Joanne F. Dorgan

Bone Mass and the Risk of Breast Cancer among Postmenopausal Women

BACKGROUND Recent studies have shown a direct relation between serum estrogen levels assessed at a single point in time and the risk of breast cancer, but no evidence links estrogen levels assessed repeatedly over an extended interval to the risk of breast cancer. Bone mass has been proposed as a marker of cumulative exposure to estrogen in women. We therefore studied the association between bone mass and the incidence of breast cancer. METHODS Between 1967 and 1970, 1373 women who were 47 to 80 years old and had no history of breast cancer underwent posteroanterior hand radiography in the Framingham Study. We used radiogrametry to measure the cortical width of each womans second metacarpal. Participants were followed until the end of 1993. All incident cases of breast cancer were confirmed by pathological reports. We used a Cox proportional-hazards model to examine the relation of metacarpal bone mass to the risk of postmenopausal breast cancer. RESULTS Postmenopausal breast cancer developed in 91 subjects. Incidence rates per 1000 person-years increased from 2.0 among the women in the lowest age-specific quartile of metacarpal bone mass to 2.6, 2.7, and 7.0 among the women in the second, third, and highest quartiles, respectively. After adjustments for age and other potential confounding factors, the rate ratios for the risk of breast cancer were 1.0, 1.3, 1.3, and 3.5 from the lowest quartile to the highest (P for trend, <0.001). CONCLUSIONS Women in the highest quartile of bone mass are at higher risk for postmenopausal breast cancer than those in the lowest quartile. The mechanisms underlying this relation are not understood, but cumulative exposure to estrogen may play a part.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

Background:Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood.Methods:Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies.Results:Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer.Conclusion:Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States)

To evaluate relationships of serum carotenoids, α-tocopherol, selenium, and retinol with breast cancer prospectively, we conducted a case-control study nested in a cohort from the Breast Cancer Serum Bank in Columbia, Missouri (United States). Women free of cancer donated blood to this bank in 1977-87. During up to 9.5 years of follow-up (median = 2.7 years), 105 cases of histologically confirmed breast cancer were diagnosed. For each case, two women alive and free of cancer at the age of the cases diagnosis and matched on age and date of blood collection were selected as controls. A nonsignificant gradient of decreasing risk of breast cancer with increasing serum β-cryptoxanthin was apparent for all women. Serum lycopene also was associated inversely with risk, and among women who donated blood at least two years before diagnosis, a significant gradient of decreasing breast cancer risk with increasing lycopene concentration was evident. Amarginally significant gradient of decreasing risk with increasing serum lutein/zeaxanthin also was apparent among these women. We did not observe any evidence for protective effects of α- and β-carotene, α-tocopherol, retinol, or selenium for breast cancer. Results of this study suggest that the carotenoids β-cryptoxanthin, lycopene, and lutein/zeaxanthin may protect against breast cancer.

Serum organochlorine pesticides and PCBs and breast cancer risk: results from a prospective analysis (USA)

Objective: To prospectively evaluate relationships of organochlorine pesticides and polychlorinated biphenyls (PCBs) with breast cancer, we conducted a case-control study nested in a cohort using the Columbia, Missouri Breast Cancer Serum Bank.Methods: Women donated blood in 1977–87, and during up to 9.5 years follow-up, 105 donors who met the inclusion criteria for the current study were diagnosed with breast cancer. For each case, two controls matched on age and date of blood collection were selected. Five DDT [2,2-bis(p-chlorophenyl)-1,1,1- trichloroethane] analogs, 13 other organochlorine pesticides, and 27 PCBs were measured in serum.Results: Women in the upper three quartiles of hexachlorobenzene were at twice the risk of breast cancer compared to those in the lowest quartile. However, there was no evidence for a dose-response relationship, and the association was limited to women whose blood was collected close to the time of diagnosis. Women with higher serum levels of other organochlorine pesticides and PCBs showed no increased risk of breast cancer overall, although positive associations were suggested for PCB-118 and PCB-138 when blood was collected close to the time of diagnosis.Conclusions: Results of this study do not support a role for organochlorine pesticides and PCBs in breast cancer etiology.

Relative risk of prostate cancer for men with affected relatives: systematic review and meta-analysis.

