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1.  Methods for Assessing and Representing Mammographic Density: An Analysis of 4 Case-Control Studies 
American Journal of Epidemiology  2013;179(2):236-244.
To maximize statistical power in studies of mammographic density and breast cancer, it is advantageous to combine data from several studies, but standardization of the density assessment is desirable. Using data from 4 case-control studies, we describe the process of reassessment and the resulting correlation between values, identify predictors of differences in density readings, and evaluate the strength of the association between mammographic density and breast cancer risk using different representations of density values. The pooled analysis included 1,699 cases and 2,422 controls from California (1990–1998), Hawaii (1996–2003), Minnesota (1992–2001), and Japan (1999–2003). In 2010, a single reader reassessed all images for mammographic density using Cumulus software (Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada). The mean difference between original and reassessed percent density values was −0.7% (95% confidence interval: −1.1, −0.3), with a correlation of 0.82 that varied by location (r = 0.80–0.89). Case status, weight status, age, parity, density assessment method, mammogram view, and race/ethnicity were significant determinants of the difference between original and reassessed values; in combination, these factors explained 9.2% of the variation. The associations of mammographic density with breast cancer and the model fits were similar using the original values and the reassessed values but were slightly strengthened when a calibrated value based on 100 reassessed radiographs was used.
doi:10.1093/aje/kwt238
PMCID: PMC3873107  PMID: 24124193
breast cancer; epidemiologic methods; ethnicity; mammographic density; pooling; risk
2.  Gene variations in oestrogen pathways, CYP19A1, daily 17β-estradiol and mammographic density phenotypes in premenopausal women 
Introduction
High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women.
Methods
Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17β-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17β-estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models.
Results
The minor alleles of rs749292 were positively (P = 0.026), and the minor alleles of rs7172156 were inversely (P = 0.002) associated with daily 17β-estradiol. We observed an 87% lower level of daily 17β-estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m2) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore, the rs749292 minor alleles were inversely associated with absolute mammographic density (P = 0.032). Lean women with rs749292 minor alleles had 70 to 80% lower risk for high absolute mammographic density (>32.4 cm2); Aa: odds ratio (OR) = 0.23 (95% CI 0.07 to 0.75). Lean women with rs7172156 minor homozygous genotype had OR 5.45 for high absolute mammographic density (aa: OR = 5.45 (95% CI 1.13 to 26.3)).
Conclusion
Our findings suggest that two SNPs in CYP19A1, rs749292 and rs7172156, are associated with both daily oestrogen levels and mammographic density phenotypes. BMI may modify these associations, but larger studies are needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0499-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0499-2
PMCID: PMC4303212  PMID: 25522654
3.  Hormone metabolism pathway genes and mammographic density change after quitting estrogen and progestin combined hormone therapy in the California Teachers Study 
Introduction
Mammographic density (MD) is a strong biomarker of breast cancer risk. MD increases after women start estrogen plus progestin therapy (EPT) and decreases after women quit EPT. A large interindividual variation in EPT-associated MD change has been observed, but few studies have investigated genetic predictors of the EPT-associated MD change. Here, we evaluate the association between polymorphisms in hormone metabolism pathway genes and MD changes when women quit EPT.
Methods
We collected mammograms before and after women quit EPT and genotyped 405 tagging single nucleotide polymorphisms (SNPs) in 30 hormone metabolism pathway genes in 284 non-Hispanic white participants of the California Teachers Study (CTS). Participants were ages 49 to 71 years at time of mammography taken after quitting EPT. We assessed percent MD using a computer-assisted method. MD change was calculated by subtracting MD of an ‘off-EPT’ mammogram from MD of an ‘on-EPT’ (that is baseline) mammogram. Linear regression analysis was used to investigate the SNP-MD change association, adjusting for the baseline ‘on-EPT’ MD, age and BMI at time of baseline mammogram, and time interval and BMI change between the two mammograms. An overall pathway and gene-level summary was obtained using the adaptive rank truncated product (ARTP) test. We calculated ‘P values adjusted for correlated tests (PACT)’ to account for multiple testing within a gene.
Results
The strongest associations were observed for rs7489119 in SLCO1B1, and rs5933863 in ARSC. SLCO1B1 and ARSC are involved in excretion and activation of estrogen metabolites of EPT, respectively. MD change after quitting was 4.2% smaller per minor allele of rs7489119 (P = 0.0008; PACT = 0.018) and 1.9% larger per minor allele of rs5933863 (P = 0.013; PACT = 0.025). These individual SNP associations did not reach statistical significance when we further used Bonferroni correction to consider the number of tested genes. The pathway level summary ARTP P value was not statistically significant.
Conclusions
Data from this longitudinal study of EPT quitters suggest that genetic variation in two hormone metabolism pathway genes, SLCO1B1 and ARSC, may be associated with change in MD after women stop using EPT. Larger longitudinal studies are needed to confirm our findings.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0477-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0477-8
PMCID: PMC4318222  PMID: 25499601
4.  Reproductive Factors, Exogenous Hormones, and Pancreatic Cancer Risk in the CTS 
American Journal of Epidemiology  2013;178(9):1403-1413.
