title: 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.
authors.affiliation: Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109-1065, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hertz
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84103, USA.
authors.forename: N Lynn
authors.initials: NL
authors.lastname: Henry
authors.affiliation: Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109-1065, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
mesh_terms: D000072956:Adult Germline Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006727:Hormone Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D011237:Predictive Value of Tests; D016896:Treatment Outcome
chemical_list: D047072:Aromatase Inhibitors; D004967:Estrogens; D006727:Hormone Antagonists; D001141:Aromatase; C561410:CYP19A1 protein, human
keywords: GWAS; aromatase inhibitors; efficacy; estrogens; pharmacogenetics; pharmacogenomics; pharmacokinetics; review; toxicity