Biomarkers of mammographic density in premenopausal women.

BACKGROUND: While mammographic density is one of the strongest risk factors for breast cancer, little is known about its determinants, especially in young women. We applied targeted metabolomics to identify circulating metabolites specifically associated with mammographic density in premenopausal women. Then, we aimed to identify potential correlates of these biomarkers to guide future research on potential modifiable determinants of mammographic density. METHODS: A total of 132 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, sphingolipids, hexose) were measured by tandem liquid chromatography/mass spectrometry in plasma samples from 573 premenopausal participants in the Mexican Teachers' Cohort. Associations between metabolites and percent mammographic density were assessed using linear regression models, adjusting for breast cancer risk factors and accounting for multiple tests. Mean concentrations of metabolites associated with percent mammographic density were estimated across levels of several lifestyle and metabolic factors. RESULTS: Sphingomyelin (SM) C16:1 and phosphatidylcholine (PC) ae C30:2 were inversely associated with percent mammographic density after correction for multiple tests. Linear trends with percent mammographic density were observed for SM C16:1 only in women with body mass index (BMI) below the median (27.4) and for PC ae C30:2 in women with a BMI over the median. SM C16:1 and PC ae C30:2 concentrations were positively associated with cholesterol (total and HDL) and inversely associated with number of metabolic syndrome components. CONCLUSIONS: We identified new biomarkers associated with mammographic density in young women. The association of these biomarkers with mammographic density and metabolic parameters may provide new perspectives to support future preventive actions for breast cancer.

Circulating leptin and adiponectin, and breast density in premenopausal Mexican women: the Mexican Teachers' Cohort.

PURPOSE: Leptin and adiponectin are produced by the adipose tissue. Mammographic density (MD) is one of the strongest predictors of breast cancer (BC) and is highly influenced by adiposity. How the interplay between MD, obesity, and obesity-related biomarkers influences BC risk, however, is still unknown, especially in premenopausal women, where adiposity seems to be protective for BC. The aim of the present study was to explore the association between circulating leptin, adiponectin, and their ratio, with MD in Mexican premenopausal women who are part of the large Mexican Teachers' Cohort (MTC). METHODS: A subsample of 2,084 women from the MTC participated in a clinical evaluation. Of them, 574 premenopausal women were randomly selected, from four MD strata. Serum leptin and adiponectin concentrations were measured by immunoassays. Multivariate regression analyses were performed to compare means of MD by quartiles of adipokines and their ratio. RESULTS: High leptin and leptin/adiponectin ratio levels were significantly associated with lower percentage MD and higher absolute and non-absolute dense tissue areas. High adiponectin levels were significantly associated with lower absolute dense and non-dense tissue areas, but not with percentage MD. After adjustment for BMI, only the associations between percentage MD and absolute non-dense tissue area with leptin remained statistically significant. CONCLUSIONS: Leptin, adiponectin, and their ratio were associated with MD; however, only the positive association with leptin seemed to be independent from overall obesity.

Determinants of percent mammographic density in women with premature ovarian insufficiency.

OBJECTIVE: To evaluate the determinants of breast density in women with premature ovarian insufficiency (POI). METHODS: In a cross-sectional study of 163 women with POI undergoing mammography, percent mammographic density (PMD) was evaluated by digitizing the image. PMD was correlated with age, age at menarche, age at POI, time since POI, body mass index (BMI), gestational history and hormone therapy (HT) use (duration, dose, regimen). RESULTS: POI was diagnosed at a mean age of 32.3 ± 5.9 years. The mean age of the women at mammography was 41.3 ± 5.4 years; mean BMI was 27.4 ± 5.4 kg/m2 and mean PMD was 24.3 ± 18.5. Mean PMD did not differ between the different age groups evaluated (29-39, 40-49 and 50-55 years) or between users and non-users of HT. Mean duration of HT use was 5.6 ± 4.7 years. PMD was higher in nulligravidas compared to women who had been pregnant (p = 0.0016); however, POI occurred earlier in nulligravidas (p < 0.0001). PMD correlated negatively with BMI (r = -0.27; p = 0.0005). CONCLUSION: In women with POI, HT use had no effect on PMD, irrespective of the duration of use, dose or regimen. Pregnancy and BMI were consistently associated with PMD, with density being greater in nulligravidas and in women with lower BMI.

