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Oxaliplatin-Induced Neurotoxicity

Glutathione-S-Transferase P1 I105V (GSTP1 I105V) Polymorphism is Associated With Early Onset of Oxaliplatin-Induced Neurotoxicity. A Grothey, HL McLeod, EM Green, DJ Sargent, C Fuchs, RK Ramanathan, S Williamson, B Findlay, RM Goldberg for the North Central Cancer Treatment Group (NCCTG).

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Oxaliplatin-Induced Neurotoxicity

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  1. Glutathione-S-Transferase P1 I105V (GSTP1 I105V) Polymorphism is Associated With Early Onset of Oxaliplatin-Induced Neurotoxicity A Grothey, HL McLeod, EM Green, DJ Sargent, C Fuchs, RK Ramanathan, S Williamson, B Findlay, RM Goldberg for the North Central Cancer Treatment Group (NCCTG)

  2. Oxaliplatin-Induced Neurotoxicity • Acute neuropathy: • Transient, cold-triggered paresthesia/dysesthesia • Frequent (85-95%) • Not dose-limiting • Chronic, cumulative neurotoxicity: • Predictable phenomenon, correlated with cumulative dose of oxaliplatin • Frequency of grade 3 15-20% in phase III trials • Dose-limiting toxicity of oxaliplatin

  3. FOLFOX4 in N9741 - Reasons for Treatment Discontinuation • 63% of 696 patients discontinued FOLFOX for other reasons than PD • Sensory neurotoxicity (sNT) was the single most important reason for treatment discontinuation due to toxicity • 74% (43%) of all patients who developed G3 (G2) neurotoxicity discontinued therapy because of it IFL: Irinotecan + 5-FU/LV RANDOMI ZAT ION FOLFOX4: Oxaliplatin + 5-FU/LV IROX: Irinotecan + oxaliplatin Goldberg et al., JCO 2004; Green et al., GI ASCO 2005

  4. Toxicity Analysis of FOLFOX4 in N9741 • Time to grade 2/3 neurotoxicity was clearly dependent on duration of therapy and cumulative oxaliplatin dose Green et al., GI ASCO 2005

  5. No correlation with neurotoxicity found in 288 pts on FOLFOX Initial Pharmacogenomic Analysis of N9741 - Candidate Genes • Genomic DNA extracted from whole blood • SNPs evaluated using pyrosequencing • 5-Fluorouracil • DPYD*2A • DPYD*5 • DPYD*9 • MTHFR variants • TYMS 1494del • TYMS TSER • Irinotecan • ABCD1 3435 • CYP3A4 • CYP3A5 • UGT1A1 7/7 • Oxaliplatin • ERCC2 K751Q - excision repair • GSTP1 I105V - detoxification • GSTM1 DEL - detoxification • XRCC1 R399Q - excision repair McLeod et al., ASCO 2003

  6. Oxaliplatin-Induced Neurotoxicity and Genetic Susceptibility • Oxaliplatin-induced neurotoxicity clearly correlated with time on treatment / cumulative dose administered • Susceptibility to neurotoxicity is rather a question of WHEN than IF a patient will develop neurotoxicity on oxaliplatin • Thus, pharmacogenomic analysis has to include time-to- or better dose-to-toxicity correlation

  7. Polymorphisms and Treatment Discontinuation Due to Neurotoxicity *Chi-square P-value

  8. Glutathione-S-Transferase P1 I105V Polymorphism • GSTP1 = detoxifying enzyme that catalyzes the conjugation of glutathione to an electrophilic center in the toxic compound • Single-nucleotide polymorphism (SNP) at residue 105 (C or T) determines enzymatic activity • T (Isoleucine)  C (Valine) substitution leads to • Lower enzymatic activity • Lower thermal stability  Reduced detoxicating properties of GSTP1 Johansson et al., J Mol Biol 1998

  9. Cumulative Oxaliplatin-Dose and Early Neurotoxicity

  10. Cumulative Oxaliplatin-Dose and Early Neurotoxicity Chi-Square P = 0.030* P = 0.143 *Fisher’s exact P-value = 0.036

  11. Development of Neurotoxicity - Extremes in Tolerability • Analysis of GSTP1 in patients who developed neurotoxicity early (low tolerability - LT) • G2 neurotoxicity <600 mg/m2 (N=43) or • G3 neurotoxicity <800 mg/m2 (N=12) cumulative oxaliplatin dose compared with • Equal number of patients who developed G2 and G3 neurotoxicity only at high cumulative doses (>1100 and >1790 mg/m2) (high tolerability - HT)

  12. C-Allele Frequency 42% 27% 56% 19% Development of Neurotoxicity - Extremes in Tolerability % pts G2 sNT G3 sNT T/T vs C/T or C/C P = 0.027 P = 0.030* *Fisher’s exact P-value = 0.080

  13. Grade 3 sNT @ 1020 mg/m2 (MOSAIC): 9% vs 23% Cumulative Oxaliplatin Dose and Grade 3 Neurotoxicity Log Rank P = 0.0496 Cumulative Oxaliplatin Dose (mg/m2)

  14. Cumulative Oxaliplatin Dose and Grade 2 Neurotoxicity Log Rank P = 0.471 Cumulative Oxaliplatin Dose (mg/m2)

  15. No Correlation Between GSTP1 I105V Polymorphism and Response RR (%) T/T C/T C/C Chi-Square P = 0.078 for T/T vs [C/C or C/T] Chi-Square P = 0.698 for C/C vs [T/T or C/T]

  16. Conclusions • Our analysis provides evidence that genetic variations in GSTP1 may serve as predictors of susceptibility to oxaliplatin-mediated neurotoxicity • These finding clearly require further validation by other retrospective analyses or prospective trials • Combining GSTP1 with other pharmacogenomic predictors of neurotoxicity might allow better identification of patients at risk for neurotoxicity

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