Erin J. Aiello

Weight Loss in Breast Cancer Patient Management

PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSION 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.

Association of CYP17, CYP19, CYP1B1 , and COMT Polymorphisms with Serum and Urinary Sex Hormone Concentrations in Postmenopausal Women

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 (Val432Leu), and COMT (Val108/158Met). We examined associations between these polymorphisms and serum concentrations of estrogens, androgens, and sex hormone-binding globulin and urinary concentrations of 2- and 16α-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 16α-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.

Effect of a yearlong, moderate-intensity exercise intervention on the occurrence and severity of menopause symptoms in postmenopausal women

Objective:To evaluate the effect of moderate-intensity exercise on the occurrence and severity of menopause symptoms. Design: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. Results: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. Conclusions: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.

Association between Mammographic Breast Density and Breast Cancer Tumor Characteristics

Objective: Few studies have examined the association between breast density and breast cancer tumor characteristics. We examined the association between hormonal, proliferative, and histologic tumor characteristics and mammographic breast density in women with breast cancer. Methods: We conducted a cross-sectional analysis in 546 women diagnosed with invasive breast cancer to evaluate the associations between breast density and tumor size, lymph node status, lymphatic or vascular invasion, histologic grade, nuclear grade, tumor differentiation, mitotic index, tumor necrosis, Ki-67 proliferation, estrogen receptor, progesterone receptor, p53, p27, cyclin E, Bcl-2, and C-erb-B2 invasion. Breast density was classified as fatty (Breast Imaging Reporting and Data System code 1 or 2; n = 373) or dense (Breast Imaging Reporting and Data System code 3 or 4; n = 173) for the cancer-free breast. A single pathologist measured all tumor markers. We examined whether the relationships were modified by interval cancer or screen-detected cancer. Results: Women with a tumor size >1.0 cm were more likely to have dense breasts compared with women with a tumor size ≤1.0 cm after adjusting for confounders (odds ratio, 2.0; 95% confidence interval, 1.2-3.4 for tumor sizes 1.1-2.0 cm; odds ratio, 2.3; 95% confidence interval, 1.3-4.4 for tumor sizes 2.1-10 cm). Tumor size, lymph node status, and lymphatic or vascular invasion were positively associated with breast density among screen-detected cancers. Histologic grade and mitotic index were negatively associated with breast density in women diagnosed with an interval cancer. Conclusions: These results suggest that breast density is related to tumor size, lymph node status, and lymphatic or vascular invasion in screen-detected cancers. Additional studies are needed to address whether these associations are due to density masking the detection of some tumors, a biological relationship, or both.

Associations among Circulating Sex Hormones, Insulin-Like Growth Factor, Lipids, and Mammographic Density in Postmenopausal Women

Objective: Hormone therapy use has been positively associated with mammographic density in several studies. However, few studies have examined the association between endogenous hormone levels and mammographic density. Therefore, we evaluated the relationship of endogenous sex hormones, insulin-like growth factor (IGF), and lipids with mammographic density in 88 overweight, postmenopausal women not taking hormone therapy. Methods: Percent density and dense area were evaluated as continuous measures using a computer-assisted program. We used multiple linear regression to evaluate the associations of sex hormones, IGF, and cholesterol with mammographic density, adjusting for confounders, including adiposity. We evaluated stratification by history of hormone therapy use (former versus never) and hormone therapy latency (<5 versus ≥5 years). Results: Among former hormone therapy users, mammographic density was inversely associated with circulating levels of estrone (P = 0.01), estradiol (P = 0.003), free estradiol (P = 0.004), testosterone (P = 0.04), free testosterone (P = 0.02), androstenedione (P < 0.001), dehydroepiandrosterone (P = 0.01), and the ratio of IGF-I to its binding protein (IGF-I/IGFBP-3; P = 0.04). We found similar associations when we limited the analyses to women who had used hormone therapy within the past 5 years. We also noted positive associations of mammographic density with total cholesterol (P = 0.03) and low-density lipoprotein (P = 0.03) among former hormone therapy users. No associations were noted among women who had never used hormone therapy. Conclusions: These results suggest that there is an inverse relationship between endogenous sex hormones and mammographic density in postmenopausal women among former users of hormone therapy. This is not consistent with the hormone therapy literature and should be confirmed in larger studies.

