Indications of Clinical and Genetic Predictors for Aromatase Inhibitors Related Musculoskeletal Adverse Events in Chinese Han Women with Breast Cancer

Abstract

BackgroundWomen with breast cancer treated with aromatase inhibitors (AIs) may experience musculoskeletal symptoms that lead to discontinuation of effective therapy. The purpose of the current study is to evaluate the clinical and genetic predictors for AIs-related musculoskeletal adverse events(MS-AEs).Methodology and Principal FindingsWe recruited 436 postmenopausal Chinese Han women receiving adjuvant AIs therapy for early-stage hormone-sensitive breast cancer. Patients completed a self-administered questionnaire assessing the presence of musculoskeletal symptoms that started or worsened after initiating AIs. 27 single nucleotide polymorphisms (SNP) of ESR1, ESR2 and PGR were analyzed by Sequenom MassARRAY assays and /or PCR-based TaqMan assays.Of the 436 enrolled women, 206 cases experienced musculoskeletal symptoms.Patients who received taxane chemotherapy were more than two times more likely than other patients to have AIs-related MS-AEs. Genetic assay had showed that only two ESR1 SNPs, rs2234693 and rs9340799 were associated with AIs-related MS-AEs.TT genotype and the T allele in rs2234693 was statistically significantly lower in AIs-Related MS-AEs group than controls (P = 0.001; P = 9.49E-7). The frequency of AA genotype and the A allele in rs9340799 was higher (P = 2.20E-5; P = 3.09E-4).Conclusions and SignificanceOur results suggested that prior taxane-based chemotherapy was the clinical predictor, while rs2234693 and rs9340799 were the genetic predictors for AIs-related MS-AEs.

The implications of genetic variation for the pharmacokinetics and pharmacodynamics of aromatase inhibitors

“…In a substudy of the BIG 1-98 international trial, letrozole-treated patients with the C allele at rs2077647 had a 25% lower risk of bone adverse events (HR=0.75 (0.58-0.98)), whereas patients with the A allele at the ESR2 3'-UTR polymorphism rs4986938 had a 37% greater risk compared with those with wild-type genotype (HR=1.37 (1.01-1.84)) [91]. However, unlike the aforementioned study in Chinese patients [86], no association was found of ESR1 rs2234693 and rs9340799 genetic variant carriers with bone adverse events in the predominantly European population. These conflicting results may be due to differences in ethnicity (and thus minor allele frequencies) and the unbalanced sample sizes.…”

“…Estrogenic effects in bone, include the regulation of bone turnover and maintenance of bone mass, result from binding of estradiol to ESR1 [82][83][84][85]. In a study of 436 postmenopausal women receiving adjuvant anastrozole or letrozole therapy for early stage breast cancer, two ESR1 SNPs have been found to have an impact on the incidence of AI-related MSAEs [86]. The intronic SNP rs2234693 influences enhancer activity levels of ESR1…”

“…[87], and carriers of the T allele at rs2234693 had a significantly lower incidence of AI-related MS-AEs (OR=0.510 (0.389-0.669)) [86]. Carriers of the G allele at the intronic SNP rs9340799 had a lower incidence of AI-related MS-AEs (OR=0.553 (0.339-0.764)).…”

Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial

“…Postmenopausal Chinese patients with breast cancer carrying an ESR1 rs2234693 CC genotype or rs9340799 AA genotype had an increased risk of AI-related musculoskeletal AEs [35]. In fact, several studies suggest that the effect of the ESR1 polymorphisms on breast cancer risk is hormone-related and dependent on the woman’s hormonal context, showing statistically significant associations mainly in premenopausal women [23].…”

Detection of Genetic Alterations by Nucleic Acid Analysis: Use of PCR and Mass Spectroscopy-Based Methods

“…Today, this technology is widely used and has become a standard in specific gene mutation detection in large cohorts of patients [88], in pharmacogenomics response prediction of the side effects in chemotherapy in cancer treatment [89,90] and in the discovery of disease susceptibility due to gene mutations [91].…”