Absolute Mammographic Density Research Articles

Abstract P2-06-01: The effect of a subcutaneous combination of testosterone (T) and anastrozole (Ai) (HAVAHT+Ai™) on volumetric mammographic breast density (MBD); an open labelled cohort study

Abstract MBD is the single greatest modifiable risk factor for the development of breast cancer; this risk can be lessened by reducing MBD. Previous studies suggest breast cancer risk is reduced in women treated with subcutaneous HAVAHT+Ai™. As well, HAVAHT+Ai™ has been suggested to be effective in managing hormone deprivation symptoms in women who have had breast cancer and in perimenopausal women with hormonal dysfunction. HAVAHT+Ai™alters the androgen/estrogen (A/E) ratio in breast tissue by delivering more bioavailable T in the presence of Ai to tissue known to contain high levels of 5alpha-reductase and aromatase, respectively facilitating production of the potent androgen dihydrotestosterone and diminishing conversion of T to estradiol. Alteration of the A/E ratio in favor of an androgenic environment reduces MBD. This study evaluates the effect of HAVAHT+Ai™on volumetric MBD. Methods: 652 women attending Wellend Health Clinic (a clinic that manages perimenopausal symptoms and/or high risk of breast cancer) received HAVAHT+Ai™and evaluated for MBD change as determined by a fully-automated volumetric density analysis (VolparaDensity™). Women received a HAVAHT+Ai™subcutaneous implant every 3-4 month containing 1mg/kg T and a fixed dose of Ai 1-4mg. 142 women had 2 or more mammograms within the analysis period and were included in the final analysis. A restricted analysis set (RAS) of 89 of these women were compared with a matched 65 women undergoing mammographic screening for high risk, but not receiving hormonal therapy. Safety and tolerability data were collected and analyzed. Results: Least squares mean estimated (LSME) change in % volumetric breast density (%VBD), by cumulative testosterone dose and time from first implant. table 1Cumulative testosterone doseTime from first implant (yrs)LSME (%)Lower 95% CIUpper 95% CIp-value500 - <700mg1-1.13-2.420.170.087500 - <700mg2-1.69-3.01-0.380.012500 - <700mg3-2.26-4.23-0.290.025700+mg1-1.87-3.62-0.120.036700+mg2-2.34-3.88-0.790.003700+mg3-2.80-4.66-0.950.003 LSME change in absolute mammographic breast density (AVBD), by cumulative testosterone dose and time from first implant. table 2Cumulative testosterone doseTime from first implant (yrs)LSME (cm3)Lower 95% CIUpper 95% CIp-value500 - <700mg10.3-12.312.80.965500 - <700mg2-4.2-19.811.40.595500 - <700mg3-8.7-34.116.70.499700+mg1-7.8-26.310.70.405700+mg2-22.0-39.5-4.50.014700+mg3-36.2-59.7-12.70.003 Comparison with control group:Analysis of RAS (n=89) versus untreated controls (N=65) revealed statistically significantly different from zero for both %VBD and AVBD between the 2 groups, respectively 2.36%, (95% CI on the difference, from 1.15 to 3.56) and 18.0cm3, (95% CI on the difference, from 4.8 cm3 to 31.1cm3). Summary of safety: The treatment was well tolerated with no serious adverse events. Conclusions: HAVAHT+Ai™ therapy significantly reduces volumetric MBD with good safety and tolerability. An accumulative dose of greater than 700mg of T and 30mg of Ai over 2-3 years is required to achieve a similar reduction in MBD as that demonstrated with tamoxifen as a preventative agent for breast cancer. Citation Format: Birrell SN, Dougherty D, Good SB, Birrell NJ, Rolan P. The effect of a subcutaneous combination of testosterone (T) and anastrozole (Ai) (HAVAHT+Ai™) on volumetric mammographic breast density (MBD); an open labelled cohort study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-01.

Polymorphisms in the estrogen receptor alpha gene (ESR1), daily cycling estrogen and mammographic density phenotypes.

