Lifetime physical activity and risk of breast cancer

We conducted a case-control study of 394 women with breast cancer and 788 control women (91% response) to investigate the association of lifetime physical activity with mainly menopausal breast cancer risk. After controlling for potential confounders, the odds ratios (95% confidence intervals) for increasing quartiles of lifetime physical activity were 1.00 (referent), 0.91 (0.60-1.37), 0.91 (0.60-1.39), and 1.10 (0.73-1.67), respectively; P, trend = 0.47. We also separately examined physical activity at ages 12-18, 19-34, 35-49 and > or =50 years; no significant trends were observed in any age group. These data do not support a role of physical activity in preventing breast cancer.     

Occupational physical activity and the risk of breast cancer

The association between occupational and the risk of breast cancer was analyzed using data from a case-control study of 257 women with breast cancer and 565 control women. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for occupations having light and medium activity compared with sedentary ones. After adjusted for potential confounders, women in sedentary occupations had a 29% higher risk, compared to those with the physically medium demanding jobs. For women at age > or =55 years higher occupational physical levels were associated with 53-60% reduction in the risk. There was a significant decreasing trend in the ORs from sedentary to medium work (P=0.001); while no association emerged in younger women. These findings demonstrate that the protective effect of higher levels activity in occupations on breast cancer appears to be confined to older women.     

Childhood and teenage physical activity and breast cancer risk

Purpose

Adult physical activity is associated with reduced breast cancer risk, but few studies have evaluated activity before adulthood. Early life may be an important period because of rapid breast development and hormonal changes. This study contributes new information by examining childhood (ages 5–12) and teenage (ages 13–19) activity separately and overall.

Methods

The Sister Study is a cohort of 50,884 women aged 35–74. Women reported age 5–19 sports/exercise activities and age 10 and 16 unstructured activities. Both hours and MET-hours of activity were considered in association with breast cancer overall, by ER status, and by menopausal status. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards models.

Results

2416 cases were diagnosed during follow-up (mean = 6.4 years). Participation in 7+ hours (vs <1 h) per week of sports/exercise during ages 5–19 was associated with reduced breast cancer risk (HR = 0.75; 95% CI 0.57–0.99). 7+ hours (vs <1 h) per week of unstructured physical activity at age 16, but not age 10, was inversely associated with breast cancer (HR = 0.81; 95% CI 0.70–0.95). Associations were more pronounced for ER+ tumors, especially for activity during the childhood (ages 5–12) period. Due to low correlation between childhood/teenage and adulthood activity in this study (r = 0.1), it is unlikely that recent activity explains our results.

Conclusions

Findings from this large cohort indicate higher levels of physical activity during ages 5–19 are inversely associated with breast cancer risk, supporting early life as a window of susceptibility for breast cancer development.

     

Tubal sterilization in relation to breast cancer risk

Tubal sterilization methods may damage surrounding tissue, potentially disrupting the ovarian blood supply and hormonal functioning, and may decrease breast cancer risk. We examined this hypothesis, within the Nurses' Health Study, among 77,511 women, aged 30-55 years and free of cancer at the start of follow-up in 1976. We documented 4,176 cases of invasive breast cancer from 1976 to 2000. Cox proportional hazards models, adjusting for multiple breast cancer risk factors, provided rate ratios (RR) and 95% confidence intervals (CI). Overall, tubal sterilization was not associated with breast cancer risk (RR=0.95, 95% CI=0.88-1.03). However, tubal sterilizations performed from 1970 to 1974 were inversely associated with risk (RR=0.84, 95% CI=0.73-0.97), while procedures performed in other years were not associated with risk. Among women with procedures performed in 1970-1974, those who were >or=35 years old at the time of sterilization were at the lowest risk (RR=0.81, 95% CI=0.66-0.98), while younger women had a suggested decreased risk (RR=0.87, 95% CI=0.72-1.06). Overall, tubal sterilization was not associated with breast cancer risk. However, a modest inverse association was observed at a time when the potentially destructive unipolar electrocautery method was commonly used, providing some support for an association between lower lifetime exposure to hormones and a decreased risk of breast cancer.     

