Germline polymorphisms (SNPs) to predict toxicity and efficacy in FLOT-treated patients with locally advanced gastroesophageal junction or gastric adenocarcinoma—data from the NeoFLOT study

Abstract

Background: Perioperative treatment is standard of care in Western Europe for locally advanced gastroesophageal cancer (GEC) [gastric and gastroesophageal junction (GEJ) adenocarcinoma]. Predictive markers for toxicity and efficacy prior to start with chemotherapy are desirable, particularly when applying a prolonged neoadjuvant treatment. Here we analyse the impact of previously published SNPs involved in drug metabolism and DNA repair. Methods: Genomic DNA was isolated from 48 tumor samples of patients treated within the NeoFLOT-study. In this trial, FLOT (5-FU, leucovorin, oxaliplatin, docetaxel) was administered every two weeks for 6 cycles chemotherapy prior to surgery. Direct DNA sequencing was carried out for rs25487 [Excision Repair Cross-Complementation Group 1 (XRCC1)], rs1805087 [5-methyltetrahydrofolate-homocysteine methyltransferase (MTR)], rs11615 and rs3212986 (both ERCC1), rs1799793 and rs13181 (both ERCC2), rs1801019 [Orotate Phosphoribosyl Transferase (OPRT)] and rs16430del [thymidylate synthase: 6-bp-deletion in the in the 3' untranslated regulatory region (TS3utrdel)]. Furthermore, thymidylate synthase: 28-bp-tandem repeats in the 5' untranslated region (TS5utr tandem repeat) polymorphism was analysed by Restriction Fragment Length Polymorphism (RFLA). Toxicity was stated according to NCI-CTC version 4.0. For efficacy analysis overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and recurrence-free survival (RFS) were used. Results: ERCC2 rs1799793 was significantly associated with thrombocytopenia ≥ grade 3 (P=0.04) and overall hematotoxicity ≥ grade 3 (P=0.04) while rs13181 was significantly associated with leukopenia ≥ grade 3 (P=0.03). Rs11615 of ERCC1 had a predictive value for leukopenia (P=0.04) and thrombocytopenia (P=0.008). Rs1805087 of MTR and TS5utr tandem repeat polymorphism were both associated with anemia (P=0.04 and 0.04, respectively). Concerning non-hematological toxicity, rs1805087 of MTR was associated with diarrhea (P=0.004). Regarding treatment efficacy, patients harbouring the minor allele of C of OPRT rs1801019 obtained a higher ORR and showed a better but statically non-significant prolonged PFS and OS while rs3212986 of ERCC1 was associated with pCR rate (P=0.006). Conclusions: For single nucleotide polymorphism (SNPs) of ERCC1/2, MTR and TS tandem repeat we could demonstrate the predictive value for toxicity of FLOT in GEC. Furthermore, OPRT rs1801019 might be useful to predict response for neoadjuvant treatment.