Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes

Objectives Genetic variations or polymorphisms within genes of the nucleotide excision repair (NER) pathway alter DNA repair capacity. Reduced DNA repair (NER) capacity may result in tumors that are more susceptible to cisplatin chemotherapy, which functions by causing DNA damage. We investigated the potential predictive significance of functional NER single nucleotide polymorphisms in esophageal cancer patients treated with (n=262) or without (n=108) cisplatin. Methods Four NER polymorphisms XPD Asp312Asn; XPD Lys751Gln, ERCC1 8092C/A, and ERCC1 codon 118C/T were each assessed in polymorphism-cisplatin treatment interactions for overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. Results No associations with ERCC1 118 were found. Polymorphism-cisplatin interactions were highly significant in both OS (P=0.002, P=0.0001, and P<0.0001) and PFS (P=0.006, P=0.008, and P=0.0007) for XPD 312, XPD 751, and ERCC1 8092, respectively. In cisplatin-treated patients, variant alleles of XPD 312, XPD 751, and ERCC1 8092 were each associated with significantly improved OS (and PFS): adjusted hazard ratios of homozygous variants versus wild-type ranged from 0.22 [95% confidence interval (Cl): 0.1-0.5] to 0.31 (95% Cl: 0.1-0.7). In contrast, in patients who did not receive cisplatin, variant alleles of XPD 751 and ERCC1 8092 had significantly worse survival, with adjusted hazard ratios of homozygous variants ranging from 2.47 (95% Cl: 1.1-5.5) to 3.73 (95% Cl: 1.6-8.7). Haplotype analyses affirmed these results. Conclusion DNA repair polymorphisms are associated with OS and PFS, and if validated may predict for benefit from cisplatin therapy in patients with esophageal cancer. Pharmacogenetics and Genomics 19:613-625 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.