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Current Pharmaceutical Design

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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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General Research Article

CYP19A1 rs10046 Pharmacogenetics in Postmenopausal Breast Cancer Patients Treated with Aromatase Inhibitors: One-year Follow-up

Author(s): Karin Baatjes*, Armand Peeters, Micheal McCaul, Maria M. Conradie, Justus Apffelstaedt, Magda Conradie and Maritha J. Kotze

Volume 26, Issue 46, 2020

Page: [6007 - 6012] Pages: 6

DOI: 10.2174/1381612826666200908141858

Price: $65

Abstract

Background: Significant individual variation in bone loss associated with aromatase inhibitors (AIs) emphasizes the importance of identifying postmenopausal breast cancer patients at high risk for this adverse effect. The study explores the clinical relevance of genetic variation in the Cytochrome P450 19A1 (CYP19A1) gene in a subset of South African patients during the first year of taking AIs for estrogen receptor (ER)-positive breast cancer.

Methods: The study population consisted of ER-positive breast cancer patients on AIs, followed in real-life clinical practice. Body mass index was measured and bone mineral density (BMD) was determined at baseline and at month 12. CYP19A1 genotyping was performed using real-time polymerase chain reaction analysis of rs10046, extended to Sanger sequencing and whole exome sequencing in 10 patients with more than 5% bone loss at month 12 at the lumbar spine.

Results: After 12 months of AI treatment, 72 patients had completed BMD and were successfully genotyped. Ten patients (14%) experienced more than 5% bone loss at the lumbar spine over the study period. Genotyping for CYP19A1 rs10046 revealed that patients with two copies of the A-allele were 10.79 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase at the lumbar spine, compared to patients with the GA or GG genotypes (CI of 1.771- 65.830, p=0.01). None of the 34 patients without lumbar spine bone loss at month 12 were homozygous for the functional CYP19A1 polymorphism. At the total hip region, patients with the AA genotype were 7. 37 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase (CI of 1.101- 49.336, p=0.04).

Conclusion: Homozygosity for the CYP19A1 rs10046 A-allele may provide information, in addition to clinical and biochemical factors that may be considered in risk stratification to optimize bone health in postmenopausal breast cancer women on AIs. Further investigation is required to place the clinical effect observed for a single CYP19A1 gene variant in a genomic context.

Keywords: Aromatase inhibitors, breast cancer, bone health, genomics, pharmacogenetics, postmenopausal.