Female steroid hormones are hypothesized to play a protective role in pancreatic cancer risk. However, results from epidemiologic studies that examined hormone-related exposures have been inconsistent. The California Teachers Study is a cohort study of female public school professionals that was established in 1995–1996. Of the 118,164 eligible study participants, 323 women were diagnosed with incident invasive pancreatic cancer through December 31, 2009. Multivariable Cox proportional hazards regression methods were used to estimate hazard ratios and 95% confidence intervals for the association of pancreatic cancer risk with reproductive factors and exogenous hormone use. Current users of estrogen-only therapy at baseline (1995–1996) had a lower risk of pancreatic cancer than did participants who had never used hormone therapy (hazard ratio = 0.59, 95% confidence interval: 0.42, 0.84). Use of estrogen-plus-progestin therapy was not associated with the risk of pancreatic cancer. A longer duration of oral contraceptive use (≥10 years of use compared with never use) was associated with an increased risk of cancer (hazard ratio = 1.72, 95% confidence interval: 1.19, 2.49). Reproductive factors, including age at menarche, parity, breastfeeding, and age at menopause, were not associated with pancreatic cancer risk. Our results suggest that increased estrogen exposure through estrogen-only therapy may reduce pancreatic cancer risk in women.
doi:10.1093/aje/kwt154
PMCID: PMC3813312  PMID: 24008905
hormone therapy; oral contraceptives; pancreatic cancer
5.  Hormone metabolism genes and mammographic density in Singapore Chinese women 
Background
Female steroid hormone levels and exogenous hormone use influence breast cancer risk. We investigated the association between genetic variation in the hormone metabolism and signaling pathway and mammographic density (MD), a strong predictor of breast cancer risk.
Methods
We genotyped 161 SNPs in 15 hormone metabolism pathway gene regions and evaluated MD in 2,038 Singapore Chinese women. Linear regression analysis was used to investigate SNP-MD association. An overall pathway summary was obtained using the adaptive ranked truncated product test.
Results
We did not find any of the individually tested SNPs to be associated with MD after a multiple testing correction. There was no evidence of an overall effect on MD of genetic variation in the hormone metabolism pathway.
Conclusions
In this cross-sectional study, genetic variation in hormone metabolism pathway was not associated with MD in Singapore Chinese women.
Impact
Consistent with existing data from Caucasian populations, polymorphisms in hormone pathway genes are not likely to be strong predictors of MD in Asian women.
doi:10.1158/1055-9965.EPI-13-0157
PMCID: PMC4197055  PMID: 23429186
Hormone metabolism; polymorphism; mammographic density; Chinese
6.  Mammographic Breast Density Response to Aromatase Inhibition 
Purpose
Mammographic breast density (MBD) is decreased by tamoxifen, but the effect of aromatase inhibitors (AI) is less clear.
Experimental Design
We enrolled early stage postmenopausal breast cancer patients initiating adjuvant AI therapy and ascertained mammograms before and at an average 10 months of AI therapy. We matched cases to healthy postmenopausal women (controls) from a large mammography screening cohort on age, baseline body mass index, baseline MBD and interval between mammograms. We estimated change in MBD using a computer-assisted thresholding program (Cumulus) and compared differences between cases and matched controls.
Results
In predominantly white women (96%), we found 14% of the 387 eligible cases had a MBD reduction of at least 5% after an average of 10 months of AI therapy. MBD reductions were associated with higher baseline MBD, AI use for more than 12 months and prior postmenopausal hormone use. Comparing each case to her matched control, there was no evidence of an association of change in MBD with AI therapy (median case-control difference among 369 pairs was −0.1% (10th and 90th percentile: −5.9%, 5.2%) p=0.51). Case-control differences were similar by type of AI (p’s 0.41 and 0.56); prior use of postmenopausal hormones (p=0.85); baseline MBD (p=0.55); or length of AI therapy (p=0.08).
Conclusions
In postmenopausal women treated with AIs, 14% of cases had a MBD reduction of >5%, but these decreases did not differ from matched controls. These data suggest that MBD is not a clinically useful biomarker for predicting the value of AI therapy in white postmenopausal women.
doi:10.1158/1078-0432.CCR-12-2789
PMCID: PMC3630282  PMID: 23468058
aromatase inhibitors; mammographic density; breast density; biomarker
7.  Genetic variation in Transforming Growth Factor beta 1 and mammographic density in Singapore Chinese women 
Cancer research  2013;73(6):1876-1882.
