Mammographic Density In Postmenopausal Women Research Articles

The Correlation Between Progesterone and Mammographic Density in Postmenopausal Women: A Systematic Review of the Literature and Meta-Analysis.

Higher mammographic breast density in premenopausal and postmenopausal women is related to a higher breast cancer risk. In this review, we analyze the correlation between estrogen, progesterone, and mammographic density in postmenopausal women and clarify whether these findings are consistent across different types of mammographic breast density. We extracted data concerning mammographic density increases in the populations treated with estrogen-only hormone replacement therapy and those treated with estrogen and progestin hormone replacement therapy. Postmenopausal women treated with estrogen and progesterone regimens had a statistically significant lesser mammographic density increase than estrogen-only hormone replacement therapy regimens.

Platelet Activation In Situ in Breasts at High Risk of Cancer: Relationship with Mammographic Density and Estradiol.

High mammographic density in postmenopausal women is an independent risk factor for breast cancer by undetermined mechanisms. No preventive therapy for this risk group is available. Activated platelets release growth factors that modulate the microenvironment into a protumorigenic state. Estrogens may affect the risk of breast cancer and platelet function. Whether platelets are activated in situ in breast cancer or in normal breast tissue at high risk of breast cancer and the association to estradiol remains elusive. To investigate whether platelets are activated in situ in breast cancers and in dense breast tissue of postmenopausal women and explore correlations between estradiol, released platelet factors, and inflammatory proteins. Sampling of in vivo proteins was performed using microdialysis in a total of 71 women: 10 with breast cancer, 42 healthy postmenopausal women with different breast densities, and 19 premenopausal women. Our data demonstrate increased levels of coagulation factors in dense breast tissue similar to that found in breast cancers, indicating excessive platelet activation. Premenopausal breasts exhibited similar levels of coagulation factors as postmenopausal dense breasts. Out of 13 coagulations factors that were upregulated in dense breasts, 5 exhibited significant correlations with estradiol, both locally in the breast and systemically. In breast tissue, positive correlations between coagulation factors and key inflammatory proteins and matrix metalloproteinases were detected. Breast density, not estradiol, is the major determinant of local platelet activation. Inactivation of platelets may be a therapeutic strategy for cancer prevention in postmenopausal women with dense breasts.

Abstract 3488: Associations of circulating hormones with mammographic density in postmenopausal women referred to diagnostic breast biopsy

Abstract Introduction Elevated mammographic density (MD) is a strong and independent risk factor for breast cancer, though underlying mechanisms are unclear. Prior studies have suggested that increased cumulative exposure to sex-steroid hormones and growth factors may impact both MD and MD-related breast cancer risk; however, most studies have only evaluated individual hormones. In this study, we simultaneously explored the relationship between 29 circulating hormones and growth factors with MD among postmenopausal women undergoing diagnostic breast biopsy. Methods We used data from 89 postmenopausal women, aged 44-65, who had complete measurements of 29 serum hormones from a single pre-biopsy blood draw (i.e., sex-steroid hormones: 15 estrogen/estrogen metabolites, 7 progesterone/progesterone metabolites; and non-sex hormones: insulin-like growth factor I and binding proteins (IGFBPs) 2-7). Volumetric MD (% fibroglandular volume) was assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Sufficient dimension reduction methods were used to compute a composite marker score that accommodates correlations among hormones and their relationship to MD. Backward elimination was applied to select log-transformed hormones contributing to the score at α=0.05; multivariable linear regression was used to further examine associations between selected hormones and MD within a single model, adjusting for age and BMI. Results Pearson correlations between hormones were moderate-to-strong. Dimension reduction methods identified 6 hormones as associated with MD (p<0.05): estradiol, 2-hydroxyestradiol, 2-methoxyestrone, 16-ketoestradiol, IGFBP-2, and 17α-hydroxyprogesterone, in models that considered MD as either continuous or dichotomous (>median vs. ≤median); BMI was consistently identified as the most significant predictor of MD (P <0.0001). In a multivariable linear regression model that included these 6 hormones, in addition to age and BMI, higher levels of 2-methoxyestrone, IGFBP-2, and 17α-hydroxyprogesterone were significantly associated with increased MD, whereas higher levels of age and BMI were significantly associated with lower MD. Conclusions We identified 6 out of 29 correlated hormones that were significantly associated with MD among postmenopausal women. For several, the directions of their associations with MD were comparable to those observed in prior studies that have separately evaluated these hormones in relation to breast cancer risk. We plan to further explore how circulating hormones concurrently affect MD in premenopausal women, accounting for menstrual cycle phase. Incorporation of dimension reduction methods in studies of multiple correlated hormones can help uncover new etiologic insights into the role of hormones and growth factors in MD and breast carcinogenesis and inform strategies for prevention. Citation Format: Shaoqi Fan, Ruth M. Pfeiffer, Manila Hada, Roni T. Falk, Maeve Mullooly, Hannah Oh, Berta Geller, Pamela Vacek, Donald Weave, John Shepherd, Jeff Wang, Sally Herschorn, Louise A. Brinton, Xia Xu, Mark E. Sherman, Britton Trabert, Gretchen L. Gierach. Associations of circulating hormones with mammographic density in postmenopausal women referred to diagnostic breast biopsy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3488.

