Germline genetic predictors of aromatase inhibitor concentrations, estrogen suppression and drug efficacy and toxicity in breast cancer patients

Abstract

The third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, are highly effective for the treatment of estrogen receptor-positive breast cancer in postmenopausal women. AIs inhibit the aromatase (CYP19A1)-mediated production of estrogens. Most patients taking AIs achieve undetectable blood estrogen concentrations resulting in drug efficacy with tolerable side effects. However, some patients have suboptimal outcomes, which may be due, in part, to inherited germline genetic variants. This review summarizes published germline genetic associations with AI treatment outcomes including systemic AI concentrations, estrogenic response to AIs, AI treatment efficacy and AI treatment toxicities. Significant associations are highlighted with commentary about prioritization for future validation to identify pharmacogenetic predictors of AI treatment outcomes that can be used to inform personalized treatment decisions in patients with estrogen receptor-positive breast cancer.

Keywords: GWAS; aromatase inhibitors; efficacy; estrogens; pharmacogenetics; pharmacogenomics; pharmacokinetics; review; toxicity.

Figure 1.. Overview of review article.

Each section of the main text summarizes the literature regarding the influence of germline genetic variation on: systemic aromatase inhibitor concentrations (Sec. 1), systemic estrogen concentrations (Sec. 2), aromatase inhibitor treatment efficacy (Sec. 3) and toxicity (Sec. 4). Polymorphisms that should be prioritized for analysis are highlighted throughout. Earlier sections on endophenotypes (drug and estrogen concentrations) also include summaries regarding their putative effect on downstream clinical phenotypes (efficacy and toxicity), as denoted by dashed lines. AI: Aromatase inhibitor; Sec: Section.

Figure 2.. Pharmacogenetics of aromatase inhibitor metabolism.

The three aromatase inhibitors have distinct metabolic pathways. Letrozole is primarily metabolized by polymorphic CYP2A6 and there is confirmed in vivo evidence that CYP2A6 genetics effects letrozole systemic concentrations. Exemestane is metabolized by several CYP, UGT and AKR enzymes, some of which have been demonstrated in vitro or in vivo to effect metabolism. Anastrozole is primarily metabolized by CYP3A4/5 and UGT1A4, with a contribution from several other CYPs and UGTs. No clinical pharmacokinetic studies have been reported for anastrozole. Polymorphic genes that have in vitro or in vivo evidence of an effect on metabolism are denoted by underlining and bolding, respectively, with superscript references. Evidence of an effect of polymorphisms in a given gene is denoted by an underline for in vitro studies and bolding for in vivo studies, with references in superscript.