McLeod, H. L.

3520 Background: This report examines UGT1A1*28, toxicity, and outcome in trial NCCTG N9741 patients (pts) receiving combination chemotherapy for advanced colorectal cancer. Methods: Blood samples were collected from 520 pts randomized between 2/18/00 and 7/18/02. Pts were treated with irinotecan/5-fluorouracil (5FU)/leucovorin (LV) (IFL, n=114), oxaliplatin/5FU/LV (FOLFOX, n=299), irinotecan/oxaliplatin (IROX, n=107). 19% of IFL pts received full-dose (125 mg/m2) irinotecan; the rest received a reduced dose (100 mg/m2). Toxicity was evaluated every cycle. Correlation of dichotomous outcomes and genotype status used Fisher’s exact tests. Univariate logistic regression was used to test the association between continuous variables and binary outcomes, including a test of trend, and multivariate logistic regression to adjust for known risk factors: performance status, age, gender. Time to progression (TTP) and overall survival (OS) were tested for association with UGT1A1 using the log-rank test. Statistical significance was prospectively set at .01 to control for multiple comparisons. Results: Frequency of UGT1A1 genotype was 44% 6/6, 42% 6/7, and 9% 7/7. In all arms, the rate of grade (G) 4 neutropenia (neut) ( Table ) and G3+ febrile neut (FN) was higher in pts with the 7/7 than in pts with 6/7 and 6/6. No association was seen between UGT1A1 and diarrhea, tumor response, TTP, or OS overall or for any treatment arm. The odds ratios for pts with 7/7 developing G4 neut and G3+ FN compared with pts with 6/6 are shown ( Table ). Statistically significant associations between the 7/7 polymorphism and G4 neut were seen in pts treated with IROX (P=.004) and in all pts (P=.007). The association between 7/7 and G3+ FN was also significant for IROX (P=.006). Conclusions: There is a higher risk of neut in 7/7 pts. Due to low frequency of the 7/7, exclusion of all pts with 7/7 reduces the overall G4 neut rate from 18% to 17%. UGT1A1 was not a predictor of response, TTP, or OS for any arm. [Table: see text] [Table: see text]

3503 Background: The association between race & toxicity or response to systemic chemotherapy is poorly understood. We correlated relevent polymorphisms with toxicity & outcome data in AA & C patients (Pts) enrolled in N9741, a large randomized MCRC trial. Methods: Toxicity, response rate (RR), time to progression (TTP), overall survival (OS), & dose intensity (DI) were examined as a function of race in 1412 Pts enrolled on IFL, both full and reduced dose, FOLFOX, or IROX including 486 Pts with pharmacogenomic data. Accrual by race permitted comparison of C (n=1297) to AA (n=112). Results: C & AA were similar in disease extent, PS, gender, prior adjuvant treatment, and DI at cycles 1, 3, 6, or 12. The impact of race on RR, toxicity & the distribution of four relevent drug metabolism genotypes are in the table . AA had lower RR overall & in each treatment arm. Lower toxicity rates were seen in AA Pts, mainly due to less diarrhea, as measured by both CTC V2 & patient reported outcome data. These relationships were maintained in multivariate models adjusting for arm, age, gender, & PS. In these multivariate models, the odds ratio between RR and race was 1.72 (p=0.012) (29% AA vs 41% C) & for severe toxicity the odds ratio was 1.76 (p=0.006) (34% AA vs 48% C). Overall, race was not a significant predictor of TTP or OS (p > 0.50 for each). The hazard ratio comparing FOLFOX to IFL for C was 0.67 and for AA was 0.55. TTP for FOLFOX was superior to both IFL and IROX for both C & AA. Significant differences in pharmacogenetic variants were observed between C & AA, although the sample size for investigating the three-way combination of Rx, race, & pharmacogenomics is too small (36 AA) to draw definitive conclusions. Conclusions: It appears that AA have less toxicity & a lower RR than C when treated with standard MCRC regimens. Different frequencies of polymorphisms in genes relevent to drug metabolism may help explain these clinical differences. [Table: see text] [Table: see text]