Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects

Abstract

Background:Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy.Methods:Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment.Results:Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ⩾20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed.Conclusion:Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.

Exemestane Use in Postmenopausal Women at High Risk for Invasive Breast Cancer: Evaluating Biomarkers of Efficacy and Safety

“…Many of the studies which have no change in MD limited AI therapy to 12 months (10-12, 35). However, our study along with at least one other study (13) which evaluated AI therapy for 24 months did note a significant decrease in MD at the 24 month evaluation point. Unfortunately, our study was powered to evaluate MD at 12 months and not at 24 months.…”

“…While the strength of our conclusions is limited by the lack of a control arm, comparable control groups of postmenopausal women have a MD change of +0.58 to −0.8 at one year follow-up (10-12) suggesting that the observed decline of 2.4% at 1 year and 4.1% at 2 years in our study may be significant. Henry et al noted (13) a similar decline of 5.8% at 2 years in the contralateral breast in women with early breast cancer on exemestane or letrozole. A small pilot study by Smith et al (32) found that letrozole use was associated with a reduction in MD over 12 months in 11 of their 16 patients.…”

“…One recent large study showed a non-statistically significant 1% decrease in MD at 12 months in the non-affected breast of women with early breast cancer compared to matched controls and concluded that changed in MD is not a biomarker of AI effect (10). Overall, studies have shown no or modest declines in MD among women taking AIs (11-13). …”

Relationship Between Breast Density and Selective Estrogen-Receptor Modulators, Aromatase Inhibitors, Physical Activity, and Diet

“…97 SERMs also decrease insulin-like growth factor (IGF)-1 levels and increase IGF binding protein (IGFBP) and sex hormone binding-globulin. 8,9,15 Other substances (AIs) inhibit the production of estrogen by aromatase. 15,56 Evidence shows that TAM mediates BD reduction in both premenopausal and postmenopausal women, but no concrete evidence exists for BD reduction with RLX, tibolone, letrozole, anastrozole, or exemestane ( Table 2).…”

“…8,9,15 Other substances (AIs) inhibit the production of estrogen by aromatase. 15,56 Evidence shows that TAM mediates BD reduction in both premenopausal and postmenopausal women, but no concrete evidence exists for BD reduction with RLX, tibolone, letrozole, anastrozole, or exemestane ( Table 2). The BD reduction in TAM studies might be explained by the prevalence of premenopausal women as shown by the stronger BD decreases in premenopausal women.…”