Polymorphisms in genes involved in estrogen and progesterone metabolism and mammographic density changes in women randomized to postmenopausal hormone therapy: results from a pilot study

Abstract

IntroductionMammographic density is a strong independent risk factor for breast cancer, and can be modified by hormonal exposures. Identifying genetic variants that determine increases in mammographic density in hormone users may be important in understanding hormonal carcinogenesis of the breast.MethodsWe obtained mammograms and DNA from 232 postmenopausal women aged 45 to 75 years who had participated in one of two randomized, double-blind clinical trials with estrogen therapy (104 women, taking 1 mg/day of micronized 17β-estradiol, E2), combined estrogen and progestin therapy (34 women, taking 17β-estradiol and 5 mg/day of medroxyprogesterone acetate for 12 days/month) or matching placebos (94 women). Mammographic percentage density (MPD) was measured on baseline and 12-month mammograms with a validated computer-assisted method. We evaluated polymorphisms in genes involved in estrogen metabolism (catechol-O-methyltransferase (COMT (Val158Met)), cytochrome P450 1B1 (CYP1B1 (Val432Leu)), UDP-glucuronosyltransferase 1A1 (UGT1A1 (<7/≥ 7 TA repeats))) and progesterone metabolism (aldo-keto reductase 1C4 (AKR1C4 (Leu311Val))) with changes in MPD.ResultsThe adjusted mean change in MPD was +4.6% in the estrogen therapy arm and +7.2% in the combined estrogen and progestin therapy arm, compared with +0.02% in the placebo arm (P = 0.0001). None of the genetic variants predicted mammographic density changes in women using estrogen therapy. Both the AKR1C4 and the CYP1B1 polymorphisms predicted mammographic density change in the combined estrogen and progestin therapy group (P < 0.05). In particular, the eight women carrying one or two low-activity AKR1C4 Val alleles showed a significantly greater increase in MPD (16.7% and 29.3%) than women homozygous for the Leu allele (4.0%).ConclusionAlthough based on small numbers, these findings suggest that the magnitude of the increase in mammographic density in women using combined estrogen and progestin therapy may be greater in those with genetically determined lower activity of enzymes that metabolize estrogen and progesterone.

Conjugated Equine Estrogen Influence on Mammographic Density in Postmenopausal Women in a Substudy of the Women's Health Initiative Randomized Trial

“…7 A report that included women from two trials found that postmenopausal women randomly assigned to 1 mg/d of micronized 17␤-estradiol (n ϭ 104) had an adjusted absolute mean increase in mammographic density of 4.6% after 12 months versus a 0.02% increase in women assigned to placebo (n ϭ 93). 25 Our finding of a 2.6 percentage point difference in percent density in women randomly assigned to CEE versus placebo is lower than the 6.9 percentage point difference observed for CEE plus MPA 2.5 mg/d in WHI, where CEE plus MPA increased percent density by a mean of 6.0 percentage points (95% CI, 4.6 to 7.5) at year 1 compared with a mean decrease of 0.9 percentage points (95% CI, Ϫ0.2 to Ϫ1.5) in the placebo group (P Ͻ .001), with differences largely persisting after 2 years. These results suggest a sizeable role for progestin on mammographic density, but our results suggest that CEE alone also can influence mammographic density.…”

Breast Cancer Susceptibility Variants and Mammographic Density Phenotypes in Norwegian Postmenopausal Women

“…[5][6][7]. Although a few genetic variants have been identified (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), the exact genetic determinants of MD are however not clear.…”

“…47). Several other genetic variants have been found to interact with EPT (8,10,14). Given that EPT use has strong effects on MD in some, but not all women (35), these gene-environment interactions reported from several studies could represent real effects.…”

Associations among Mammographic Density, Circulating Sex Hormones, and Polymorphisms in Sex Hormone Metabolism Genes in Postmenopausal Women

“…Haiman et al examined whether polymorphisms in genes involved in steroid hormone biosynthesis and metabolism were related to density (11). In 2005, the same group conducted a further study of women from a randomized controlled trial of estrogen therapy (12). Maskarinec et al (13) examined premenopausal women for several polymorphisms.…”