In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 289-289
Abstract:
Introduction: SU is an oral, multitargeted inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET. In a phase III mCRC study, adding SU to FOLFIRI did not improve progression-free survival (PFS) vs. FOLFIRI/placebo. Potential correlations were investigated between germline genotype and safety/efficacy endpoints among patients (pts) in this trial. Methods: Blood sample donation for genotype analysis was optional. Selection of genes and polymorphisms was based on prior reported associations. Twenty-one single-nucleotide polymorphisms (SNPs) in 10 genes (VEGF-A, VEGFR-2, CYP1A1, ABCG2, ABCB1, ABCC2, MTHFR, UGT1A1, FLT1 and FLT3) were analyzed by TaqMan allelic discrimination assay or fragment analysis, using DNA isolated from peripheral blood samples. All 21 polymorphisms were analyzed for associations with efficacy (PFS; overall survival [OS]) and selected safety endpoints. Results were adjusted for multiple testing of SNPs in linkage disequilibrium. Results: Genotyping was performed in 139/768 pts (18%). Age and gender were similar between genotyped and non-genotyped pts, but the genotyped subset had fewer non-Caucasians (13% vs. 39%; Fisher's exact P & lt;0.0001). Therefore, the statistical analysis reported here included Caucasians only. OS was superior in genotyped vs. non-genotyped pts (log rank P & lt;0.0001). For the FOLFIRI/placebo arm only, the ABCC2 gene SNP rs717620 was associated with increased grade 3/4 diarrhea for those with the T allele (0/37 for C/C, 2/15 for C/T, 2/2 for T/T; Fisher's exact P=0.0003), and remained statistically significant after multiple testing adjustment. In the SU/FOLFIRI arm only, the common homozygous genotype A/A in the CYP1A1 gene at rs1048943 was associated with increased grade 3/4 neutropenia (39/59 for A/A, 1/6 for A/G, # of G/G = 0; Fisher's exact P=0.028), but lost significance after multiple testing adjustment. In the FOLFIRI/placebo arm only, a weak association was observed between poorer PFS and the common homozygous genotype T/T for the rs1045642 SNP (C3435T) in the ABCB1 gene (median [T/T] = 36 weeks [95% CI 24.9-40.6] ; median [T/C] = 45 weeks [41.9-83.6] ; median [C/C] = 55.1 weeks [31.8-55.1] , HR [T/C vs. T/T] = 0.21 [95% CI 0.07-0.64] ; HR [C/C vs. T/T] = 0.23 [95% CI 0.07-0.81] ; log rank P=0.008; not significant after multiple testing adjustment). Conclusions: Presence of the T allele in the ABCC2 gene at rs717620 was associated with increased risk of grade 3/4 diarrhea in a small number of Caucasian pts receiving FOLFIRI/placebo. No significant associations were identified between genotype and safety/efficacy endpoints in pts who received SU/FOLFIRI. As OS was superior in genotyped vs. non-genotyped pts, correlative findings may not be extrapolated beyond the genotyped subset. Further analysis of baseline characteristics is underway in the genotyped group to investigate this difference. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 289. doi:10.1158/1538-7445.AM2011-289
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-289
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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