Abstract
10503 Background: Genetic factors that contribute to endogenous estrogen synthesis and postmenopausal breast cancer risk are unknown. We set out to test the hypothesis that homozygous inheritance of the common 1245A→C missense-encoding polymorphism in HSD3B1, which is common (8-10%) in White populations, functionally adrenal permissive and increases synthesis of the aromatase substrate, androstenedione, is associated with postmenopausal estrogen receptor-positive breast cancer. Methods: A prospective single institution study of postmenopausal estrogen receptor-driven breast cancer for determination of HSD3B1 genotype, circulating steroid concentrations, and adrenal-permissive genotype frequency compared with the genotype frequency in the general population and in estrogen receptor-negative breast cancer. Validation was performed in 2 breast cancer genomic studies with estrogen receptor documentation. The primary outcome is the adrenal-permissive genotype frequency in postmenopausal estrogen receptor-positive breast cancer and the general population. Genotype comparisons were also done with postmenopausal estrogen receptor-negative breast cancer and the association with circulating adrenal androgen concentrations determined. Results: The prospective and validation studies had 199 and 1628 women, respectively. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 9.6% (429/4451) in the general population [p = 0.0077]. The adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using the Cambridge and TCGA genomic datasets together: 14.4% (56/389) compared with 6.0% (9/149) for estrogen receptor-negative breast cancer (p = 0.007) and the general population (p = 0.005). Circulating androstenedione concentration was significantly higher for women with the adrenal-permissive genotype compared with the other genotypes (p = 0.03). Conclusions: The adrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer and have broad implications for risk stratification, prevention, potential biomarkers for hormonal therapy response and possibly other clinical outcomes related to estrogen physiology in postmenopausal women.
Highlights
Estrogen exposure increases the risk of estrogen receptor–driven (ER-driven) breast cancer
Twenty-one of 120 (17.5%) White women with ER-positive breast cancer had the adrenal-permissive genotype, which was significantly higher than the general population (P = 0.0077; Table 1)
Because the hypothesis being tested was specific to postmenopausal breast cancer, enrollment in our prospective single-institution study was limited to patients who were postmenopausal at diagnosis, but we examined the adrenal-permissive genotype frequencies of premenopausal patients with breast cancer in the validation cohorts
Summary
Estrogen exposure increases the risk of estrogen receptor–driven (ER-driven) breast cancer. Mutations in DNA repair pathway components and certain tumor-suppressive genes, inherited genetics of estrogen synthesis has not been causally and reproducibly linked to endogenous estrogen exposure that in turn drives increased risk of breast cancer [4]. This may be due to inadequate power for such studies that interrogate multiple loci, the need to account for genetic variability in geography and race, other variations in hormonal physiology that might dilute such an effect, a combination of these factors, or the absence of such a link. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor–positive (ER-positive) breast cancer
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