BackgroundSingle nucleotide polymorphisms (SNPs) involved in the estrogen pathway and SNPs in the estrogen receptor alpha gene (ESR1 6q25) have been linked to breast cancer development, and mammographic density is an established breast cancer risk factor. Whether there is an association between daily estradiol levels, SNPs in ESR1 and premenopausal mammographic density phenotypes is unknown.MethodsWe assessed estradiol in daily saliva samples throughout an entire menstrual cycle in 202 healthy premenopausal women in the Norwegian Energy Balance and Breast Cancer Aspects I study. DNA was genotyped using the Illumina Golden Gate platform. Mammograms were taken between days 7 and 12 of the menstrual cycle, and digitized mammographic density was assessed using a computer-assisted method (Madena). Multivariable regression models were used to study the association between SNPs in ESR1, premenopausal mammographic density phenotypes and daily cycling estradiol.ResultsWe observed inverse linear associations between the minor alleles of eight measured SNPs (rs3020364, rs2474148, rs12154178, rs2347867, rs6927072, rs2982712, rs3020407, rs9322335) and percent mammographic density (p-values: 0.002–0.026), these associations were strongest in lean women (BMI, ≤23.6 kg/m2.). The odds of above-median percent mammographic density (>28.5 %) among women with major homozygous genotypes were 3–6 times higher than those of women with minor homozygous genotypes in seven SNPs. Women with rs3020364 major homozygous genotype had an OR of 6.46 for above-median percent mammographic density (OR: 6.46; 95 % Confidence Interval 1.61, 25.94) when compared to women with the minor homozygous genotype. These associations were not observed in relation to absolute mammographic density. No associations between SNPs and daily cycling estradiol were observed. However, we suggest, based on results of borderline significance (p values: 0.025–0.079) that the level of 17β-estradiol for women with the minor genotype for rs3020364, rs24744148 and rs2982712 were lower throughout the cycle in women with low (<28.5 %) percent mammographic density and higher in women with high (>28.5 %) percent mammographic density, when compared to women with the major genotype.ConclusionOur results support an association between eight selected SNPs in the ESR1 gene and percent mammographic density. The results need to be confirmed in larger studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2804-1) contains supplementary material, which is available to authorized users.

Association of infertility and fertility treatment with mammographic density in a large screening-based cohort of women: a cross-sectional study.

BackgroundOvarian stimulation drugs, in particular hormonal agents used for controlled ovarian stimulation (COS) required to perform in vitro fertilization, increase estrogen and progesterone levels and have therefore been suspected to influence breast cancer risk. This study aims to investigate whether infertility and hormonal fertility treatment influences mammographic density, a strong hormone-responsive risk factor for breast cancer.MethodsCross-sectional study including 43,313 women recruited to the Karolinska Mammography Project between 2010 and 2013. Among women who reported having had infertility, 1576 had gone through COS, 1429 had had hormonal stimulation without COS and 5958 had not received any hormonal fertility treatment. Percent and absolute mammographic densities were obtained using the volumetric method Volpara™. Associations with mammographic density were assessed using multivariable generalized linear models, estimating mean differences (MD) with 95 % confidence intervals (CI).ResultsAfter multivariable adjustment, women with a history of infertility had 1.53 cm3 higher absolute dense volume compared to non-infertile women (95 % CI: 0.70 to 2.35). Among infertile women, only those who had gone through COS treatment had a higher absolute dense volume than those who had not received any hormone treatment (adjusted MD 3.22, 95 % CI: 1.10 to 5.33). No clear associations were observed between infertility, fertility treatment and percent volumetric density.ConclusionsOverall, women reporting infertility had more dense tissue in the breast. The higher absolute dense volume in women treated with COS may indicate a treatment effect, although part of the association might also be due to the underlying infertility. Continued monitoring of cancer risk in infertile women, especially those who undergo COS, is warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0693-5) contains supplementary material, which is available to authorized users.

Cyclic endogenous estrogen and progesterone vary by mammographic density phenotypes in premenopausal women.