Traditional breast cancer risk factors in relation to molecular subtypes of breast cancer

At least four major categories of invasive breast cancer have been reproducibly identified by gene expression profiling: luminal A, luminal B, HER2-type, and basal-like. These subtypes have been shown to differ in their outcome and response to treatment. Whether this heterogeneity reflects the evolution of these subtypes through distinct etiologic pathways has not been clearly defined. We evaluated the association between traditional breast cancer risk factors and risk of previously defined molecular subtypes of breast cancer in the Nurses’ Health Study. This analysis included 2,022 invasive breast cancer cases for whom we were able to obtain archived breast cancer tissue specimens. Tissue microarrays (TMAs) were constructed, and slides were immunostained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6 (CK5/6), and epidermal growth factor receptor (EGFR). Using immunostain results in combination with histologic grade, cases were grouped into molecularly defined subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We observed differences in the association between risk factors and subtypes of breast cancer. In general, many reproductive factors were most strongly associated with the luminal A subtype, although these differences were not statistically significant. Weight gain since age 18 showed significant differences in its association with molecular subtypes (P-heterogeneity = 0.05) and was most strongly associated with the luminal B subtype (P-trend 0.001). Although there was not significant heterogeneity for lactation across subtypes, an inverse association was strongest for basal-like tumors (HR = 0.6, 95% CI 0.4–0.8; P-heterogeneity = 0.88). These results support the hypothesis that different subtypes of breast cancer have different etiologies and should not be considered as a single group. Identifying risk factors for less common subtypes such as luminal B, HER2-type and basal-like tumors has important implications for prevention of these more aggressive subtypes.     

Adolescent diet and risk of breast cancer

Background

Early life exposures, including diet, have been implicated in the etiology of breast cancer.

Methods

A nested case-control study was conducted among participants in the Nurses' Health Study who completed a 24-item questionnaire about diet during high school. There were 843 eligible cases diagnosed between onset of study (1976) and before the return of the high school diet questionnaire (1986), who were matched 10:1 with controls on the basis of age.

Results

Women who had, during adolescence, a higher consumption of eggs, vegetable fat and fiber had a lower risk of breast cancer, whereas risk of breast cancer was increased among women who consumed more butter.

Conclusions

A possible association of elements of adolescent diet with risk of breast cancer is reported, but the findings require confirmation in prospective study.

     

Fertility in relation to the risk of breast cancer

Data from an ongoing case-control study of breast cancer were used to analyze the reason women with breast cancer tend to have a later 1st term pregnancy than controls. The 655 cases with breast cancer had their 1st term birth at a mean age of 25.38 years compared with 24.18 years for controls. The mean interval between age at onset of sexual intercourse and 1st birth was 3.08 years among cases and 2.82 among controls. That is, about 80% of the differences between women with breast cancer and matched controls with regard to age at 1st term birth was accounted for by differences between the groups in age at onset of sexualy activity. Women with breast cancer reported 1.32 years/woman of contraceptive use before 1st pregnancy compared with 1.09 years/woman among controls. However, there was little difference between the 2 groups either in the reported duration of unprotected intercourse preceding the 1st planned conception or in the reported frequency with which intercourse took place during that period. Finally, multivariate analysis indicated that the reason women with breast cancer tended to have a later 1st term pregnancy than controls is because they tended to start intercourse at a later age and to use contraception more. There was no evidence that women with breast cancer were less fertile than unaffected controls. These findings support the view that the higher risk of breast cancer in women having a later 1st birth is attributable to early pregnancy itself having a direct protective effect against the disease.     

Intensity and timing of physical activity in relation to postmenopausal breast cancer risk: the prospective NIH-AARP Diet and Health Study

Background  

Despite strong evidence of an inverse association of physical activity with postmenopausal breast cancer risk, whether a certain intensity or time of life of physical activity is most effective for lowering breast cancer risk is not known.     

