Polymorphisms of DNA repair and glutathione s-transferase genes and progression-free survival (PFS) in treated advanced esophageal cancer (EC) patients

9564 Background: DNA repair capacity may influence the level of platinum-DNA adducts formed by platinum compounds. In turn, platinum compounds are metabolized by glutathione s-transferases (GSTs). We hypothesized that variant alleles of DNA repair genes and the presence of (or efficient) GST metabolic activity would be detrimental to the therapeutic functions of platinum.

METHODS: We evaluated PFS and genetic polymorphisms of GSTM1(deletion), GSTT1(deletion), GSTP1(Ile105Val), and the DNA repair genes, XPD (Asp312Asn, Lys751Gln) and XRCC1 (Arg399Gln), in 70 patients with locally advanced (Tany NanyM0-1a, 86%) or metastatic (Tany NanyM1b, 14%) EC treated with 2-4 cycles of platinum-based chemotherapy.

RESULTS: Median age was 64 (range: 37-88) years. 96% were male. 86% were adenocarcinomas. 97% had performance status ECOG 0 or 1. Median PFS was 16.3 months; by stage, median PFS were 23.0 mos (M0-1a) and 9.2 mos (M1b), respectively. Median follow-up was 23.6 months, while median overall survival was 30.1 months. Stage was not associated with any of the genotypes. After adjusting for stage (M0-1a versus M1b), the XPD751 Gln/Gln genotype was associated with shorter PFS (p=0.06, by Cox proportional hazards model, CPHM; see table), while the GSTM1-null genotype was associated with improved PFS (p=0.04 by CPHM). When combined, the XPD751 Gln/Gln + GSTM1 present genotypes had the shortest PFS (p=0.01 by CPHM). There were similar but non-significant trends (p>0.05) for the following polymorphisms: XPD Asp312Asn (Asn/Asn had shortest median PFS) and GSTT1-deletion (null genotype had longer median PFS). No polymorphisms were associated with overall survival.

CONCLUSION: Genetic polymorphisms in XPD and GSTM1 may be important predictive factors of PFS in platinum-treated EC patients. [Figure: see text] No significant financial relationships to disclose.