Faculty Bibliography

Epidemiologic studies addressing the association of alcohol consumption with breast cancer consistently suggest a modest association and a dose-response relationship. The epidemiologic evidence does not point to a single mechanism to explain the association, and several mechanisms have been proposed. Alcohol consumption is shown to increase levels of endogenous estrogens, known risk factors for breast cancer. This hypothesis is further supported by data showing that the alcohol-breast cancer association is limited to women with estrogen-receptor positive tumors. Products of alcohol metabolism are known to be toxic and are hypothesized to cause DNA modifications that lead to cancer. Recent research has focused on genes that influence the rate of alcohol metabolism, with genes that raise blood concentrations of acetaldehyde hypothesized to heighten breast cancer risk. Mounting evidence suggests that antioxidant intake(e.g.folate)mayreducealcohol-associatedbreast cancer risk, because it neutralizes reactive oxygen species, a second-stage product of alcohol metabolism. Diets lacking sufficient antioxidant intake, as a result, may further elevate the risk of breast cancer among alcohol consumers. Given that alcohol consumption is increasing worldwide and especially among women in countries of rapid economic growth, a greater understanding of the mechanisms underlying the known alcohol-breast cancer association is warranted. Avoiding overconsumption of alcohol is recommended, especially for women with known risk factors for breast cancer.

CONTEXT: Oral contraceptive (OC) use is common, but bone changes associated with use of contemporary OC remain unclear. OBJECTIVE: The objective of the study was to compare bone mineral density (BMD) change in adolescent and young adult OC users and discontinuers of two estrogen doses, relative to nonusers. DESIGN AND SETTING: This was a prospective cohort study, Group Health Cooperative. PARTICIPANTS: Participants included 606 women aged 14-30 yr (50% adolescents aged 14-18 yr): 389 OC users [62% 30-35 mug ethinyl estradiol (EE)] and 217 age-similar nonusers; there were 172 OC discontinuers. The 24-month retention was 78%. MAIN OUTCOME MEASURE: The main outcome measure was BMD measured at 6-month intervals for 24-36 months. RESULTS: After 24 months, adolescents using 30-35 mug EE OCs, but not those using lower-dose OCs, had significantly smaller adjusted mean percentage BMD gains than nonusers at the spine [group means (95% confidence interval for between group differences) 1.32 vs. 2.26% (-1.89, -0.13%)] and whole body [1.45 vs. 2.03% (-1.29%, -0.13%)]. Adolescents who discontinued 30-35 mug EE OC showed significantly smaller gains than nonusers at the spine after 12 months [0.51 vs. 1.72% (-2.38%, -0.30%)]. Young adult OC users did not differ from nonusers. However, OC discontinuers of both doses differed significantly from nonusers at the spine 12 months after discontinuation [-1.32% < 30 mug EE, -0.92% 30-35 mug EE vs. +0.27% nonusers (-2.48, -0.54, and -1.94%, -0.55%, respectively)]. Results were similar for mean absolute BMD change (grams per square centimeter). CONCLUSIONS: Both OC use and discontinuation were associated with BMD losses/smaller gains relative to nonusers (differences < 2% after 12-24 months for all skeletal sites). The clinical significance of these results regarding future fracture risk is unknown. Study of longer-term trends after discontinuation is needed.

BACKGROUND: Self-report of dietary energy and protein intakes has been shown to be systematically and differentially underreported. OBJECTIVE: We assessed and compared the association of diabetes among postmenopausal women with biomarker-calibrated and uncalibrated dietary energy and protein intakes from food-frequency questionnaires (FFQs). DESIGN: The analyses were performed for 74,155 participants of various race-ethnicities from the Women's Health Initiative. Uncalibrated and calibrated energy and protein intakes from FFQs were assessed for associations with incident diabetes by using HR estimates based on Cox regression. RESULTS: A 20% increment in uncalibrated energy consumption was associated with increased diabetes risk (HR) of 1.03 (95% CI: 1.01, 1.05), 2.41 (95% CI: 2.06, 2.82) with biomarker calibration, and 1.30 (95% CI: 0.96, 1.76) after adjustment for BMI. A 20% increment in uncalibrated protein (g/d) resulted in an HR of 1.05 (95% CI: 1.03, 1.07), 1.82 (95% CI: 1.56, 2.12) with calibration, and 1.16 (95% CI: 1.05, 1.28) with adjustment for BMI. A 20% increment in uncalibrated protein density (% of energy from protein) resulted in an HR of 1.13 (95% CI: 1.09, 1.17), 1.01 (95% CI: 0.75, 1.37) with calibration, and 1.19 (95% CI: 1.07, 1.32) with adjustment for BMI. CONCLUSIONS: Higher protein and total energy intakes (calibrated) appear to be associated with a substantially increased diabetes risk that may be mediated by an increase in body mass over time. Diet-disease associations without correction of self-reported measurement error should be viewed with caution. This trial is registered at clinicaltrials.gov as NCT00000611.

