Betsy C. Wertheim

Nutrition and physical activity cancer prevention guidelines, cancer risk, and mortality in the women's health initiative.

Healthy lifestyle behaviors are recommended to reduce cancer risk and overall mortality. Adherence to cancer-preventive health behaviors and subsequent cancer risk has not been evaluated in a diverse sample of postmenopausal women. We examined the association between the American Cancer Society (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines score and risk of incident cancer, cancer-specific mortality, and all-cause mortality in 65,838 postmenopausal women enrolled in the Womens Health Initiative Observational Study. ACS guidelines scores (0–8 points) were determined from a combined measure of diet, physical activity, body mass index (current and at age 18 years), and alcohol consumption. After a mean follow-up of 12.6 years, 8,632 incident cancers and 2,356 cancer deaths were identified. The highest ACS guidelines scores compared with the lowest were associated with a 17% lower risk of any cancer [HR, 0.83; 95% confidence interval (CI), 0.75–0.92], 22% lower risk of breast cancer (HR, 0.78; 95% CI, 0.67–0.92), 52% lower risk of colorectal cancer (HR, 0.48; 95% CI, 0.32–0.73), 27% lower risk of all-cause mortality, and 20% lower risk of cancer-specific mortality (HR, 0.80; 95% CI, 0.71–0.90). Associations with lower cancer incidence and mortality were generally strongest among Asian, black, and Hispanic women and weakest among non-Hispanic whites. Behaviors concordant with Nutrition and Physical Activity Cancer Prevention Guidelines were associated with lower risk of total, breast, and colorectal cancers and lower cancer-specific mortality in postmenopausal women. Cancer Prev Res; 7(1); 42–53. ©2014 AACR.

Trends of Incidence and Survival of Gastrointestinal Neuroendocrine Tumors in the United States: A Seer Analysis

OBJECTIVES: To examine trends in detection and survival of hollow viscus gastrointestinal neuroendocrine tumors (NETs) across time and geographic regions of the U.S. METHODS: We used the Surveillance, Epidemiology and End Results (SEER) database to investigate 19,669 individuals with newly diagnosed gastrointestinal NETs. Trends in incidence were tested using Poisson regression. Cox proportional hazards regression was used to examine survival. RESULTS: Incidence increased over time for NETs of all gastrointestinal sites (all P < 0.001), except appendix. Rates have risen faster for NETs of the small intestine and rectum than stomach and colon. Rectal NETs were detected at a faster pace among blacks than whites (P < 0.001) and slower in the East than other regions (P < 0.001). We observed that appendiceal and rectal NETs carry the best prognosis and survival of small intestinal and colon NETs has improved for both men and women. Colon NETs showed different temporal trends in survival according to geographic region (Pinteraction = 0.028). Improved prognosis was more consistent across the country for small intestinal NETs. CONCLUSIONS: Incidence of gastrointestinal NETs has increased, accompanied by inconsistently improved survival for different anatomic sites among certain groups defined by race and geographic region.

Biomarker-calibrated protein intake and physical function in the Women's Health Initiative.

To determine whether preservation of physical function with aging may be partially met through modification in dietary protein intake.

Relationship between sleep quality and quantity and weight loss in women participating in a weight-loss intervention trial

Evidence suggests that individuals who report fewer total hours of sleep are more likely to be overweight or obese. Few studies have prospectively evaluated weight‐loss success in relation to reported sleep quality and quantity. This analysis sought to determine the association between sleep characteristics and weight loss in overweight or obese women enrolled in a randomized clinical trial of a weight‐loss program. We hypothesized that in overweight/obese women, significant weight loss would be demonstrated more frequently in women who report a better Pittsburgh Sleep Quality Index (PSQI) Global Score or sleep >7 h/night as compared to women who report a worse PSQI score or sleep ≤7 h/night. Women of ages 45.5 ± 10.4 (mean ± SD) years and BMI of 33.9 ± 3.3 (n = 245) were randomized and completed PSQI at baseline and 6 months; 198 had weight change assessed through 24 months. At baseline, 52.7% reported PSQI scores above the clinical cutoff of 5. Better subjective sleep quality increased the likelihood of weight‐loss success by 33% (relative risk (RR), 0.67; 95% confidence interval (CI), 0.52–0.86), as did sleeping >7 h/night. A worse Global Score at 6 months was associated with a 28% lower likelihood of continued successful weight loss at 18 months, but unassociated by 24 months. These results suggest that sleep quality and quantity may contribute to weight loss in intervention‐based studies designed to promote weight control in overweight/obese adult women.

