The final results of the SWOG S9304 phase III intergroup trial’s pharmacogenetic analysis: Association of polymorphisms with survival and toxicity in stage II/III rectal cancer patients treated with 5-fluorouracil (5-FU) and pelvic radiation (RT).

Abstract

3542 Background: Postoperative chemoradiation (CRT) for locally advanced rectal cancers has improved overall survival (OS) and pelvic control. The SWOG S9304 (INT 0144) trial was designed to investigate the benefit of protracted venous infusion (PVI) versus bolus 5-FU before, during and after postoperative RT. All arms provided similar disease-free survival (DFS) and OS. We tested whether 16 functional polymorphisms in 12 genes (GSTP1, TS, ERCC1, VEGF, VEGFR, IL8, CXCR2, COX2, CCND1, EGF, EGFR, ICAM1) predicted survival and toxicity. Methods: Tissue samples from 746 stage II/III rectal patients enrolled in the S9304 phase III trial were analysed. Genomic DNA was extracted from FFPE tumor tissue. The polymorphisms were analysed using direct DNA-sequencing or PCR-RFLP. 383 out of 746 patients were still alive at the time of data analysis with a median follow-up of 123 months. The median age of our cohort is 61 years old (range 16-86). Most patients are males (64%) and Caucasian (93%). 30% have N0 tumor, 42% have N1 tumor and 27% have N2-3 tumor. Results: In univariate analyses, GSTP1-Ile105Val (rs1695) appeared to be associated with DFS and OS (p=0.02 for each, no adjustment for multiple comparisons). The 3-year DFS was 60% for the low activity genotype (Val/Val), 72% for Val/Ile and 65% for Ile/Ile patients (and 78%, 83% and 79% for OS respectively). In patients treated with PVI 5-FU combined with RT, the homozygous IL8-251A/A genotype (rs4073) was associated with a lower risk of any grade 3-5 toxicities compared to A/T or T/T genotypes (41%, 62% and 62%; p=0.04). Also, the homozygous VEGFR2 exon 11 A/A genotype (rs1870377) was associated with a higher risk of grade 3-5 esophagitis/stomatitis compared to A/T or T/T genotypes (17%, 5% and 8%; p=0.037) in the PVI arm only. However, exon 11 A/A was associated with lower risk in the bolus 5-FU arm (p=0.004). Conclusions: Our data suggest that GSTP1-Ile105Val is associated with DFS and OS and IL8-251A/T and VEGFR exon 11 with toxicity in rectal cancer patients treated with adjuvant CRT. Validation would be required to confirm these relationships.