Germline Genetic Predictors of Aromatase Inhibitor Concentrations, Estrogen Suppression and Drug Efficacy and Toxicity in Breast Cancer Patients

Overview

Journal Pharmacogenomics

Specialties Genetics
Pharmacology

Date 2017 Mar 28

PMID 28346074

Citations 23

Authors

Daniel L Hertz

N Lynn Henry

James M Rae

Affiliations

Soon will be listed here.

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.

Citing Articles

Lessons learned from a candidate gene study investigating aromatase inhibitor treatment outcome in breast cancer.

Hoppe R, Winter S, Lo W, Michailidou K, Bolla M, Keeman R NPJ Breast Cancer. 2025; 11(1):18.

PMID: 39971965 PMC: 11840073. DOI: 10.1038/s41523-025-00733-y.

Incorporation of emergent symptoms and genetic covariates improves prediction of aromatase inhibitor therapy discontinuation.

Rattsev I, Stearns V, Blackford A, Hertz D, Smith K, Rae J JAMIA Open. 2024; 7(1):ooae006.

PMID: 38250582 PMC: 10799747. DOI: 10.1093/jamiaopen/ooae006.

Identifying determinants of adherence to adjuvant endocrine therapy following breast cancer: A systematic review of reviews.

Todd A, Waldron C, McGeagh L, Norris R, Bolnykh I, Stewart S Cancer Med. 2024; 13(3):e6937.

PMID: 38240343 PMC: 10905548. DOI: 10.1002/cam4.6937.

Effects of and genotype on systemic anastrozole and fulvestrant concentrations in SWOG S0226.

Rutherford D, Medley S, Henderson N, Gersch C, Vandenberg T, Albain K Pharmacogenomics. 2023; 24(12):665-673.

PMID: 37615099 PMC: 10565537. DOI: 10.2217/pgs-2023-0097.

Long-term effects of aromatase inhibitors on body mass index among postmenopausal breast cancer survivors in Africa: observational cohort study.

Milambo J, Nyasulu P, Akudugu J, Ndirangu J BMC Res Notes. 2023; 16(1):37.

PMID: 36915158 PMC: 10012500. DOI: 10.1186/s13104-023-06301-6.

References

Wang L, Ellsworth K, Moon I, Pelleymounter L, Eckloff B, Martin Y . Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors. Cancer Res. 2010; 70(1):319-28. PMC: 2804935. DOI: 10.1158/0008-5472.CAN-09-3224. View

Geisler J, King N, Anker G, Ornati G, Di Salle E, Lonning P . In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res. 1998; 4(9):2089-93. View

Garcia-Giralt N, Rodriguez-Sanz M, Prieto-Alhambra D, Servitja S, Torres-Del Pliego E, Balcells S . Genetic determinants of aromatase inhibitor-related arthralgia: the B-ABLE cohort study. Breast Cancer Res Treat. 2013; 140(2):385-95. DOI: 10.1007/s10549-013-2638-3. View

Tanii H, Shitara Y, Horie T . Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women. Eur J Clin Pharmacol. 2011; 67(10):1017-25. DOI: 10.1007/s00228-011-1042-3. View

Lintermans A, Van Asten K, Jongen L, Van Brussel T, Laenen A, Verhaeghe J . Genetic variant in the osteoprotegerin gene is associated with aromatase inhibitor-related musculoskeletal toxicity in breast cancer patients. Eur J Cancer. 2016; 56:31-36. DOI: 10.1016/j.ejca.2015.12.013. View

Hertz D, Kidwell K, Seewald N, Gersch C, Desta Z, Flockhart D . Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer. Pharmacogenomics J. 2016; 17(6):521-527. PMC: 5323433. DOI: 10.1038/tpj.2016.60. View