Transforming growth factor-beta (TGF-β) plays a critical role in normal mammary development and morphogenesis. Decreased TGF-β signaling has been associated with increased mammographic density. Percent mammographic density (PMD) adjusted for age and body mass index (BMI) is a strong risk factor and predictor of breast cancer risk. PMD is highly heritable, but few genetic determinants have been identified. We investigated the association between genetic variation in TGFB1 and PMD using a cross-sectional study of 2,038 women who were members of the population-based Singapore Chinese Health Study cohort. We assessed PMD using a computer-assisted method. We used linear regression to examine the association between 9 tagging SNPs of TGFB1 and PMD and their interaction with parity, adjusting for age, BMI, and dialect group. We calculated ‘P-values adjusted for correlated tests’ (PACT) to account for multiple testing. The strongest association was observed for rs2241716. Adjusted PMD was higher by 1.5% per minor allele (PACT =0.04). When stratifying by parity, this association was limited to nulliparous women. For nulliparous women, adjusted PMD was higher by 8.6% per minor allele (PACT=0.003; P for interaction with parity=0.002). Three additional TGFB1 tagging SNPs, which were in linkage disequilibrium with rs2241716, were statistically significantly associated with adjusted PMD (PACT<0.05) for nulliparous women. However, none of these three SNPs showed statistically significant association after adjusting for rs2241716. Our data support that TGFB1 genetic variation may be an important genetic determinant of mammographic density measure that predicts breast cancer risk, particularly in nulliparous women.
doi:10.1158/0008-5472.CAN-12-1870
PMCID: PMC3740538  PMID: 23333936
TGFB1; polymorphism; mammographic density; Chinese
8.  Food items contributing most to variation in antioxidant intake; a cross-sectional study among Norwegian women 
BMC Public Health  2014;14:45.
Background
Fruit and vegetable intake has been found to reduce the risk of cardiovascular disease, certain types of cancer and diabetes mellitus. It is possible that antioxidants play a large part in this protective effect. However, which foods account for the variation in antioxidant intake in a population is not very clear. We used food frequency data from a population-based sample of women to identify the food items that contributed most to the variation in antioxidant intake in Norwegian diet.
Methods
We used data from a study conducted among participants in the Norwegian Breast Cancer Screening Program (NBCSP), the national program which invites women aged 50–69 years to mammographic screening every 2 years. A subset of 6514 women who attended the screening in 2006/2007 completed a food frequency questionnaire (FFQ). Daily intake of energy, nutrients and antioxidant intake were estimated. We used multiple linear regression analysis to capture the variation in antioxidant intake.
Results
The mean (SD) antioxidant intake was 23.0 (8.5) mmol/day. Coffee consumption explained 54% of the variation in antioxidant intake, while fruits and vegetables explained 22%. The twenty food items that contributed most to the total variation in antioxidant intake explained 98% of the variation in intake. These included different types of coffee, tea, red wine, blueberries, walnuts, oranges, cinnamon and broccoli.
Conclusions
In this study we identified a list of food items which capture the variation in antioxidant intake among these women. The major contributors to dietary total antioxidant intake were coffee, tea, red wine, blueberries, walnuts, oranges, cinnamon and broccoli. These items should be assessed in as much detail as possible in studies that wish to capture the variation in antioxidant intake.
doi:10.1186/1471-2458-14-45
PMCID: PMC3902183  PMID: 24433390
Antioxidants; Epidemiology; Nutrition; Fruits; Coffee; Vegetables
9.  Alcohol consumption and breast cancer risk among postmenopausal women following the cessation of hormone therapy use: the California Teachers Study 
Background
Alcohol consumption increases breast cancer risk, but its effect may be modified by hormone therapy (HT) use, such that exposure to both may be synergistic. Because many women stopped taking HT after mid-2002, it is important to quantify risks associated with alcohol consumption in the context of HT cessation, as these risks may be more relevant to cancer prevention efforts today.
Methods
Among 40,680 eligible postmenopausal California Teachers Study cohort participants, 660 were diagnosed with invasive breast cancer before 2010. Multivariate Cox proportional hazards regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI).
Results
Increased breast cancer risk associated with alcohol consumption was observed among postmenopausal women who were current HT users (RR=1.60, 95% CI: 1.13–2.26 and RR=2.11, 95% CI: 1.41–3.15 for <20 and ≥20 g/d of alcohol), with risks being similar by HT preparation. Alcohol did not increase risk among women who had stopped using HT within 3 years or 3–4 years before completing the follow-up questionnaire or in the more distant past. Results were similar for ER+ and ER+PR+ tumors; while power was limited, no increase in risk was observed for ER- tumors.
Conclusions
Following the cessation of HT use, alcohol consumption is not significantly associated with breast cancer risk, although a non-significant increased risk was observed among women who never used HT.
Impact
Our findings confirm that concurrent exposure to HT and alcohol has a substantial adverse impact on breast cancer risk. However, after HT cessation, this risk is reduced.
doi:10.1158/1055-9965.EPI-12-0418
PMCID: PMC3721729  PMID: 22832206
breast cancer; alcohol; hormone therapy; cessation; epidemiology
10.  Timing of Menarche and First Full-Term Birth in Relation to Breast Cancer Risk 
American journal of epidemiology  2007;167(2):230-239.
