose Emerging evidence suggests that metformin may reduce breast cancer incidence, but reports are mixed and few provide information on tumor characteristics. Therefore, we assessed associations among diabetes, metformin use, and breast cancer in postmenopausal women participating in Women's Health Initiative clinical trials. Patients and Methods In all, 68,019 postmenopausal women, including 3,401 with diabetes at study entry, were observed over a mean of 11.8 years with 3,273 invasive breast cancers diagnosed. Diabetes incidence status was collected throughout follow-up, with medication information collected at baseline and years 1, 3, 6, and 9. Breast cancers were confirmed by review of central medical records and pathology reports. Cox proportional hazards regression, adjusted for breast cancer risk factors, compared breast cancer incidence in women with diabetes who were metformin users or nonusers with breast cancer incidence in women without diabetes. Results Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04). Women with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio [HR], 1.16; 95% CI, 0.93 to 1.45), and women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2. Conclusion Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention.

The purpose of the present study was to systematically review the complex associations between energy balance-related factors and breast cancer risk, for which previous evidence has suggested different associations in the life course of women and by hormone receptor (HR) status of the tumor.Relevant publications on adulthood physical activity, sedentary behavior, body mass index (BMI), waist and hip circumferences, waist-to-hip ratio, and weight change and pre- and postmenopausal breast cancer risk were identified in PubMed up to 30 April 2017. Random-effects meta-analyses were conducted to summarize the relative risks across studies.One hundred and twenty-six observational cohort studies comprising over 22,900 premenopausal and 103,000 postmenopausal breast cancer cases were meta-analyzed. Higher physical activity was inversely associated with both pre- and postmenopausal breast cancers, whereas increased sitting time was positively associated with postmenopausal breast cancer. Although higher early adult BMI (ages 18-30 years) was inversely associated with pre- and postmenopausal breast cancers, adult weight gain and greater body adiposity increased breast cancer risk in postmenopausal women, and the increased risk was evident for HR+ but not HR- breast cancers, and among never but not current users of postmenopausal hormones. The evidence was less consistent in premenopausal women. There were no associations with adult weight gain, inverse associations with adult BMI (study baseline) and hip circumference, and non-significant associations with waist circumference and waist-to-hip ratio that were reverted to positive associations on average in studies accounting for BMI. No significant associations were observed for HR-defined premenopausal breast cancers.Better understanding on the impact of these factors on pre- and postmenopausal breast cancers and their subtypes along the life course is needed.

Purpose: Overweight and obese women with breast cancer have poorer survival compared with thinner women. One possible reason is that breast cancer survivors with higher degrees of adiposity have higher concentrations of tumor-promoting hormones. This study examined the association between adiposity and concentrations of estrogens, androgens, and sex hormone–binding globulin (SHBG) in a population-based sample of postmenopausal women with breast cancer. Methods: We studied the associations between body mass index (BMI), body fat mass, and percent body fat, measured by dual-energy x-ray absorptiometry scan, waist circumference, and waist-to-hip circumference ratio, with concentrations of estrone, estradiol, testosterone, SHBG, dehydroepiandrosterone sulfate, free estradiol, and free testosterone in 505 postmenopausal women in western Washington and New Mexico with incident stage 0 to IIIA breast cancer. Blood and adiposity measurements were performed between 4 and 12 months after diagnosis. Results: Obese women (BMI ≥ 30) had 35% higher concentrations of estrone and 130% higher concentrations of estradiol compared with lighter-weight women (BMI &lt; 22.0; P = .005 and .002, respectively). Similar associations were observed for body fat mass, percent body fat, and waist circumference. Testosterone concentrations also increased with increasing levels of adiposity (P = .0001). Concentrations of free estradiol and free testosterone were two to three times greater in overweight and obese women compared with lighter-weight women (P = .0001). Conclusion: These data provide information about potential hormonal explanations for the association between adiposity and breast cancer prognosis. These sex hormones may be useful biomarkers for weight loss intervention studies in women with breast cancer.

Limited information is available from large clinical investigations about the agreement among sources of diagnoses for endpoints. The authors used data from the Women's Health Initiative clinical trials and observational study from January 1994 to November 2000 to evaluate the agreement among self-report, hospital discharge codes, and two different levels of physician review of medical records for cardiovascular endpoints. For myocardial infarction, stroke, pulmonary embolism, and venous thrombosis, the agreement of hospital discharge codes or self-report with review by study physicians at clinical centers was substantial (kappa = 0.64-0.84). For coronary revascularization, agreement among these sources of information was substantial to almost perfect (kappa = 0.79-0.92), but for angina, congestive heart failure, and peripheral vascular disease, concordance was only fair to moderate (kappa = 0.37-0.56), indicating that these endpoints remain difficult to classify reliably. Agreement between physician adjudicators at clinical centers and central physician adjudicators was substantial to almost perfect (kappa = 0.67-0.94). The findings also suggest that, for the endpoint of myocardial infarction, physician review of events with hospital discharge codes for angina and congestive heart failure is an important source of validated events, and for stroke, review of all events with cerebrovascular codes is important.

Cancer survivors are often highly motivated to seek information about food choices, physical activity, dietary supplement use, and complementary nutritional therapies to improve their treatment outcomes, quality of life, and survival. To address these concerns, the American Cancer Society (ACS) convened a group of experts in nutrition, physical activity, and cancer to evaluate the scientific evidence and best clinical practices related to optimal nutrition and physical activity after the diagnosis of cancer. This report summarizes their findings and is intended to present health care providers with the best possible information on which to help cancer survivors and their families make informed choices related to nutrition and physical activity. The report discusses nutrition and physical activity issues during the phases of cancer treatment and recovery, living after recovery from treatment, and living with advanced cancer; selected nutritional and physical activity issues such as body weight, food choices, and complementary and alternative nutritional options; and selected issues related to breast, colorectal, lung, prostate, head and neck, and upper gastrointestinal cancers. In addition, handouts containing commonly asked questions and answers and a resource list are provided for survivors and families. Tables that grade the scientific evidence for benefit versus harm related to nutrition and physical activity for breast, colorectal, lung, and prostate cancers are also included for this growing body of knowledge to provide guidance for informed decision making and to identify areas for future research.

The American Cancer Society (ACS) has set aggressive challenge goals for the nation to decrease cancer incidence and mortality—and to improve the quality of life of cancer survivors—by the year 2015. To address these critical goals, the ACS publishes the Nutrition and Physical Activity Guidelines to serve as a foundation for its communication, policy, and community strategies and ultimately, to affect dietary and physical activity patterns among Americans. These guidelines, published every five years, are developed by a national panel of experts in cancer research, prevention, epidemiology, public health, and policy, and as such, they represent the most current scientific evidence related to dietary and activity patterns and cancer risk. The American Cancer Society guidelines include recommendations for individual choices regarding diet and physical activity patterns, but those choices occur within a community context that either facilitates or interferes with healthy behaviors. Therefore, this committee presents one key recommendation for community action to accompany the four recommendations for individual choices for nutrition and physical activity to reduce cancer risk. This recommendation for community action underscores just how important community measures are to the support of healthy behaviors by means of increasing access to healthful food choices and opportunities to be physically active. The ACS guidelines are consistent with guidelines from the American Heart Association for the prevention of coronary heart disease as well as for general health promotion, as defined by the Department of Health and Human Services' 2000 Dietary Guidelines for Americans.1,2

Increased mammographic density reduces the sensitivity of screening mammography, is associated with increased breast cancer risk, and may be hormone related. We assessed the effect of estrogen-plus-progestin therapy on mammographic density.In a racially and ethnically diverse ancillary study of the Women's Health Initiative, we examined data from 413 postmenopausal women who had been randomly assigned to receive daily combined conjugated equine estrogens (0.625 mg) plus medroxyprogesterone acetate (i.e., progestin; 2.5 mg) (n = 202) or daily placebo (n = 211). We assessed the effect of estrogen plus progestin on measured mammographic percent density and abnormal findings over a 1-year and 2-year period. All tests of statistical significance were two-sided and were based on F tests or t tests from mixed-effects models.Mean mammographic percent density increased by 6.0% at year 1, compared with baseline, in the estrogen-plus-progestin group but decreased by 0.9% in the placebo group (difference = 6.9%, 95% confidence interval [CI] = 5.3% to 8.5%; P < .001). The mean changes in mammographic density persisted but were attenuated slightly after 2 years, with an absolute increase of 4.9% in the estrogen-plus-progestin group and a decrease of 0.8% in the placebo group (difference = 5.7%, 95% CI = 4.3% to 7.3%; P < .001). These effects were consistent across racial/ethnic groups but were higher among women aged 70-79 years in the estrogen-plus-progestin group (mean increase at year 1 = 11.6%) than in the placebo group (mean decrease at year 1 = 0.1%) (difference of the means = 11.7%, 95% CI = 8.2% to 15.4%; P < .001, comparing across age groups). At year 1, women who were adherent to treatment in the estrogen-plus-progestin group had a mean increase in density of 7.7% (95% CI = 5.9% to 9.5%), and women in the placebo group had a mean decrease in density of 1.1% (95% CI = 0.3% to 1.9%). Use of estrogen plus progestin was associated with an increased risk of having an abnormal mammogram at year 1 (relative risk = 3.9, 95% CI = 1.5 to 10.2; P = .003), compared with placebo, that was not explained by an increase in density.Use of up to 2 years of estrogen plus progestin was associated with increases in mammographic density.

A key determinant of breast cancer outcome in any population is the degree to which cancers are detected at early stages of disease. Populations in which cancers are detected at earlier stages have lower breast cancer mortality rates. The Breast Health Global Initiative (BHGI) held its third Global Summit in Budapest, Hungary in October 2007, bringing together internationally recognized experts to address the implementation of breast healthcare guidelines for early detection, diagnosis, and treatment in low- and middle-income countries (LMCs). A multidisciplinary panel of experts specifically addressed the implementation of BHGI guidelines for the early detection of disease as they related to resource allocation for public education and awareness, cancer detection methods, and evaluation goals. Public education and awareness are the key first steps, because early detection programs cannot be successful if the public is unaware of the value of early detection. The effectiveness and efficiency of screening modalities, including screening mammography, clinical breast examination (CBE), and breast self-examination, were reviewed in the context of resource availability and population-based need by the panel. Social and cultural barriers should be considered when early detection programs are being established, and the evaluation of early detection programs should include the use of well developed, methodologically sound process metrics to determine the effectiveness of program implementation. The approach and scope of any screening program will determine the success of any early detection program as measured by cancer stage at diagnosis and will drive the breadth of resource allocation needed for program implementation.