Estrogen and progesterone are key factors in the development of breast cancer, but it remains unclear whether these hormones are associated with mammographic density phenotypes in premenopausal women. We measured percent mammographic density, nondense area, and absolute mammographic density using computer-assisted breast density readings (Madena) from digitized mammograms taken on a scheduled day of the menstrual cycle (day 7–12) among 202 healthy, premenopausal women (Energy Balance and Breast cancer Aspects Study-I). Daily salivary concentrations of 17β-estradiol and progesterone throughout an entire menstrual cycle and fasting morning serum concentrations of hormones on 3 specific days of the menstrual cycle were assessed. Salivary and serum 17β-estradiol and progesterone were positively associated with percent mammographic density, we observed by 1 SD increase in overall salivary estradiol (β-value equal to 2.07, P=0.044), luteal salivary progesterone (β-value equal to 2.40, P=0.020). Women with above-median percent mammographic density had a 20% higher mean salivary 17β-estradiol level throughout the menstrual cycle. The odds ratio for having above-median percent mammographic density (>28.5%) per 1 SD increase in overall salivary 17β-estradiol was 1.66 (95% confidence interval 1.13–2.45). Women in the top tertile of the overall average daily 17β-estradiol concentrations had an odds ratio of 2.54 (confidence interval 1.05–6.16) of above-median percent mammographic density compared with women in the bottom tertile. Our finding of a relationship between estrogen, progesterone, and percent mammographic density and not with other mammographic density phenotypes in premenopausal women is biologically plausible, but needs to be replicated in larger studies.

Alcohol consumption, endogenous estrogen and mammographic density among premenopausal women.

IntroductionAlcohol consumption may promote aromatization of androgens to estrogens, which may partly explain the observations linking alcohol consumption to higher breast cancer risk. Whether alcohol consumption is associated with endogenous estrogen levels, and mammographic density phenotypes in premenopausal women remains unclear.MethodsAlcohol consumption was collected by self-report and interview, using semi quantitative food frequency questionnaires, and a food diary during seven days of a menstrual cycle among 202 premenopausal women, participating in the Energy Balance and Breast Cancer Aspects (EBBA) study I. Estrogen was assessed in serum and daily in saliva across an entire menstrual cycle. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms taken between days 7–12 of the menstrual cycle. Multivariable regression models were used to investigate the associations between alcohol consumption, endogenous estrogen and mammographic density phenotypes.ResultsCurrent alcohol consumption was positively associated with endogenous estrogen, and absolute mammographic density. We observed 18 % higher mean salivary 17β-estradiol levels throughout the menstrual cycle, among women who consumed more than 10 g of alcohol per day compared to women who consumed less than 10 g of alcohol per day (p = 0.034). Long-term and past-year alcohol consumption was positively associated with mammographic density. We observed a positive association between alcohol consumption (past year) and absolute mammographic density; high alcohol consumers (≥7 drinks/week) had a mean absolute mammographic density of 46.17 cm2 (95 % confidence interval (CI) 39.39, 52.95), while low alcohol consumers (<1 drink/week) had a mean absolute mammographic density of 31.26 cm2 (95 % CI 25.89, 36.64) (p-trend 0.001). After adjustments, high consumers of alcohol (≥7 drinks/week), had 5.08 (95 % CI 1.82, 14.20) times higher odds of having absolute mammographic density above median (>32.4 cm2), compared to low (<1 drink/week) alcohol consumers.ConclusionAlcohol consumption was positively associated with daily endogenous estrogen levels and mammographic density in premenopausal women. These associations could point to an important area of breast cancer prevention.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0620-1) contains supplementary material, which is available to authorized users.