Ages at menarche and first birth are established risk factors for breast cancer. The interval between these ages may also affect risk, since the breast is more susceptible to carcinogenic insults during this period than during the parous period. However, few investigators have studied this relation. Using logistic regression, the authors evaluated associations between the timing of reproductive events and breast cancer risk among 4,013 cases and 4,069 controls enrolled in a multicenter, population-based US case-control study of White and African-American women (1994–1998). For White, parous premenopausal and postmenopausal women, those who had an interval of ≥16 years between the ages of menarche and first birth had 1.5-fold (95% confidence interval (CI): 1.0, 2.2) and 1.4-fold (95% CI: 1.1, 1.8) increased risks of breast cancer, respectively, in comparison with those who had ≤5 years between these ages. Adjusting for age at first birth altered these risk estimates somewhat, to odds ratios of 1.5 (95% CI: 0.8, 2.9) and 1.0 (95% CI: 0.6, 1.5), respectively. These associations were stronger for lobular and hormone-receptor-positive tumors but were absent among premenopausal African-American women. The authors conclude that the interval between age at menarche and age at first birth is associated with the risk of hormonally sensitive types of breast cancer, particularly among White women.
doi:10.1093/aje/kwm271
PMCID: PMC3804121  PMID: 17965112
breast neoplasms; histology; menarche; menopause; pregnancy; premenopause; receptors, estrogen; receptors, progesterone
11.  Oral contraceptive formulation and risk of breast cancer☆,☆☆ 
Contraception  2011;85(4):342-350.
Background
While evidence on the association between oral contraceptive (OC) use and breast cancer generally suggests little or no increased risk, the question of whether breast cancer risk varies by OC formulation remains controversial. Few studies have examined this issue because large samples and extensive OC histories are required.
Study Design
We used data from a multicenter, population-based, case–control investigation. Women aged 35–64 years were interviewed. To explore the association between OC formulation and breast cancer risk, we used conditional logistic regression to derive adjusted odds ratios, and we used likelihood ratio tests for heterogeneity to assess whether breast cancer risk varied by OC formulation. Key OC exposure variables were ever use, current or former use, duration of use and time since last use. To strengthen inferences about specific formulations, we restricted most analyses to the 2282 women with breast cancer and the 2424 women without breast cancer who reported no OC use or exclusive use of one OC.
Results
Thirty-eight formulations were reported by the 2674 women who used one OC; most OC formulations were used by only a few women. We conducted multivariable analyses on the 10 formulations that were each used by at least 50 women and conducted supplemental analyses on selected formulations of interest based on recent research. Breast cancer risk did not vary significantly by OC formulation, and no formulation was associated with a significantly increased breast cancer risk.
Conclusions
These results add to the small body of literature on the relationship between OC formulation and breast cancer. Our data are reassuring in that, among women 35–64 years of age, we found no evidence that specific OC formulations increase breast cancer risk.
doi:10.1016/j.contraception.2011.08.007
PMCID: PMC3790909  PMID: 22067757
Oral contraceptives; Breast cancer; Hormones; Epidemiology; Case–control studies
12.  Higher alcohol intake may modify the association between mammographic density and breast cancer: An analysis of three case-control studies 
Cancer epidemiology  2012;36(5):458-460.
Alcohol consumption and mammographic density are established risk factors for breast cancer. This study examined whether the association of mammographic density with breast cancer varies by alcohol intake. Mammographic density was assessed in digitized images for 1,207 cases and 1,663 controls from three populations (Japan, Hawaii, California) using a computer-assisted method. Associations were estimated by logistic regression. When comparing ever to never drinking, mean density was similar and consumption was not associated with breast cancer risk. However, within the Hawaii/Japan subset, women consuming >1 drink/day had a non-significantly elevated relative risk compared to never drinkers. Also in the Hawaii/Japan population, alcohol intake only modified the association between mammographic density and breast cancer in women consuming >1 drink/day (pinteraction=0.05) with significant risk estimates of 3.65 and 6.58 for the 2nd and 3rd density tertiles as compared to 1.57 and 1.61 for never drinkers in Hawaii/Japan. Although these findings suggest a stronger association between mammographic density and breast cancer risk for alcohol consumers, the small number of cases requires caution in interpreting the results.
doi:10.1016/j.canep.2012.06.007
PMCID: PMC3438372  PMID: 22785031
breast cancer; alcohol; mammographic density; case-control study; pooling
13.  Breast Cancer Receptor Status: Do Results from a Centralized Pathology Laboratory Agree with SEER Registry Reports? 
We investigated the extent to which estrogen receptor (ER) and progesterone receptor (PR) status results from a centralized pathology laboratory agree with ER and PR results from community pathology laboratories reported to two Surveillance, Epidemiology and End Results (SEER) registries (Los Angeles County and Detroit) and whether statistical estimates for the association between reproductive factors and breast cancer receptor subtypes differ by the source of data. The agreement between the centralized laboratory and SEER registry classifications was substantial for ER (κ = 0.70) and nearly so for PR status (κ = 0.60). Among the four subtypes defined by joint ER and PR status, the agreement between the two sources was substantial for the two major breast cancer subtypes (ER−/PR−, κ = 0.69; ER+/PR+, κ = 0.62) and poor for the two rarer subtypes (ER+/PR−, κ = 0.30; ER−/PR+, κ = 0.05). Estimates for the association between reproductive factors (number of full-term pregnancies, age at first full-term pregnancy, and duration of breastfeeding) and the two major subtypes (ER+/PR+ and ER−/PR−) differed minimally between the two sources of data. For example, parous women with at least four full-term pregnancies had 40% lower risk for ER+/PR+ breast cancer than women who had never been pregnant [centralized laboratory, odds ratio, 0.60 (95% confidence interval, 0.39–0.92); SEER, odds ratio, 0.57 (95% confidence interval, 0.38–0.85)]; no association was observed for ER−/PR− breast cancer (both Ptrend > 0.30). Our results suggest that conclusions based on SEER registry data are reasonably reliable for ER+/PR+ and ER−/PR− subtypes.
