Glutathione S-transferase P1 I105V (GSTP1 I105V) polymorphism is associated with early onset of oxaliplatin-induced neurotoxicity.

3509 Background: Sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, the integral component of the FOLFOX regimen which has emerged as standard therapy in colorectal cancer. Variations in genes potentially involved in the detoxification (glutathione system: GSTP1, GSTM1) or the cytotoxic mechanism (nucleotide excision repair: ERCC2, XRCC1) of oxaliplatin could serve as genetic predictors of susceptibility to oxaliplatin's neurotoxic effects.,Germline DNA was extracted from whole blood of 299 patients (pts) who received FOLFOX4 on Intergroup study N9741. Four genetic variants (GSTP1 I105V, GSTM1 del, ERCC2 K751Q, XRCC1 R399Q) were tested for association with the time to development of grade 2/3 sNT and sNT as reason for treatment discontinuation. In addition, pts who developed grade 2 (3) neurotoxicity before a cumulative oxaliplatin dose of 600 (800) mg/m2 was reached were compared to an equal number of pts that tolerated extremely high cumulative doses of oxaliplatin.,Pts with GSTP1 I105V C/C polymorphism were more likely to discontinue FOLFOX due to sNT (23.7%) than pts with T/T (9.2%) or C/T (10%) variants (p=0.039). Pts with GSTP1 I105V C/C also had lower cumulative dose to onset of grade 3 sNT compared to T/T or C/C pts (p=0.05). Pts carrying at least one GSTP1 I105V C-allele (C/C or C/T) were more likely to experience rapid onset grade 3 neurotoxicity than T/T pts, who were more likely to be able to tolerate high doses (p=0.027 for grade 2, p=0.030 for grade 3). No significant correlation of GSTM1, ERCC2, and XRCC1 polymorphisms with the onset of sNT on FOLFOX was observed.,Our study provides early evidence that genetic variations in GSTP1 may serve as predictors of susceptibility to oxaliplatin-mediated sNT. These findings require prospective validation before GSTP1 polymorphisms can be used to identify pts in whom neurotoxicity prevention strategies on oxaliplatin-based chemotherapy are warranted. [Table: see text].