Identification of two novel mammographic density loci at 6Q25.1

IntroductionMammographic density (MD) is a strong heritable and intermediate phenotype for breast cancer, but much of its genetic variation remains unexplained. We performed a large-scale genetic association study including 8,419 women of European ancestry to identify MD loci.MethodsParticipants of three Swedish studies were genotyped on a custom Illumina iSelect genotyping array and percent and absolute mammographic density were ascertained using semiautomated and fully automated methods from film and digital mammograms. Linear regression analysis was used to test for SNP-MD associations, adjusting for age, body mass index, menopausal status and six principal components. Meta-analyses were performed by combining P values taking sample size, study-specific inflation factor and direction of effect into account.ResultsGenome-wide significant associations were observed for two previously identified loci: ZNF365 (rs10995194, P = 2.3 × 10−8 for percent MD and P = 8.7 × 10−9 for absolute MD) and AREG (rs10034692, P = 6.7 × 10−9 for absolute MD). In addition, we found evidence of association for two variants at 6q25.1, both of which are known breast cancer susceptibility loci: rs9485370 in the TAB2 gene (P = 4.8 × 10−9 for percent MD and P = 2.5 × 10−8 for absolute MD) and rs60705924 in the CCDC170/ESR1 region (P = 2.2 × 10−8 for absolute MD). Both regions have been implicated in estrogen receptor signaling with TAB2 being a potential regulator of tamoxifen response.ConclusionsWe identified two novel MD loci at 6q25.1. These findings underscore the importance of 6q25.1 as a susceptibility region and provide more insight into the mechanisms through which MD influences breast cancer risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0591-2) contains supplementary material, which is available to authorized users.

High-density lipoprotein-cholesterol, daily estradiol and progesterone, and mammographic density phenotypes in premenopausal women.

High-density lipoprotein-cholesterol (HDL-C) may influence the proliferation of breast tumor cells, but it is unclear whether low HDL-C levels, alone or in combination with cyclic estrogen and progesterone, are associated with mammographic density, a strong predictor of breast cancer development. Fasting morning serum concentrations of HDL-C were assessed in 202 premenopausal women, 25 to 35 years of age, participating in the Norwegian Energy Balance and Breast Cancer Aspects (EBBA) I study. Estrogen and progesterone were measured both in serum, and daily in saliva, throughout an entire menstrual cycle. Absolute and percent mammographic density was assessed by a computer-assisted method (Madena), from digitized mammograms (days 7-12). Multivariable models were used to study the associations between HDL-C, estrogen and progesterone, and mammographic density phenotypes. We observed a positive association between HDL-C and percent mammographic density after adjustments (P = 0.030). When combining HDL-C, estradiol, and progesterone, we observed among women with low HDL-C (<1.39 mmol/L), a linear association between salivary 17β-estradiol, progesterone, and percent and absolute mammographic density. Furthermore, in women with low HDL-C, each one SD increase of salivary mid-menstrual 17β-estradiol was associated with an OR of 4.12 (95% confidence intervals; CI, 1.30-13.0) of having above-median percent (28.5%), and an OR of 2.5 (95% CI, 1.13-5.50) of having above-median absolute mammographic density (32.4 cm(2)). On the basis of plausible biologic mechanisms linking HDL-C to breast cancer development, our findings suggest a role of HDL-C, alone or in combination with estrogen, in breast cancer development. However, our small hypothesis generating study requires confirmation in larger studies.

Gene variations in oestrogen pathways, CYP19A1, daily 17β-estradiol and mammographic density phenotypes in premenopausal women.

IntroductionHigh 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.MethodsBased 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.ResultsThe 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)).ConclusionOur 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 materialThe online version of this article (doi:10.1186/s13058-014-0499-2) contains supplementary material, which is available to authorized users.

Comparison of mammographic density assessed as volumes and areas among women undergoing diagnostic image-guided breast biopsy.

Mammographic density (MD), the area of non-fatty-appearing tissue divided by total breast area, is a strong breast cancer risk factor. Most MD analyses have used visual categorizations or computer-assisted quantification, which ignore breast thickness. We explored MD volume and area, using a volumetric approach previously validated as predictive of breast cancer risk, in relation to risk factors among women undergoing breast biopsy. Among 413 primarily white women, ages 40 to 65 years, undergoing diagnostic breast biopsies between 2007 and 2010 at an academic facility in Vermont, MD volume (cm(3)) was quantified in craniocaudal views of the breast contralateral to the biopsy target using a density phantom, whereas MD area (cm(2)) was measured on the same digital mammograms using thresholding software. Risk factor associations with continuous MD measurements were evaluated using linear regression. Percent MD volume and area were correlated (r = 0.81) and strongly and inversely associated with age, body mass index (BMI), and menopause. Both measures were inversely associated with smoking and positively associated with breast biopsy history. Absolute MD measures were correlated (r = 0.46) and inversely related to age and menopause. Whereas absolute dense area was inversely associated with BMI, absolute dense volume was positively associated. Volume and area MD measures exhibit some overlap in risk factor associations, but divergence as well, particularly for BMI. Findings suggest that volume and area density measures differ in subsets of women; notably, among obese women, absolute density was higher with volumetric methods, suggesting that breast cancer risk assessments may vary for these techniques.