Adolescent diet and risk of breast cancer

OBJECTIVES: To investigate the components of adolescent diet that may influence risk of breast cancer as an adult. METHODS: Retrospective cohort study among 47,355 participants in the Nurses Health Study II who answered a 131-item food frequency questionnaire about diet during high school. Cox proportional hazards regression was used to estimate relative risks and 95% confidence intervals among incident cases of breast cancer between 1989 (inception of the study) and 1998 (when high school diet was assessed). RESULTS: Intakes of fat and fiber were not significantly related to risk of breast cancer in multivariate analysis, but increased intake of vegetable fat ( Q (5) versus Q (1) multivariate RR = 0.58, 95% CI (0.38-0.86); test for trend p = 0.005) and vitamin E ( Q (5) versus Q (1) multivariate RR = 0.61, 95% CI (0.42-0.89); test for trend p = 0.003) were associated with a lower risk. A higher dietary glycemic index ( Q (5) versus Q (1) multivariate RR = 1.47, 95% CI (1.04-2.08); test for trend p = 0.01) was associated with increased risk of breast cancer. CONCLUSIONS: The apparent protective effects of vegetable fat and vitamin E and adverse effect of high glycemic foods on risk of breast cancer need confirmation in prospective analyses.     

Adolescent meat intake and breast cancer risk

The breast is particularly vulnerable to carcinogenic influences during adolescence due to rapid proliferation of mammary cells and lack of terminal differentiation. We investigated consumption of adolescent red meat and other protein sources in relation to breast cancer risk in the Nurses' Health Study II cohort. We followed prospectively 44,231 women aged 33–52 years who, in 1998, completed a detailed questionnaire about diet during adolescence. Relative risks (RR) and 95% confidence intervals (95%CI) were estimated using Cox proportional hazard regression. We documented 1132 breast cancer cases during 13‐year follow‐up. In multivariable Cox regression models with major breast cancer risk factors adjustment, greater consumption of total red meat in adolescence was significantly associated with higher premenopausal breast cancer risk (highest vs. lowest quintiles, RR, 1.43; 95%CI, 1.05–1.94; P_trend = 0.007), but not postmenopausal breast cancer. Adolescent intake of poultry was associated with lower risk of breast cancer overall (RR, 0.76; 95%CI, 0.60–0.97; for each serving/day). Adolescent intakes of iron, heme iron, fish, eggs, legumes and nuts were not associated with breast cancer. Replacement of one serving/day of total red meat with one serving of combination of poultry, fish, legumes, and nuts was associated with a 15% lower risk of breast cancer overall (RR, 0.85; 95%CI, 0.74–0.96) and a 23% lower risk of premenopausal breast cancer (RR, 0.77; 95%CI, 0.64–0.92). In conclusion, higher consumption of red meat during adolescence was associated with premenopausal breast cancer. Substituting other dietary protein sources for red meat in adolescent diet may decrease premenopausal breast cancer risk.     

Prospective study of physical activity and risk of postmenopausal breast cancer

Introduction

To prospectively examine the relation of total, vigorous and non-vigorous physical activity to postmenopausal breast cancer risk.

Methods

We studied 32,269 women enrolled in the Breast Cancer Detection Demonstration Project Follow-up Study. Usual physical activity (including household, occupational and leisure activities) throughout the previous year was assessed at baseline using a self-administered questionnaire. Postmenopausal breast cancer cases were identified through self-reports, death certificates and linkage to state cancer registries. A Cox proportional hazards regression was used to estimate the relative risk and 95% confidence intervals of postmenopausal breast cancer associated with physical activity.

Results

During 269,792 person-years of follow-up from 1987 to 1998, 1506 new incident cases of postmenopausal breast cancer were ascertained. After adjusting for potential risk factors of breast cancer, a weak inverse association between total physical activity and postmenopausal breast cancer was suggested (relative risk comparing extreme quintiles = 0.87; 95% confidence interval = 0.74 to 1.02; p for trend = 0.21). That relation was almost entirely contributed by vigorous activity (relative risk comparing extreme categories = 0.87; 95% confidence interval = 0.74 to 1.02; p for trend = 0.08). The inverse association with vigorous activity was limited to women who were lean (ie, body mass index <25.0 kg/m²: relative risk = 0.68; 95% confidence interval = 0.54 to 0.85). In contrast, no association with vigorous activity was noted among women who were overweight or obese (ie, body mass index ≥ 25.0 kg/m²: relative risk = 1.18; 95% confidence interval = 0.93 to 1.49; p for interaction = 0.008). Non-vigorous activity showed no relation to breast cancer (relative risk comparing extreme quintiles = 1.02; 95% confidence interval = 0.87 to 1.19; p for trend = 0.86). The physical activity and breast cancer relation was not specific to a certain hormone receptor subtype.