An increased risk of prostate cancer associated with a family history of prostate cancer has been documented in multiple published reports. Risk has been shown to vary by degree of relationship and age of onset of disease in the affected relative. Several studies, using various designs, have estimated the relative risk (RR) for these associations. The purpose of our study was to identify and summarize published reports on the relationship between risk of prostate cancer and family history, which is defined as having a father, brother, any first‐ or second‐degree relative or other relative affected with prostate cancer. A Medline and manual search from 1982 to 2000 identified 24 studies that reported RR and confidence intervals (CI) and satisfied inclusion criteria. Pooled RR estimates based upon a weighted average model were as follows: any affected family member RR = 1.93, CI 1.65–2.26; affected first‐degree relative RR = 2.22, CI 2.06–2.40; affected second‐degree relative RR = 1.88, CI 1.54–2.30; father with prostate cancer RR = 2.12, CI 1.82–2.51; and brother with prostate cancer RR = 2.87, CI 2.21–3.73). Statistical comparison of pooled data demonstrated that the RR is significantly higher for affected brother than for affected father (p < 0.03). A sensitivity analysis demonstrated that these results are robust with respect to population bias. This meta‐analysis confirms that risk of prostate cancer is associated with family history of disease and improves the quantification of this risk.

Serum hormone levels in relation to reproductive and lifestyle factors in postmenopausal women (United States).

Objectives: Endogenous sex hormones are thought to be involved in breast and endometrial cancers, but few studies have evaluated the relationships between hormones and risk factors for these diseases. Methods: We related serum hormone and sex-hormone binding globulin (SHBG) levels to reproductive and lifestyle risk factors in a cross-sectional study of 125 postmenopausal women in five geographic regions of the United States. Results: The estrogens were associated positively, while SHBG was associated negatively with body mass index (wt/ht 2). Estrone, (E1), estrone sulfate, and bioavailable estradiol (BioE2) were inversely associated with height. Androstenedione was positively associated with age at menopause, while androstenedione, E1, estradiol, and BioE2 were inversely associated with age at menarche. Weekly alcohol drinkers had higher hormone levels, and lower SHBG levels than those who abstained. Androstenedione and E1 decreased with increasing levels of nonrecreational activity. Conclusions: Several of these findings support the hypothesis that breast and endometrial cancer risk factors are mediated, in part, through increased endogenous hormone levels. The androstenedione findings are of interest in light of studies relating androstenedione to endometrial and possibly breast cancer. An association of age at menarche with E2, independent of androstenedione, may reflect increased aromatase activity in women with earlier menarche.

Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies

BACKGROUND Associations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies. METHODS Individual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided. FINDINGS We included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1·19, 95% CI 1·06-1·35), calculated free oestradiol (1·17, 1·03-1·33), oestrone (1·27, 1·05-1·54), androstenedione (1·30, 1·10-1·55), dehydroepiandrosterone sulphate (1·17, 1·04-1·32), testosterone (1·18, 1·03-1·35), and calculated free testosterone (1·08, 0·97-1·21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1·00, 95% CI 0·92-1·09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors. INTERPRETATION Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.

Circulating Carotenoids and Risk of Breast Cancer: Pooled Analysis of Eight Prospective Studies

