title: Genetic variant in the osteoprotegerin gene is associated with aromatase inhibitor-related musculoskeletal toxicity in breast cancer patients.
abstract: BACKGROUND
  Aromatase inhibitor (AI) therapy is associated with musculoskeletal (MS) toxicity, which adversely affects quality of life and therapy adherence. Our objective was to evaluate whether genetic variants may predict endocrine therapy-related MS pain and hot flashes in a prospective observational cohort study.
  
  
  METHODS
  254 early breast cancer patients starting AI (n = 159) or tamoxifen therapy (n = 95) were included in this genetic biomarker study. MS and vasomotor symptoms were assessed at baseline and after 3, 6 and 12 months of therapy. AI-induced MS pain was defined as an increase in arthralgia or myalgia relative to baseline. Single nucleotide polymorphisms (SNP) in candidate genes involved in oestrogen signalling or previously associated with AI-related MS pain or oestrogen levels were selected.
  
  
  RESULTS
  Overall, 13 SNPs in CYP19, CYP17, osteoprotegerin (OPG) and oestrogen receptor 1 exhibited an allele frequency >0.05 and were included in the analysis. Patients carrying the G allele of rs2073618 in OPG experienced significantly more AI-induced MS toxicity compared to the wildtype allele, after correction for multiple testing (P = 0.046). Furthermore, this SNP was associated with severity of pain (P = 0.018). No association was found with regard to the other SNPs, both in AI and tamoxifen-treated patients. Neither could an association with vasomotor symptoms be demonstrated.
  
  
  CONCLUSIONS
  The SNP rs2073618 in OPG is associated with an increased risk of MS symptoms and pain with AI therapy, which has not been reported previously. Validation of this finding in larger cohorts and further functional studies are required.
authors.affiliation: Department of Gynecology & Obstetrics, University Hospitals Leuven, Leuven, Belgium. Electronic address: anneleen.lintermans@uzleuven.be.
authors.forename: A
authors.initials: A
authors.lastname: Lintermans
authors.affiliation: Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Van Asten
authors.affiliation: Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Jongen
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Van Brussel
authors.affiliation: Leuven Biostatistics and Statistical Bioinformatics Centre, KU Leuven, Leuven, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Laenen
authors.affiliation: Department of Gynecology & Obstetrics, University Hospitals Leuven, Leuven, Belgium; Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Verhaeghe
authors.affiliation: Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium; Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Vanderschueren
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Department of Gynecology & Obstetrics, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Neven
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D047072:Aromatase Inhibitors / Q000009:adverse effects*; D018771:Arthralgia / Q000139:chemically induced / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D059352:Musculoskeletal Pain / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics*; D063806:Myalgia / Q000139:chemically induced / Q000235:genetics; D053244:Osteoprotegerin / Q000235:genetics*; D010147:Pain Measurement; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human
keywords: AIMSS; Aromatase inhibitor; Breast cancer; Hot flashes; Musculoskeletal pain; OPG; SNP; Tamoxifen