BACKGROUND: Most of the millions of oral contraceptive (OC) users are under 30 years of age and in the critical period for bone mass accrual. STUDY DESIGN: This cross-sectional study of 606 women aged 14-30 years examined both OC duration and estrogen dose and their association with bone mineral density (BMD) at the hip, spine, and whole body (dual-energy X-ray absorptiometry). RESULTS: Of 389 OC users and 217 nonusers enrolled, 50% were adolescents (14-18 years). Of OC users, 38% used "low-dose" OCs [<30 mcg ethinyl estradiol (EE)]. In adolescents, mean BMD differed by neither OC duration nor EE dose. However, 19- to 30-year-old women's mean BMD was lower with longer OC use for spine and whole body (p=.004 and p=.02, respectively) and lowest for >12 months of low-dose OCs for the hip, spine and whole body (p=.02, .003 and .002, respectively). CONCLUSIONS: Prolonged use of today's OCs, particularly <30 mcg EE, may adversely impact young adult women's bone density while using these agents.

OBJECTIVE: Effective dietary intervention strategies that can be widely disseminated and have the potential for sustainable dietary modifications are needed. The purpose of this study was to describe and evaluate the effectiveness of a telephone-based soy intervention. DESIGN: A randomized controlled trial comparing self-reported intake and serum measures of soy during a 1-year dietary soy (Soy) to fruit and vegetable (Placebo) intervention conducted in two of five arms from the Herbal Alternatives Trial between May 2001 and September 2004. SUBJECTS/SETTING: One hundred sixty-three peri- and postmenopausal women (mean age=52 years) consuming self-selected diets in the Pacific Northwest, United States. INTERVENTION: Five telephone contacts with a registered dietitian during a 12-month intervention with the goal to increase soy food consumption to two servings daily. MAIN OUTCOME MEASURES: Change from baseline in self-reported soy servings and serum isoflavone (daidzein and genistein) concentrations were estimated using analysis of variance and generalized estimating equations. Proportions of participants achieving the intervention goal were compared using chi(2) tests. RESULTS: Ninety-four percent (n=74) of participants in the Soy arm and 89% (n=75) in the Placebo arm completed the trial, and slightly more than one third (n=27) received five phone contacts. Mean (+/-standard deviation) intakes of soy were similar for the Soy and Placebo arms at baseline (0.6+/-1.0 vs 0.4+/-0.8 servings/day; P>0.05). At 12-month follow-up visit, mean+/-standard deviation servings of soy per day were 1.6+/-1.4 for the Soy intervention compared to 0.5+/-0.9 within the Placebo arm (P<0.001). There were concomitant increases in serum isoflavones at 3 and 6 months from baseline in the Soy arm only, with approximately twofold increases in both daidzein (mean=66.4 nmol/L, 95% confidence interval [CI]: 39.0 to 93.9 [mean 16.9 ng/mL, 95% CI: 9.9 to 23.8]) and genistein (mean=100.4 nmol/L, 95% CI: 60.9 to 139.9 [mean 27.1 ng/mL, 95% CI: 16.5 to 37.8]) concentrations. Mean weight changed by <1 kg during the 12-month period in each group and physical activity remained stable, suggesting that participants incorporated soy foods into their diet by substituting for non soy foods rather than adding them to their diet. CONCLUSIONS: A brief telephone-based intervention with a focused message delivered by a registered dietitian is a feasible approach for encouraging targeted dietary changes, such as an increase in soy intake among peri- and postmenopausal women.

INTRODUCTION: Evidence has been inconsistent regarding the impact of social networks on survival after breast cancer diagnosis. We prospectively examined the relation between components of social integration and survival in a large cohort of breast cancer survivors. METHODS: Women (N=4,589) diagnosed with invasive breast cancer were recruited from a population-based, multi-center, case-control study. A median of 5.6 years (Interquartile Range 2.7-8.7) after breast cancer diagnosis, women completed a questionnaire on recent post-diagnosis social networks and other lifestyle factors. Social networks were measured using components of the Berkman-Syme Social Networks Index to create a measure of social connectedness. Based on a search of the National Death Index, 552 deaths (146 related to breast cancer) were identified. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. RESULTS: Higher scores on a composite measure of social connectedness as determined by the frequency of contacts with family and friends, attendance of religious services, and participation in community activities was associated with a 15-28% reduced risk of death from any cause (p-trend=0.02). Inverse trends were observed between all-cause mortality and frequency of attendance at religious services (p-trend=0.0001) and hours per week engaged in community activities (p-trend=0.0005). No material associations were identified between social networks and breast cancer-specific mortality. CONCLUSIONS: Engagement in activities outside the home was associated with lower overall mortality after breast cancer diagnosis.

