Analysis of pharmacogenetic biomarkers in rectal patients trated with chemoradiotherapy

Resumo

Background: 5FU-based chemoradiotherapy before total mesorectal excision (TME) is currently the gold standard treatment for stage II and III rectal cancer patients. Pathological complete response (pCR) is related with a longer survival. We have used known predictive pharmacogenetics biomarkers to identify in our series responders and non responders to preoperative RQ. Methods: 77 stage II/III rectal patients were genotyped using direct sequencing (TS VNTR) and SNAPshot (DPYD, EGFR) techniques. DNA was obtained from peripheral blood samples. We have studied Thymidylate synthetase (TS VNTR; high expression haplotypes: TSER 2R/3R, 3C/3G, 3G/3G and low expression: TSER 2R/2R, 2R/3C, 3C/3C; TS 1494del6: associated to a better efficay of 5Fu), dihydropyrimidine dehydrogenase (DPYD; DPYD*2 associated to worse toxicity), EGFR (CA repeats in intron 1: 16/16 associated to worse efficacy) polymorphisms. Median age of our study cohort was 65 years old (37–85). There were 24 female and 53 male patients. All of them were Caucasian. 21 patients (27.3%) had stage II and 56 (72.7%) stage III. They were staged by TC, colonoscopy and endorectal ultrasonography. The patients received 5fu 325 mg/m2/day continuous infusion along the hyperfractionated accelerated radiotherapy schedule (50,4 Gy). All were submitted to TME. Outcomes after surgery are measured by tumour regression grade (from TRG1= complete pathological response, to TRG5=no regression). Data were studied by univariate and multivariate analysis. Results: The sample was in Hardy-Weinberg equilibrium for all polymorphisms, irrespectively of the response status. 50 patients (64.9%) and 27 (35.1%) had low and high expression genotype for TS respectively. pCR (TRG1) was obtained in 24 patients (31,6%) and microscopic foci (TRG2) in 14 (18,2%), TRG 3–4 in 38 (49,3%), and 1 patient had no response (TRG5). We haven’t found a statistically significant relationship between TRG1 and TS status, or any other biomarker studied. There's no relationship also with initial clinical stage. Conclusions: Biomarkers EGFR (intron 1 CA repeats), TS (TS 1494del6, TS VNTR) and DPYD in blood samples, are not good enough to predict response to RQ in rectal cancer.No significant financial relationships to disclose.