Conclusions

In this cohort of postmenopausal women, breast cancer risk reduction appeared to be limited to vigorous forms of activity; it was apparent among normal weight women but not overweight women, and the relation did not vary by hormone receptor status. Our findings suggest that physical activity acts through underlying biological mechanisms that are independent of body weight control.     

Timing of weight gain in relation to breast cancer risk

Excessive weight gain in women at the time of intense hormonalchange can result in metabolic dysfunction. The metabolic/endocrineeffect of puberty, pregnancy or menopause on breast tissue ‘aging’is likely tobe more relevant to a woman's breast cancer riskthan is her degree of obesity at the time when the cancer presents.Experimental evidence suggests that the susceptibility of mammarytissue to carcinogenesis is greatest in early adultlife, andmultiple studies show that a history of weight gain in earlyadult life is associated with increased breastcancer risk inWestern women. Excessive weight gain in that age group is associatedwith the development of hyperinsulinaemia in individuals withgenetic susceptibility to insulin resistance. The insulin resistance syndrome may be a metabolic link betweenweight gain and breast cancer risk in Western women. Some studiessuggest that in postmenopausal women, hyperinsulinaemia is relatedmore to overall obesity, whereas in premenopausal women it isrelated more to abdominal localisation of fat. This may explainwhy an increased body mass index is a risk marker for breastcancer in postmenopausal but not premenopausal women. (A premenopausalwoman withanaverage body mass index may have a large intra-abdominalfat mass associated with the presence of hyperinsulinaemia.)Itis hypothesised thatovernutrition and inadequate physical exercisefavour the development of hyperinsulinaemia and also increasebreast cancerrisk in women with a genetic susceptibility toboth conditions. The hypothesis can betested by specific interventionstudies. breast cancer, aetiology, hyperinsulinaemia, obesity, weight gain     

Loss of heterozygosity in benign breast epithelium in relation to breast cancer risk

The multistage model of breast carcinogenesis suggests that errors in DNA replication and repair generate diversity in the breast epithelium (the mutator phenotype), resulting in selection and expansion of premalignant clones with an acquired survival advantage. We measured loss of heterozygosity (LOH) in breast epithelial cells obtained by random fine-needle aspiration (FNA) biopsy from 30 asymptomatic women whose risk of breast cancer had been defined by the Gail model. Polymorphic microsatellite markers were selected on the basis of their relevance to breast cancer. Breast epithelium of 11 (37%) of 30 women had normal cytology, and that of 19 (63%) had proliferative cytology (eight with atypia and 11 without atypia). LOH was detected in two women with normal cytology and in 14 women (seven with atypia and seven without atypia) with proliferative cytology (P =.007). The frequency of LOH was associated with the cytological diagnosis, as well. The mean proportion (range) of informative markers demonstrating LOH was 0.02 (0-0.20) for the 11 women with normal cytology, as compared with 0.15 (0-0.50) for the 19 women with proliferative cytology (P =.02). Mean lifetime risk for developing breast cancer, as calculated by the Gail model, was 16.7% for women with no LOH compared with 22.9% for women with any LOH (P =.05). These observations support a multistage model of breast carcinogenesis where the initiating events are those that result in genomic instability. Accurate individualized breast cancer risk assessment may be possible based on molecular analysis of breast epithelial cells obtained by random FNA.     

Polymorphisms in DNA repair genes,recreational physical activity and breast cancer risk