UDP-glucuronosyltransferase and sulfotransferase polymorphisms, sex hormone concentrations, and tumor receptor status in breast cancer patients

IntroductionUDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes are involved in removing sex hormones from circulation. Polymorphic variation in five UGT and SULT genes – UGT1A1 ((TA)6/(TA)7), UGT2B4 (Asp458Glu), UGT2B7 (His268Tyr), UGT2B15 (Asp85Tyr), and SULT1A1 (Arg213His) – may be associated with circulating sex hormone concentrations, or the risk of an estrogen receptor-negative (ER-) or progesterone receptor-negative (PR-) tumor.MethodsLogistic regression analysis was used to estimate the odds ratios of an ER- or PR- tumor associated with polymorphisms in the genes listed above for 163 breast cancer patients from a population-based cohort study of women in western Washington. Adjusted geometric mean estradiol, estrone, and testosterone concentrations were calculated within each UGT and SULT genotype for a subpopulation of postmenopausal breast cancer patients not on hormone therapy 2–3 years after diagnosis (n = 89).ResultsThe variant allele of UGT1A1 was associated with reduced risk of an ER- tumor (P for trend = 0.03), and variants of UGT2B15 and SULT1A1 were associated with non-statistically significant risk reductions. There was some indication that plasma estradiol and testosterone concentrations varied by UGT2B15 and SULT1A1 genotypes; women with the UGT2B15 Asp/Tyr and Tyr/Tyr genotypes had higher concentrations of estradiol than women with the Asp/Asp genotype (P = 0.004). Compared with women with the SULT1A1 Arg/Arg and Arg/His genotypes, women with the His/His genotype had elevated concentrations of testosterone (P = 0.003).ConclusionsThe risk of ER- breast cancer tumors may vary by UGT or SULT genotype. Further, plasma estradiol and testosterone concentrations in breast cancer patients may differ depending on some UGT and SULT genotypes.

Physical Activity, Body Mass Index, and Mammographic Density in Postmenopausal Breast Cancer Survivors

PURPOSE To investigate the association between physical activity, body mass index (BMI), and mammographic density in a racially/ethnically diverse population-based sample of 522 postmenopausal women diagnosed with stage 0-IIIA breast cancer and enrolled in the Health, Eating, Activity, and Lifestyle Study. METHODS We collected information on BMI and physical activity during a clinic visit 2 to 3 years after diagnosis. Weight and height were measured in a standard manner. Using an interview-administered questionnaire, participants recalled the type, duration, and frequency of physical activities they had performed in the last year. We estimated dense area and percentage density as a continuous measure using a computer-assisted software program from mammograms imaged approximately 1 to 2 years after diagnosis. Analysis of covariance methods were used to obtain mean density across WHO BMI categories and physical activity tertiles adjusted for confounders. RESULTS We observed a statistically significant decline in percentage density (P for trend = .0001), and mammographic dense area (P for trend = .0052), with increasing level of BMI adjusted for potential covariates. We observed a statistically significant decline in mammographic dense area (P for trend = .036) with increasing level of sports/recreational physical activity in women with a BMI of at least 30 kg/m2. Conversely, in women with a BMI less than 25 kg/m2, we observed a non-statistically significant increase in mammographic dense area and percentage density with increasing level of sports/recreational physical activity. CONCLUSION Increasing physical activity among obese postmenopausal breast cancer survivors may be a reasonable intervention approach to reduce mammographic density.

