1. for the North Central Cancer Treatment Group (NCCTG)
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 % in phase III trials
Dose-limiting toxicity of oxaliplatin

3. FOLFOX4 in N9741 - Reasons for Treatment Discontinuation
RANDOMI
ZAT
ION
IFL:
Irinotecan +
5-FU/LV
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
FOLFOX4: Oxaliplatin 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
% pts
Cumulative Oxaliplatin-dose (mg/m2)
600
680
800
1020 G2 19 21 27 46 G3 3 4 6 18
G2/3 22 25 33 64
Green et al., GI ASCO 2005

5. 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
No correlation with neurotoxicity found
in 288 pts on FOLFOX
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
Off Due to Neurotoxicity
P-Value*
GSTP1
T/T (N=120)
C/T (N=130)
C/C (N=38)
11 (9%)
13 (10%)
9 (24%)
0.039
ERCC2
Other
G/G
30 (12%)
5 (13%)
0.779
XRCC1
C/C
16 (10%)
17 (13%)
0.572
GSTM1
Absent
Present
16 (11%)
19 (12%)
0.742
*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
GSTP1
< 600 mg/m2
< 800 mg/m2
Grade 2
Grade 3
Grade2
C/C (N=38)
16% 3%
24% 8%
C/T (N=130)
18% 2%
22%
T/T (N=120)
11% 0%
17%

10. Cumulative Oxaliplatin-Dose and Early Neurotoxicity
GSTP1
< 600 mg/m2
< 800 mg/m2
Grade 2/3
C/C (N=38)
20%
27%
C/T (N=130)
T/T (N=120)
11%
18%
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. Development of Neurotoxicity - Extremes in Tolerability
% pts
C-Allele Frequency
42%
27%
56%
19%
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. Cumulative Oxaliplatin Dose and Grade 3 Neurotoxicity
Grade mg/m2
(MOSAIC): 9% vs 23%
Log Rank P =
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
T/T
C/T
C/C
Chi-Square P = for T/T vs [C/C or C/T]
Chi-Square P = 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