doi:10.1158/1055-9965.EPI-09-0301
PMCID: PMC3782852  PMID: 19661080
14.  Age at Last Birth in Relation to Risk of Endometrial Cancer: Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium 
American Journal of Epidemiology  2012;176(4):269-278.
Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (Ptrend < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.
doi:10.1093/aje/kws129
PMCID: PMC3491967  PMID: 22831825
endometrial neoplasms; parity; reproductive history
15.  Body Size and the Risk of Postmenopausal Breast Cancer Subtypes in the California Teachers Study Cohort 
Cancer causes & control : CCC  2012;10.1007/s10552-012-9897-x.
Purpose
To evaluate how the association between body size and breast cancer risk varies by tumor receptor subtype, host factors and other exposures among women in the California Teacher Study cohort.
Methods
Among 52,642 postmenopausal women, 2,321 developed invasive breast cancer with known estrogen- and progesterone-receptor status (1,652 ER+PR+, 338 ER+PR−, 312 ER−PR−) between 1995 and 2007. In a subset of 35,529 with waist circumference data, 1,377 developed invasive breast cancer with known ERPR status (991 ER+PR+, 208 ER+PR−, 169 ER−PR−) between 1997 and 2007. Multivariate Cox regression was performed to estimate relative risks (RR) and 95% confidence intervals (CI).
Results
Obesity, adult weight gain of ≥40 pounds, greater abdominal adiposity and greater height increased risk of ER+PR+ breast cancer. The increased risk associated with postmenopausal obesity was limited to those who did not use hormone therapy (HT) at cohort entry (RR=1.37, 95% CI: 1.05–1.78 for BMI ≥30 vs. <25 kg/m2; P-interaction=0.14) and those who were not overweight or obese at age 18 (P-interaction=0.06). The increased risk associated with greater abdominal adiposity was limited to those who were not also overweight or obese (P-interaction=0.01). Neither obesity, abdominal adiposity nor height were associated with the risk of ER−PR− tumors.
Conclusions
The effects of body size on postmenopausal breast cancer risk differed by hormone receptor subtype, and among women with ER+PR+ tumors, by HT use and early adult body size.
doi:10.1007/s10552-012-9897-x
PMCID: PMC3366039  PMID: 22286371
breast cancer; obesity; hormone receptor status; abdominal adiposity; hormone therapy
16.  Variation in Inflammatory Cytokine/Growth-Factor Genes and Mammographic Density in Premenopausal Women Aged 50–55 
PLoS ONE  2013;8(6):e65313.
Background
Mammographic density (MD) has been found to be an independent risk factor for breast cancer. Although data from twin studies suggest that MD has a strong genetic component, the exact genes involved remain to be identified. Alterations in stromal composition and the number of epithelial cells are the most predominant histopathological determinants of mammographic density. Interactions between the breast stroma and epithelium are critically important in the maturation and development of the mammary gland and the cross-talk between these cells are mediated by paracrine growth factors and cytokines. The potential impact of genetic variation in growth factors and cytokines on MD is largely unknown.
Methods
We investigated the association between 89 single nucleotide polymorphisms (SNPs) in 7 cytokine/growth-factor genes (FGFR2, IGFBP1, IGFBP3, TGFB1, TNF, VEGF, IL6) and percent MD in 301 premenopausal women (aged 50 to 55 years) participating in the Norwegian Breast Cancer Screening Program. We evaluated the suggestive associations in 216 premenopausal Singapore Chinese Women of the same age.
Results
We found statistically significant associations between 9 tagging SNPs in the IL6 gene and MD in Norwegian women; the effect ranged from 3–5% in MD per variant allele (p-values = 0.02 to 0.0002). One SNP in the IL6 (rs10242595) significantly influenced MD in Singapore Chinese women.
Conclusion
Genetic variations in IL6 may be associated with MD and therefore may be an indicator of breast cancer risk in premenopausal women.
