Attempted replication of SNPs in RANKL and OPG with musculoskeletal adverse events during aromatase inhibitor treatment for breast cancer

Jacqueline M. Dempsey,Jingyue Xi,James M. Rae,Daniel L. Hertz,N. Lynn Henry

doi:10.1152/physiolgenomics.00085.2017

Abstract

Aromatase inhibitor (AI) therapy is highly efficacious in the treatment of estrogen receptor-positive breast cancer; however, in a subset of patients AI use is discontinued due to drug-induced musculoskeletal adverse events (MS-AE). Several studies have investigated the role of germline single nucleotide polymorphisms (SNPs) on patients’ risk of MS-AEs; however, no associations have yet to be validated for translation into clinical practice. This study attempted to replicate SNPs in RANKL (rs7984870) and OPG (rs2073618) on the risk of AI-induced MS-AEs and screen for secondary associations with MS-AE-related treatment discontinuation and serum and urine markers of bone health. Previously reported associations were not replicated with our primary hypothesis, change in MS-AE from baseline to 3 mo; however, patients homozygous for the G allele of rs7984870 in RANKL had lower risk of MS-AE-associated treatment discontinuation in analyses of secondary phenotypes without statistical correction.

Highlights

Third-generation aromatase inhibitors (AIs) are highly efficacious in the treatment of estrogen receptor-positive (ERϩ) breast cancer and are a first line option in postmenopausal patients
The rs7984870 single nucleotide polymorphisms (SNPs) has been associated with RANKL expression and the minor (G) allele reported by Wang et al (5) for an exclusively Asian cohort was protective for musculoskeletal adverse events (MS-AEs)
Rs7984870 was significantly associated with time to MS-AE-related discontinuation of AI therapy (␤ ϭ 0.309, STD ϭ 0.139 P ϭ 0.0261, Fig. 1)

Summary

Introduction

Third-generation aromatase inhibitors (AIs) are highly efficacious in the treatment of estrogen receptor-positive (ERϩ) breast cancer and are a first line option in postmenopausal patients. The rs7984870 SNP has been associated with RANKL expression and the minor (G) allele reported by Wang et al (5) for an exclusively Asian cohort was protective for MS-AEs. The rs2073618 SNP has been associated with expression of OPG, a decoy receptor of RANKL. These conflicting results (see supplemental material: Appendix 2, Table 3) warrant additional replication in independent cohorts to validate these associations for potential translation into clinical practice.

Results

Conclusion