P-148 Perfect concordance between blood-based and normal tissue-based dihydropyrimidine dehydrogenase polymorphisms suggests that pharmacogenetic screening could be contextual to tumour molecular profiling

Abstract

5–fluorouracil (5-FU) represents the chemotherapy backbone of almost all GI cancers. Important 5-FU-related toxicities have been traced back to impaired or reduced enzymatic catabolism secondary to dihydropyrimidine dehydrogenase (DPYD) allelic polymorphisms. International guidelines recommend pharmacogenetic DPYD test prior to treatment with fluorouracil, capecitabine, tegafur and flucytosine, and this usually requires an additional blood draw. The aim of our work was to evaluate the concordance of DPYD allelic variants detection from blood and normal tissue derived DNA in order to make the pharmacogenetic screening contextual to tumor mutation screening. 5 standard DPYD gene polymorphisms (IVS14+1G>A, c.1905+1G>A; c.1679T>G, p I560S; c.2846A>T, p. D949V; c.1129–5923C>G, IVS10C>G; c.2194G>A, V732I) were tested both in blood-derived and paraffin-embedded normal tissue-derived cell DNA of consecutive GI cancers patients with Realtime Polymerase Chain Reaction (PCR) (Easy PGX ready DPYD – Diatech Pharmacogenetics). The adequacy of normal tissue availability on biopsy or surgical material had to be declared before testing by two dedicated pathologists (G.P and E.D.). The concordance of paired results was retrospectively evaluated. Nine colorectal, 2 esophago-gastric junction and 1 pancreatic cancer patients were enrolled. Tissue samples were obtained from previous surgery or endoscopic biopsies. Pharmacogenetic evaluation was made before treatment start. Heterozygosis of rs1801160 polymorphism (c.2194G>A, V732I) was found in 4 out of 12 patients. Evaluation of heterozygous cases on paired blood and tissue samples showed a 100% overall agreement (Pearson’s coefficient = 1). Concordance between blood and tissue-based results was also confirmed for the remaining 8 wild-type homozygous patients. As for international guidelines, 5–FU administered dose was reduced by 15% in heterozygous patients. No grade > 1 fluoropyrimidine-related adverse events were reported in the whole cohort. The fully concordant results in DPYD assessment between blood and tissue samples support testing with Realtime PCR for genotyping of DPYD polymorphisms of GI patients on normal tissue when adequately available in routine clinical practice concomitantly with tumor genetic profiling (e.g. concomitant to RAS and BRAF mutation screening), thus avoiding the distress of an additional blood draw.