The European Intergroup Cooperative Ewing's Sarcoma Study investigated whether cyclophosphamide has a similar efficacy as ifosfamide in standard-risk (SR) patients and whether the addition of etoposide improves survival in high-risk (HR) patients.SR patients (localized tumors, volume <100 mL) were randomly assigned to receive four courses of vincristine, dactinomycin, ifosfamide, and doxorubicin (VAIA) induction therapy followed by 10 courses of either VAIA or vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA; cyclophosphamide replacing ifosfamide). HR patients (volume >or=100 mL or metastases) were randomly assigned to receive 14 courses of either VAIA or VAIA plus etoposide (EVAIA). Outcome measures were event-free survival (EFS; defined as the time to first recurrence, progression, second malignancy, or death) and overall survival (OS).A total of 647 patients were randomly assigned: 79 SR patients were assigned to VAIA, 76 SR patients were assigned to VACA, 240 HR were assigned to VAIA, and 252 HR patients were assigned to EVAIA. The median follow-up was 8.5 years. In the SR group, the hazard ratios (VACA v VAIA) for EFS and OS were 0.91 (95% CI, 0.55 to 1.53) and 1.08 (95% CI, 0.58 to 2.03), respectively. There was a higher incidence of hematologic toxicities in the VACA arm. In the HR group, the EFS and OS hazard ratios (EVAIA v VAIA) indicated a 17% reduction in the risk of an event (95% CI, -35% to 5%; P = .12) and 15% reduction in dying (95% CI, -34% to 10%), respectively. The effect seemed greater among patients without metastases (hazard ratio = 0.79; P = .16) than among those with metastases (hazard ratio = 0.96; P = .84).Cyclophosphamide seemed to have a similar effect on EFS and OS as ifosfamide in SR patients but was associated with increased toxicity. In HR patients, the addition of etoposide seemed to be beneficial.

To assess the extent to which prior hormone therapy modifies the breast cancer risk found with estrogen plus progestin (E+P) in the Women's Health Initiative (WHI) randomized trial.Subgroup analyses of prior hormone use on invasive breast cancer incidence in 16,608 postmenopausal women in the WHI randomized trial of E+P over an average 5.6 years of follow-up.Small but statistically significant differences were found between prior HT users and non-users for most breast cancer risk factors but Gail risk scores were similar. Duration of E+P use within the trial (mean 4.4 years, S.D. 2.0) did not vary by prior use. Among 4311 prior users, the adjusted hazard ratio (HR) for E+P versus placebo was 1.96 (95% confidence interval [CI]: 1.17-3.27), significantly different (p=0.03) from that among 12,297 never users (HR 1.02; 95% CI: 0.77-1.36). The interaction between study arm and follow-up time was significant overall (p=0.01) and among never users (p=0.02) but not among prior users (p=0.10). The cumulative incidence over time for the E+P and placebo groups appeared to cross after about 3 years in prior users, and after about 5 years in women with no prior use. No interaction was found with duration (p=0.08) or recency of prior use (p=0.17). Prior hormone use significantly increased the E+P hazard ratio for larger, more advanced tumors.A safe interval for combined hormone use could not be reliably defined with these data. However, the significant increase in breast cancer risk in the trial overall after only 5.6 years of follow-up, initially concentrated in women with prior hormone exposure, but with increasing risk over time in women without prior exposure, suggests that durations only slightly longer than those in the WHI trial are associated with increased risk of breast cancer. Longer-term exposure and follow-up data are needed.

Journal Article Occupational Exposure to Electromagnetic Fields and Breast Cancer in Men Get access Paul A. Demers, Paul A. Demers 1Department of Epidemiology, University of WashingtonSeattle, WA Search for other works by this author on: Oxford Academic PubMed Google Scholar David B. Thomas, David B. Thomas 1Department of Epidemiology, University of WashingtonSeattle, WA2Fred Hutchinson Cancer Research CenterSeattle, WA Reprint requests to David B. Thomas, Program in Epidemiology, MP 474, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104. Search for other works by this author on: Oxford Academic PubMed Google Scholar Karin A. Rosenblatt, Karin A. Rosenblatt 1Department of Epidemiology, University of WashingtonSeattle, WA2Fred Hutchinson Cancer Research CenterSeattle, WA Search for other works by this author on: Oxford Academic PubMed Google Scholar L. Margarita Jimenez, L. Margarita Jimenez 1Department of Epidemiology, University of WashingtonSeattle, WA2Fred Hutchinson Cancer Research CenterSeattle, WA Search for other works by this author on: Oxford Academic PubMed Google Scholar Anne McTiernan, Anne McTiernan 2Fred Hutchinson Cancer Research CenterSeattle, WA Search for other works by this author on: Oxford Academic PubMed Google Scholar Helge Stalsberg, Helge Stalsberg 3University of TromsøTromsø, Norway Search for other works by this author on: Oxford Academic PubMed Google Scholar Annette Stemhagen, Annette Stemhagen 4New Jersey Department of HealthTrenton, NJ Search for other works by this author on: Oxford Academic PubMed Google Scholar W. Douglas Thompson, W. Douglas Thompson 5Department of Applied Medical Sciences, University of Southern MainePortland, ME Search for other works by this author on: Oxford Academic PubMed Google Scholar Mary G. McCrea Curnen, Mary G. McCrea Curnen 6Department of Epidemiology and Public Health, Yale UniversityNew Haven, CT Search for other works by this author on: Oxford Academic PubMed Google Scholar William Satariano, William Satariano 7Michigan Cancer FoundationDetroit. MI Search for other works by this author on: Oxford Academic PubMed Google Scholar ... Show more Donald F. Austin, Donald F. Austin 8Cancer Epidemiology Unit, California Department of Health ServicesEmeryville, CA Search for other works by this author on: Oxford Academic PubMed Google Scholar Peter Isacson, Peter Isacson 9State Health Registry of lowalowa City, IA Search for other works by this author on: Oxford Academic PubMed Google Scholar Raymond S. Greenberg, Raymond S. Greenberg 10School of public Health, Emory UniversityAtlanta, GA Search for other works by this author on: Oxford Academic PubMed Google Scholar Charles Key, Charles Key 11New Mexico Tumor RegistryAlbuquerque, NM Search for other works by this author on: Oxford Academic PubMed Google Scholar Laurence N. Kolonel, Laurence N. Kolonel 12Epidemiology Program, Cancer Research Center of HawaiiHonolulu, HI Search for other works by this author on: Oxford Academic PubMed Google Scholar Dee W. West Dee W. West 13Northern California Cancer CenterAlameda, CA Search for other works by this author on: Oxford Academic PubMed Google Scholar American Journal of Epidemiology, Volume 134, Issue 4, 15 August 1991, Pages 340–347, https://doi.org/10.1093/oxfordjournals.aje.a116095 Published: 15 August 1991 Article history Received: 11 February 1991 Revision received: 26 April 1991 Published: 15 August 1991

Purpose We examined how an aerobic exercise intervention influenced circulating estradiol, estrone, sex hormone–binding globulin (SHBG), androstenedione, and testosterone levels, which may be involved in the association between physical activity and breast cancer risk. Methods A two-center, two-arm randomized controlled trial of exercise was conducted in 320 postmenopausal, sedentary women age 50 to 74 years. Participants were randomly assigned to a 1-year aerobic exercise intervention of 225 min/wk (n = 160) or to a control group who maintained their usual level of activity (n = 160). Baseline, 6-month, and 12-month assessments of estrone, estradiol, androstenedione, and testosterone were quantified by radioimmunoassay after extraction, and SHBG was quantified by an immunometric assay. Intent-to-treat analyses were performed using linear mixed models. Results Blood data were available on 309 women (96.6%) at 12 months. Women in the intervention group exercised an average of 3.6 d/wk for 178 min/wk. At 12 months, statistically significant reductions in estradiol (treatment effect ratio [TER] = 0.93; 95% CI, 0.88 to 0.98) and free estradiol (TER = 0.91; 95% CI, 0.87 to 0.96) and increases in SHBG (TER = 1.04; 95% CI, 1.02 to 1.07) were observed in the exercise group compared with the control group. No significant differences in estrone, androstenedione, and testosterone levels were observed between exercisers and controls at 12 months. Conclusion This trial found that previously sedentary postmenopausal women can adhere to a moderate- to vigorous-intensity exercise program that results in changes in estradiol and SHBG concentrations that are consistent with a lower risk for postmenopausal breast cancer.

Diet, physical activity, and weight may affect prognosis among women who are diagnosed with breast or gynecologic cancer. Observational studies show associations between being overweight or obese and weight gain with several measures of reduced prognosis in women with breast cancer and some suggestion of poor prognosis in underweight women. Observational studies have shown an association between higher levels of physical activity and improved breast cancer–specific and all-cause mortality, although a dose-response relationship has not been established. One large randomized controlled trial reported increased disease-free survival after a mean of 5 years in patients with breast cancer randomly assigned to a low-fat diet versus control. However, another trial of similar size found no effect from a high vegetable/fruit, low-fat diet on breast cancer prognosis. The few reported studies suggest that obesity negatively affects endometrial cancer survival, while the limited data are mixed for associations of weight with ovarian cancer prognosis. Insufficient data exist for assessing associations of weight, physical activity, or diet with prognosis in other gynecologic cancers. Associations of particular micronutrient intake and alcohol use with prognosis are not defined for any of these cancers. The effects of dietary weight loss and increase in physical activity on survival or recurrence in breast and gynecologic cancers are not yet established, and randomized controlled trials are needed for definitive data.

The effect of national exercise recommendations on adiposity is unknown and may differ by sex. We examined long-term effects of aerobic exercise on adiposity in women and men.This was a 12-month randomized, controlled clinical trial testing exercise effect on weight and body composition in men (N = 102) and women (N = 100). Sedentary/unfit persons, 40 to 75 years old, were recruited through physician practices and media. The intervention was facility- and home-based moderate-to-vigorous intensity aerobic activity, 60 min/d, 6 days/wk vs. controls (no intervention).Exercisers exercised a mean 370 min/wk (men) and 295 min/wk (women), and seven dropped the intervention. Exercisers lost weight (women, -1.4 vs. +0.7 kg in controls, p = 0.008; men, -1.8 vs. -0.1 kg in controls, p = 0.03), BMI (women, -0.6 vs. +0.3 kg/m(2) in controls, p = 0.006; men, -0.5 kg/m(2) vs. no change in controls, p = 0.03), waist circumference (women, -1.4 vs. +2.2 cm in controls, p < 0.001; men, -3.3 vs. -0.4 cm in controls, p = 0.003), and total fat mass (women, -1.9 vs. +0.2 kg in controls, p = 0.001; men, -3.0 vs. +0.2 kg in controls, p < 0.001). Exercisers with greater increases in pedometer-measured steps per day had greater decreases in weight, BMI, body fat, and intra-abdominal fat (all p trend < 0.05 in both men and women). Similar trends were observed for increased minutes per day of exercise and for increases in maximal oxygen consumption.These data support the U.S. Department of Agriculture and Institute of Medicine guidelines of 60 min/d of moderate-to-vigorous physical activity.

