Association of single nucleotide polymorphism of ERα gene and aromatase inhibitor-associated musculoskeletal symptoms

Abstract

Purpose/Aims

The purpose of this study was to investigate the correlation between aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) and ERα gene rs9340799,rs2234693 single nucleotide polymorphisms (SNPs) in breast cancer.

Rationale/Background

Aromatase inhibitor (AI) has a better effect on adjuvant therapy of hormone receptor-positive (HR+) breast cancers. AIs inhibit aromatase activity, reduce estrogen concentration, and improve survival rates for HR+ breast cancer patients. Despite the potential benefits, up to 50% of patients stop using AIs early. This is because AI can interfere with bone turnover, increasing the incidence of AIMSS. It has been confirmed that the risk of abnormal bone metabolism in healthy women is related to single nucleotide polymorphism (SNP) at two sites (rs9340799 and rs2234693) in the first intron of estrogen receptor alpha (ERα), but there have been few studies related to the risk of AIMSS. Our primary hypothesis was that ERα rs9340799 and rs2234693 would be associated with AIMSS.

Methods

From June 2015 to February 2022, 251 postmenopausal women with ER+ breast cancer who were receiving third-generation therapy were participated in this study. People with a medical history that included drug use or disease symptoms that were known to affect bone mineral metabolism were excluded. Each participant's peripheral blood was used to extract their entire genome, which was then amplified and sequenced for the chosen region. Dual energy X-ray absorptiometry was used to calculate the entire lumbar spine (spinal BMD) and the entire femur (femoral BMD).

Results

The BMD and T values of lumbar vertebrae in all ER α gene subtypes at rs9340799 were statistically significant (P=0.031,P<0.01), and the T value of lumbar vertebrae in A/A was higher than those in A/G and G/G (-0.957 ± 1.112 vs -1.313 ± 1.289 vs -1.76 ± 1.304). There were also significant differences in BMD and T values of lumbar vertebrae among rs2234693 genotypes (P=0.011, P < 0.01). The T values of T/T and C/T lumbar vertebrae were higher than those of C/C (-0.801 ± 1.085 vs -1.342 ± 1.067 vs -1.502 ± 1.591).

Although the femoral BMD trend of both SNPs is similar to that of lumbar vertebrae, there is no statistical difference.

Implications

Our findings suggest that C and G alleles may be susceptible genes for AMISS. These findings have potential clinical implications. In patients with C and G alleles, AMISS prevention is crucial, or tamoxifen may be appropriate for these patients to reduce risk.