The mechanisms driving the inverse association between recreational physical activity (RPA) and breast cancer risk are complex. While exercise is associated with increased reactive oxygen species production it may also improve damage repair systems, particularly those that operate on single‐strand breaks including base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR). Of these repair pathways, the role of MMR in breast carcinogenesis is least investigated. Polymorphisms in MMR or other DNA repair gene variants may modify the association between RPA and breast cancer incidence. We investigated the individual and joint effects of variants in three MMR pathway genes (MSH3, MLH1 and MSH2) on breast cancer occurrence using resources from the Long Island Breast Cancer Study Project. We additionally characterized interactions between RPA and genetic polymorphisms in MMR, BER and NER pathways. We found statistically significant multiplicative interactions (p < 0.05) between MSH2 and MLH1, as well as between postmenopausal RPA and four variants in DNA repair (XPC‐Ala499Val, XPF‐Arg415Gln, XPG‐Asp1104His and MLH1‐lle219Val). Significant risk reductions were observed among highly active women with the common genotype for XPC (OR = 0.54; 95% CI, 0.36–0.81) and XPF (OR = 0.62; 95% CI, 0.44–0.87), as well as among active women who carried at least one variant allele in XPG (OR = 0.46; 95% CI, 0.29–0.77) and MLH1 (OR = 0.46; 95% CI, 0.30–0.71). Our data show that women with minor alleles in both MSH2 and MLH1 could be at increased breast cancer risk. RPA may be modified by genes in the DNA repair pathway, and merit further investigation.     

Lifetime physical activity and breast cancer risk in the Shanghai Breast Cancer Study

Overall physical activity in adolescence and adulthood, and changes in activity over the lifespan were analysed by in-person interviews among 1459 women newly diagnosed with breast cancer and 1556 age-matched controls in urban Shanghai. Physical activity from exercise and sports, household, and transportation (walking and cycling) was assessed in adolescence (13-19 y) and adulthood (last 10 y), as was lifetime occupational activity. Logistic regression was used to estimate odds ratios (OR) and 95% confidence limits (OR (95% CL)) while controlling for confounders. Risk was reduced for exercise only in adolescence (OR = 0.84 (0.70-1.00)); exercise only in adulthood (OR = 0.68 (0.53-0.88)), and was further reduced for exercise in both adolescence and adulthood (OR = 0.47 (0.36-0.62)). Graded reductions in risk were noted with increasing years of exercise participation (OR(1-5 yrs)= 0.81 (0.67-0.94); OR(6-10 yrs)= 0.74 (0.59-0.93); OR(11-15 yrs)= 0.55 (0.38-0.79); OR(16 + yrs)= 0.40 (0.27-0.60);P(trend,)< 0.01). Lifetime occupational activity also was inversely related to risk (P(trend)< 0.01). These findings demonstrate that consistently high activity levels throughout life reduce breast cancer risk. Furthermore, they suggest that women may reduce their risk by increasing their activity levels in adulthood.     

Leisure-time physical activity in relation to breast cancer among young women (Washington, United States)

It has been hypothesized that women who participate in vigorous physical activity may have lower risk of breast cancer due to lower lifetime exposure to ovarian hormones. A population-based case-control study was conducted to investigate the association between leisure-time physical activity and risk of breast cancer among women aged 21 to 45 years. Cases were 747 women diagnosed with invasive breast cancer between 1983 and 1990 in three counties of western Washington state (United States), and were identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) registry. Controls were 961 women selected from the same area by random-digit telephone dialing. Physical activity was assessed through personal interview, with questions on frequency and duration of each type of recreational activity during the two-year period immediately prior to reference date (date of diagnosis for cases and a comparable assigned date for controls) and between ages 12 and 21. For the two-year time period before diagnosis, there was no association with frequency of activity (age-adjusted odds ratio [OR]=0.93, 95 percent confidence interval [CI]=0.71-1.22 for four or more episodes per week cf none), total hours spent in physical activity (age-adjusted OR=0.92, CI=0.71-1.22 for four or more hours per week cf none) or MET (metabolic equivalent energy expenditure unit) (age-adjusted OR=0.95, CI=0.73-1.23 for 18 or more METs per week cf none), nor any trend in risk with increasing activity levels. Similarly, there was no association between leisure activity during adolescence and breast cancer risk. These results were not confounded further by body mass index (wt/ht2), age at menarche, age at first full-term pregnancy, parity, family history of breast cancer, or other measured health behaviors. Our findings do not support a protective effect of leisure-time physical activity either in the adolescent years or in adulthood on breast cancer in young women.     

Polymorphisms in oxidative stress genes, physical activity, and breast cancer risk

Purpose

The mechanisms driving the physical activity–breast cancer association are unclear. Exercise both increases reactive oxygen species production, which may transform normal epithelium to a malignant phenotype, and enhances antioxidant capacity, which could protect against subsequent oxidative insult. Given the paradoxical effects of physical activity, the oxidative stress pathway is of interest. Genetic variation in CAT or antioxidant-related polymorphisms may mediate the physical activity–breast cancer association.