Reproductive Factors, Heterogeneity, and Breast Tumor Subtypes in Women of Mexican Descent

Background: Published data support the presence of etiologic heterogeneity by breast tumor subtype, but few studies have assessed this in Hispanic populations. Methods: We assessed tumor subtype prevalence and associations between reproductive factors and tumor subtypes in 1,041 women of Mexican descent enrolled in a case-only, binational breast cancer study. Multinomial logistic regression comparing HER2+ tumors and triple-negative breast cancer (TNBC) to luminal A tumors was conducted. Results: Compared with women with luminal A tumors, those with a later age at first pregnancy were less likely to have TNBC [OR, 0.61; 95% confidence interval (CI), 0.39–0.95], whereas those with three or more full-term pregnancies were more likely to have TNBC (OR, 1.68; 95% CI, 1.10–2.55). A lower odds of TNBC was shown for longer menstruation duration, whether before first pregnancy (OR, 0.78; 95% CI, 0.65–0.93 per 10 years) or menopause (OR, 0.79; 95% CI, 0.69–0.91 per 10 years). Patients who reported breastfeeding for more than 12 months were over twice as likely to have TNBC than luminal A tumors (OR, 2.14; 95% CI, 1.24–3.68). Associations comparing HER2+ with luminal A tumors were weak or nonexistent except for the interval between last full-term pregnancy and breast cancer diagnosis. Conclusions: Findings show etiologic heterogeneity by tumor subtype in a population of Hispanic women with unique reproductive profiles. Impact: Identification of etiologically distinct breast tumor subtypes can further improve our understanding of the disease and help provide personalized prevention and treatment regimens. Cancer Epidemiol Biomarkers Prev; 22(10); 1853–61. ©2013 AACR.

Levels of Rectal Mucosal Polyamines and Prostaglandin E2 Predict Ability of DFMO and Sulindac to Prevent Colorectal Adenoma

BACKGROUND & AIMS Combination of polyamine and prostaglandin E2 (PGE2)-synthesis inhibitors reduced the risk of colorectal adenoma (CRA) by 70% in patients who received polypectomies. We studied effects of the combination of difluoromethylornithine (DFMO) and sulindac on biomarkers and investigated factors that modify their efficacy. METHODS We analyzed rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment regimens, and risk of CRA in 267 participants of a phase IIb/III chemoprevention trial of DFMO/sulindac. RESULTS In the group that received DFMO/sulindac, spermidine-to-spermine ratio (Spd:Spm) in rectal mucosa decreased between baseline and 12- and 36-month follow-up examinations (0.30, 0.23, and 0.24, respectively; P < .001 for both comparisons to baseline). Putrescine levels decreased between baseline and 12 months (0.46 vs 0.15 nmol/mg protein; P < .001) but rebounded between 12 and 36 months (0.15 vs 0.36 nmol/mg protein; P = .001). PGE2 levels did not change, although aspirin use was significantly associated with lower baseline levels of PGE2. No significant associations were observed between changes in biomarker levels and efficacy. However, drug efficacy was greatest in subjects with low Spd:Spm and high PGE2 at baseline; none of these subjects, versus 39% of those given placebo, developed CRA (P < .001). Efficacy was lowest in subjects with high Spd:Spm and low PGE2 at baseline; 28% developed CRA, compared with 36% of patients given placebo (P = .563). CONCLUSIONS A combination of DFMO and sulindac significantly suppressed production of rectal mucosal polyamines but not PGE2. No relationship was found between changes in biomarker levels and response. However, baseline biomarker levels modified the effect of DFMO/sulindac for CRA prevention.

Gender Modifies the Effect of Ursodeoxycholic Acid in a Randomized Controlled Trial in Colorectal Adenoma Patients

Purpose: Ursodeoxycholic acid (UDCA) was one of the earliest agents investigated as a drug for colorectal cancer prevention. However, UDCA failed to show efficacy to prevent the development of colorectal adenomas in a large, phase III, randomized, placebo-controlled trial. We re-evaluated the effect of UDCA in men and women separately, based on sex-specific differences in bile acid metabolism and suspected variation in etiologic factors contributing to colorectal cancer risk. Experimental Design: We conducted a secondary analysis of the efficacy of UDCA to prevent colorectal adenoma in men (n = 804) and women (n = 388). Results: We found no reduction in risk of any metachronous adenoma with UDCA treatment in men or women. However, UDCA treatment significantly lowered the odds of advanced lesions [odds ratio (OR), 0.62; 95% confidence interval (CI), 0.43-0.89] in men, but not women. We also observed significantly higher odds of advanced lesions with UDCA treatment in women who were younger (age, <65 years; OR, 3.24; 95% CI, 1.10-9.56), obese (body mass index, ≥30 kg/m2; OR, 5.45; 95% CI, 1.42-20.9), or in the highest tertile of total dietary fat (≥56.2 g/day; OR, 3.48; 95% CI, 1.35-8.95). In a multivariate model, the interactive effect of fat intake accounted for the modulating effects of age and body mass index in women. Conclusion: Our findings support the use of UDCA for preventing advanced colorectal adenomas in men. The increased odds of adenoma among women with high fat intake suggest a previously unrecognized harm that warrants further study, especially given the chronic exposure to UDCA in patients with primary biliary cirrhosis and the increasing investigational use of UDCA for several other conditions.

