Reply to S.D. Richman et al

Abstract

We thank Richman et al for their interest in our work and provision of additional pharmacogenetic data from patients included in the FOCUS (Fluorouracil [FU], Oxaliplatin and CPT11 [irinotecan]: Use and Sequencing) trial. Of the 2,135 patients enrolled onto the FOCUS trial—in which one of three patients was randomly assigned to receive first-line FU alone and one of six to receive first-line FU plus oxaliplatin—the authors analyzed TS-5 UTR polymorphism in 938 patients (44%) for whom DNA was available. First, they saw no effect on overall survival, which is in accordance with our results. Second, in 910 patients (43%) with complete data, the authors showed a prognostic effect of the polymorphism on progression-free survival (PFS), the 2R allele being protective, whereas in the FFCD (Federation Francophone de la Cancerologie Digestive) 2000-05 trial, we saw no overall prognostic effect on PFS. However, this effect was weak (perallele hazard ratio [HR], 0.9; 95% CI, 0.82 to 0.99; P .03). Third, they failed to validate our finding that genotyping of TS-5 UTR may be a valuable tool in identifying patients who will and will not benefit from first-line combination therapy. This was mainly because of the observed results in patients with 3R/3R genotype (HR for PFS with first-line FU plus oxaliplatin v FU alone, 0.68; 95% CI, 0.48 to 0.96, in FOCUS trial compared with HR, 0.96; 95% CI, 0.66 to 1.40 in FFCD 2000-05 trial). However, it is not possible to assert that the results of the two trials are discordant, because of the large overlap of the CIs (Fig 1). This was confirmed by the absence of significant heterogeneity between the two trials. Furthermore, we pooled the results of the two trials. A significant trend (P .02) was observed between TS-5 UTR genotype and treatment effect on PFS. The addition of oxaliplatin to first-line FU had no significant impact on PFS in patients with the 3R/3R genotype (HR, 0.80; 95% CI, 0.62 to 1.03). We have no clear explanation for the differences observed between the pharmacogenetic analyses in the FOCUS and FFCD 2000-05 trials. In particular, we do not know whether these differences may be the result of differences in FU dosage (2,400 mg/m in FFCD 2000-05 trial v 2,800 mg/m in FOCUS trial), oxaliplatin dosage (100 mg/m v 85 mg/m), prior history of adjuvant FU-based chemotherapy (11% v 23% to 27%), number of disease sites (single-disease site, 52% v 29% to 36%), tumor assessment periodicity (every 8 weeks v 12 weeks), or pattern of DNA extraction (blood v normal bowel mucosa; normal tissue not available in 25% of patients in pharmacogenetic analysis of FOCUS trial). In conclusion, because the FOCUS pharmacogenetic analysis failed to validate our results, additional large prospective studies are mandatory to determine definitively the predictive impact of TS-5 UTR genotype and the effect (or absence of effect) on PFS of the addition of oxaliplatin to FU in 3R/3R patients.