We analyzed data from the prospective Women's Health Initiative (WHI) Observational Study to examine the effects of regular use of aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs (NSAIDs) on breast cancer risk. We studied a population of 80,741 postmenopausal women between 50 and 79 years of age who reported no history of breast cancer or other cancers (excluding nonmelanoma skin cancer), and we completed a personal baseline interview that elicited comprehensive health information including data on breast cancer risk factors and NSAID use. All of the cases were adjudicated by WHI physicians using pathology reports. Our analysis was based on 1392 confirmed cases of breast cancer. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated with adjustment for age and other breast cancer risk factors. Regular NSAID use (two or more tablets/week) for 5-9 years produced a 21% reduction in the incidence of breast cancer (RR, 0.79; 95% CI, 0.60-1.04); regular NSAID use for 10 or more years produced a 28% reduction (RR, 0.72; CI, 0.56-0.91), and there was a statistically significant inverse linear trend of breast cancer incidence with the duration of NSAID use (P < 0.01). The estimated risk reduction for long-term use of ibuprofen (RR, 0.51; CI, 0.28-0.96) was greater than for aspirin (RR, 0.79; CI, 0.60-1.03). Subgroup analysis by breast cancer risk factors did not result in effect modification. Regular use of acetaminophen (an analgesic agent with little or no anti-inflammatory activity) or low-dose aspirin (<100 mg) was unrelated to the incidence of breast cancer. Our results indicate that the regular use of aspirin, ibuprofen, or other NSAIDs may have a significant chemopreventive effect against the development of breast cancer and underscore the need for clinical trials to confirm this effect.

Purpose Emerging clinical evidence suggests intravenous bisphosphonates may inhibit breast cancer while oral bisphosphonates have received limited evaluation regarding breast cancer influence. Patients and Methods The association between oral bisphosphonate use and invasive breast cancer was examined in postmenopausal women enrolled onto the Women's Health Initiative (WHI). We compared a published hip fracture prediction model, which did not incorporate bone mineral density (BMD), with total hip BMD in 10,418 WHI participants who had both determinations. To adjust for potential BMD difference based on bisphosphonate use, the hip fracture prediction score was included in multivariant analyses as a BMD surrogate. Results Of the 154,768 participants, 2,816 were oral bisphosphonate users at entry (90% alendronate, 10% etidronate). As calculated hip fracture risk score was significantly associated with both BMD (regression line = 0.79 to 0.0478 log predicted fracture; P &lt; .001; r = 0.43) and breast cancer incidence (P = .03), this variable was incorporated into regression analyses to adjust for BMD difference between users and nonusers of bisphopshonate. After 7.8 mean years of follow-up (standard deviation, 1.7), invasive breast cancer incidence was lower in bisphosphonate users (hazard ratio [HR], 0.68; 95% CI, 0.52 to 0.88; P &lt; .01) as was incidence of estrogen receptor (ER) –positive invasive cancers (HR, 0.70; 95% CI, 0.52 to 0.94, P = .02). A similar but not significant trend was seen for ER-negative invasive cancers. The incidence of ductal carcinoma in situ was higher in bisphosphonate users (HR, 1.58; 95% CI, 1.08 to 2.31; P = .02). Conclusion Oral bisphosphonate use was associated with significantly lower invasive breast cancer incidence, suggesting bisphosphonates may have inhibiting effects on breast cancer.

This study examined the effects of exercise on metabolic risk variables insulin, leptin, glucose, and triglycerides in overweight/obese postmenopausal women.Sedentary women (n = 173) who were overweight or obese (BMI > or = 25 kg/m(2) or > or =24 kg/m(2) with > or =33% body fat), 50 to 75 years of age, were randomized to 12 months of exercise (> or =45 minutes of moderate-intensity aerobic activity 5 d/wk) or to a stretching control group. Body composition (DXA) and visceral adiposity (computed tomography) were measured at baseline and 12 months. Insulin, glucose, triglycerides, and leptin were measured at baseline and 3 and 12 months. Insulin resistance was evaluated by the homeostasis model assessment formula. Differences from baseline to follow-up were calculated and compared across groups.Exercisers had a 4% decrease and controls had a 12% increase in insulin concentrations from baseline to 12 months (p = 0.0002). Over the same 12-month period, leptin concentrations decreased by 7% among exercisers compared with remaining constant among controls (p = 0.03). Homeostasis model assessment scores decreased by 2% among exercisers and increased 14% among controls from baseline to 12 months (p = 0.0005). The exercise effect on insulin was modified by changes in total fat mass (trend, p = 0.03), such that the exercise intervention abolished increases in insulin concentrations associated with gains in total fat mass.Regular moderate-intensity exercise can be used to improve metabolic risk variables such as insulin and leptin in overweight/obese postmenopausal women. These results are promising for health care providers providing advice to postmenopausal women for lifestyle changes to reduce risk of insulin resistance, coronary heart disease, and diabetes.

Weight loss resulting from decreased caloric intake raises levels of the orexigenic hormone, ghrelin. Because ingested nutrients suppress ghrelin, increased ghrelin levels in hypophagic weight loss may result from decreased inhibitory input by ingested food, rather than from lost weight. We assessed whether ghrelin levels increase in response to exercise-induced weight loss without decreased caloric intake. We randomized 173 sedentary, overweight, postmenopausal women to an aerobic exercise intervention or stretching control group. At baseline, 3 months, and 12 months, we measured body weight and composition, food intake, cardiopulmonary fitness (maximal oxygen consumption), leptin, insulin, and ghrelin. Complete data were available for 168 women (97%) at 12 months. Exercisers lost 1.4 +/- 0.4 kg (P < 0.05 compared with baseline; P = 0.01 compared with stretchers) and manifested a significant, progressive increase in ghrelin levels, whereas neither measure changed among stretchers. Ghrelin increased 18% in exercisers who lost more than 3 kg (P < 0.001). There was no change in caloric intake in either group and no effect on ghrelin of exercise per se independent of its impact on body weight. In summary, ghrelin levels increase with weight loss achieved without reduced food intake, consistent with a role for ghrelin in the adaptive response constraining weight loss and, thus, in long-term body weight regulation.

Triple-negative breast cancer, characterized by a lack of hormone receptor and HER2 expression, is associated with a particularly poor prognosis. Focusing on potentially modifiable breast cancer risk factors, we examined the relationship between body size, physical activity, and triple-negative disease risk.Using data from 155,723 women enrolled in the Women's Health Initiative (median follow-up, 7.9 years), we assessed associations between baseline body mass index (BMI), BMI in earlier adulthood, waist and hip circumference, waist-hip ratio, recreational physical activity, and risk of triple-negative (n=307) and estrogen receptor-positive (ER+, n=2,610) breast cancers.Women in the highest versus lowest BMI quartile had 1.35-fold (95% CI, 0.92-1.99) and 1.39-fold (95% CI, 1.22-1.58) increased risks of triple-negative and ER+ breast cancers, respectively. Waist and hip circumferences were positively associated with risk of ER+ breast cancer (Ptrend=0.01 for both measures) but were not associated with triple-negative breast cancer. Compared with women who reported no recreational physical activity, women in the highest activity tertile had similarly lower risks of triple-negative and ER+ breast cancers (HR=0.77; 95% CI, 0.51-1.13; and HR=0.85; 95% CI, 0.74-0.98, respectively).Despite biological and clinical differences, triple-negative and ER+ breast cancers are similarly associated with BMI and recreational physical activity in postmenopausal women. The biological mechanisms underlying these similarities are uncertain and these modest associations require further investigation.If confirmed, these results suggest potential ways postmenopausal women might modify their risk of both ER+ and triple-negative breast cancers.

Estrogens and androgens are elevated in obesity and associated with increased postmenopausal breast cancer risk, but the effect of weight loss on these biomarkers is unknown. We evaluated the individual and combined effects of a reduced-calorie weight loss diet and exercise on serum sex hormones in overweight and obese postmenopausal women.We conducted a single-blind, 12-month, randomized controlled trial from 2005 to 2009. Participants (age 50 to 75 years; body mass index > 25.0 kg/m(2), exercising < 100 minutes/wk) were randomly assigned using a computer-generated sequence to (1) reduced-calorie weight loss diet ("diet"; n = 118), (2) moderate- to vigorous-intensity aerobic exercise ("exercise"; n = 117), (3) combined reduced-calorie weight loss diet and moderate- to vigorous-intensity aerobic exercise ("diet + exercise"; n = 117), or (4) control (n = 87). Outcomes were estrone concentration (primary) and estradiol, free estradiol, total testosterone, free testosterone, androstenedione, and sex hormone-binding globulin (SHBG) concentrations (secondary).Mean age and body mass index were 58 years and 30.9 kg/m(2), respectively. Compared with controls, estrone decreased 9.6% (P = .001) with diet, 5.5% (P = .01) with exercise, and 11.1% (P < .001) with diet + exercise. Estradiol decreased 16.2% (P < .001) with diet, 4.9% (P = .10) with exercise, and 20.3% (P < .001) with diet + exercise. SHBG increased 22.4% (P < .001) with diet and 25.8% (P < .001) with diet + exercise. Free estradiol decreased 21.4% (P < .001) with diet and 26.0% (P < .001) with diet + exercise. Free testosterone decreased 10.0% (P < .001) with diet and 15.6% (P < .001) with diet + exercise. Greater weight loss produced stronger effects on estrogens and SHBG.Weight loss significantly lowered serum estrogens and free testosterone, supporting weight loss for risk reduction through lowering exposure to breast cancer biomarkers.

BackgroundNeoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted.Patients and methodsBetween 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m2 and cisplatin 100 mg/m2. Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome.ResultsFive- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3–40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival.ConclusionsLocalised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments.