Serum Levels of Commonly Detected Persistent Organic Pollutants and Per- and Polyfluoroalkyl Substances (PFASs) and Mammographic Density in Postmenopausal Women.

There are little epidemiological data on the impact of persistent organic pollutants (POPs) and endocrine disruptors on mammographic density (MD), a strong predictor of breast cancer. We assessed MD in 116 non-Hispanic white post-menopausal women for whom serum concentrations of 23 commonly detected chemicals including 3 polybrominated diphenyl ethers (PBDEs), 8 per- and polyfluoroalkyl substances (PFASs), and 12 polychlorinated biphenyls (PCBs) had been measured. Linear regression analyses adjusting for potential confounders were used to examine the associations between the levels of the chemical compounds, modeled as continuous and dichotomized (above/below median) variables, and square-root-transformed MD. None of the associations were statistically significant after correcting for multiple testing. Prior to correction for multiple testing, all chemicals with un-corrected p-values < 0.05 had regression coefficients less than zero, suggesting inverse associations between increased levels and MD, if any. The smallest p-value was observed for PCB-153 (regression coefficient for above-median vs. below-median levels: −0.87, un-corrected p = 0.008). Neither parity nor body mass index modified the associations. Our results do not support an association between higher MD and serum levels of PBDEs, PCBs, or PFASs commonly detected in postmenopausal women.

Abstract 1585: Genetic variations in progesterone receptor (PGR)-related genes and mammographic density in premenopausal women: Are the associations mediated by circulating progesterone