BACKGROUND Carotenoids, micronutrients in fruits and vegetables, may reduce breast cancer risk. Most, but not all, past studies of circulating carotenoids and breast cancer have found an inverse association with at least one carotenoid, although the specific carotenoid has varied across studies. METHODS We conducted a pooled analysis of eight cohort studies comprising more than 80% of the worlds published prospective data on plasma or serum carotenoids and breast cancer, including 3055 case subjects and 3956 matched control subjects. To account for laboratory differences and examine population differences across studies, we recalibrated participant carotenoid levels to a common standard by reassaying 20 plasma or serum samples from each cohort together at the same laboratory. Using conditional logistic regression, adjusting for several breast cancer risk factors, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using quintiles defined among the control subjects from all studies. All P values are two-sided. RESULTS Statistically significant inverse associations with breast cancer were observed for α-carotene (top vs bottom quintile RR = 0.87, 95% CI = 0.71 to 1.05, P(trend) = .04), β-carotene (RR = 0.83, 95% CI = 0.70 to 0.98, P(trend) = .02), lutein+zeaxanthin (RR = 0.84, 95% CI = 0.70 to 1.01, P(trend) = .05), lycopene (RR = 0.78, 95% CI = 0.62 to 0.99, P(trend) = .02), and total carotenoids (RR = 0.81, 95% CI = 0.68 to 0.96, P(trend) = .01). β-Cryptoxanthin was not statistically significantly associated with risk. Tests for heterogeneity across studies were not statistically significant. For several carotenoids, associations appeared stronger for estrogen receptor negative (ER(-)) than for ER(+) tumors (eg, β-carotene: ER(-): top vs bottom quintile RR = 0.52, 95% CI = 0.36 to 0.77, P(trend) = .001; ER(+): RR = 0.83, 95% CI = 0.66 to 1.04, P(trend) = .06; P(heterogeneity) = .01). CONCLUSIONS This comprehensive prospective analysis suggests women with higher circulating levels of α-carotene, β-carotene, lutein+zeaxanthin, lycopene, and total carotenoids may be at reduced risk of breast cancer.

Measurement of steroid sex hormones in serum: a comparison of radioimmunoassay and mass spectrometry.

Concern has been raised about the adequacy of radioimmunoassays to measure steroid sex hormones in population studies. We compared steroid sex hormone measurements in serum by radioimmunoassay with mass spectrometry. Four male and four female serum pools with known relative concentrations of steroid sex hormones were measured multiple times by both methods. Because measurements are expected to increase linearly with concentration for each sex, we examined whether the linear regressions of hormone measurements on concentration were the same for radioimmunoassay and mass spectrometry. Estradiol, estrone, androstenedione, testosterone, and dehydroepiandrosterone sulfate were measured in female pools; testosterone, dihydrotestosterone, androstenedione, and dehydroepiandrosterone sulfate were measured in male pools. Regression slopes for radioimmunoassay and mass spectrometry measurements were comparable for all hormones except androstenedione, which had a steeper slope when measured by mass spectrometry (P < or = 0.02). Intercepts for radioimmunoassay and mass spectrometry were similar and close to zero for estradiol, androstenedione, dehydroepiandrosterone sulfate, and in male samples, testosterone. For testosterone in female samples, estrone, and dihydrotestosterone, radioimmunoassay and mass spectrometry intercepts differed significantly. Standard deviations of individual measurements by radioimmunoassay and mass spectrometry differed by hormone and serum concentration; neither method consistently measured hormone concentrations with less variability. Our findings suggest that although absolute concentrations may differ for some hormones, radioimmunoassay and mass spectrometry can yield similar estimates of between subject differences in serum concentrations of most steroid sex hormones commonly measured in population studies. Relative power of studies using radioimmunoassay and mass spectrometry will depend on the hormones measured and their serum concentrations.

The relation of reported alcohol ingestion to plasma levels of estrogens and androgens in premenopausal women (Maryland, United States)

We undertook a cross-sectional study in 107 premenopausal women in Maryland (United States) of alcohol intake and hormonal status in order to evaluate whether plasma hormone levels might mediate the reported positive relation between alcohol ingestion and breast cancer risk. Alcohol ingestion was estimated using a drinking pattern questionnaire, a food frequency questionnaire, and seven-day food records. Fasting blood specimens were collected on days 5–7, 12–15, and 21–23 of each participants menstrual cycle and pooled to create follicular, midcycle, and luteal phase samples, respectively, for analysis. Estrone, estrone sulfate, estradiol, androstenedione, and dehydropiandrosterone sulfate (DHEAS) in plasma were measured by radioimmunoassay, and sex-hormone binding globulin (SHBG) was measured by an immunoradiometric assay. After adjusting for age, weight, and total energy intake, alcohol ingestion was not associated with plasma estrogens in the follicular, midcycle, or luteal phases of the menstrual cycle, nor with the level of SHBG or DHEAS in plasma averaged from the three phases of the cycle. Alcohol, however, was significantly positively associated with the average level of plasma androstenedione. Based on these cross-sectional findings among premenopausal women, the increased risk of breast cancer related to alcohol ingestion does not appear to be mediated by elevated plasma estrogen levels. Androstenedione, however, may mediate the alcohol/breast cancer-association.