University of Michigan College of Pharmacy, Ann Arbor, MI
Jacqueline M Dempsey , Kelley M. Kidwell , Christina L Gersch , Zeruesenay Desta , Anna Maria Storniolo , Vered Stearns , Todd C Skaar , Daniel F. Hayes , Norah Lynn Henry , James M. Rae , Daniel Louis Hertz
Background: Three aromatase inhibitors (AI), the steroid exemestane, and the azoles anastrozole and letrozole, are effective in the treatment of estrogen receptor positive (ER+) breast cancer by preventing biosynthesis of estrogens including estradiol (E2), estrone (E1), and estrone-sulfate (E1S) in postmenopausal women. OATP1B1, encoded by SLCO1B1, transports E1S into the liver for desulfation to active E1. Women carrying the low-expression SLCO1B1 rs4149056 single nucleotide polymorphism (SNP) have higher E1-conjugate levels (Dudenkov Breast Cancer Res Treat 2017). We hypothesized that patients carrying this SNP would have increased E1S at baseline, and this E1S reserve could resupply E1 and E2 resulting in detectable estrogen levels during AI treatment. Methods: Five hundred postmenopausal women with ER+ breast cancer were randomized 1:1 to either exemestane 25 mg/day or letrozole 2.5 mg/day. Plasma estrogen concentrations were measured prior to and after 3 months of AI treatment using LC/MS/MS (LLOQ for E2 = 0.625 pg/mL, E1 = 1.56 pg/mL, E1S = 3.13 pg/mL). The additive genetic associations between rs4149056 and 1) log-transformed concentrations of E2, E1, and E1S at baseline and 2) detectable ( > LLOQ) concentrations of E2, E1, and E1S after 3 months of AI treatment, were tested using linear and logistic regression, respectively. Results: Patients carrying the low-expression rs4149056 (minor allele frequency = 0.18) SNP had 51% (per allele) higher baseline E1S concentrations (n = 438, 95% CI (29%-76%), p < 0.0001). After 3 months of AI treatment, 15% (58/378) of patients had detectable E1; carrying rs4149056 increased risk of maintaining detectable E1 by 84% (per allele) (odds ratio = 1.84, 95% CI (1.08-3.14), p = 0.025). Conclusions: Patients carrying a low-expression OATP1B1/SLCO1B1 SNP have higher pre-treatment E1S and greater risk of maintaining detectable E1 during AI treatment, possibly due to replenishment from E1S reserves. Further studies are needed to assess whether this common SNP is associated with increased risk of AI treatment failure.
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