Abstract BACKGROUND: Progesterone is a proliferative hormone in the breast. Combined estrogen plus progestin use in postmenopausal women increases mammographic density; a very strong risk for breast cancer. Circulating progesterone and genetic variations in progesterone receptor (PGR)-related genes are positively associated with mammographic density in postmenopausal women, but there are limited data in premenopausal women, with conflicting results. Notably, besides hormone therapy, genetic variation in PGR genes are known to modulate circulating progesterone levels. We, therefore, investigated the associations of genetic variations in PGR-related genes (PGR and Progesterone Receptor Membrane Component 1 (PGRMC1) with mammographic density in premenopausal women and determine, for the first time, whether these associations are mediated via circulating progesterone. METHODS: We genotyped 179 PGR-related single nucleotide polymorphisms (SNPs) (155 for PGR and 24 for PGRMC1 - 17 of which were synonymous variants and were filtered) in 364 cancer-free premenopausal women who had screening mammography at the Joanne Knight Breast Health Center at Washington University School of Medicine, St. Louis in 2016. We used Volpara to determine volumetric percent density, and dense volume. Variants were coded in dominant mode of inheritance. For causal mediation analysis, multivaraite linear regression models were applied to both the mediator (circulating PGR in logarithm scale) with variants and volumetric percent density, and dense volume with variant, PGR in logarithm scale and their interaction, both adjusting for age, body mass index, family history of breast cancer, and parity. The causal mediation effect, direct effect and total effect, by gentoype and averaged across genotypes were estimated with 95% confidence intervals and p values. Significance was claimed with p-value≤0.05. RESULTS: The mean age of the study participants was 47.5 years. Most participants (42.1%) had volumetric percent density between 3.5-7.5%, equivalent to BI-RADS® category b. Rs2020875 (PGR11) had a positive average direct effect (estimate=0.22, 95% CI, 0.016~0.44, p-value=0.024) and rs645213 (PGR11) had a borderline inverse direct effect (-0.25, -0.48~0.0004, p-value=0.052) on volumetric percent density. Further, rs11224565 (PGR11): 0.19, 0.04~0.34, p-value=0.028 had positive average direct effects on dense volume. None of the mediation effects were statistically signficiant. CONCLUSIONS: SNPs in PGR-related genes are associated with mammographic density in premenopausal women. Circulating progesterone levels did not mediate the associations between variants in PGR-related genes and mammographic density. Larger studies are needed to confirm our findings. Citation Format: Favour A. Akinjiyan, Yunan Han, Jingqin R. Luo, Aldi Kraja, Catherine M. Appleton, Graham A. Colditz, Adetunji T. Toriola. Genetic variations in progesterone receptor (PGR)-related genes and mammographic density in premenopausal women: Are the associations mediated by circulating progesterone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1585.

A Longitudinal Study of the Association between Mammographic Density and Gene Expression in Normal Breast Tissue

High mammographic density (MD) is associated with a 4–6 times increase in breast cancer risk. For post-menopausal women, MD often decreases over time, but little is known about the underlying biological mechanisms. MD reflects breast tissue composition, and may be associated with microenvironment subtypes previously identified in tumor-adjacent normal tissue. Currently, these subtypes have not been explored in normal breast tissue. We obtained biopsies from breasts of healthy women at two different time points several years apart and performed microarray gene expression analysis. At time point 1, 65 samples with both MD and gene expression were available. At time point 2, gene expression and MD data were available from 17 women, of which 11 also had gene expression data available from the first time point. We validated findings from our previous study; negative correlation between RBL1 and MD in post-menopausal women, indicating involvement of the TGFβ pathway. We also found that breast tissue samples from women with a large decrease in MD sustained higher expression of genes in the histone family H4. In addition, we explored the previously defined active and inactive microenvironment subtypes and demonstrated that normal breast samples of the active subtype had characteristics similar to the claudin-low breast cancer subtype. Breast biopsies from healthy women are challenging to obtain, but despite a limited sample size, we have identified possible mechanisms relevant for changes in breast biology and MD over time that may be of importance for breast cancer risk and tumor initiation.

Mammographic density and breast cancer risk: a mediation analysis.

BackgroundHigh mammographic density (MD) is a strong risk factor for breast cancer. However, it is unclear whether high MD is an intermediate phenotype or whether breast cancer risk factors influence breast cancer risk and MD independently.MethodsOur study population included 1290 invasive breast cancer cases and 3422 controls from the Nurses’ Health Studies. We estimated the percent of the total association between the risk factor and breast cancer that was mediated by MD.ResultsIn both pre- and postmenopausal women, the association between history of biopsy-confirmed benign breast disease and risk was partially mediated by percent MD (percent mediated (PM) = 17 %, p < 0.01 and PM = 33 %, p = 0.04, respectively). In premenopausal women, the associations between early life body size (adolescent somatotype and BMI at age 18) and breast cancer risk were substantially mediated by percent MD (PM = 73 %, p = 0.05 and PM = 82 %, p = 0.04, respectively). In postmenopausal women, the proportion of the associations of childhood somatotype and adolescent somatotype that were mediated by percent MD were lower (PM = 26 %, p = 0.01 for both measures). Hormone therapy use at mammogram was significantly mediated by percent MD in postmenopausal women (PM = 22 %, p < 0.01). Associations with other risk factors, such as age at menarche or family history of breast cancer, were not mediated by percent MD.ConclusionsPercent MD partially mediated some of the associations between risk factors and breast cancer, though the magnitude varied by risk factor and menopausal status. These findings suggest that high MD may be an intermediate in some biological pathways for breast cancer development.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0750-0) contains supplementary material, which is available to authorized users.