BACKGROUND: The range of protein intakes for optimizing bone health among premenopausal women is unclear. Protein is a major constituent of bone, but acidic amino acids may promote bone resorption. OBJECTIVE: The objective was to examine cross-sectional and longitudinal associations between baseline dietary protein and bone mineral density (BMD) among 560 females aged 14-40 y at baseline enrolled in a Pacific Northwest managed-care organization. The role of protein source (animal or vegetable) and participant characteristics were considered. DESIGN: Dietary protein intake was assessed by using a semiquantitative food-frequency questionnaire in participants enrolled in a study investigating associations between hormonal contraceptive use and bone health. Annual changes in hip, spine, and whole-body BMD were measured by using dual-energy X-ray absorptiometry. Cross-sectional and longitudinal associations between baseline protein intake (% of energy) and BMD were examined by using linear regression analysis and generalized estimating equations adjusted for confounders. RESULTS: The mean (+/-SD) protein intake at baseline was 15.5 +/- 3.2%. After multivariable adjustment, the mean BMD was similar across each tertile of protein intake. In cross-sectional analyses, low vegetable protein intake was associated with a lower BMD (P = 0.03 for hip, P = 0.10 for spine, and P = 0.04 for whole body). For every percentage increase in the percentage of energy from protein, no significant longitudinal changes in BMD were observed at any anatomic site over the follow-up period. CONCLUSIONS: Data from this longitudinal study suggest that a higher protein intake does not have an adverse effect on bone in premenopausal women. Cross-sectional analyses suggest that low vegetable protein intake is associated with lower BMD.

OBJECTIVES: To evaluate the association between protein intake and incident frailty. DESIGN: Prospective cohort study. SETTING: Subset of the Women's Health Initiative Observational Study conducted at 40 clinical centers. PARTICIPANTS: Twenty-four thousand four hundred seventeen women aged 65 to 79 who were free of frailty at baseline with plausible self-reported energy intakes (600-5,000 kcal/day) according to the Food Frequency Questionnaire (FFQ). MEASUREMENTS: Baseline protein intake was estimated from the FFQ. Calibrated estimates of energy and protein intake were corrected for measurement error using regression calibration equations estimated from objective measures of total energy expenditure (doubly labeled water) and dietary protein (24-hour urinary nitrogen). After 3 years of follow-up, frailty was defined as having at least three of the following components: low physical function (measured using the Rand-36 questionnaire), exhaustion, low physical activity, and unintended weight loss. Multinomial logistic regression models estimated associations for uncalibrated and calibrated protein intake. RESULTS: Of the 24,417 eligible women, 3,298 (13.5%) developed frailty over 3 years. After adjustment for confounders, a 20% increase in uncalibrated protein intake (%kcal) was associated with a 12% (95% confidence interval (CI)=8-16%) lower risk of frailty, and a 20% increase in calibrated protein intake was associated with a 32% (95% CI=23-50%) lower risk of frailty. CONCLUSION: Higher protein consumption, as a fraction of energy, is associated with a strong, independent, dose-responsive lower risk of incident frailty in older women. Using uncalibrated measures underestimated the strength of the association. Incorporating more protein into the diet may be an intervention target for frailty prevention.

BACKGROUND: Little is known about the relationship between alcohol intake and breast cancer risk among Mexican women. This association may be modified by folate and Vitamin B12. METHODS: A population-based case-control study conducted in Mexico recruited 1,000 incident breast cancer cases aged 35-69 and 1,074 controls matched on age, region, and health care system. In-person interviews were conducted to assess breast cancer risk factors and recent diet using a food frequency questionnaire. Conditional logistic regression models estimated adjusted odds ratios and 95% confidence intervals. RESULTS: Over one-half (57%) of cases and less than one-half of controls (45%) reported any lifetime alcohol consumption. Compared with never drinkers, women reporting ever drinking (Adjusted OR = 1.25, 95% CI = 0.99-1.58) had a greater odds of breast cancer. There was evidence for interaction in the association between ever consuming any alcohol and breast cancer by folate (p for interaction = 0.04) suggesting women with lower folate intake had a higher odds of breast cancer (Adjusted OR = 1.99, 95% CI = 1.26-3.16) compared to women with higher folate intake (OR = 1.12, 95% CI = 0.69-1.83). CONCLUSIONS: Our findings support evidence that any alcohol intake increases risk of breast cancer. Insufficient intake of folate may further elevate risk for developing breast cancer among women who consume alcohol.