doi:10.1371/journal.pone.0065313
PMCID: PMC3676419  PMID: 23762340
17.  Mammographic density and risk of breast cancer by adiposity: An analysis of four case-control studies 
The association of mammographic breast density with breast cancer risk may vary by adiposity. To examine effect modification by body mass index (BMI), the authors standardized mammographic density data from four case-control studies (1994–2002) conducted in California, Hawaii, and Minnesota, and Gifu, Japan. The 1,699 cases and 2,422 controls included 45% Caucasians, 40% Asians, and 9% African-Americans. Using ethnic-specific BMI cut points, 34% were classified as overweight and 19% as obese. A single reader assessed density from mammographic images using a computer-assisted method. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) while adjusting for potential confounders. Modest heterogeneity in the relation between percent density and breast cancer risk across studies was observed (pheterogeneity = 0.08). Cases had a greater age-adjusted mean percent density than controls: 31.7% versus 28.5%, respectively (p <0.001). Relative to <20 percent density, the ORs for >35 were similar across BMI groups whereas the OR for 20–35 was slightly higher in overweight (OR = 1.69, 95% CI: 1.28, 2.24) and obese (OR = 1.62, 95% CI: 1.12, 2.33) than in normal weight women (OR = 1.49, 95% CI: 1.11, 2.01). Furthermore, limited evidence of effect modification by BMI of the OR per 10% increase in percent density (pinteraction = 0.06) was observed, including subgroup analyses by menopausal status and in analyses that excluded women at the extremes of the BMI scale. Our findings indicate little, if any, modification by BMI of the effects of breast density on breast cancer risk.
doi:10.1002/ijc.26205
PMCID: PMC3254813  PMID: 21630258
Adiposity; breast cancer incidence; body mass index; ethnicity; mammographic density; risk factor
18.  Variations in Sex Hormone Metabolism Genes, Postmenopausal Hormone Therapy, and Risk of Endometrial Cancer 
We investigated whether variants in sex steroid hormone metabolism genes modify the effect of hormone therapy (HT) on endometrial cancer risk in postmenopausal non-Hispanic white women. A nested-case control study was conducted within the California Teachers Study (CTS). We genotyped htSNPs in six genes involved in the hormone metabolism in 286 endometrial cancer cases and 488 controls. Odds ratio (OR) and 95% confidence interval (CI) were estimated for each haplotype using unconditional logistic regression, adjusting for age. The strongest interaction was observed between duration of estrogen therapy (ET) use and haplotype 1A in CYP11A1 (Pinteraction=0.0027; Pinteraction=0.027 after correcting for multiple testing within each gene). The OR for endometrial cancer per copy of haplotype 1A was 2.00 (95%CI: 1.05-3.96) for long-term ET users and 0.90 (95% CI: 0.69-1.18) for never users. The most significant interaction with estrogen-progestin therapy (EPT) was found for two haplotypes on CYP19A1 and EPT use (haplotype 4A, Pinteraction=0.024 and haplotype 3B, Pinteraction=0.043. However, neither this interaction, nor the ET or EPT interactions for any other genes, was statistically significant after correction for multiple testing. Variations in CYP11A1 may modify the effect of ET use on risk of postmenopausal endometrial cancer; however, larger studies are needed to explore these findings further.
doi:10.1002/ijc.26163
PMCID: PMC3267886  PMID: 21544810
menopausal hormone therapy; genetic polymorphism; hormone metabolism gene; endometrial cancer
19.  Mammographic density, parity and age at first birth, and risk of breast cancer: an analysis of four case-control studies 
Breast Cancer Research and Treatment  2012;132(3):1163-1171.
Mammographic density is strongly and consistently associated with breast cancer risk. To determine if this association was modified by reproductive factors (parity and age at first birth), data were combined from four case-control studies conducted in the United States and Japan. To overcome the issue of variation in mammographic density assessment among the studies, a single observer re-read all the mammograms using one type of interactive thresholding software. Logistic regression was used to estimate odds ratios (OR) while adjusting for other known breast cancer risk factors. Included were 1699 breast cancer cases and 2422 controls, 74% of whom were postmenopausal. A positive association between mammographic density and breast cancer risk was evident in every group defined by parity and age at first birth (OR per doubling of percent mammographic density ranged between 1.20 and 1.39). Nonetheless, the association appeared to be stronger among nulliparous than parous women (OR per doubling of percent mammographic density = 1.39 vs 1.24; P-interaction = 0.054). However, when examined by study location, the effect modification by parity was apparent only in women from Hawaii and when examined by menopausal status, it was apparent in postmenopausal, but not premenopausal, women. Effect modification by parity was not significant in subgroups defined by body mass index or ethnicity. Adjusting for mammographic density did not attenuate the OR for the association between parity and breast cancer risk by more than 16.4% suggesting that mammographic density explains only a small proportion of the reduction in breast cancer risk associated with parity. In conclusion, this study did not support the hypothesis that parity modifies the breast cancer risk attributed to mammographic density. Even though an effect modification was found in Hawaiian women, none was found in women from the other three locations.
doi:10.1007/s10549-011-1929-9
PMCID: PMC3336030  PMID: 22222356
Breast neoplasms; mammographic density; reproductive factors; epidemiology; risk factor; effect modification
20.  Genetic variation in peroxisome proliferator-activated receptor gamma, soy, and mammographic density in Singapore Chinese women 
Background
Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor important for adipogenesis and adipocyte differentiation. Data from animal studies suggest that PPARγ may be involved in breast tumorigenesis, but results from epidemiologic studies on the association between PPARγ variation and breast cancer risk have been mixed. Recent data suggest that soy isoflavones can activate PPARγ. We investigated the inter-relations of soy, PPARγ, and mammographic density (MD), a biomarker of breast cancer risk in a cross-sectional study of 2,038 women who were members of the population-based Singapore Chinese Health Study Cohort.