Factors Associated with Mammographic Density in Postmenopausal Women.

ObjectivesBreast density increases the risk of breast cancer, but also in the interpretation of mammography is also important. This study examine the risk factors affecting breast density in postmenopausal women.MethodsBetween January 2013 and January 2014, 215 patients admitted to The Clinics of Gynecology and Obstetrics with complaints of menopause were taken. According to the results of mammography, Group I (non-dense, n = 175) and Group II (dense, n = 40) were created. The informations of the caseswere analyzed retrospectively.ResultsIn Group I, body mass index (BMI), number of pregnancies, parity were significantly higher than group II (P < 0.05). In group II, the withdrawal period of menstruation and progesterone levels were significantly higher (P < 0.05). In logistic regression analysis, BMI for dense breasts and number of pregnancies were found to be an independent risk factor (P < 0.05).ConclusionIncreased BMI, pregnancy and parity, result of reduction in density , but longer duration of menopause and increased progesterone cause an increase in density. BMI and the number of pregnancy was found to be independent risk factors for reducing breast density.

Highlights of This Issue

Twin studies suggest that variation in mammographic density (MD) is genetically determined. To examine if breast cancer susceptibility genes affect MD, Ellingjord-Dale and colleagues assessed breast cancer gene SNPs and MD in postmenopausal women from the Norwegian Breast Cancer Screening Program. They determined the association between 17 established breast cancer gene variants and MD. The authors identified two gene variants (6q25.1-rs9383938 and TXNRD2-rs8141691) with statistically significant associations with percent MD. This study provides novel evidence of possible MD genetic–environmental interactions.The clinical utility of mammographic density is hampered by the lack of objective and automated measures. Brand and colleagues evaluated the performance of Volpara, a fully automated volumetric method to assess mammographic density. The study included 41,102 women and percent and absolute dense volume were estimated from raw digital mammograms. The method showed good agreement of percent and absolute dense volumes across several mammography systems. In a high-throughput setting, Volpara performed well and is a promising tool for widespread breast cancer risk assessment.High nicotine metabolite ratios (NMR) are strongly associated with heavy smoking and low smoking cessation rates. CYP2A6-gene variants influence NMR, as do demographic and hormonal factors, but the sizes of these effects were not clear. Chenoweth and colleagues analyzed demographic and hormonal sources of variation on NMR in active smokers. They report that these two factors contributed little to total NMR and are unlikely to cause NMR misclassification.Smoking is detrimental to recovery and survival from cancer, but many cancer survivors continue to smoke. Information is lacking on smoking patterns of cancer survivors many years after diagnosis. Westmaas and colleagues performed cross-sectional analyses among survivors of 10 cancers recruited from cancer registries. Nine years after diagnosis, fewer than 10% of all survivors were current smokers but most of these current smokers smoked daily. Current smoking was associated with younger age, lower education and income, and greater alcohol consumption. This study indicates that smoking can persist long after initial cancer diagnosis.

Correction: Estrogen Metabolism and Mammographic Density in Postmenopausal Women: A Cross-Sectional Study

Correction: Estrogen Metabolism and Mammographic Density in Postmenopausal Women: A Cross-Sectional Study

Clinical Factors Associated with High Mammographic Density in Postmenopausal Women and their Relationship with Dinucleotide Gtn Repeat Polymorphism in the Estrogen Receptor Alpha Gene