Abstract P2-01-04: High-density lipoprotein cholesterol is associated with mammographic density in premenopausal women

Abstract Background: High-Density Lipoprotein Cholesterol (HDL-C), and ovarian steroid hormones and mammographic density have independently been associated with breast cancer development. However, little is known regarding the association between HDL-C, ovarian hormones and mammographic density in premenopausal women. Material and Methods: We assessed fasting HDL-C among 202 healthy women, aged 25-35 years, participating in the Energy Balance and Breast cancer Aspects (EBBA) study-I. Progesterone and estrogen were assessed both in serum (three times) and daily saliva across an entire menstrual cycle. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms taken at days 7-12 of the menstrual cycle during a narrow time frame, thereby avoiding potential bias due to variations in mammographic density during the menstrual cycle. The association between HDL-C, in combination with progesterone or estrogen and absolute mammographic density were studied in multivariable linear and logistic regression models, and potential confounding factors and effect modifiers were tested. Results: The participating women had a mean age of 30.7, mean HDL-C of 1.54 mmol/l, and absolute breast density of 34.7 cm2 (median 32.4 cm2). Among women in the lowest tertile of HDL-C (≤1.38mmol/l), we observed a positive association between midmenstrual salivary 17β-estradiol and absolute breast density (p = 0.014), and between luteal salivary progesterone and absolute breast density (p = 0.029). Among these women in the lowest tertile of HDL-C, we also observed that high 17β-estradiol throughout the menstrual cycle was associated with higher absolute mammographic density (above median absolute density, &amp;gt;32.4 cm2). Odds Ratio (OR) per standard deviation (SD) increase in salivary midmenstrual 17β-estradiol was 2.49 (95% confidence interval [CI] 1.12-5.53) for having a higher absolute mammographic density (&amp;gt;32.4 cm2). These associations between HDL-C, ovarian steroids and absolute mammographic density were not observed in the middle or highest tertiles of HDL-C. Conclusion: Our findings suggest that low HDL-C, a marker of dyslipidemia, in combination with high levels of either progesterone or estradiol may be associated with higher absolute mammographic density in premenopausal women. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-01-04.

Mammographic Density and Intake of Selected Nutrients and Vitamins in Norwegian Women

Investigating the association between dietary factors and mammographic density (MD) could shed light on the relationship between diet and breast cancer risk. We took advantage of a national mammographic screening program to study the association between intake of nutrients and MD. In this study, we analyzed data of 2,252 postmenopausal women aged 50–69 yr who participated in the Norwegian Breast Cancer Screening Program in 2004. MD was assessed on digitized mammograms using a computer-assisted method. We used multivariate linear regression models to determine least square means of percent and absolute MD. Overall, we observed no associations between MD and intake of total calories, protein, carbohydrates, cholesterol, and dietary fiber. There was a positive borderline statistically significant association between absolute MD and total fat intake (P = 0.10) and between percent MD and intake of saturated fat (P = 0.06). There was no association between MD and intake of calcium, retinol, vitamins A, B12, C, or D, or combined intake of vitamin D and calcium. This study provides some evidence of an association between MD and dietary intake. Our study highlights the importance of adequate adjustments for BMI in studies of diet and MD.

