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

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.

Genome-wide association study of aromatase inhibitor discontinuation due to musculoskeletal symptoms

“…Six candidate variants, rs912571, rs9322336, and rs2347868 in ESR1, rs7984870 in RANKL, and rs2369049 and rs11849538 in TCL1A, were signi cantly associated with AIMSS risk in either the combined cohort or the exemestane-treated group (p-value<0.05) (Table 3 and Supplementary Table 2). However, these associations have been previously reported in similar analyses of the ELPh cohort 22,23 . None of the variants that were previously reported to be associated with AIMSS that had not been previously tested in ELPh were associated with AIMSS in this analysis (Supplementary Table 2).…”

“…For the twenty-ve variants in 11 genes that were previously reported to be associated with AIMSS risk 16,[18][19][20][21][30][31][32][33] , p-values less than 0.05 were considered statistically signi cantly. Where noted below, associations for a subset of these variants were previously reported in the ELPh cohort 22,23 .…”

“…A substudy of the Exemestane and Letrozole Pharmacogenetics (ELPh) study was conducted to document the clinical course of AIMSS and identify clinical and genetic risk factors, primarily using candidate gene approaches. 22,23 We recently performed genome-wide genotyping within ELPh to validate that CYP2A6 genetics was a major determinant of letrozole pharmacokinetics 24 . The objective of the current study was to identify new genetic variants associated with discontinuation of AI therapy due to AIMSS in ELPh participants using a genome-wide approach and, secondarily, replicate previously reported pharmacogenetic associations.…”

Further Evidence That OPG rs2073618 Is Associated With Increased Risk of Musculoskeletal Symptoms in Patients Receiving Aromatase Inhibitors for Early Breast Cancer

“…Wang et al initially hypothesized that SNPs in OPG, which encodes osteoprotegerin, could be associated with risk of AIMSS. Using a large cohort ( n = 420) of AI-treated patients, these investigators found that patients who carried the allele encoding lysine had lower OPG expression and higher AIMSS risk ( Dempsey et al, 2018 ). They also found that carriers of this variant had greater levels of the bone turnover markers carboxy terminal telopeptide and procollagen type I N-terminal propeptide and greater reduction in bone mineral density at the lumbar spine.…”

“…Many studies have used candidate-gene or candidate-single nucleotide polymorphism (SNP) approaches to investigate whether inherited germline variants affect AIMSS risk ( Ingle et al, 2010 ; Park et al, 2011 ; Garcia-Giralt et al, 2013 ; Henry et al, 2013 ; Wang et al, 2013 , 2015 ; Fontein et al, 2014 ; Leyland-Jones et al, 2015 ; Lintermans et al, 2016 ; Dempsey et al, 2018 ). These studies have reported several discovery-phase associations including inherited polymorphism in the genes that encode for the AI drug target CYP19A1 ( Garcia-Giralt et al, 2013 ; Henry et al, 2013 ; Fontein et al, 2014 ; Leyland-Jones et al, 2015 ), proteins responsible for bone resorption OPG / RANKL ( Wang et al, 2013 ; Lintermans et al, 2016 ; Dempsey et al, 2018 ), and the estrogen receptor ESR1 ( Ingle et al, 2010 ; Park et al, 2011 ). In addition, a hypothesis-agnostic genome-wide association study of the MA.27 clinical trial comparing anastrozole and exemestane reported that patients who carried rs11849538 near TCL1A had increased AIMSS risk ( Liu et al, 2012 ).…”