Abstract LB-332: Hormone metabolism pathway genes associated with mammographic density change induced by postmenopausal combined estrogen and progestin therapy

Abstract

Abstract Mammographic density (MD) is a strong risk factor for breast cancer. Estrogen and progestin therapy (EPT) in postmenopausal women, which is known to increase women's breast cancer risk, has also been associated with a substantial increase in MD. However, there is large inter-individual variation in the MD increase following EPT use. Since longitudinal ‘increases/decreases’ in MD have been associated with ‘increased/decreased’ breast cancer risk, it is important to identify factors that predict MD change in women who use EPT. Few studies have investigated genetic determinants of MD change with longitudinal mammogram data. Using data from a mammogram substudy of the California Teachers Study, we investigated 405 single nucleotide polymorphisms (SNPs) in 28 genes involved in the metabolism of EPT and their associations with MD changes following starting or stopping EPT use. We studied 345 women with genotypes and MD data from at least two mammograms, one mammogram when the participant was using EPT, and one mammogram when not using EPT. MD was determined as a percentage of dense area of the total breast area. We used linear regression models to estimate the difference in MD between the ‘off-EPT’ and ‘on-EPT’ mammograms, adjusting for age and body mass index (BMI) both at the time of ‘on-EPT’ and ‘off-EPT’ mammograms. This model controls for the length of time between the two mammograms. We did not observe strong evidence that the hormone pathway SNPs were associated with EPT-related density change. Considering that the effect of genetic variation on the density change may be weaker in women with substantial BMI change, we restricted the analysis to 172 women who had smaller (below-median) BMI change between the two time points: -0.5 kg/m2 to 0.5 kg/m2. Upon restriction, there was suggestive evidence that hormone pathway SNPs were associated with EPT-related density change: the pathway-level summary P-value was 0.096 based on Adaptive Rank Truncated Product statistic. Rs523535 in PGR and two SNPs that are in linkage-disequilibrium with rs523535 (rs480851 and rs481775; r2=0.8) showed significant association (P values adjusted for multiple correlated tests within a gene (P_ACT): 0.002, 0.045, 0.046, respectively); The estimated difference in density changes per minor allele of these SNPs ranged from -2.3% to -2.9% (i.e. EPT-related density changes are smaller in women who carry the minor allele(s)). In addition, several SNPs in UGT1A8 (rs12479208, rs12466997), COMT (rs4646316), and PGR (rs619487, rs561610, rs613120) showed some evidence of associations with borderline statistical significance (P_ACT ranging from 0.056 to 0.095). While our findings need to be replicated, our results suggest that genetic variation in EPT metabolism and signaling genes, particularly PGR, may determine mammographic density change following EPT use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-332. doi:1538-7445.AM2012-LB-332