Impact of MDR1 (C3435T) polymorphism on lymph node regression in multimodality treatment of upper GI cancer: Comparative analysis of patients with gastric cancer and adenocarcinoma of the esophagus

Abstract

Background: Neoadjuvant treatment strategies have been developed to improve survival of patients with locally advanced upper gastrointestinal cancer (upper GI cancer). The multidrug resistance protein MDR1 (syn. ABCB1) belongs to the ATP-binding cassette family of membrane transporters. By exporting positively charged drugs, it plays a role in the acquisition of resistance in anticancer therapy. We examined the MDR1 gene polymorphism C3435T to elucidate the molecular and clinical differences relevant for neoadjuvant treatment strategies in locally advanced gastric cancer (GC) and adenocarcinoma of the esophagus (EAC). Materials/methods: A total of 210 patients with locally advanced (uT3) GC (n = 56; , m:41 males, and f:15 females) and EAC (n = 154; , m:135 males and f:19 females) were studied. Patients with GC received chemotherapy (5-fluorouracil, cisplatin), whereas EAC were treated with radiochemotherapy (36 Gy, 5-fluorouracil, cisplatin) before surgery. Genomic DNAwas extracted from paraffin-embedded tissues of all study patients. Allelic genotyping was performed for MDR1 (rs1045642) by real-time PCR using two allele-specific TaqMan probes in competition and was correlated with clinical parameters. Results: Allelic discrimination for MDR1- polymorphism revealed for GC the following pattern: GC-TT = 19%, CC = 23%, C/T = 58% and for ; EAC- TT = 30%, CC = 16%, C/T = 54%. Matching patients without induction therapy analyzsed for control expressed lymph node metastases (LNM) in 80%. In the study cohort, neoadjuvant treatment resulted for both tumour entities in a significant decrease of LNM (GC 68%, EAC 41%, p < 0.05). In gastric cancer, the TT genotype was associated with LNM in 90%, with a median amount of LNM of 10 (LQ:, 5-; UQ:, 17). Contrary to this, the TT genotype in EAC presented with significantly less patients with LNM (26%) and a lower frequency of LNM in those patients with metastasis (median = 4, (, LQ:, 2-; UQ:, 7). A favourable survival was associated in both tumour entities with the C/T genotype. Conclusion: Our data supports the effectiveness of neoadjuvant treatment in upper GI cancer. SNPs of MDR1 could be helpful in predicting lymph node regression.