Background: Despite experimental observations suggesting that 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) have antitumor activity, clinical studies have reached mixed conclusions about the relationship between statin use and breast cancer risk. Methods: To investigate associations between potency, duration of use, and type of statin used and risk of invasive breast cancer, we examined data for 156 351 postmenopausal women who were enrolled in the Women's Health Initiative. Information was collected on breast cancer risk factors and on the use of statins and other lipid-lowering drugs. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical tests were two-sided. Results: Over an average follow-up of 6.7 years, 4383 invasive breast cancers were confirmed by medical record and pathology report review. Statins were used by 11 710 (7.5%) of the cohort. Breast cancer incidence was 4.09 per 1000 person-years (PY) among statin users and 4.28 per 1000 PY among nonusers. In multivariable models, the hazard ratio of breast cancer among users of any statin, compared with nonusers, was 0.91 (95% CI = 0.80 to 1.05, P = .20). There was no trend in risk by duration of statin use, with HR = 0.80 (95% CI = 0.63 to 1.03) for <1 year of use, HR = 0.99 (95% CI = 0.80 to 1.23) for 1–<3 years of use, and HR = 0.94 (95% CI = 0.75 to 1.18) for ≥3 years of use. Hydrophobic statins (i.e., simvastatin, lovastatin, and fluvastatin) were used by 8106 women, and their use was associated with an 18% lower breast cancer incidence (HR = 0.82, 95% CI = 0.70 to 0.97, P = .02). Use of other statins (i.e., pravastatin and atorvastatin) or nonstatin lipid-lowering agents was not associated with breast cancer incidence. Conclusions: Overall statin use was not associated with invasive breast cancer incidence. Our finding that use of hydrophobic statins may be associated with lower breast cancer incidence suggests possible within-class differences that warrant further evaluation.

Growing interest in promoting cross-disciplinary collaboration among health scientists has prompted several federal agencies, including the NIH, to establish large, multicenter initiatives intended to foster collaborative research and training. In order to assess whether these initiatives are effective in promoting scientific collaboration that ultimately results in public health improvements, it is necessary to develop new strategies for evaluating research processes and products as well as the longer-term societal outcomes associated with these programs. Ideally, evaluative measures should be administered over the entire course of large initiatives, including their near-term and later phases. The present study focuses on the development of new tools for assessing the readiness for collaboration among health scientists at the outset (during the first year) of their participation in the National Cancer Institute's Transdisciplinary Research on Energetics and Cancer (TREC) initiative. Indexes of collaborative readiness, along with additional measures of near-term collaborative processes, were administered as part of the TREC Year-One evaluation survey. Additionally, early progress toward scientific collaboration and integration was assessed, using a protocol for evaluating written research products. Results from the Year-One survey and the ratings of written products provide evidence of cross-disciplinary collaboration among participants during the first year of the initiative, and also reveal opportunities for enhancing collaborative processes and outcomes during subsequent phases of the project. The implications of these findings for future evaluations of team science initiatives are discussed.

Obesity and weight gain are negative prognostic factors for breast cancer survival. Physical activity (PA) prevents weight gain and may decrease obesity. Little information exists on PA levels among cancer survivors. We assessed PA, including the proportion of breast cancer survivors engaging in recommended levels, by categories of adiposity, age, disease stage, and ethnicity in 806 women with stage 0-IIIA breast cancer participating in the Health, Eating, Activity, and Lifestyle Study.Black, non-Hispanic white, and Hispanic breast cancer survivors were recruited into the study through Surveillance Epidemiology End Results registries in New Mexico, Western Washington, and Los Angeles County, CA. Types of sports and household activities and their frequency and duration within the third yr after diagnosis were assessed during an in-person interview.Thirty-two percent of breast cancer survivors participated in recommended levels of PA defined as 150 min x wk(-1) of moderate- to vigorous-intensity sports/recreational PA. When moderate-intensity household and gardening activities were included in the definition, 73% met the recommended level of PA. Fewer obese breast cancer survivors met the recommendation than overweight and lean breast cancer survivors (P < 0.05). Fewer black breast cancer survivors met the recommendation compared with non-Hispanic white and Hispanic breast cancer survivors (P < 0.05).Most of the breast cancer survivors were not meeting the PA recommendations proposed for the general adult population. Efforts to encourage and facilitate PA among these women would be an important tool to decrease obesity, prevent postdiagnosis weight gain, and improve breast cancer prognosis.

Although lifestyle interventions targeting multiple lifestyle behaviors are more effective in preventing unhealthy weight gain and chronic diseases than intervening on a single behavior, few studies have compared individual and combined effects of diet and/or exercise interventions on health-related quality of life (HRQOL). In addition, the mechanisms of how these lifestyle interventions affect HRQOL are unknown. The primary aim of this study was to examine the individual and combined effects of dietary weight loss and/or exercise interventions on HRQOL and psychosocial factors (depression, anxiety, stress, social support). The secondary aim was to investigate predictors of changes in HRQOL.This study was a randomized controlled trial. Overweight/obese postmenopausal women were randomly assigned to 12 months of dietary weight loss (n = 118), moderate-to-vigorous aerobic exercise (225 minutes/week, n = 117), combined diet and exercise (n = 117), or control (n = 87). Demographic, health and anthropometric information, aerobic fitness, HRQOL (SF-36), stress (Perceived Stress Scale), depression [Brief Symptom Inventory (BSI)-18], anxiety (BSI-18) and social support (Medical Outcome Study Social Support Survey) were assessed at baseline and 12 months. The 12-month changes in HRQOL and psychosocial factors were compared using analysis of covariance, adjusting for baseline scores. Multiple regression was used to assess predictors of changes in HRQOL.Twelve-month changes in HRQOL and psychosocial factors differed by intervention group. The combined diet + exercise group improved 4 aspects of HRQOL (physical functioning, role-physical, vitality, and mental health), and stress (p ≤ 0.01 vs. controls). The diet group increased vitality score (p < 0.01 vs. control), while HRQOL did not change differently in the exercise group compared with controls. However, regardless of intervention group, weight loss predicted increased physical functioning, role-physical, vitality, and mental health, while increased aerobic fitness predicted improved physical functioning. Positive changes in depression, stress, and social support were independently associated with increased HRQOL, after adjusting for changes in weight and aerobic fitness.A combined diet and exercise intervention has positive effects on HRQOL and psychological health, which may be greater than that from exercise or diet alone. Improvements in weight, aerobic fitness and psychosocial factors may mediate intervention effects on HRQOL.

Journal Article EVIDENCE FOR A PROTECTIVE EFFECT OF LACTATION ON RISK OF BREAST CANCER IN YOUNG WOMEN: RESULTS FROM A CASE-CONTROL STUDY Get access ANNE McTIERNAN, ANNE McTIERNAN 2Present addreas: New York Medid CollegeMB-159, Valhalla, NY 10595. Search for other works by this author on: Oxford Academic PubMed Google Scholar DAVID B. THOMAS DAVID B. THOMAS 1 Reprint requests to Dr. David B. Thomas at this address Search for other works by this author on: Oxford Academic PubMed Google Scholar American Journal of Epidemiology, Volume 124, Issue 3, September 1986, Pages 353–358, https://doi.org/10.1093/oxfordjournals.aje.a114405 Published: 01 September 1986 Article history Received: 02 August 1985 Revision received: 17 January 1986 Published: 01 September 1986

BackgroundObesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic β-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic β-cell dysfunction.

To investigate the effect of a yearlong moderate-intensity aerobic exercise intervention on C-reactive protein (CRP), serum amyloid A (SAA), and interleukin 6 (IL-6) among overweight or obese postmenopausal women.In a randomized controlled trial, 115 postmenopausal, overweight or obese, sedentary women, aged 50-75 yr were randomized to an aerobic exercise intervention of moderate-intensity (60%-75% observed maximal HR), for > or = 45 min x d(-1), 5 d x wk (n = 53), or to a 1-d x wk(-1) stretching control (n = 62), on an intent-to-treat basis. CRP, SAA, and IL-6 were measured at baseline, at 3 months, and at 12 months.From baseline to 12 months, CRP decreased 10% in exercisers and increased 12% in controls (P = 0.01); no effects were observed for SAA and IL-6. Among participants at baseline who were obese (body mass index (BMI) > or = 30 kg x m(-2)) or had abdominal obesity (waist circumference (WC) > or = 88 cm), exercise resulted in a more pronounced reduction in CRP (BMI > or = 30 kg x m(-2), P = 0.002; WC > or = 88 cm, P < 0.0001), borderline for SAA (BMI > or = 30 kg x m(-2), P = 0.08; WC > or = 88 cm, P = 0.04); no intervention effects were observed among women who did not have these characteristics. Overall, weight loss was minimal in the exercise intervention ( approximately 1.8 kg). Linear trends were observed between CRP and 12-month changes in aerobic fitness (Ptrend = 0.006), exercise adherence (Ptrend = 0.004), percentage body fat (Ptrend = 0.002), body weight (Ptrend = 0.002), WC (Ptrend = 0.02), and intra-abdominal fat (Ptrend = 0.03).A moderate-intensity exercise intervention reduced CRP for 12 months among women who were obese at baseline. These findings support the role of exercise in modulating inflammatory processes that are related to increased risk of chronic disease among obese women.

To examine the association between serum C-peptide, a marker of insulin secretion, measured 3 years after a breast cancer diagnosis, and death resulting from all causes and breast cancer.This was a prospective, observational study of 604 women enrolled onto the Health, Eating, Activity, and Lifestyle (HEAL) Study who were diagnosed with local or regional breast cancer between 1995 and 1998 and observed until death or December 31, 2006, whichever came first. The hazard ratio (HR) for all deaths and deaths owing to breast cancer and 95% CIs for the HR were estimated using multivariable stratified Cox regression analyses.Among women without type 2 diabetes, fasting C-peptide levels were associated with an increased risk of death resulting from all causes and from breast cancer. A 1-ng/mL increase in C-peptide was associated with a 31% increased risk of any death (HR = 1.31; 95% CI, 1.06 to 1.63; P = .013) and a 35% increased risk of death as a result of breast cancer (HR = 1.35; 95% CI, 1.02 to 1.87, P = .048). Associations between C-peptide levels and death as a result of breast cancer were stronger in certain subgroups, including women with type 2 diabetes, women with a body mass index less than 25 kg/m(2), women diagnosed with a higher stage of disease, and women whose tumors were estrogen receptor positive.Treatment strategies to reduce C-peptide levels in patients with breast cancer, including dietary-induced weight loss, physical activity, and/or use of insulin-lowering medications, should be explored.