Introduction: Epidemiological evidence shows that variations in estrogen receptor (ER) genes cause alterations in the effect of estrogen in breast tissue, which may explain individual variations in mammographic density. High mammographic density (HMD) is an important risk factor for breast cancer. Objective: To evaluate the association of clinical features and polymorphism of ERα-(GT)n gene and mammographic density in post-menopause women. Casuistry and method: According to ACR-BIRADS criteria, 463 post-menopause women of ages between 45 and 60 have been prospectively analyzed through computer objective assessment, being 308 with HMD and 155 with non-dense breasts (Control group). The participants had not used hormone therapies 12 months prior to assessments and had no personal history of breast cancer. Risk factors for breast cancer considered by other studies also have been analyzed in this paper. Peripheral blood samples have been obtained to extract DNA and to analyze the presence of polymorphism in the ERα-(GT)n promoter region. Results: From the risk factors considered for breast cancer, there was association with high mammographic density in: age (p=0.005); waist circumference (p=0.001); number of pregnancies (p=0.007); age at 1st birth (p=0.035); family history (p=0.035); time after menopause (p=0.007), and body mass index (p=0.022). Differences between HMD and controls for distribution of tanden repeats polymorphism genotype STRs-(GT)n (p=0.151) was verified as non-significant. Conclusion: Our data showed that age, waist circumference, number of pregnancies, age at 1st birth, family history of breast cancer, time after menopause, and body mass index were associated to post-menopause HMD. However, tanden repeats polymorphism (GT)n may not be associated with HMD but it will be necessary studies with a larger number of cases as we have obtained few genotypes (GT)n higher than 17 repeats.

Influence of Lifestyle Factors on Mammographic Density in Postmenopausal Women

BackgroundMammographic density is a strong risk factor for breast cancer. Apart from hormone replacement therapy (HRT), little is known about lifestyle factors that influence breast density.MethodsWe examined the effect of smoking, alcohol and physical activity on mammographic density in a population-based sample of postmenopausal women without breast cancer. Lifestyle factors were assessed by a questionnaire and percentage and area measures of mammographic density were measured using computer-assisted software. General linear models were used to assess the association between lifestyle factors and mammographic density and effect modification by body mass index (BMI) and HRT was studied.ResultsOverall, alcohol intake was positively associated with percent mammographic density (P trend = 0.07). This association was modified by HRT use (P interaction = 0.06): increasing alcohol intake was associated with increasing percent density in current HRT users (P trend = 0.01) but not in non-current users (P trend = 0.82). A similar interaction between alcohol and HRT was found for the absolute dense area, with a positive association being present in current HRT users only (P interaction = 0.04). No differences in mammographic density were observed across categories of smoking and physical activity, neither overall nor in stratified analyses by BMI and HRT use.ConclusionsIncreasing alcohol intake is associated with an increase in mammography density, whereas smoking and physical activity do not seem to influence density. The observed interaction between alcohol and HRT may pose an opportunity for HRT users to lower their mammographic density and breast cancer risk.

Assessment of mammographic density in postmenopausal women during long term hormone replacement therapy

Objective: To assess long-term effects of different hormone replacement therapy (HRT) regimens on mammographic density.Methods: One hundred sixty-five postmenopausal women were treated with the same HRT during 5 years: 38 received transdermal estradiol, 78 cyclic combined therapy and 49 continuous combined therapy. Mammograms were obtained at baseline, at 1-year and 5-year treatment. Breast density changes were categorized as slight focal increased density, considerable focal increased density, slight diffuse increased density and considerable diffuse increased density.Results: Mammographic density increased in 7.9% of women receiving estrogen alone versus 25.2% of women receiving combined therapy (p < 0.022) during 1 year, and in 7.9% of women versus 28.3% of women (p < 0.009) after 5 years of therapy, respectively. There were significant statistical differences in women treated with estrogen alone versus those treated with combined HRT after 1 and 5 years. After 5 years of HRT, breast density increased 21.8% in women receiving cyclic combined therapy versus 38.8% in those under continuous combined therapy (p < 0.039).Conclusion: An increase in breast density is significantly more frequent in women receiving combined estrogen-progestin therapy than in women receiving estrogen alone. There are differences between cyclic and continuous combined therapy at 5 years of treatment.