Methods

We investigated the main and joint effects of three previously unreported polymorphisms in CAT on breast cancer risk. We also estimated interactions between recreational physical activity (RPA) and 13 polymorphisms in oxidative stress-related genes. Data were from the Long Island Breast Cancer Study Project, with interview and biomarker data available on 1,053 cases and 1,102 controls.

Results

Women with ≥1 variant allele in CAT rs4756146 had a 23?% reduced risk of postmenopausal breast cancer compared with women with the common TT genotype (OR?=?0.77; 95?% CI?=?0.59–0.99). We observed two statistical interactions between RPA and genes in the antioxidant pathway (p?=?0.043 and 0.006 for CAT and GSTP1, respectively). Highly active women harboring variant alleles in CAT rs1001179 were at increased risk of breast cancer compared with women with the common CC genotype (OR?=?1.61; 95?% CI, 1.06–2.45). Risk reductions were observed among moderately active women carrying variant alleles in GSTP1 compared with women homozygous for the major allele (OR?=?0.56; 95?% CI, 0.38–0.84).

Conclusions

Breast cancer risk may be jointly influenced by RPA and genes involved in the antioxidant pathway, but our findings require confirmation.     

Occupational and leisure time physical activity and the risk of breast cancer

The relationship between occupational and leisure-time activity and the risk of breast cancer was analysed using data from a case–control study conducted in the Swiss Canton of Vaud between 1993 and 1998 on 246 incidents, histologically confirmed breast cancer cases and 374 controls below the age of 75 years, admitted to the same network of hospitals for acute, non neoplastic non hormone-related conditions. For occupational physical activity, the multivariate odds ratios (OR) for the highest versus the lowest level of physical activity were 0.6 (95% confidence interval, CI=0.35–1.04) when aged 15 to 19 years, 0.5 (95% CI=0.26–0.98) when aged 30 to 39 years, and 0.68 (95% CI=0.36–1.28) when aged 50 to 59. For leisure time physical activity, the ORs were 0.4 (95% CI=0.26–0.69), 0.5 (95% CI=0.30–0.81), and 0.4 (95% CI=0.22–0.80) for the highest versus the lowest level, respectively, in the three age groups, and an inverse trend in risk was significant in all groups. This study, based on one of the few European datasets on the issue, further suggests that physical activity is a favourable indicator of breast cancer risk.     

Promoter hypermethylation in benign breast epithelium in relation to predicted breast cancer risk.

INTRODUCTION: The tumor suppressor genes RASSF1A, APC, H-cadherin, RARbeta2, and cyclin D2 are methylated more frequently in breast cancer than in adjacent benign tissue. However, it is unclear whether promoter methylation of tumor suppressor genes in benign breast tissue is associated with an increased risk for breast cancer. METHODS: Promoter hypermethylation was measured in benign and malignant breast samples obtained by fine needle aspiration biopsy from 27 breast cancer patients and 55 unaffected women whose risk of breast cancer had been defined using the Gail, Claus, and BRCAPRO models. RESULTS: Cyclin D2 methylation occurred in 57% of tumor samples but not in corresponding benign breast samples and in only one sample from an unaffected patient (P < 0.0001). RARbeta2 methylation occurred in 32% of benign breast samples from cancer patients but only 9% of similar samples from unaffected women (P = 0.002). Promoter methylation of RASSF1A and APC occurred more frequently (70% and 56%, respectively) in unaffected women at high-risk for breast cancer as defined by the Gail model than in low/intermediate risk women (29% and 20%, P = 0.04 and P = 0.03). Of the Gail model risk factors, only number of prior breast biopsies was highly correlated with APC and RASSF1A methylation (P = 0.0001 and 0.02, respectively). CONCLUSIONS: Since cyclin D2 promoter methylation occurs almost exclusively in tumors, it may be possible to exploit it for the early detection of breast cancer. Promoter methylation of APC, RARbeta2, and RASSF1A in benign breast epithelium is associated with epidemiologic markers of increased breast cancer risk.