Thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase expression, and histological tumour regression after 5-FU-based neo-adjuvant chemoradiotherapy in rectal cancer

e15051 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.

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Polymorphisms of thymidylate synthase as prognostic factor in rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.433 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 433-433

Author(s):

V. Arrazubi ◽

J. Suarez ◽

D. Guerrero ◽

K. Cambra ◽

M. L. Gomez Dorronsoro ◽

...

Keyword(s):

Rectal Cancer ◽

Thymidylate Synthase ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Disease Free Survival ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Tumour Regression ◽

The Difference

433 Background: Neoadjuvant fluoropyrimidine-based chemotherapy (ChT) plus radiotherapy (Rt) is a standard approach for locally advanced rectal cancer. Polymorphisms of thymidylate synthase (TS), the target for fluoropyrimidines, are recognized prognostic factors in colon cancer. The aim of this study was to evaluate the prognostic value of the polymorphisms of TS in rectal cancer after neoadjuvant ChT plus Rt. Methods: We studied one-hundred consecutive patients with stage II/III rectal cancer between November 2001 and March 2009. Patients underwent surgery 6-8 weeks after neoadjuvant Rt (5,040 cGy) plus fluoropyrimidine-based ChT. DNA was extracted from paraffin embedded biopsies. TS1494del6 and 5′-28bp repeat +G/C SNP polymorphisms were determined. Results: Sixty-seven percent were men and median age was 67 years. ypT stage was: T0 9%, T1 2%, T2 27%, T3 60% and T4 2%; 32% had locoregional adenopathies. The median follow-up was 45 months and relapse occurred in 20% of patients. Polimorphisms could be determined in 98% of pt: -6bp/-6bp 10%, - 6bp/+6bp 39%, +6bp/+6bp 51% and 2R/2R 72%, 2R/3R 21%, 3R/3R 6%. The grade of pathological tumour regression was not associated with polymorphisms. Relapses occurred in 40% of patients -6bp/-6bp, 22% of patients -6bp/+6bp and 21% of patients +6bp/+6bp. The difference in disease- free survival (DFS) between the first and the third groups was stadistically significative (p=0.049). No relation between 5′-28bp repeat +G/C SNP polymorphism and DFS was found. Conclusions: Our data suggest that the TS1494del6 polimorphism may be an important prognosis factor in rectal cancer receiving neoadjuvant chemoradiotherapy. No significant financial relationships to disclose.

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