The Relative Importance of Genetics and Environment on Mammographic Density

Although several environmental factors predict mammographic density, estimates of its heritability have been quite high. We investigated whether part of the presumed heritability might be attributed to differential sharing of modifiable risk factors in monozygotic (MZ) and dizygotic (DZ) twins. We measured percent and absolute mammographic density using mammograms from 257 MZ and 296 DZ twin pairs. The correlation of intrapair mammographic density was compared according to zygosity across strata of modifiable risk factors. Portions of variance attributable to additive genetic factors, shared environment, and individual environment were calculated using a variance component methodology in the entire set, and within twin pairs stratified by environmental trait similarity. Both percent density and absolute mammographic density were more highly correlated between MZ twins than DZ twins, but the correlations varied across strata. Body mass index (BMI) and parity strongly predicted differences in mammographic density within MZ twin pairs. After adjusting for covariates, 53% of the total variance in percent density and 59% of that in absolute density seemed attributable to genetic effects, but these estimates varied greatly by stratum. For twins dissimilar on BMI (difference >2.5 kg/m(2)), the additive genetic component of absolute density was estimated at only 20% (+/-19%), and the common and individual environment at 21% (+/-14%) and 49%, respectively (P value for heterogeneity across BMI = 0.0001). Our results confirm that the genome is an important determinant of mammographic density but suggest that an unknown portion of the mammographic density effect attributed to the genome may be due to shared modifiable environmental factors.

Different measures of smoking exposure and mammographic density in postmenopausal Norwegian women: a cross-sectional study

BackgroundRecent cohort studies have suggested an increased risk of breast cancer with long duration of smoking, and with smoking initiation before first birth. Cigarette smoking may have both carcinogenic effects and antiestrogenic effects on the breast tissue. We decided to examine the relationship between different measures of smoking exposure and mammographic density.MethodsLifetime smoking history was collected through interview and questionnaires among 907 postmenopausal participants in the Tromsø Mammography and Breast Cancer study. The mammograms were obtained from the governmental Norwegian Breast Cancer Screening Program. Mammograms were classified according to the percentage and absolute mammographic densities using a previously validated computer-assisted method.ResultsSixty-five percent of the women reported having ever smoked cigarettes, while 34% were current smokers. After adjustment for age, age at first birth, parity, age at menopause, postmenopausal hormone therapy use, and body mass index, smoking was inversely associated with both measures of mammographic density (both trends P < 0.01). Both current smokers and former smokers had significantly lower adjusted mean percentage mammographic density compared with never smokers (P = 0.003 and P = 0.006, respectively). An inverse dose–response relationship with mammographic density was found between both the number of cigarettes and the number of pack-years smoked among current smokers. Current smokers who smoked 11 cigarettes or more daily had a 3.7% absolute (36% relative difference) lower percentage mammographic density compared with current smokers who smoked seven cigarettes or less daily (P = 0.008). When former smokers were stratified according to time since smoking cessation, we found that women who had stopped smoking less than 24 years ago had a significantly lower mean percentage mammographic density compared with never smokers (P < 0.001).ConclusionWe found modest inverse dose–response associations between numbers of cigarettes and of pack-years smoked and both measures of mammographic density among current smokers. Former smokers who had stopped smoking less than 24 years ago also had a statistically significantly lower mean percentage mammographic density when compared with never smokers. These findings are consistent with an antiestrogenic effect of cigarette smoking on the breast tissue.

Endogenous sex hormones, prolactin and mammographic density in postmenopausal Norwegian women

The associations between endogenous sex hormone levels and breast cancer risk in postmenopausal women are well established. Mammographic density is a strong risk factor for breast cancer, and possibly an intermediate marker. However, the results from studies on the associations between endogenous sex hormones and mammographic density are conflicting. The authors examined the associations between circulating levels of sex hormones, sex hormone binding globulin (SHBG) and prolactin and mammographic densities among postmenopausal women not currently using postmenopausal hormone therapy (HT). The authors also examined if insulin-like growth factor-I (IGF-I) levels influenced the association between estrogen and mammographic density. Altogether, 722 postmenopausal participants in the Norwegian governmental mammographic screening program had endogenous hormone concentrations measured. Mammograms were classified according to percent and absolute mammographic density using a previously validated computer-assisted method. After adjustment for age, number of children, age at menopause, body mass index and HT use, both plasma concentrations of SHBG (p-trend = 0.003) and estrone (p-trend = 0.07) were positively associated with percent mammographic density. When the analyses were stratified according to median IGF-I concentration, the weak association between estrone and mammographic density was strengthened among women with IGF-I levels below median, while the association disappeared among women with over median IGF-I levels (p for interaction = 0.02). In summary, the authors found a positive association between plasma SHBG levels and mammographic densities among 722 postmenopausal Norwegian women not currently using HT. Further, the authors found a positive but weak association between plasma estrone concentration and mammographic density, which appeared to be modified by IGF-I levels.