Association of Urinary Levels of Estrogens and Estrogen Metabolites with Mammographic Density in Postmenopausal Women

The association between urinary estrogen metabolites and mammographic density (MD) has not been well studied in postmenopausal women. In a cross‐sectional study of non‐current hormone users, we investigated the relationship between urinary estrogen metabolites and percent MD in 200 healthy postmenopausal women at high risk of breast cancer (age = 60.0 +/−5.1 years, body mass index (BMI) = 25.1 +/−4.0 kg/m2, percent MD= 32.3+/−16.8). MD was measured using a highly reproducible computer‐assisted Madena method, and the 12 urinary estrogens and estrogen metabolites were analyzed by liquid chromatography‐tandem mass spectrometry. Multivariate linear regression analyses adjusted for age, BMI, and past use of hormone therapy showed that when compared with women in the bottom quartile, women in the top quartile of the ratio of 2‐hydroxylated to parent estrogens showed a trend toward higher percent MD (+3.9%, p=0.07) and women in the top quartile of 4‐hydroxylated estrogens showed a trend toward lower percent MD (−5.6%, p=0.06). We found no associations for any other individual estrogen, or their metabolites or ratios with percent MD. In conclusion, these findings suggest that urinary excretion of estrogen metabolites in certain metabolic pathways may exert an impact on MD, an established risk marker of breast cancer. This work was funded by NIH/NCI and the Department of Defense.

Abstract B97: Vitamin D and mammographic density in postmenopausal women: A cohort study nested within the NCIC CTG MAP.3 chemoprevention trial

Abstract Background: Vitamin D may be important in the causal pathway to breast cancer (BC) by influencing breast density, a potential intermediate biomarker for carcinogenesis. However, previous study results are inconsistent, particularly among postmenopausal women. Our objectives were to prospectively examine the relationship between blood biomarkers of vitamin D (serum 25-OH-D) and mammographic breast density (MD) in postmenopausal women at northern latitudes. Potential effect modifications by calcium or exemestane therapy on the relationship between serum 25-OH-D and follow-up MD were also examined. Methods: The NCIC Clinical Trials Group conducted a randomized controlled trial (RCT) comparing exemestane (E) with placebo (P) in 4560 postmenopausal women at high risk for developing BC (MAP.3) (Goss, NEJM 2011). Using a nested observational design, we evaluated a cohort of participants from across Canada and Buffalo, NY. BC risk factor information was previously collected; primary exposure and outcome data were obtained from serum samples and mammograms. Serum 25-OH-D was measured using state-of-the-art LC-MS/MS from samples collected at baseline and year 1. Values for year 1 samples were adjusted to match the month of sampling for the baseline sample month and these samples were averaged. Baseline and ≥ 3 year follow-up percent MD were centrally assessed, blinded to treatment allocation and vitamin D levels, using Cumulus software. Linear regression was used to estimate the effect of serum 25-OH-D on log transformed percent MD at ≥ 3 year follow-up controlling for month of sampling and potential confounders of age, body mass index, first degree family history of BC and calcium. Results: Percent MD was measured for 568 participants (E=287, P=281) with a ≥ 3 year follow-up mammogram obtained from 21 (91%) Canadian sites participating in MAP.3 and one US site in Buffalo, NY. The mean age of these women at study entry was 62 years and they were followed for a mean of 3.7 years. The geometric mean percent MD of the follow-up mammograms was 4.3%. A random sample of 10% (N=102) of mammograms was repeated with high intra-rater reliability (correlation coefficient = 0.95). Unadjusted for month of blood collection, the mean serum 25-OH-D concentration was 36.5 ng/mL (SD=10.6) based on pooled baseline and year one serum samples. After controlling for month of sampling and potential confounders, serum 25-OH-D was not predictive of log transformed percent MD (p=0.25). Statistically significant interactions with calcium (above vs. below the median calcium value p=0.30) or exemestane (p=0.99) on the serum 25-OH-D and MD relationship were not detected. Preliminary results suggest some evidence that low vitamin D (&amp;lt;25 ng/mL) is associated with increased breast density in the presence of low calcium. Final results will be reported at the time of the AACR meeting. Conclusion: In this nested observational study, no association between serum 25-OH-D levels and percent MD at ≥ 3 year follow-up was detected after controlling for month of sampling and many well established BC risk factors. This study was funded by the Canadian Breast Cancer Foundation. The MAP.3 trial was supported by Pfizer. The NCIC CTG is supported by the Canadian Cancer Society Research Institute. Citation Format: Melanie Walker, Harriet Richardson, Paul Goss, Doris Jabs, Glenville Jones, Martin Kaufmann, Jean Wactawski-Wende, Angela Cheung, Eric Winquist, Silvana Spadafora, Susan Ellard, Amanda Hey, Andrew Cooke, Andrea Eisen, Shailendra Verma, Lavina Lickley, Dongsheng Tu, Karen Gelmon, Ralph Meyer, Will King. Vitamin D and mammographic density in postmenopausal women: A cohort study nested within the NCIC CTG MAP.3 chemoprevention trial. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B97.