Methods
We assessed MD using a computer-assisted method. We used linear regression to examine the association between 26 tagging SNPs of PPARγ and their interaction with soy intake and MD. To correct for multiple testing, we calculated P-values adjusted for multiple correlated tests (PACT).
Results
Out of the 26 tested SNPs in the PPARγ, 6 SNPs were individually shown to be statistically significantly associated with MD (PACT=0.004∼0.049). A stepwise regression procedure identified that only rs880663 was independently associated with MD which decreased by 1.89% per minor allele (PACT=0.008).This association was significantly stronger in high soy consumers as MD decreased by 3.97% per minor allele of rs880663 in high soy consumers (PACT=0.006; P for interaction with lower soy intake=0.017).
Conclusions
Our data support that PPARγ genetic variation may be important in determining MD, particularly in high soy consumers.
Impact
Our findings may help to identify molecular targets and lifestyle intervention for future prevention research.
doi:10.1158/1055-9965.EPI-11-1042
PMCID: PMC3408217  PMID: 22301832
PPARγ; PPARG; polymorphism; soy; mammographic density; Chinese
21.  Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk 
Vachon, Celine M. | Scott, Christopher G. | Fasching, Peter A. | Hall, Per | Tamimi, Rulla M. | Li, Jingmei | Stone, Jennifer | Apicella, Carmel | Odefrey, Fabrice | Gierach, Gretchen L. | Jud, Sebastian M. | Heusinger, Katharina | Beckmann, Matthias W. | Pollan, Marina | Fernández-Navarro, Pablo | González-Neira, Anna | Benítez, Javier | van Gils, Carla H. | Lokate, Mariëtte | Onland-Moret, N. Charlotte | Peeters, Petra H.M. | Brown, Judith | Leyland, Jean | Varghese, Jajini S. | Easton, Douglas F. | Thompson, Deborah J. | Luben, Robert N. | Warren, Ruth ML | Wareham, Nicholas J. | Loos, Ruth JF | Khaw, Kay-Tee | Ursin, Giske | Lee, Eunjung | Gayther, Simon A. | Ramus, Susan J. | Eeles, Rosalind A. | Leach, Martin O. | Kwan-Lim, Gek | Couch, Fergus J. | Giles, Graham G. | Baglietto, Laura | Krishnan, Kavitha | Southey, Melissa C. | Le Marchand, Loic | Kolonel, Laurence N. | Woolcott, Christy | Maskarinec, Gertraud | Haiman, Christopher A | Walker, Kate | Johnson, Nichola | McCormack, Valerie A. | Biong, Margarethe | Alnæs, Grethe I.G. | Gram, Inger Torhild | Kristensen, Vessela N. | Børresen-Dale, Anne-Lise | Lindström, Sara | Hankinson, Susan E. | Hunter, David J. | Andrulis, Irene L. | Knight, Julia A. | Boyd, Norman F. | Figueroa, Jonine D. | Lissowska, Jolanta | Wesolowska, Ewa | Peplonska, Beata | Bukowska, Agnieszka | Reszka, Edyta | Liu, JianJun | Eriksson, Louise | Czene, Kamila | Audley, Tina | Wu, Anna H. | Pankratz, V. Shane | Hopper, John L. | dos-Santos-Silva, Isabel
Background
Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biological mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to inter-individual differences in mammographic density measures.
Methods
We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and non-dense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, body mass index (BMI) and menopausal status.
Results
Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (p=0.00005) and adjusted percent density (p=0.001) whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (p=0.003), but not with adjusted dense area (p=0.07).
Conclusion
We identified two common breast cancer susceptibility variants associated with mammographic measures of radio-dense tissue in the breast gland.
Impact
We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association.
doi:10.1158/1055-9965.EPI-12-0066
PMCID: PMC3569092  PMID: 22454379
breast density; breast cancer; genetics; biomarkers; mammography
22.  Mediterranean Dietary Pattern and Risk of Breast Cancer 
PLoS ONE  2013;8(2):e55374.
Background
A Mediterranean diet has a recognized beneficial effect on health and longevity, with a protective influence on several cancers. However, its association with breast cancer risk remains unclear.
Objective
We aimed to investigate whether adherence to a Mediterranean dietary pattern influences breast cancer risk.
Design
The Swedish Women’s Lifestyle and Health cohort study includes 49,258 women aged 30 to 49 years at recruitment in 1991–1992. Consumption of foods and beverages was measured at enrollment using a food frequency questionnaire. A Mediterranean diet score was constructed based on the consumption of alcohol, vegetables, fruits, legumes, cereals, fish, the ratio of unsaturated to saturated fat, and dairy and meat products. Relative risks (RR) for breast cancer and specific tumor characteristics (invasiveness, histological type, estrogen/progesterone receptor status, malignancy grade and stage) associated with this score were estimated using Cox regression controlling for potential confounders.