Reduced Mammographic Density with Use of a Gonadotropin-Releasing Hormone Agonist–Based Chemoprevention Regimen in BRCA1 Carriers

Women with a BRCA1 mutation (BRCA1(mut)) need risk reduction options beyond mastectomy and oophorectomy. We evaluated the efficacy, safety, and tolerability of hormonal chemoprevention with a gonadotropin-releasing hormone agonist (GnRHA) with low-dose add-back steroids in BRCA1(mut) carriers. The 12-month open label clinical trial used the GnRHA deslorelin, ultra-low-dose estradiol (E(2)), and replacement testosterone, administered via daily intranasal spray in premenopausal women with a BRCA1(mut), and intermittent oral medroxyprogesterone acetate. The end points included mammographic percent density, bone mineral density, endometrial hyperplasia, symptom inventory, and quality of life (Medical Outcomes SF-36 survey). Six of eight BRCA1(mut) women (mean age, 30.3 years; range, 25-36 years) completed the study. Mammographic percent density was significantly reduced at 12 months (median absolute mammographic percent density decrease, 8.3%; P = 0.043), representing a 29.2% median reduction in mammographic percent density. Bone mineral density remained within reference limits for all participants; there were no cases of atypical endometrial hyperplasia and menses resumed within a median of 67 days (range, 35-110 days) after last drug treatment day. The treatment was well tolerated; hypoestrogenic side effects were minimal and transient; and there were no significant changes in quality of life. The GnRHA deslorelin, with low-dose add-back steroids, was well tolerated and significantly decreased mammographic percent density in BRCA1(mut) carriers. This regimen may reduce breast cancer risk and improve the usefulness of mammographic surveillance by reducing density. This is the first demonstration, to our knowledge, of a direct reduction of mammographic densities in young BRCA1(mut) carriers.

Insulin-like Growth Factor and Mammographic Density in Postmenopausal Norwegian Women

Insulin-like growth factor-I (IGF-I) is associated with breast cancer risk among premenopausal women but rarely among postmenopausal women. Recent data from two European studies suggested an increased risk of breast cancer with increasing levels of IGF-I among women >50 years old or among postmenopausal hormone therapy users >or=55 years old. Mammographic density is one of the strongest risk factors, and possibly an intermediate marker, for breast cancer. We examined the relationship between IGF and mammographic density among postmenopausal women overall and according to hormone therapy use. Altogether, 977 postmenopausal participants in the Norwegian governmental mammographic screening program had IGF concentrations measured by ELISA. Mammograms were classified according to percent and absolute mammographic densities using a previously validated computer-assisted method. After adjustment for age, number of children, age at menopause, body mass index, and hormone therapy use, both plasma IGF-I concentration (P(trend) = 0.02) and IGF-I/IGF binding protein 3 ratio (P(trend) = 0.02) were positively associated with percent mammographic density. The magnitudes of differences in percent mammographic density between women in the lowest and highest quartiles of IGF-I concentrations were 1.5% absolute difference and 21% relative difference. These associations were similar with absolute mammographic density as the outcome variable. When the analyses were stratified according to hormone therapy use, the associations between IGF-I and mammographic density were significant among noncurrent users (P(trend) = 0.03). In conclusion, we found a positive but weak association between plasma IGF-I concentrations and both percent and absolute mammographic densities among postmenopausal women. These associations were found among noncurrent hormone therapy users but not among current users.

