title: Replication of genetic polymorphisms reported to be associated with taxane-related sensory neuropathy in patients with early breast cancer treated with Paclitaxel.
abstract: OBJECTIVE
  Associations between taxane-related sensory neuropathy (TRSN) and single-nucleotide polymorphisms (SNP) have previously been reported, but few have been replicated in large, independent validation studies. This study evaluates the association between previously investigated SNPs and TRSN, using genotype data from a study of chemotherapy-related toxicity in patients with breast cancer.
  
  
  METHODS
  We investigated 73 SNPs in 50 genes for their contribution to TRSN risk, using genotype data from 1,303 European patients. TRSN was assessed using National Cancer Institute common toxicity criteria for adverse events classification. Unconditional logistic regression evaluated the association between each SNP and TRSN risk (primary analysis). Cox regression analysis assessed the association between each SNP and cumulative taxane dose causing the first reported moderate/severe TRSN (secondary analysis). The admixture likelihood (AML) test, which considers all SNPs with a prior probability of association with TRSN together, tested the hypothesis that certain SNPs are truly associated.
  
  
  RESULTS
  The AML test provided strong evidence for the association of some SNPs with TRSN (P = 0.023). The two most significantly associated SNPs were rs3213619(ABCB1) [OR = 0.47; 95% confidence interval (CI), 0.28-0.79; P = 0.004] and rs9501929(TUBB2A) (OR = 1.80; 95% CI, 1.20-2.72; P = 0.005). A further 9 SNPs were significant at P-value ≤ 0.05.
  
  
  CONCLUSIONS
  This is currently the largest study investigating SNPs associated with TRSN. We found strong evidence that SNPs within genes in taxane pharmacokinetic and pharmacodynamic pathways contribute to TRSN risk. However, a large proportion of the inter-individual variability in TRSN remains unexplained. Further validated results from GWAS will help to identify new pathways, genes, and SNPs involved in TRSN susceptibility.
authors.affiliation: Authors' Affiliations: Department of Oncology and Strangeways Research Laboratory, University of Cambridge; Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals; Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way; Cambridge Experimental Cancer Medicine Centre, Cambridge; Warwick Clinical Trials Unit, University of Warwick; and Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, United Kingdom.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Abraham
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.forename: Leila
authors.initials: L
authors.lastname: Dorling
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tyrer
authors.forename: Susan
authors.initials: S
authors.lastname: Ingle
authors.forename: Richard
authors.initials: R
authors.lastname: Hardy
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Vallier
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
authors.forename: Russell
authors.initials: R
authors.lastname: Burns
authors.forename: Linda
authors.initials: L
authors.lastname: Jones
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bowden
authors.forename: Janet A
authors.initials: JA
authors.lastname: Dunn
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Poole
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: Paul P D
authors.initials: PP
authors.lastname: Pharoah
authors.forename: Helena M
authors.initials: HM
authors.lastname: Earl
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D017239:Paclitaxel / Q000008:administration & dosage; D010523:Peripheral Nervous System Diseases / Q000209:etiology*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; D017239:Paclitaxel