Female residents of western Washington state aged 18-80 years in whom thyroid cancer was diagnosed between January 1974 and December 1979 were interviewed concerning their reproductive histories and their prior use of exogenous estrogens. Their responses were compared with those of a sample of women from the same population, individually matched to cases on telephone prefix. Use of each of several estrogen-containing preparations was associated with a small increased risk of thyroid cancer; parous women who had ever used a lactation suppressant had 1.7 times the risk of parous nonusers (95% confidence interval, 1.1-2.8); ever users of oral contraceptives had 1.6 times the risk of never users (95% confidence interval, 0.98-2.5); and ever users of postmenopausal estrogens had 1.4 times the risk of never users (95% confidence interval, 0.89-2.3). Among the low risk group of women, i.e., those who had never undergone radiation therapy and who had never had a goiter, a history of one or more pregnancies was also associated with a small increase in the risk of thyroid cancer (relative risk = 1.8, 95% confidence interval, 1.1-3.1). However, no increase in risk with increasing duration of use of oral contraceptives or menopausal estrogens or with increasing number of pregnancies was noted. While pregnancy and use of exogenous estrogens have an impact on the production of thyroid-stimulating hormone, their effect on the incidence of thyroid carcinoma, if present at all, appears to be small.Female residents of western Washington state between 18-80 years of age in whom thyroid cancer was diagnosed between January 1974-December 1979 were interviewed concerning their reproductive histories and their prior use of exogenous estrogens. Their responses were compared with those of a sample of women from the same population, individually matched to cases on telephone prefix. Use of each of several estrogen-containing preparations was associated with a small risk of increased thyroid cancer; parous women who had ever used a lactation suppressant had 1.7 times the risk of parous nonusers (95% confidence interval, 1.1-2.8); ever users of oral contraceptives (OCs) had 1.6 times the risk of never users (95% confidence interval, 0.98-25.5); and ever users of postmenopausal estrogens had 1.4 times the risk of never users (95% confidence interval, 0.89-23). Among the low risk group of women; i.e. those who had never undergon radiation therapy and who had never had a goiter, a history of 1 or more pregnancies was also associated with a small increase in the risk of thyroid cancer (relative risk-1.8, 95% confidence interval, 1.1-3.1). However, no increase in risk with increasing duration of OC use of menopausal estrogens or with increasing number of pregnancies was noted. While pregnancy and use of exogenous estrogens have an impact on the production of thyroid-stimulating hormone, their effect on the incidence of thyroid carcinoma, if present at all, appears to be small.

The Women's Health Initiative trial found a modestly increased risk of invasive breast cancer with daily 0.625-mg conjugated equine estrogens plus 2.5-mg medroxyprogesterone acetate, with most evidence among women who had previously received postmenopausal hormone therapy. In comparison, observational studies mostly report a larger risk increase. To explain these patterns, the authors examined the effects of this regimen in relation to both prior hormone therapy and time from menopause to first use of postmenopausal hormone therapy (“gap time”) in the Women's Health Initiative trial and in a corresponding subset of the Women's Health Initiative observational study. Postmenopausal women with a uterus enrolled at 40 US clinical centers during 1993–1998. The authors found that hazard ratios agreed between the two cohorts at a specified gap time and time from hormone therapy initiation. Combined trial and observational study data support an adverse effect on breast cancer risk. Women who initiate use soon after menopause, and continue for many years, appear to be at particularly high risk. For example, for a woman who starts soon after menopause and adheres to this regimen, estimated hazard ratios are 1.64 (95% confidence interval: 1.00, 2.68) over a 5-year period of use and 2.19 (95% confidence interval: 1.56, 3.08) over a 10-year period of use.

Abstract Background: Physical activity is associated with reduced mortality and higher quality of life in breast cancer survivors; however, limited data on the prevalence of activity and long-term trends after diagnosis are available. Methods: A multiethnic cohort of 631 women (18–64 years) with stage 0 to IIIA breast cancer was followed for 10 years. Recreational aerobic activity (MET-h/wk) was ascertained for the year before diagnosis (baseline), 24 months, 5 years, and 10 years after enrollment. Women were classified according to U.S. physical activity guidelines (≥150 min/wk moderate or ≥75 min/wk vigorous activity). The OR for meeting guidelines at 5 and 10 years according to baseline factors was estimated using logistic regression. The change in MET-h/wk was predicted using linear regression. Results: Prediagnosis, 34% of women met physical activity guidelines; 34.0%, 39.5%, and 21.4% met guidelines at 24 months, 5 years, and 10 years after enrollment, respectively. Less than 8% of survivors met guidelines at all follow-up periods. Over 10 years, recreational aerobic activity decreased by a mean ± SD of 4.3 ± 16.2 MET-h/wk. Meeting guidelines pre-diagnosis was strongly associated with meeting guidelines at 5 years [OR (95% confidence interval; CI): 2.76 (1.85–4.1)] and 10 years [OR (95% CI): 3.35 (2.13–5.28)]. No other demographic or prognostic factors were significantly associated with the 10-year change in MET-h/wk. Conclusion: The vast majority of early breast cancer survivors do not meet national exercise recommendations 10 years postdiagnosis. Impact: Physical activity levels are low in breast cancer survivors across the 10 years postdiagnosis; nonetheless, the predictors of activity in this population remain poorly understood. Cancer Epidemiol Biomarkers Prev; 22(6); 1153–61. ©2013 AACR.

Comprehensive lifestyle interventions are effective in preventing diabetes and restoring glucose regulation; however, the key stimulus for change has not been identified and effects in older individuals are not established. The aim of the study was to investigate the independent and combined effects of dietary weight loss and exercise on insulin sensitivity and restoration of normal fasting glucose in middle-aged and older women.Four-arm RCT, conducted between 2005 and 2009 and data analyzed in 2010.439 inactive, overweight/obese postmenopausal women.Women were assigned to: dietary weight loss (n=118); exercise (n=117); exercise+diet (n=117); or control (n=87). The diet intervention was a group-based reduced-calorie program with a 10% weight-loss goal. The exercise intervention was 45 min/day, 5 days/week of moderate-to-vigorous intensity aerobic activity.12-month change in serum insulin, C-peptide, fasting glucose, and whole body insulin resistance (HOMA-IR).A significant improvement in HOMA-IR was detected in the diet (-24%, p<0.001) and exercise+ diet (-26%, p<0.001) groups but not in the exercise (-9%, p=0.22) group compared with controls (-2%); these effects were similar in middle-aged (50-60 years) and older women (aged 60-75 years). Among those with impaired fasting glucose (5.6-6.9 mmol/L) at baseline (n=143; 33%), the odds (95% CI) of regressing to normal fasting glucose after adjusting for weight loss and baseline levels were 2.5 (0.8, 8.4); 2.76 (0.8, 10.0); and 3.1 (1.0, 9.9) in the diet, exercise+diet, and exercise group, respectively, compared with controls.Dietary weight loss, with or without exercise, significantly improved insulin resistance. Older women derived as much benefit as did the younger postmenopausal women.This study is registered at Clinicaltrials.govNCT00470119.

Low concentrations of serum 25-hydroxyvitamin D [25(OH)D] may be associated with cardiometabolic disorders; however, little is known about their relation to intermediate metabolic and lipid markers.We investigated the relation of serum 25(OH)D concentrations to fasting insulin, glucose, dyslipidemia, adiposity, and prevalent metabolic syndrome.We conducted this cross-sectional analysis in 292 postmenopausal women aged 50-79 y in the Women's Health Initiative Calcium-Vitamin D (WHI-CaD) trial. Data were collected from 3 nested case-control studies that measured baseline serum 25(OH)D concentrations. Inverse probability weighting was used to approximate parameter estimates for the WHI-CaD population.In weighted linear regression models adjusted for age, race-ethnicity, month of blood draw, region, case-control status, smoking, alcohol, physical activity, and history of cardiometabolic risk factors, there was an inverse association of serum 25(OH)D with adiposity [body mass index (BMI): β = -1.12 ± 0.30, P = 0.0002; waist circumference: β = -3.57 ± 0.49, P < 0.0001; waist-hip ratio: β = -0.01 ± 0.002, P < 0.0001], triglycerides (β = -0.10 ± 0.02, P < 0.0001), and triglyceride:HDL-cholesterol ratio (β = -0.11 ± 0.03, P = 0.0003). The multivariable-adjusted odds ratio for metabolic syndrome for the highest (≥52 nmol/L) compared with the lowest (<35 nmol/L) tertile of serum 25(OH)D concentrations was 0.28 (95% CI: 0.14, 0.56). Significant associations remained after adjustment for BMI. We observed no significant associations with LDL cholesterol, HDL cholesterol, insulin, glucose, homeostatic model assessment of insulin resistance (HOMA-IR), or homeostatic model assessment of β cell function (HOMA-β).Higher serum 25(OH)D concentrations may be inversely associated with adiposity, triglycerides, triglyceride:HDL-cholesterol ratio, and metabolic syndrome but are not associated with LDL and HDL cholesterol, insulin, glucose, HOMA-IR, or HOMA-β in postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00000611.

To investigate, among women with breast cancer, how postdiagnosis diet quality and the combination of diet quality and recreational physical activity are associated with prognosis. This multiethnic, prospective observational cohort included 670 women diagnosed with local or regional breast cancer. Thirty months after diagnosis, women completed self-report assessments on diet and physical activity and were followed for 6 years. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals for death from any cause and breast cancer death. Women consuming better-quality diets, as defined by higher Healthy Eating Index-2005 scores, had a 60% reduced risk of death from any cause (HRQ4:Q1: 0.40, 95% CI: 0.17, 0.94) and an 88% reduced risk of death from breast cancer (HRQ4:Q1: 0.12, 95% CI: 0.02, 0.99). Compared with inactive survivors consuming poor-quality diets, survivors engaging in any recreational physical activity and consuming better-quality diets had an 89% reduced risk of death from any cause (HR: 0.11, 95% CI: 0.04, 0.36) and a 91% reduced risk of death from breast cancer (HR: 0.09, 95% CI: 0.01, 0.89). Associations observed were independent of obesity status. Women diagnosed with localized or regional breast cancer may improve prognosis by adopting better-quality dietary patterns and regular recreational physical activity. Lifestyle interventions emphasizing postdiagnosis behavior changes are advisable in breast cancer survivors.

Evidence suggests that inflammation may drive fatigue in cancer survivors. Research in healthy populations has shown reduced inflammation with higher dietary intake of ω-3 polyunsaturated fatty acids (PUFAs), which could potentially reduce fatigue. This study investigated fatigue, inflammation, and intake of ω-3 and ω-6 PUFAs among breast cancer survivors.Six hundred thirty-three survivors (mean age, 56 years; stage I to IIIA) participating in the Health, Eating, Activity, and Lifestyle Study completed a food frequency/dietary supplement questionnaire and provided a blood sample assayed for C-reactive protein (CRP) and serum amyloid A (30 months after diagnosis) and completed the Piper Fatigue Scale and Short Form-36 (SF-36) vitality scale (39 months after diagnosis). Analysis of covariance and logistic regression models tested relationships between inflammation and fatigue, inflammation and ω-3 and ω-6 PUFA intake, and PUFA intake and fatigue, controlling for three incremental levels of confounders. Fatigue was analyzed continuously (Piper scales) and dichotomously (SF-36 vitality ≤ 50).Behavioral (P = .003) and sensory (P = .001) fatigue scale scores were higher by increasing CRP tertile; relationships were attenuated after adjustment for medication use and comorbidity. Survivors with high CRP had 1.8 times greater odds of fatigue after full adjustment (P < .05). Higher intake of ω-6 relative to ω-3 PUFAs was associated with greater CRP (P = .01 after full adjustment) and greater odds of fatigue (odds ratio, 2.6 for the highest v lowest intake; P < .05).Results link higher intake of ω-3 PUFAs, decreased inflammation, and decreased physical aspects of fatigue. Future studies should test whether ω-3 supplementation may reduce fatigue among significantly fatigued breast cancer survivors.