The relationship between estrogen receptor gene polymorphism and mammographic density in postmenopausal women

ABSTRACTObjective To assess the relationship between the presence of PVUII and XBAI polymorphisms in the estrogen receptor α gene and mammographic density in postmenopausal women.Methods For the present analysis, 189 postmenopausal women who had never used hormonal therapy and who did not have clinical or mammographic features were selected. Based on the ACR-BIRADS® 2003 classification, the mammographic density was determined by three independent readers (two subjective ratings and one computerized). Blood samples were available to extract DNA according to KIT GFX® protocol. PCR-RFLP was then used to identify the polymorphisms.Results There was a high degree of agreement among the three readers to determine the mammographic density (κ > 0.75). Sixty women (32%) had dense breasts and 129 (68%) had non-dense breasts. The PVUII polymorphism was found in 132 (69.8%) of 189 women, while the XBAI polymorphism was found in 135 (71.4%) women. Parity (p = 0.02) and body mass index (p < 0.0001) were associated with mammographic density. It was observed that, for the XBAI polymorphism, women with two mutated alleles were approximately 2.5 times more likely to be classified in the dense breasts group (p = 0.003) and the presence of both wild alleles was associated with fibroglandular tissue replacement by fat (p = 0.02).Conclusions There was no significant association of the PVUII polymorphism in the estrogen receptor α gene with mammographic density (p = 0.34). However, the XBAI polymorphism was observed at a higher mutated homozygous frequency in women with dense breasts and there was an increased frequency of wild-type homozygous and heterozygous women with fat-replaced breasts (p = 0.01).

Mammographic Breast Density and Serum Phytoestrogen Levels

Some forms of estrogen are associated with breast cancer risk as well as with mammographic density (MD), a strong marker of breast cancer risk. Whether phytoestrogen intake affects breast density, however, remains unclear. We evaluated the association between serum levels of phytoestrogens and MD in postmenopausal women. We enrolled 269 women, ages 55–70 yr, who received a screening mammogram and had no history of postmenopausal hormone use. Subjects completed a survey on diet and factors related to MD and provided a blood sample for analysis of 3 phytoestrogens: genistein, daidzein, and coumestrol. We examined whether mean percent MD was related to serum level of phytoestrogens, adjusting for age and body mass index. Genistein and daidzein levels correlated with self-reported soy consumption. Mean percent MD did not differ across women with different phytoestrogen levels. For example, women with nondetectable genistein levels had mean density of 11.0% [95% confidence intervals (CI) = 9.9–12.4], compared to 10.5% (95% CI = 8.0–13.7) and 11.2% (95% CI = 8.7–14.6) for < and ≥median detectable levels, respectively. In a population with relatively low soy intake, serum phytoestrogens were not associated with mammographic density. Additional studies are needed to determine effects of higher levels, particularly given patterns of increasing phytoestrogen intake.

