Cisplatin pharmacogenetics, DNA repair polymorphisms, and esophageal cancer outcomes.
OBJECTIVE
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 (CI): 0.1-0.5] to 0.31 (95% CI: 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% CI: 1.1-5.5) to 3.73 (95% CI: 1.6-8.7). Haplotype analyses affirmed these results.


CONCLUSIONS
DNA repair polymorphisms are associated with OS and PFS, and if validated may predict for benefit from cisplatin therapy in patients with esophageal cancer.
Bradbury
Penelope A
PA
Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada.
Kulke
Matthew H
MH
Heist
Rebecca S
RS
Zhou
Wei
W
Ma
Clement
C
Xu
Wei
W
Marshall
Ariela L
AL
Zhai
Rihong
R
Hooshmand
Susanne M
SM
Asomaning
Kofi
K
Su
Li
L
Shepherd
Frances A
FA
Lynch
Thomas J
TJ
Wain
John C
JC
Christiani
David C
DC
Liu
Geoffrey
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D018572:Disease-Free Survival; D004720:Endonucleases / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D016896:Treatment Outcome; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D002945:Cisplatin