To obtain estimates of time to recruit the study sample, retention, facility-based class attendance and home practice for a study of yoga in breast cancer survivors, and its efficacy on fatigue, quality of life (QOL), and weight change. Sixty-three post-treatment stages 0–III borderline overweight and obese (body mass index ≥24 kg/m2) breast cancer survivors were randomly assigned to a 6-month, facility- and home-based viniyoga intervention (n = 32) or a waitlist control group (n = 31). The yoga goal was five practices per week. Primary outcome measures were changes in QOL, fatigue, and weight from baseline to 6 months. Secondary outcomes included changes in waist and hip circumference. It took 12 months to complete recruitment. Participants attended a mean of 19.6 classes and practiced at home a mean of 55.8 times during the 6-month period. At follow-up, 90% of participants completed questionnaires and 87% completed anthropometric measurements. QOL and fatigue improved to a greater extent among women in the yoga group relative to women in the control group, although no differences were statistically significant. Waist circumference decreased 3.1 cm (95% CI, −5.7 and −0.4) more among women in the yoga compared with the control group, with no difference in weight change. This study provides important information regarding recruitment, retention, and practice levels achieved during a 6-month, intensive yoga intervention in overweight and obese breast cancer survivors. Yoga may help decrease waist circumference and improve quality of life; future studies are needed to confirm these results.

Background Recurrence after osteosarcoma usually leads to death; thus prognostic factors for survival are of great importance. Methods Between 1983 and 2002, the European Osteosarcoma Intergroup accrued 1067 patients to 3 randomized controlled trials of pre- and post-operative chemotherapy for patients with resectable non-metastatic high-grade osteosarcoma of the extremity. Control treatment in all trials was doxorubicin 75 mg/m2 and cisplatin 100 mg/m2. The comparators were additional high-dose methotrexate (BO02), T10-based multi-drug regimen (BO03) and G-CSF intensified-DC (BO06). Post-recurrence survival (PRS) was investigated on combined data with standard survival analysis methods. Results Median recurrence-free survival was 31 months; 8 recurrences were reported more than 5 years after the diagnosis. In 564 patients with a recurrence (median 13 months post-randomisation), there was no difference in post-relapse survival between treatment arms. Patients whose disease recurred within 2 years after randomization had a worse prognosis than those recurring after 2 years. Patients with good initial histological response to pre-operative chemotherapy had a better overall survival after recurrence than poor responders. Local relapse was more often reported after limb-saving procedures (2 versus 8%; amputation versus limb-saving), independent of the primary tumour site. Site of first recurrence (local 20%, lung 62%, “other” 19%) affected survival, as patients recurring with non-lung distant metastases only or any combination of local relapse, lung metastases and non-lung metastases (=group “other”) had significantly worse overall survival (local 39%, lung 19%, “other” 9% at 5 years). Conclusions These data describing a large series of patients with recurrent extremity osteosarcoma confirm the relationship between early recurrence and poor survival. There was better PRS in patients after good histological response to pre-operative chemotherapy, or with local-only recurrence.

Substantial observational epidemiological evidence exists that physical activity and weight control are associated with decreased risk of postmenopausal breast cancer. Uncertainty remains regarding several aspects of these associations, including the effect of possible confounding factors on these associations. We present the rationale and design for two randomized controlled trials that can help resolve this uncertainty. In a 5-year prevention trial conducted among women at high risk of breast cancer, the primary endpoint would be breast cancer incidence. For a comparable survivorship trial, the primary endpoint would be the disease-free interval and secondary endpoints would be breast cancer recurrence-free interval, second primary breast cancer, and total invasive plus in situ breast cancer. A set of inclusion and exclusion criteria is proposed for both trials. Intervention goals are the same for both trials. Goals for the weight control intervention would be, for women whose body mass index (BMI) is greater than 25 kg/m(2), to lose 10% of body weight and, for women whose BMI is less than or equal to 25 kg/m(2), to avoid weight gain. The goal for the physical activity intervention would be to achieve and maintain regular participation in a moderate-intensity physical activity program for a total of 150-225 minutes over at least 5 days per week. Sample size calculations are based on alternative assumptions about hazard ratio, adherence, follow-up duration, and power and are presented for the primary prevention and survivorship trials. Although both studies could enhance our understanding of breast cancer etiology and benefit public health, practical considerations, including smaller sample size, ease of recruitment, and reduced likelihood of early termination, favor the survivorship trial at this time.

Physical activity is a known modifiable lifestyle means for reducing postmenopausal breast cancer risk, but the biologic mechanisms are not well understood.Metabolic factors may be involved.In this study, we aimed to determine the effects of exercise on insulin resistance (IR) indicators, IGF1, and adipokines in postmenopausal women.The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-armed randomized controlled trial in postmenopausal, inactive, cancer-free women.A year-long aerobic exercise intervention of 225 min/week (nZ160) was compared with a control group asked to maintain usual activity levels (nZ160).Baseline, 6-and 12-month serum levels of insulin, glucose, IGF1, IGF-binding protein 3 (IGFBP3), adiponectin, and leptin were assayed, and after data collection, homeostasis model assessment of IR (HOMA-IR) scores were calculated.Intentionto-treat analyses were performed using linear mixed models.The treatment effect ratio (TER) of exercisers to controls was calculated.Data were available on 308 (96.3%) women at 6 months and 310 (96.9%) women at 12 months.Across the study period, statistically significant reductions in insulin (TERZ0.87,95% confidence interval (95% CI)Z0.81-0.93),HOMA-IR (TERZ0.86,95% CIZ0.80-0.93),and leptin (TERZ0.82,95% CIZ0.78-0.87),and an increase in the adiponectin/leptin ratio (TERZ1.21,95% CIZ1.13-1.28)were observed in the exercise group compared with the control group.No significant differences were observed for glucose, IGF1, IGFBP3, adiponectin or the IGF1/IGFBP3 ratio.Previously inactive postmenopausal women who engaged in a moderate-to-vigorous intensity exercise program experienced changes in insulin, HOMA-IR, leptin, and adiponectin/leptin that might decrease the risk for postmenopausal breast cancer.

Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations.Overweight/obese postmenopausal women (n = 439) were randomized as follows: (i) a reduced calorie, weight-loss diet (diet; N = 118), (ii) moderate-to-vigorous intensity aerobic exercise (exercise; N = 117), (iii) a combination of a reduced calorie, weight-loss diet and moderate-to-vigorous intensity aerobic exercise (diet + exercise; N = 117), and (iv) control (N = 87). The reduced calorie diet had a 10% weight-loss goal. The exercise intervention consisted of 45 min of moderate-to-vigorous aerobic activity 5 days per week. Adiponectin and leptin levels were measured at baseline and after 12 months of intervention using a radioimmunoassay.Adiponectin increased by 9.5% in the diet group and 6.6% in the diet + exercise group (both P ≤ 0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet + exercise, -40.1%, P < 0.0001; diet, -27.1%, P < 0.0001; exercise, -12.7%, P = 0.005). The results were not influenced by the baseline body mass index (BMI). The degree of weight loss was inversely associated with concentrations of adiponectin (diet, P-trend = 0.0002; diet + exercise, P-trend = 0.0005) and directly associated with leptin (diet, P-trend < 0.0001; diet + exercise, P-trend < 0.0001).Weight loss through diet or diet + exercise increased adiponectin concentrations. Leptin concentrations decreased in all of the intervention groups, but the greatest reduction occurred with diet + exercise. Weight loss and exercise exerted some beneficial effects on chronic diseases via effects on adiponectin and leptin.

This study examined the effect of a yearlong exercise intervention on F2-isoprostane, a specific marker of lipid peroxidation and a general marker of oxidative stress.In a randomized, controlled trial, 173 overweight or obese, postmenopausal, sedentary women were randomized either to an aerobic exercise intervention (60%-75% observed maximal HR) for > or =45 min.d-1, 5 d.wk-1 (n = 87), or to a stretching control group (n = 86), on an intent-to-treat basis. Baseline and 12-month measures included urinary F2-isoprostane, maximal O2 uptake, body weight, body fat percentage, waist circumference, and intra-abdominal fat surface area. Urine samples were available from 172 and 168 women at baseline and 12 months, respectively.During the 12-month study, controls minimally changed maximal O2 uptake (+0.2%) and body weight (+0.1 kg), whereas exercisers increased maximal O2 uptake (+13.6%; P < 0.0001 vs controls) and decreased body weight (-1.3 kg; P = 0.007 vs controls). F2-isoprostane increased slightly among controls (+3.3%) and decreased in exercisers (-6.2%), although the effect was not statistically significant (P = 0.26). In planned subgroup analyses, F2-isoprostane decreased linearly with gain in maximal O2 uptake (Ptrend = 0.005) relative to controls; exercisers who increased maximal O2 uptake by >15% decreased F2-isoprostane by 14.1% (P = 0.005 vs controls). A borderline statistically significant trend was observed between decreased waist circumference and F2-isoprostane (P = 0.06). Similar subgroup analyses by 12-month changes in body fat percentage, weight, and intra-abdominal fat were not statistically significant.These findings suggest that aerobic exercise, when accompanied by relatively marked gains in aerobic fitness, decreases oxidative stress among previously sedentary older women and that these effects occur with minimal change in mass or body composition.