« Previous Next »
[1]
Eastell R, Hannon RA, Cuzick J, Dowsett M, Clack G, Adams JE. Effect of an aromatase inhibitor on bmd and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res 2006; 21(8): 1215-23.
[http://dx.doi.org/10.1359/jbmr.060508] [PMID: 16869719]
[2]
Zaman K, Thürlimann B, Huober J, et al. Bone mineral density in breast cancer patients treated with adjuvant letrozole, tamoxifen, or sequences of letrozole and tamoxifen in the BIG 1-98 study (SAKK 21/07). Ann Oncol 2012; 23(6): 1474-81.
[http://dx.doi.org/10.1093/annonc/mdr448] [PMID: 22003243]
[3]
Baatjes KJ, Apffelstaedt JP, Kotze MJ, Conradie M. Postmenopausal breast cancer, aromatase inhibitors, and bone health: what the surgeon should know. World J Surg 2016; 40(9): 2149-56.
[http://dx.doi.org/10.1007/s00268-016-3555-5] [PMID: 27189076]
[4]
Rodríguez-Sanz M, García-Giralt N, Prieto-Alhambra D, et al. CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss. J Mol Endocrinol 2015; 55(1): 69-79.
[http://dx.doi.org/10.1530/JME-15-0079] [PMID: 26108486]
[5]
Mullis PE, Yoshimura N, Kuhlmann B, Lippuner K, Jaeger P, Harada H. Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries, and bone densitometry in childhood. J Clin Endocrinol Metab 1997; 82(6): 1739-45.
[http://dx.doi.org/10.1210/jc.82.6.1739] [PMID: 9177373]
[6]
Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995; 80(12): 3689-98.
[http://dx.doi.org/10.1210/jcem.80.12.8530621] [PMID: 8530621]
[7]
Payne EJ, Ingley E, Dick IM, Wilson SG, Bond CS, Prince RL. In vitro kinetic properties of the Thr201Met variant of human aromatase gene CYP19A1: functional responses to substrate and product inhibition and enzyme inhibitors. J Clin Endocrinol Metab 2009; 94(8): 2998-3002.
[http://dx.doi.org/10.1210/jc.2008-2309] [PMID: 19470632]
[8]
Dunning AM, Dowsett M, Healey CS, et al. Polymorphisms associated with circulating sex hormone levels in postmenopausal women. J Natl Cancer Inst 2004; 96(12): 936-45.
[http://dx.doi.org/10.1093/jnci/djh167] [PMID: 15199113]
[9]
Kristensen VN, Harada N, Yoshimura N, et al. Genetic variants of CYP19 (aromatase) and breast cancer risk. Oncogene 2000; 19(10): 1329-33.
[http://dx.doi.org/10.1038/sj.onc.1203425] [PMID: 10713674]
[10]
Baatjes KJ, Conradie M, Apffelstaedt JP, Kotze MJ. Pharmacogenetics of aromatase inhibitors in endocrine responsive breast cancer: lessons learnt from tamoxifen and CYP2D6 genotyping. Anticancer Agents Med Chem 2017; 17(13): 1805-13.
[http://dx.doi.org/10.2174/1871521409666170412124226] [PMID: 28403774]
[11]
Bigos KL, Mattay VS, Callicott JH, et al. Genetic variation in CACNA1C affects brain circuitries related to mental illness. Arch Gen Psychiatry 2010; 67(9): 939-45.
[http://dx.doi.org/10.1001/archgenpsychiatry.2010.96] [PMID: 20819988]
[12]
Baatjes KJ, Kotze MJ, McCaul M, Conradie M. Baseline bone health status in multi-ethnic South African postmenopausal breast cancer patients at initiation of aromatase inhibitor therapy: A descriptive study. PLoS One 2019; 14(4)e0214153
[http://dx.doi.org/10.1371/journal.pone.0214153] [PMID: 30939140]
[13]
van der Merwe N, Peeters AV, Pienaar FM, Bezuidenhout J, van Rensburg SJ, Kotze MJ. Exome sequencing in a family with luminal-type breast cancer underpinned by variation in the methylation pathway. Int J Mol Sci 2017; 18(2): 467.
[http://dx.doi.org/10.3390/ijms18020467] [PMID: 28241424]
[14]
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42(2): 377-81.
[http://dx.doi.org/10.1016/j.jbi.2008.08.010] [PMID: 18929686]
[15]
Hong AR, Kim JH, Lee KH, et al. Long-term effect of aromatase inhibitors on bone microarchitecture and macroarchitecture in non-osteoporotic postmenopausal women with breast cancer. Osteoporos Int 2017; 28(4): 1413-22.
[http://dx.doi.org/10.1007/s00198-016-3899-6] [PMID: 28083668]
[16]
Reid DM, Doughty J, Eastell R, et al. Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group. Cancer Treat Rev 2008; 34(Suppl. 1): S3-S18.
[http://dx.doi.org/10.1016/j.ctrv.2008.03.007] [PMID: 18515009]
[17]
Raskin L, Lejbkowicz F, Barnett-Griness O, Dishon S, Almog R, Rennert G. BRCA1 breast cancer risk is modified by CYP19 polymorphisms in Ashkenazi Jews. Cancer Epidemiol Biomarkers Prev 2009; 18(5): 1617-23.
[http://dx.doi.org/10.1158/1055-9965.EPI-09-0060] [PMID: 19366906]
[18]
Sestak I, Singh S, Cuzick J, et al. Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, double-blind, randomised, placebo-controlled trial. Lancet Oncol 2014; 15(13): 1460-8.
[http://dx.doi.org/10.1016/S1470-2045(14)71035-6] [PMID: 25456365]
[19]
Leyland-Jones B, Gray KP, Abramovitz M, et al. 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.
[http://dx.doi.org/10.1007/s10549-015-3378-3] [PMID: 25935582]
[20]
Johansson H, Gray KP, Pagani O, et al. Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial. Breast Cancer Res 2016; 18(1): 110.
[http://dx.doi.org/10.1186/s13058-016-0771-8] [PMID: 27825388]

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