Mammographic Breast Density, Dense Area, and Breast Area Differences by Phase in the Menstrual Cycle

Background: Mammographic breast density may be greater in the luteal phase (days 15-30) than the follicular phase (days 1-14) of the menstrual cycle; this may have implications for when mammography screening should occur. Objective: Examine whether percent breast density, breast area, or dense area differ by menstrual phase. Methods: We identified 204 premenopausal women with regular periods who were <55 years (mean = 45.0 years) and had two screening mammograms within 9 to 18 months, with one screening between days 9 and 14, and one screening between days 22 and 35 of the menstrual cycle. We measured percent breast density, breast area, and dense area using the Cumulus software. We used linear regression to test for differences in breast density, breast area, and dense area from follicular to luteal phase, adjusting for change in weight and time between exams. Results: The mean (SD) percent breast density was 35.8% (21.3) in the follicular phase and 36.7% (21.3) in the luteal phase. Multivariable analyses showed small but not statistically significant increases in percent density [1.1%; 95% confidence interval (95% CI), −0.2% to 2.3%] and breast area (16.7 cm2; 95% CI, −2.8 to 36.2) and a statistically significant increase in dense area (13.1 cm2; 95% CI, 0.1-26.1) in the luteal compared with the follicular phase. Conclusions: Breast density, breast area, and dense area have small, but probably not clinically meaningful, increases in the luteal phase of the menstrual cycle. However, there are other factors that may differ by menstrual cycle phase that we were unable to assess (e.g., breast compression), which may ultimately influence mammographic sensitivity by menstrual cycle phase. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2303–6)

Reactions to Uncertainty and the Accuracy of Diagnostic Mammography

BackgroundReactions to uncertainty in clinical medicine can affect decision making.ObjectiveTo assess the extent to which radiologists’ reactions to uncertainty influence diagnostic mammography interpretation.DesignCross-sectional responses to a mailed survey assessed reactions to uncertainty using a well-validated instrument. Responses were linked to radiologists’ diagnostic mammography interpretive performance obtained from three regional mammography registries.ParticipantsOne hundred thirty-two radiologists from New Hampshire, Colorado, and Washington.MeasurementMean scores and either standard errors or confidence intervals were used to assess physicians’ reactions to uncertainty. Multivariable logistic regression models were fit via generalized estimating equations to assess the impact of uncertainty on diagnostic mammography interpretive performance while adjusting for potential confounders.ResultsWhen examining radiologists’ interpretation of additional diagnostic mammograms (those after screening mammograms that detected abnormalities), a 5-point increase in the reactions to uncertainty score was associated with a 17% higher odds of having a positive mammogram given cancer was diagnosed during follow-up (sensitivity), a 6% lower odds of a negative mammogram given no cancer (specificity), a 4% lower odds (not significant) of a cancer diagnosis given a positive mammogram (positive predictive value [PPV]), and a 5% higher odds of having a positive mammogram (abnormal interpretation).ConclusionMammograms interpreted by radiologists who have more discomfort with uncertainty have higher likelihood of being recalled.

Do breast cancer risk factors modify the association between hormone therapy and mammographic breast density? (United States).

ObjectiveTo evaluate whether the association between hormone therapy (HT) and breast density differs by levels of breast cancer risk factors.MethodsWe evaluated 80,867 screening mammograms from 39,296 postmenopausal women from Washington State. We estimated odds ratios and 95% confidence intervals for dense breasts (Breast Imaging Reporting and Data System categories 3 “heterogeneously dense” and 4 “extremely dense”) compared to fatty breasts (categories 1 “almost entirely fat” and 2 “scattered fibroglandular”) among HT users compared to never users. We separately examined former HT use and current HT use by type (estrogen plus progestin therapy (EPT) and estrogen-only therapy (ET)). We stratified the associations by age, BMI, race, family history, and reproductive and menopausal factors.ResultsCurrent EPT users had a 98% (1.87–2.09) greater odds of having dense breasts and current ET users had a 71% (1.56–1.87) greater odds compared to never users. Current HT users were more likely to have dense breasts if they were older, had more children, or younger at first birth compared to never users; these associations were stronger among EPT users than ET users.ConclusionsHT, particularly EPT, may reduce protective effects of older age, parity, and younger age at first birth on mammographic density.