Vitamin D deficiency is associated with obesity; whether repletion supports weight loss and changes obesity-related biomarkers is unknown.We compared 12 mo of vitamin D3 supplementation with placebo on weight, body composition, insulin, and C-reactive protein (CRP) in postmenopausal women in a weight-loss intervention.A total of 218 overweight/obese women (50-75 y of age) with serum 25-hydroxyvitamin D [25(OH)D] ≥10 ng/mL but <32 ng/mL were randomly assigned to weight loss + 2000 IU oral vitamin D3/d or weight loss + daily placebo. The weight-loss intervention included a reduced-calorie diet (10% weight loss goal) and 225 min/wk of moderate-to-vigorous aerobic activity. Mean 12-mo changes in weight, body composition, serum insulin, CRP, and 25(OH)D were compared between groups (intent-to-treat) by using generalized estimating equations.A total of 86% of participants completed the 12-mo measurements. The mean (95% CI) change in 25(OH)D was 13.6 (11.6, 15.4) ng/mL in the vitamin D3 arm compared with -1.3 (-2.6, -0.3) ng/mL in the placebo arm (P < 0.0001). Changes in weight [-7.1 (-8.7, -5.7) compared with -7.4 (-8.1, -5.4) kg], body mass index (in kg/m(2): both -2.8), waist circumference [-4.9 (-6.7, -2.9) compared with -4.5 (-5.6, -2.6) cm], percentage body fat [-4.1 (-4.9, -2.9) compared with -3.5 (-4.5, -2.5)], trunk fat [-4.1 (-4.7, -3.0) compared with -3.7 (-4.3, -2.9) kg], insulin [-2.5 (-3.4, -1.7) compared with -2.4 (-3.3, -1.4) μU/mL], and CRP [-0.9 (-1.2, -0.6) compared with -0.79 (-0.9, -0.4) mg/L] [corrected] were similar between groups (all P > 0.05). Compared with women who achieved 25(OH)D <32 ng/mL, women randomly assigned to vitamin D who became replete (ie, 25(OH)D ≥32 ng/mL) lost more weight [-8.8 (-11.1, -6.9) compared with -5.6 (-7.2, -5.0) kg; P = 0.05], waist circumference [-6.6 (-9.3, -4.3) compared with -2.5 (-4.6, -2.0) cm; P = 0.02], and percentage body fat [-4.7 (-6.1, -3.5) compared with -2.6 (-3.9, -2.2); P = 0.04]. Among women with complete pill counts (97% adherence), the mean decrease in CRP was 1.18 mg/mL (46%) in the vitamin D arm compared with 0.46 mg/mL (25%) in the placebo arm (P = 0.03).Vitamin D3 supplementation during weight loss did not increase weight loss or associated factors compared with placebo; however, women who became replete experienced greater improvements. This trial was registered at clinicaltrials.gov as NCT01240213.

Although pain is common among post-treatment breast cancer survivors, studies that are longitudinal, identify a case definition of clinically meaningful pain, or examine factors contributing to pain in survivors are limited. This study describes longitudinal patterns of pain in long-term breast cancer survivors, evaluating associations of body mass index (BMI), physical activity, sedentary behavior with mean pain severity and above-average pain. Women newly diagnosed with stages 0-IIIA breast cancer (N = 1183) were assessed, on average, 6 months (demographic/clinical characteristics), 30 months (demographics), 40 months (demographics, pain), 5 years (BMI, physical activity, and sedentary behavior), and 10 years (demographics, pain, BMI, physical activity, and sedentary behavior) post-diagnosis. This analysis includes survivors who completed pain assessments 40 months post-diagnosis (N = 801), 10 years post-diagnosis (N = 563), or both (N = 522). Above-average pain was defined by SF-36 bodily pain scores ≥1/2 standard deviation worse than age-specific population norms. We used multiple regression models to test unique associations of BMI, physical activity, and sedentary behavior with pain adjusting for demographic and clinical factors. The proportion of survivors reporting above-average pain was higher at 10 years than at 40 months (32.3 vs. 27.8 %, p < 0.05). Approximately one-quarter of survivors reported improved pain, while 9.0 % maintained above-average pain and 33.1 % reported worsened pain. Cross-sectionally at 10 years, overweight and obese survivors reported higher pain than normal-weight survivors and women meeting physical activity guidelines were less likely to report above-average pain than survivors not meeting these guidelines (p < 0.05). Longitudinally, weight gain (>5 %) was positively associated, while meeting physical activity guidelines was inversely associated, with above-average pain (OR, 95 % CI = 1.76, 1.03-3.01 and 0.40, 0.20-0.84, respectively) (p < 0.05). Weight gain and lack of physical activity place breast cancer survivors at risk for pain long after treatment ends. Weight control and exercise interventions should be tested for effects on long-term pain in these women.

Lymphedema is a potentially debilitating condition that occurs among breast cancer survivors. This study examines the incidence of self-reported lymphedema, timing of lymphedema onset, and associations between sociodemographic, clinical and lifestyle factors and lymphedema risk across racial-ethnic groups using data from a multicenter, multiethnic prospective cohort study of breast cancer survivors, the Health, Eating, Activity and Lifestyle Study.A total of 666 women diagnosed with breast cancer staged as in situ, localized or regional disease at ages 35 to 64 years were recruited through the Surveillance, Epidemiology, and End Results registries in New Mexico (non-Hispanic white and Hispanic white), Los Angeles County (black), and Western Washington (non-Hispanic white) and followed for a median of 10.2 years. We evaluated sociodemographic factors, breast cancer- and treatment-related factors, comorbidities, body mass index (BMI), hormonal factors, and lifestyle factors in relation to self-reported lymphedema by fitting Cox proportional hazards models, estimating hazard ratios (HR) and 95% confidence intervals (CI).Over the follow-up period, 190 women (29%) reported lymphedema. The median time from breast cancer diagnosis to onset of lymphedema was 10.5 months (range: 0.5 to 134.9 months). Factors independently associated with lymphedema were total/modified radical mastectomy (versus partial/less than total mastectomy; HR = 1.37, 95% CI: 1.01 to 1.85), chemotherapy (versus no chemotherapy; HR = 1.48, 95% CI: 1.09 to 2.02), no lymph nodes removed (versus ≥10 lymph nodes removed; HR = 0.17, 95% CI: 0.08 to 0.33), pre-diagnostic BMI ≥30 kg/m2 (versus BMI <25 kg/m2; HR = 1.59, 95% CI: 1.09 to 2.31), and hypertension (versus no hypertension; HR = 1.49, 95% CI: 1.06 to 2.10). After adjusting for demographics and breast cancer- and treatment-related factors, no significant difference in lymphedema risk was observed across racial/ethnic groups. Analyses stratified by race/ethnicity showed that hypertension and chemotherapy were lymphedema risk factors only for black women.Breast cancer patients who have undergone extensive surgery or extensive lymph node dissection, or who have a higher BMI should be closely monitored for detection and treatment of lymphedema. Further studies are needed to understand the roles of chemotherapy and hypertension in the development of lymphedema.

Estrogen plus progestin therapy increases both mammographic density and breast cancer incidence. Whether mammographic density change associated with estrogen plus progestin initiation predicts breast cancer risk is unknown.We conducted an ancillary nested case-control study within the Women's Health Initiative trial that randomly assigned postmenopausal women to daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg or placebo. Mammographic density was assessed from mammograms taken prior to and one year after random assignment for 174 women who later developed breast cancer (cases) and 733 healthy women (controls). Logistic regression analyses included adjustment for confounders and baseline mammographic density when appropriate.Among women in the estrogen plus progestin arm (97 cases/378 controls), each 1% positive change in percent mammographic density increased breast cancer risk 3% (odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01 to 1.06). For women in the highest quintile of mammographic density change (>19.3% increase), breast cancer risk increased 3.6-fold (95% CI = 1.52 to 8.56). The effect of estrogen plus progestin use on breast cancer risk (OR = 1.28, 95% CI = 0.90 to 1.82) was eliminated in this study, after adjusting for change in mammographic density (OR = 1.00, 95% CI = 0.66 to 1.51).We found the one-year change in mammographic density after estrogen plus progestin initiation predicted subsequent increase in breast cancer risk. All of the increased risk from estrogen plus progestin use was mediated through mammographic density change. Doctors should evaluate changes in mammographic density with women who initiate estrogen plus progestin therapy and discuss the breast cancer risk implications.

Adipokines and inflammation may provide a mechanistic link between obesity and postmenopausal breast cancer, yet epidemiologic data on their associations with breast cancer risk are limited. In a case-cohort analysis nested within the Women’s Health Initiative Observational Study, a prospective cohort of postmenopausal women, baseline plasma samples from 875 incident breast cancer case patients and 839 subcohort participants were tested for levels of seven adipokines, namely leptin, adiponectin, resistin, interleukin-6, tumor necrosis factor-α, hepatocyte growth factor, and plasminogen activator inhibitor-1, and for C-reactive protein (CRP), an inflammatory marker. Data were analyzed by multivariable Cox modeling that included established breast cancer risk factors and previously measured estradiol and insulin levels. All statistical tests were two-sided. The association between plasma CRP levels and breast cancer risk was dependent on hormone therapy (HT) use at baseline (Pinteraction = .003). In a model that controlled for multiple breast cancer risk factors including body mass index (BMI), estradiol, and insulin, CRP level was positively associated with breast cancer risk among HT nonusers (hazard ratio for high vs low CRP levels = 1.67, 95% confidence interval = 1.04 to 2.68, Ptrend = .029). None of the other adipokines were statistically significantly associated with breast cancer risk. Following inclusion of CRP, insulin, and estradiol in a multivariable model, the association of BMI with breast cancer was attenuated by 115%. These data indicate that CRP is a risk factor for postmenopausal breast cancer among HT nonusers. Inflammatory mediators, together with insulin and estrogen, may play a role in the obesity–breast cancer relation.