Results
1,278 incident breast cancers were diagnosed. Adherence to a Mediterranean dietary pattern was not statistically significantly associated with reduced risk of breast cancer overall, or with specific breast tumor characteristics. A RR (95% confidence interval) for breast cancer associated with a two-point increment in the Mediterranean diet score was 1.08 (1.00–1.15) in all women, and 1.10 (1.01–1.21) and 1.02 (0.91–1.15) in premenopausal and postmenopausal women, respectively. When alcohol was excluded from the Mediterranean diet score, results became not statistically significant.
Conclusions
Adherence to a Mediterranean dietary pattern did not decrease breast cancer risk in this cohort of relatively young women.
doi:10.1371/journal.pone.0055374
PMCID: PMC3563544  PMID: 23390532
23.  Bilateral oophorectomy is not associated with increased mortality: the California Teachers Study 
Fertility and sterility  2011;97(1):111-117.
Objective
To investigate the effect of surgical menopause due to bilateral oophorectomy on mortality, in light of evidence that bilateral oophorectomy among premenopausal women rapidly reduces endogenous hormone levels thereby modifying risks of cardiovascular disease and breast cancer.
Design
The California Teachers Study (CTS) is a prospective cohort study of 133,479 women initiated in 1995–1996 through a mailed, self-administered questionnaire. Relative risks (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression.
Subjects
CTS participants who, at baseline, reported having surgical menopause due to bilateral oophorectomy (n=9,785), were compared to participants with natural menopause (n=32,219).
Main outcome measures
We investigated whether bilateral oophorectomy was associated with all-cause, cardiovascular, or cancer mortality, overall and by menopausal hormone therapy (HT) use status.
Results
Among participants younger than 45 years of age at menopause, multivariable relative risks were 0.86 (95% CI, 0.74–1.00), 0.85 (95% CI, 0.66–1.11) and 0.91 (95% CI, 0.67–1.23) for all-cause mortality, cardiovascular mortality and cancer mortality, respectively. Among participants with an age at menopause of 45 years or later, multivariable relative risks were 0.87 (95% CI, 0.80–0.94), 0.83 (95% CI, 0.71–0.96) and 0.84 (95% CI, 0.72–0.98) for all-cause, cardiovascular and cancer mortality, respectively. The association between bilateral oophorectomy and mortality did not differ by baseline status of HT use.
Conclusions
Surgical menopause due to bilateral oophorectomy vs. natural menopause does not increase all-cause, cardiovascular, or cancer mortality.
doi:10.1016/j.fertnstert.2011.10.004
PMCID: PMC3245786  PMID: 22088205
surgical menopause and mortality; bilateral oophorectomy; mortality; California Teachers Study
24.  Physical activity and mammographic density in a cohort of postmenopausal Norwegian women; a cross-sectional study 
SpringerPlus  2012;1(1):75.
Mammographic density (MD) is a strong risk factor for breast cancer and may represent a useful intermediate marker for breast cancer risk. Physical activity (PA) is known to be associated with a reduced risk of breast cancer. If PA is associated with MD then this would be useful for breast cancer prevention studies. MD was assessed on digitized mammograms using a computer assisted method (Madena) in 2218 postmenopausal women. A questionnaire assessed PA, by asking about the duration and intensity of light, moderate, strenuous PA/week. We used multivariate linear regression models to estimate least square means of percent MD by total and intensity of PA with adjustment for confounders. The mean age (± s.d) was 58.4 (±5.3) and mean BMI was 24.6 (±4.6). We observed a statistically significant inverse association between total PA and MD in the over-weight (BMI = 25.0-29.9) women, where mean MD among women with highest activity (>360 mins/week) was 12.6% (95%CI; 11.2%-14.0%), while among women with no activity it was 15.9% (95 CI; 13.6%-18.2%, p for trend = 0.04). There was no association in the other BMI strata. MD was 12.1% (11.2%-13.0%) in the highest group (> 180 mins/week) of moderate/strenuous activity and in the no activity group 14.8% (14.2%-15.5%, p for trend = 0.001) in the over-weight women. There was no association between light PA and MD in all women combined or in any other BMI strata. We found some evidence of an inverse association between PA and MD among overweight women.
doi:10.1186/2193-1801-1-75
PMCID: PMC3565086  PMID: 23397025
Epidemiology; Mammographic density; Physical activity; Breast cancer; Screening
25.  Mammographic screening debate on study design: a need to move the field forward 
BMC Medicine  2012;10:164.
The mammographic screening debate has been running for decades. The temperature of this debate is unusually high, and all participants, regardless of viewpoint, seem to have a conflict of interest. Another unusual aspect of this debate is the focus on study design, and in particular on designs that some think exceeded their usefulness decades ago. What are the questions that remain to be answered in this debate? Are there methodological issues that have not been adequately addressed? Do we have the right tools to provide up-to-date answers to how women can best protect themselves against dying from breast cancer? This commentary discusses some of the current issues.
See related Opinion articles http://www.biomedcentral.com/1741-7015/10/106 and http://www.biomedcentral.com/1741-7015/10/163
doi:10.1186/1741-7015-10-164
PMCID: PMC3599232  PMID: 23234258
breast cancer; mammographic screening; study design

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