No evidence for association of inherited variation in genes involved in mitosis and percent mammographic density

IntroductionIncreased mammographic breast density is one of the strongest risk factors for breast cancer. While two-thirds of the variation in mammographic density appears to be genetically influenced, few variants have been identified. We examined the association of inherited variation in genes from pathways that mediate cell division with percent mammographic density (PMD) adjusted for age, body mass index (BMI) and postmenopausal hormones, in two studies of healthy postmenopausal women.MethodsWe investigated 2,058 single nucleotide polymorphisms (SNPs) in 378 genes involved in regulation of mitosis for associations with adjusted PMD among 484 unaffected postmenopausal controls (without breast cancer) from the Mayo Clinic Breast Cancer Study (MCBCS) and replicated the findings in postmenopausal controls (n = 726) from the Singapore and Sweden Breast Cancer Study (SASBAC) study. PMD was assessed in both studies by a computer-thresholding method (Cumulus) and linear regression approaches were used to assess the association of SNPs and PMD, adjusted for age, BMI and postmenopausal hormones. A P-value threshold of 4.2 × 10-5 based on a Bonferroni correction of effective number of independent tests was used for statistical significance. Further, a pathway-level analysis was conducted of all 378 genes using the self-contained gene-set analysis method GLOSSI.ResultsA variant in PRPF4, rs10733604, was significantly associated with adjusted PMD in the MCBCS (P = 2.7 × 10-7), otherwise, no single SNP was associated with PMD. Additionally, the pathway analysis provided no evidence of enrichment in the number of associations observed between SNPs in the mitotic genes and PMD (P = 0.60). We evaluated rs10733604 (PRPF4), and 73 other SNPs at P < 0.05 from 51 genes in the SASBAC study. There was no evidence of an association of rs10733604 (PRPF4) with adjusted PMD in SASBAC (P = 0.23). There were, however, consistent associations (P < 0.05) of variants at the putative locus, LOC375190, Aurora B kinase (AURKB), and Mini-chromosome maintenance complex component 3 (MCM3) with adjusted PMD, although these were not statistically significant.ConclusionsOur findings do not support a role of inherited variation in genes involved in regulation of cell division and adjusted percent mammographic density in postmenopausal women.

P4-02-10: The Relationship between Estrogen Receptor Gene Polymorphism and Mammographic Density in Postmenopausal Women.

Abstract Background Assess the relation between the presence of PVUII and XBAI polymorphisms in the estrogen receptor alpha gene and mammographic density in postmenopausal women. Methods For the present analysis, 189 postmenopausal women who had never used hormonal therapy and who did not have clinical or mammographic features were selected. Based on the ACR-BIRADSâ 2003 classification, the mammographic density was determined by three independent readers (two subjective ratings and one computerized - Adobe Photoshop â 7.0 software). Blood samples were available to extract DNA according to KIT GFX â protocol. PCR-RFLP (Polymerase Chain Reaction - Restriction Fragment Length Polymorphism) was then used to identify the polymorphisms. Results There was a high degree of agreement among the three readers to determine the mammographic density (Kappa&amp;gt;0.75). Sixty women (32%) had dense breasts and 129 (68%) had non-dense breasts. The PVUII polymorphism was found in 132 (69.8%) of 189 women, while the XBAI was found in 135 (71.4%) of women. Parity (p=0.02) and body mass index (p&amp;lt;0.0001) were associated with mammographic density. It was observed that for the XBAI polymorphism, women with two mutated alleles were approximately 2.5 times more likely to be classified in dense breasts group (p=0.003) and the presence of both wild alleles was associated with fibroglandular tissue replacement by fat (p=0.02). Conclusions There was no significant association of the PVUII polymorphism in the estrogen receptor alpha gene with mammographic density (p=0.34). However, the XBAI polymorphism was observed at a higher mutated homozygous frequency in women with dense breasts and there was an increased frequency of wild-type homozygous and heterozygous women with fat-replaced breasts (p=0.01). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-10.

Breast density is influenced by local oestrogen production in postmenopausal women

Studies have shown that high serum insulin-like growth factor-1 (IGF-1) and oestradiol levels can increase mammographic density (MD) in premenopausal women and subsequently increase breast cancer risk. We aim to see if local IGF-1 and oestrogen production in breast cancer tissue can correlate with MD in postmenopausal women.