Abstract Purpose: Exercise after breast cancer diagnosis is associated with lower cancer-specific mortality, but the biological mechanisms through which exercise impacts breast cancer are not fully understood. The Pre-Operative Health and Body (PreHAB) Study was a randomized window-of-opportunity trial designed to test the impact of exercise on Ki-67, gene expression, and other biomarkers in women with breast cancer. Experimental Design: Inactive women with newly diagnosed breast cancer were randomized to an exercise intervention or mind–body control group, and participated in the study between enrollment and surgery (mean 29.3 days). Tumor and serum were collected at baseline and surgery. Results: Forty-nine women were randomized (27 exercise, 22 control). At baseline, mean age was 52.6, body mass index was 30.2 kg/m2, and exercise was 49 minutes/week. Exercise participants significantly increased exercise versus controls (203 vs. 23 minutes/week, P &amp;lt; 0.0001). There were no differences in changes of expression of Ki-67, insulin receptor, and cleaved caspase-3 in exercise participants versus controls. KEGG pathway analysis demonstrated significant upregulation of 18 unique pathways between the baseline biopsy and surgical excision in exercise participants and none in control participants (q &amp;lt; 0.1). Top-ranked pathways included several implicated in immunity and inflammation. Exploratory analysis of tumor immune infiltrates demonstrated a trend toward a decrease in FOXP3+ cells in exercise versus control participants over the intervention period (P = 0.08). Conclusions: A window-of-opportunity exercise intervention did not impact proliferation but led to alterations in gene expression in breast tumors, suggesting that exercise may have a direct effect on breast cancer. See related commentary by Koelwyn and Jones, p. 5179

Abstract Previous evidence on postdiagnosis body fatness and mortality after breast cancer was graded as limited‐suggestive. To evaluate the evidence on body mass index (BMI), waist circumference, waist‐hip‐ratio and weight change in relation to breast cancer prognosis, an updated systematic review was conducted. PubMed and Embase were searched for relevant studies published up to 31 October, 2021. Random‐effects meta‐analyses were conducted to estimate summary relative risks (RRs). The evidence was judged by an independent Expert Panel using pre‐defined grading criteria. One randomized controlled trial and 225 observational studies were reviewed (220 publications). There was strong evidence (likelihood of causality: probable) that higher postdiagnosis BMI was associated with increased all‐cause mortality (64 studies, 32 507 deaths), breast cancer‐specific mortality (39 studies, 14 106 deaths) and second primary breast cancer (11 studies, 5248 events). The respective summary RRs and 95% confidence intervals per 5 kg/m 2 BMI were 1.07 (1.05‐1.10), 1.10 (1.06‐1.14) and 1.14 (1.04‐1.26), with high between‐study heterogeneity ( I 2 = 56%, 60%, 66%), but generally consistent positive associations. Positive associations were also observed for waist circumference, waist‐hip‐ratio and all‐cause and breast cancer‐specific mortality. There was limited‐suggestive evidence that postdiagnosis BMI was associated with higher risk of recurrence, nonbreast cancer deaths and cardiovascular deaths. The evidence for postdiagnosis (unexplained) weight or BMI change and all outcomes was graded as limited‐no conclusion. The RCT showed potential beneficial effect of intentional weight loss on disease‐free‐survival, but more intervention trials and well‐designed observational studies in diverse populations are needed to elucidate the impact of body composition and their changes on breast cancer outcomes.

The International Agency for Research on Cancer estimates that 25% of breast cancer cases worldwide are due to overweight/obesity and a sedentary lifestyle. The preponderance of epidemiologic studies indicates that women who engage in 3-4 hours per week of moderate to vigorous levels of exercise have a 30%-40% lower risk for breast cancer than sedentary women. Women who are overweight or obese have a 50%-250% greater risk for postmenopausal breast cancer. Alcohol use, even at moderate levels (two drinks per day) increases risk for both premenopausal and postmenopausal breast cancer. Certain dietary patterns, such as high fat, low vegetables/fruits, low fiber, and high simple carbohydrates, may increase risk, but definitive data are lacking. These lifestyle factors are likely associated with breast cancer etiology through hormonal mechanisms. The worldwide trends of increasing overweight and obesity and decreasing physical activity may lead to an increasing incidence of breast cancer unless other means of risk reduction counteract these effects. Thus, adoption of lifestyle changes by individuals and populations may have a large impact on the future incidence of this disease.

To examine the effects of a moderate-intensity exercise or stretching intervention and changes in fitness, body mass index, or time spent outdoors on self-reported sleep quality and to examine the relationship between the amount and timing of exercise and sleep quality.A randomized intervention trial.A cancer research center in Seattle, Washington.Postmenopausal, overweight or obese, sedentary women not taking hormone replacement therapy, aged 50 to 75 years, and recruited from the Seattle metropolitan area.A yearlong moderate-intensity exercise (n=87) and a low-intensity stretching (n=86) program.Among morning exercisers, those who exercised at least 225 minutes per week had less trouble falling asleep (odds ratio [OR]: 0.3, P < or = .05) compared with those who exercised less than 180 minutes per week. However, among evening exercisers, those who exercised at least 225 minutes per week had more trouble falling asleep (OR: 3.3, P < or = .05) compared to those who exercised less than 180 minutes per week. Stretchers were less likely to use sleep medication (OR = 0.4, P < or = .05) and have trouble falling asleep (OR: 0.7, P < or = .10) during the intervention period compared with baseline. A greater than 10% versus a 1% or less increase in maximum O2 consumption over the year was associated with longer sleep duration (P < or = .05), less frequently falling asleep during quiet activities (P < or = .05), and less use of sleep medication (P < or = .05). Reductions in body mass index and increases in time spent outdoors had inconsistent effects on sleep quality.Both stretching and exercise interventions may improve sleep quality in sedentary, overweight, postmenopausal women. Increased fitness was associated with improvements in sleep. However, the effect of moderate-intensity exercise may depend on the amount of exercise and time of day it is performed.

Women with high circulating estrogen concentrations have an increased risk of breast cancer; thus, it is important to understand factors, including genetic variability, that influence estrogen concentrations. Several genetic polymorphisms that may influence sex hormone concentrations have been identified, including CYP17 (5'-untranslated region T-->C), CYP19 [intron 4 (TTTA)(n = 7-13) and a 3-bp deletion (-3)], CYP1B1 (Val(432)Leu), and COMT (Val(108/158)Met). We examined associations between these polymorphisms and serum concentrations of estrogens, androgens, and sex hormone-binding globulin and urinary concentrations of 2- and 16alpha-hydroxyestrone in 171 postmenopausal women, using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, not taking hormone therapy, and had a body mass index >24.0. Compared with noncarriers, women carrying two CYP19 7r(-3) alleles had 26% lower estrone (P < 0.001), 19% lower estradiol (P = 0.01), 23% lower free estradiol (P = 0.01), and 22% higher sex hormone-binding globulin concentrations (P = 0.06). Compared with noncarriers, women carrying at least one CYP19 8r allele had 20% higher estrone (P = 0.003), 18% higher estradiol (P = 0.02), and 21% higher free estradiol concentrations (P = 0.01). Women with the COMT Met/Met genotype had 28% higher 2-hydroxyestrone (P = 0.08) and 31% higher 16alpha-hydroxyestrone concentrations (P = 0.02), compared with Val/Val women. Few associations were found for CYP17 and CYP1B1 or with serum androgen concentrations. This study provides further evidence that genetic variation may appreciably alter sex hormone concentrations in postmenopausal women not taking hormone therapy.

Abstract Postmenopausal women with elevated circulating androgen concentrations have an increased risk of developing breast cancer, yet interventions to reduce androgen levels have not been identified. We examined the effects of a 12-month moderate intensity exercise intervention on serum androgens. The study was a randomized clinical trial in 173 sedentary, overweight (body mass index ≥ 24.0 kg/m2, body fat &amp;gt; 33%), postmenopausal women, ages 50 to 75 years, not using hormone therapy and living in the Seattle, WA area. The exercise intervention included facility-based and home-based exercise (45 minutes, 5 days per week of moderate intensity sports/recreational exercise). A total of 170 (98.3%) women completed the study, with exercisers averaging 171 minutes per week of exercise. Women in the exercise and control groups experienced similar, nonsignificant declines in most androgens. Among women who lost &amp;gt;2% body fat, testosterone and free testosterone concentrations fell by 10.1% and 12.2% between baseline and 12 months in exercisers compared with a decrease of 1.6% and 8.0% in controls (P = 0.02 and 0.03 compared with exercisers, respectively). Concentrations of testosterone and free testosterone among exercisers who lost between 0.5% and 2% body fat declined by 4.7% and 10.4%. In controls who lost this amount of body fat, concentrations of testosterone and free testosterone declined by only 2.8% and 4.3% (P = 0.03 and 0.01 compared with exercisers, respectively). In summary, given similar levels of body fat loss, women randomized to a 12-month exercise intervention had greater declines in testosterone and free testosterone compared with controls. The association between exercise and breast cancer risk may be partly explained by the effects of exercise on these hormones.

Patients with asthma commonly have other medical problems such as obesity, but it is unclear if obesity independently relates to asthma occurrence.To examine the association between asthma and obesity.We studied enrollees aged 17 to 96 years in region 11 of TRICARE, a military managed health care program encompassing Washington, Oregon, and northern Idaho, using an enrollment questionnaire from January 1997 to December 1998. We performed case-control analyses on 2788 asthma cases and 39 637 controls. From these cases and controls, we selected a random sample of 1000 asthma cases and 1000 controls, linking them to a computerized military health record system to verify if medications indicated for asthma therapy were prescribed. After excluding cases not prescribed bronchodilator medications and excluding controls prescribed bronchodilator medications or steroids, we used logistic regression to estimate associations among asthma, body mass index, and demographic, lifestyle, and comorbid risk factors in 386 verified cases and 744 verified controls.Increasing body mass index, younger age, female sex, non-active duty beneficiary status, and arthritis were significant independent predictors of asthma prevalence in both our larger analysis and our verified substudy, whereas stomach ulcer, depression, hypertension, and white race are also independent predictors of asthma prevalence in our larger analysis.Increasing body mass index is a key factor predicting prevalence of asthma and, if determined to be etiologically related to asthma incidence, is a potentially modifiable risk factor for asthma.

To evaluate the effect of moderate-intensity exercise on the occurrence and severity of menopause symptoms.A yearlong, randomized, clinical trial, conducted in Seattle, WA, with 173 overweight, postmenopausal women not taking hormone therapy in the previous 6 months. The intervention was a moderate-intensity exercise intervention (n = 87) versus stretching control group (n = 86). Using logistic regression, odds ratios comparing exercise with controls were calculated at 3, 6, 9, and 12 months for menopause symptoms and their severity.There was a significant increase in hot flash severity and decreased risk of memory problems in exercisers versus controls over 12 months, although the numbers affected were small. No other significant changes in symptoms were observed.Exercise does not seem to decrease the risk of having menopause symptoms in overweight, postmenopausal women not taking hormone therapy and may increase the severity of some symptoms in a small number of women.

The Women's Health Initiative randomized controlled trial found a trend (p = 0.09) toward a lower breast cancer risk among women assigned to daily 0.625-mg conjugated equine estrogens (CEEs) compared with placebo, in contrast to an observational literature that mostly reports a moderate increase in risk with estrogen-alone preparations. In 1993-2004 at 40 US clinical centers, breast cancer hazard ratio estimates for this CEE regimen were compared between the Women's Health Initiative clinical trial and observational study toward understanding this apparent discrepancy and refining hazard ratio estimates. After control for prior use of postmenopausal hormone therapy and for confounding factors, CEE hazard ratio estimates were higher from the observational study compared with the clinical trial by 43% (p = 0.12). However, after additional control for time from menopause to first use of postmenopausal hormone therapy, the hazard ratios agreed closely between the two cohorts (p = 0.82). For women who begin use soon after menopause, combined analyses of clinical trial and observational study data do not provide clear evidence of either an overall reduction or an increase in breast cancer risk with CEEs, although hazard ratios appeared to be relatively higher among women having certain breast cancer risk factors or a low body mass index.