Valle M, Di Salle E, Jannuzzo M, Poggesi I, Rocchetti M, Spinelli R . A predictive model for exemestane pharmacokinetics/pharmacodynamics incorporating the effect of food and formulation. Br J Clin Pharmacol. 2005; 59(3):355-64. PMC: 1884784. DOI: 10.1111/j.1365-2125.2005.02335.x. View

Ingle J, Kalari K, Buzdar A, Robson M, Goetz M, Desta Z . Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole. Steroids. 2014; 99(Pt A):32-8. PMC: 4339673. DOI: 10.1016/j.steroids.2014.08.007. View

Oesterreich S, Henry N, Kidwell K, Van Poznak C, Skaar T, Dantzer J . Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover. Breast Cancer Res Treat. 2015; 154(2):263-73. PMC: 4807610. DOI: 10.1007/s10549-015-3608-8. View

10.

Chen S, Atchley D, Murphy M, Gurley B, Kamdem L . Impact of UGT2B17 Gene Deletion on the Pharmacokinetics of 17-Hydroexemestane in Healthy Volunteers. J Clin Pharmacol. 2015; 56(7):875-84. PMC: 4882280. DOI: 10.1002/jcph.673. View

11.

Kamdem L, Flockhart D, Desta Z . In vitro cytochrome P450-mediated metabolism of exemestane. Drug Metab Dispos. 2010; 39(1):98-105. PMC: 3014267. DOI: 10.1124/dmd.110.032276. View

12.

Ingle J, Buzdar A, Schaid D, Goetz M, Batzler A, Robson M . Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer. Cancer Res. 2010; 70(8):3278-86. PMC: 2855746. DOI: 10.1158/0008-5472.CAN-09-3024. View

13.

Gellert P, Segal C, Gao Q, Lopez-Knowles E, Martin L, Dodson A . Impact of mutational profiles on response of primary oestrogen receptor-positive breast cancers to oestrogen deprivation. Nat Commun. 2016; 7:13294. PMC: 5105193. DOI: 10.1038/ncomms13294. View

14.

Folkerd E, Dixon J, Renshaw L, AHern R, Dowsett M . Suppression of plasma estrogen levels by letrozole and anastrozole is related to body mass index in patients with breast cancer. J Clin Oncol. 2012; 30(24):2977-80. DOI: 10.1200/JCO.2012.42.0273. View

15.

Buzdar A, Jonat W, Howell A, Jones S, Blomqvist C, Vogel C . Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group. J Clin Oncol. 1996; 14(7):2000-11. DOI: 10.1200/JCO.1996.14.7.2000. View

16.

Lunardi G, Piccioli P, Bruzzi P, Notaro R, Lastraioli S, Serra M . Plasma estrone sulfate concentrations and genetic variation at the CYP19A1 locus in postmenopausal women with early breast cancer treated with letrozole. Breast Cancer Res Treat. 2012; 137(1):167-74. PMC: 3528956. DOI: 10.1007/s10549-012-2306-z. View

17.

Hertz D, Barlow W, Kidwell K, Albain K, Vandenberg T, Dakhil S . Fulvestrant decreases anastrozole drug concentrations when taken concurrently by patients with metastatic breast cancer treated on SWOG study S0226. Br J Clin Pharmacol. 2016; 81(6):1134-41. PMC: 4876171. DOI: 10.1111/bcp.12904. View

18.

Erlik Y, Meldrum D, Judd H . Estrogen levels in postmenopausal women with hot flashes. Obstet Gynecol. 1982; 59(4):403-7. View

19.

Leyland-Jones B, Gray K, Abramovitz M, Bouzyk M, Young B, Long B . CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial. Breast Cancer Res Treat. 2015; 151(2):373-84. PMC: 4763278. DOI: 10.1007/s10549-015-3378-3. View

20.

Simpson E, Mahendroo M, Means G, Kilgore M, Hinshelwood M, Amarneh B . Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev. 1994; 15(3):342-55. DOI: 10.1210/edrv-15-3-342. View