title: Germline variants in the CYP19A1 gene are related to specific adverse events in aromatase inhibitor users: a substudy of Dutch patients in the TEAM trial.
abstract: Musculoskeletal adverse events (MSAEs) and vasomotor symptoms (VMSs) are known side-effects of aromatase inhibitors, and may be related to genetic variations of the aromatase gene (CYP19A1). We investigated the relationship between these specific AEs and single nucleotide polymorphisms (SNPs) in the CYP19A1 gene in postmenopausal, hormone receptor-positive early breast cancer (BC) patients treated with adjuvant exemestane for 5 years. Dutch patients who were randomized to receive 5 years of exemestane in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. A tagging-SNP approach was performed, covering 80 % of variations of the CYP19A1 gene with 30 SNPs. Logistic regression analyses were used to assess the risk of reporting VMSs or MSAEs in relation to genotypes within selected SNPs. Of 737 included patients, 281 patients reported at least one MSAE (n = 210) or VMS (n = 163). Homozygous AA genotype of rs934635 was associated with a significantly higher odds of MSAEs (multivariate odds ratio (OR) 4.66, p = 0.008) and VMSs (multivariate OR 2.78, p = 0.044). Regarding both rs1694189 and rs7176005, the homozygous variant genotypes (TT) were associated with a higher odds of VMSs, but not MSAEs (OR 1.758, p = 0.025 and OR 6.361, p = 0.021, respectively). Our exploratory analysis demonstrated that some CYP19A1 gene variations may be associated with MSAEs and/or VMSs. Specifically, patients with the homozygous variant rs934635 genotype reported more MSAEs and VMSs. Although further confirmatory studies are warranted, genomic profiling can help identify patients at an increased risk of reporting these specific AEs, potentiating further personalized BC treatment.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Duveken B Y
authors.initials: DB
authors.lastname: Fontein
authors.forename: Daniel
authors.initials: D
authors.lastname: Houtsma
authors.forename: Johan W R
authors.initials: JW
authors.lastname: Nortier
authors.forename: Renee F
authors.initials: RF
authors.lastname: Baak-Pablo
authors.forename: Elma Meershoek-Klein
authors.initials: EM
authors.lastname: Kranenbarg
authors.forename: Tahar R J H M
authors.initials: TR
authors.lastname: van der Straaten
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.forename: Caroline
authors.initials: C
authors.lastname: Seynaeve
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001141:Aromatase / Q000235:genetics*; D047072:Aromatase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D003131:Combined Modality Therapy; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009426:Netherlands; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D047072:Aromatase Inhibitors; D001141:Aromatase; C561410:CYP19A1 protein, human