Effects of CYP3A4 and CYP2C9 genotype on systemic anastrozole and fulvestrant concentrations in SWOG S0226
Delaney V Rutherford, Sarah Medley, Nicholas C Henderson, Christina L Gersch, Ted A Vandenberg, Kathy S Albain, Shaker R Dakhil, Nagendra R Tirumali, Julie R Gralow, Gabriel N Hortobagyi, Lajos Pusztai, Rita S Mehta, Daniel F Hayes, Kelley M Kidwell, N Lynn Henry, William E Barlow, James M Rae, Daniel L Hertz- Pharmacology
- Genetics
- Molecular Medicine
Objective & methods: This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes and SLC28A7 (rs11648166) and ALPPL2 (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Results: Participants in the anastrozole-only arm with low CYP3A4 activity (i.e., CYP3A4*22 carriers) had higher systemic anastrozole concentrations than patients with high CYP3A4 activity (β-coefficient = 10.03; 95% CI: 1.42, 18.6; p = 0.025). In an exploratory analysis, participants with low CYP2C9 activity had lower anastrozole concentrations and higher fulvestrant concentrations than participants with high CYP2C9 activity. Conclusion: Inherited genetic variation in CYP3A4 and CYP2C9 may affect concentrations of endocrine therapy and may be useful to personalize dosing and improve treatment outcomes.