Reproductive and lifestyle risk factors and mammographic density in Mexican women.

PURPOSE: Several breast cancer risk factors have been consistently associated with mammographic density (MD); however, data are limited for Hispanic women. METHODS: We examined data from 1007 premenopausal and 600 postmenopausal women in the Mexican Teachers' Cohort. Multivariable linear regression was used to estimate associations between risk factors and MD. RESULTS: Among premenopausal women, age, current body mass index (BMI), BMI at age 18 years, and weight change since age 18 years were inversely associated with percent MD, whereas benign breast disease, alcohol intake, and breastfeeding 12 months or more were associated with higher percent MD. Among postmenopausal women, age, current BMI, BMI at age 18 years, weight change since age 18 years, and speaking or having parents who speak an indigenous language were inversely associated with percent MD, whereas benign breast disease and greater age at natural menopause were positively associated with percent MD. Other breast cancer risk factors, such as age at menarche, parity, and age at first pregnancy, were not significantly associated with density in either premenopausal or postmenopausal women. CONCLUSIONS: Results from the Mexican Teachers' Cohort are generally consistent with predictors of mammographic density observed in primarily non-Hispanic white populations; however, certain risk factors (e.g., parity) were not significantly associated with MD.

Circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-binding protein-3, genetic polymorphisms and mammographic density in premenopausal Mexican women: results from the ESMaestras cohort.

The insulin-like growth factor (IGF) axis plays an essential role in the development of the mammary gland. High circulating levels of IGF-I and of its major binding protein IGFBP3 have been related with increased mammographic density in Caucasian premenopausal women. Some common single nucleotide polymorphisms (SNPs) in genes of the IGF pathway have also been suggested to play a role in mammographic density. We conducted a cross-sectional study nested within the large Mexican ESMaestras cohort to investigate the relation between circulating levels of IGF-I, IGFBP-3, the IGF-I/IGFBP-3 ratio, five common SNPs in the IGF-1, IGFBP-3 and IGF-1R genes and mammographic density in 593 premenopausal Mexican women. Mean age at mammogram was 43.1 (standard deviation, SD = 3.7) years, and average body mass index (BMI) at recruitment was 28.5 kg/m(2). Mean percent mammographic density was 36.5% (SD: 17.1), with mean dense tissue area of 48.3 (SD: 33.3) cm(2) . Mean IGF-I and IGFBP-3 concentrations were 15.33 (SD: 5.52) nmol/l and 114.96 (SD: 21.34) nmol/l, respectively. No significant associations were seen between percent density and biomarker concentrations, but women with higher IGF-I and IGF-I/IGFBP-3 concentrations had lower absolute dense (p(trend) = 0.03 and 0.09, respectively) and nondense tissue areas (p(trend) < 0.001 for both parameters). However, these associations were null after adjustment by BMI. SNPs in specific genes were associated with circulating levels of growth factors, but not with mammographic density features. These results do not support the hypothesis of a strong association between circulating levels of growth hormones and mammographic density in Mexican premenopausal women.

Prevalence of the STK15 F31I polymorphism and its relationship with mammographic density

Several studies have identified the single nucleotide polymorphism STK15 F31I as a low-penetrance risk allele for breast cancer, but its prevalence and risk association in the Brazilian population have not been determined. The goal of this study was to identify the frequency of this polymorphism in the Brazilian setting. Considering the high degree of admixture of our population, it is of fundamental importance to validate the results already reported in the literature and also to verify the relationship between this variant and breast cancer risk. A total of 750 women without breast cancer were genotyped using the TaqMan PCR assay for STK15 F31I polymorphism. Clinical information was obtained from review of the medical records and mammographic density from the images obtained using the BI-RADS System. The estimated risk of developing cancer was calculated according to the Gail model. The genotypic frequencies observed in this study were 4.5, 38.7, and 56.6 percent, respectively, for the STK15 F31I AA, AT and TT genotypes. The AT and AA genotypes were encountered significantly more often in premenopausal women with moderately dense, dense and heterogeneously dense breast tissue (P = 0.023). In addition, the presence of the TT genotype was significantly associated with age at menarche ≥12 years (P = 0.023). High mammographic density, associated with increased breast cancer risk, was encountered more frequently in premenopausal women with the risk genotypes STK15 F31I AA and AT. The genotypic frequencies observed in our Brazilian sample were similar to those described in other predominantly European populations.