Alcohol consumption and body weight change in postmenopausal women: results from the Women's Health Initiative

Objective:To determine whether alcohol consumption is associated with incident overweight or obesity in normal-weight, postmenopausal women.Design:Prospective cohort study considering baseline alcohol consumption and subsequent weight change over 7 years.Subjects:15 920 normal-weight (body mass index (BMI): 18.5 to <25 kg m−2), postmenopausal women enrolled in the Women′s Health Initiative Clinical Trial.Measurements:Body weight change, and incident overweight and obesity (BMI, 25.0 to <30 and ⩾30 kg m−2) over 7 years.Results:One-third of the 13 822 women included in the analytical cohort reported no alcohol consumption. BMI differed little between abstainers (22.8±1.58 kg m−2) and alcohol consumers in the upper quintile (22.7±1.53 kg m−2). Among normal-weight women, the risk of becoming overweight or obese over a 7-year follow-up period was 35% or 88% lower, respectively, for women in the upper quintile of alcohol intake relative to abstainers (hazard ratio (HR), 0.65; 95% confidence interval (CI), 0.58–0.73; or HR, 0.12; 95% CI, 0.05–0.25, respectively). Risk for overweight and obesity was not significantly modified by age. Wine consumption showed the greatest protective association for risk of overweight (HR, 0.75; 95% CI, 0.68–0.84), followed by liquor (HR, 0.85; 95% CI, 0.78–0.93) and beer (HR, 0.90; 95% CI, 0.82–1.00).Conclusion:Postmenopausal women of normal weight who report moderate alcohol intake have a reduced risk of becoming overweight or obese over time. Perhaps, weight control measures in this population should target behaviors other than reduction in alcohol for those of normal BMI consuming moderate amounts.

Diet quality and survival after ovarian cancer: results from the Women's Health Initiative.

BACKGROUND Survival after an ovarian cancer diagnosis is poor. Given the high mortality in these patients, efforts to identify modifiable lifestyle behaviors that could influence survival are needed. Earlier evidence suggests a protective role for vegetables, but no prior studies have evaluated overall dietary quality and ovarian cancer survival. The purpose of this analysis was to evaluate the role of prediagnosis diet quality in ovarian cancer survival. METHODS We identified 636 centrally adjudicated cases of ovarian cancer within the Womens Health Initiative Observational Study or Clinical Trials of 161808 postmenopausal women followed from 1995 to 2012. Dietary quality was assessed for the Healthy Eating Index (2005) using a food frequency questionnaire, covariables were obtained from standardized questionnaires, and adiposity was measured by clinic-based measurements of height, weight, and waist circumference. The association between diet quality and mortality was analyzed using Cox proportional hazards regression, adjusted for potential confounders, and stratified by waist circumference, physical activity level, and diabetes status. Tests of statistical significance were two-sided. RESULTS Overall, higher diet quality was associated with lower all-cause mortality after ovarian cancer (hazard ratio [HR] for highest vs lowest tertile = 0.73; 95% confidence interval [CI] = 0.55 to 0.97, P(trend) = .03). The effect was strongest among women with waist circumference of 88 cm or less and with no history of diabetes (HR = 0.73, 95% CI = 0.54 to 0.98). Physical activity level did not modify the association between diet quality and survival. CONCLUSION Our results suggest that overall higher prediagnosis diet quality may protect against mortality after ovarian cancer.

Physical Activity as a Determinant of Fecal Bile Acid Levels

Physical activity is protective against colon cancer, whereas colonic bile acid exposure is a suspected risk factor. Although likely related, the association between physical activity and bile acid levels has not been well-studied. Furthermore, the effect of triglycerides, which are known to modify bile acid levels, on this relationship has not been investigated. We conducted a cross-sectional analysis of baseline fecal bile acid levels for 735 colorectal adenoma formers obtained from participants in a phase III ursodeoxycholic acid chemoprevention trial. Compared with the lowest quartile of recreational physical activity duration, the highest quartile was associated with a 17% lower fecal bile acid concentration, adjusted for age, sex, dietary fiber intake, and body mass index (P = 0.042). Furthermore, consistent with a previously established relationship between serum triglyceride levels and bile acid metabolism, we stratified by triglyceride level and observed a 34% lower fecal bile acid concentration (highest versus lowest quartiles of physical activity) in individuals with low triglycerides (<136 mg/dL; P = 0.002). In contrast, no association between physical activity and fecal bile acid concentration was observed for subjects with high triglycerides (≥136 mg/dL). Our results suggest that the biological mechanism responsible for the protective effect of physical activity on the incidence of colon cancer may be partially mediated by decreasing colonic bile acid exposure. However, this effect may be limited to individuals with lower triglyceride levels. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1591–8)