Different types of postmenopausal hormone therapy and mammographic density in Norwegian women

Postmenopausal hormone therapy (HT) is associated with increased risk of breast cancer. The HTs used in Scandinavia is associated with higher risk estimates than those used in most other countries. Mammographic density is one of the strongest risk factors for breast cancer, and possibly an intermediate marker for breast cancer. We decided to examine the relationship between use of different types of HT and mammographic density in Norwegian women. Altogether, 1,007 postmenopausal participants in the governmental mammographic screening program were asked about current and previous HT use. Mammograms were classified according to percent and absolute mammographic density. Overall, current users of HT had on average 3.6% higher mean percent mammographic density when compared with never users (p < 0.001). After adjustment for age at screening, number of children and BMI in a multivariate model, women using the continuous estradiol (E(2)) plus norethisterone acetate (NETA) combination had a mean percent mammographic density significantly higher than never users (6.1% absolute difference). Those using the continuous E(2) plus NETA combination had an 4.8% (absolute difference) higher mean percent mammographic density after <5 years of use when compared with never users, while the corresponding number for >or=5 years of use was 7% (p-trend < 0.001). We found similar associations when absolute mammographic density was used as the outcome variable. In summary, our study shows a statistical significant positive dose-response association between current use of the continuous E(2) plus NETA combination and both measures of mammographic density.

Plasma levels of leptin and mammographic density among postmenopausal women: a cross-sectional study

IntroductionObesity has been linked to increased risk of breast cancer in postmenopausal women. Increased peripheral production of estrogens has been regarded as the main cause for this association, but other features of increased body fat mass may also play a part. Leptin is a protein produced mainly by adipose tissue and may represent a growth factor in cancer. We examined the association between leptin plasma levels and mammographic density, a biomarker for breast cancer risk.MethodsWe included data from postmenopausal women aged 55 and older, who participated in a cross-sectional mammography study in Tromsø, Norway. Mammograms, plasma leptin measurements as well as information on anthropometric and hormonal/reproductive factors were available from 967 women. We assessed mammographic density using a previously validated computer-assisted method. Multiple linear regression analysis was applied to investigate the association between mammographic density and quartiles of plasma leptin concentration. Because we hypothesized that the effect of leptin on mammographic density could vary depending on the amount of nondense or fat tissue in the breast, we also performed analyses on plasma leptin levels and mammographic density within tertiles of mammographic nondense area.ResultsAfter adjusting for age, postmenopausal hormone use, number of full-term pregnancies and age of first birth, there was an inverse association between leptin and absolute mammographic density (Ptrend = 0.001). When we additionally adjusted for body mass index and mammographic nondense area, no statistically significant association between plasma leptin and mammographic density was found (Ptrend = 0.16). Stratified analyses suggested that the association between plasma leptin and mammographic density could differ with the amount of nondense area of the mammogram, with the strongest association between leptin and mammographic absolute density in the stratum with the medium breast fat content (Ptrend = 0.003, P for interaction = 0.05).ConclusionWe found no overall consistent association between the plasma concentration of leptin and absolute mammographic density. Although weak, there was some suggestion that the association between leptin and mammographic density could differ with the amount of fat tissue in the breast.

Does mammographic density reflect ethnic differences in breast cancer incidence rates?

Breast cancer incidence rates in the United States are substantially lower among Asian-American women than among White or African-American women. The authors determined whether mammographic density reflects these ethnic differences by evaluating mammograms from 442 White, African-American, and Asian-American women without breast cancer who served as controls in one of two population-based, breast cancer case-control studies conducted in Los Angeles, California, in 1994-1998. Absolute and percent mammographic densities were determined with a previously developed and validated computer-assisted method. Data were analyzed using multiple regression methods. Mean age-adjusted percent mammographic density was significantly higher in Asian Americans (35.9%) than in African Americans (27.8%, p < 0.05) but was no longer significant after further adjustment for body mass index. After adjustment for age, body mass index, selected menstrual/reproductive factors, and family history, absolute mammographic density was statistically significantly lower in Asian Americans than in African Americans (p < 0.05) but not than in Whites. The ethnic difference in absolute mammographic density was particularly evident among women older than age 50 years. Additional adjustment for breast size reduced these ethnic differences. This study suggests that absolute but not percent mammographic density reflects the lower breast cancer incidence rates of Asian Americans in relation to those of African Americans and Whites.