A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer.
In this marker evaluation study, we tested whether distinct patterns of functional genomic polymorphisms in genes involved in drug metabolic pathways and DNA repair that predict clinical outcome to 5-fluorouracil (5-FU)/oxaliplatin chemotherapy in patients with advanced colorectal cancer could be identified. Functional polymorphisms in DNA-repair genes XPD, ERCC1, XRCC1, XPA, and metabolising genes glutathione S-transferase GSTP1, GSTT1, GSTM1, and thymidylate synthase (TS) were assessed retrospectively in 106 patients with refractory stage IV disease who received 5-FU/oxaliplatin combination chemotherapy, using a polymerase chain reaction-based RFLP technique. Favourable genotypes from polymorphisms in XPD-751, ERCC1-118, GSTP1-105, and TS-3'-untranslated region (3'UTR) that are associated with overall survival were identified. After adjustment for performance status, the relative risks of dying for patients who possessed the unfavourable genotype were: 3.33 for XPD-751 (P=0.037), 3.25 for GSTP1-105 (P=0.072), 2.05 for ERCC1-118 (P=0.037), and 1.65 for TS-3'UTR (P=0.091) when compared to their respective beneficial genomic variants. Combination analysis with all four polymorphisms revealed that patients possessing > or =2 favourable genotypes survived a median of 17.4 months (95% confidence interval (CI): 9.4, 26.5) compared to 5.4 months (95% CI: 4.3, 6.0) in patients with no favourable genotype. Patients who carried one favourable genotype demonstrated intermediate survival of 10.2 months (95% CI: 6.8, 15.3; P<0.001). Polymorphisms in the TS-3'UTR and GSTP1-105 gene were also associated with time to progression. After adjustment for performance status, patients with an unfavourable TS-3'UTR genotype had a relative risk of disease progression of 1.76 (P=0.020) and those with the unfavourable GSTP1-105 genotype showed a relative risk of progression of 2.00 (P=0.018). The genomic polymorphisms XPD-751, ERCC1-118, GSTP1-105, and TS-3'UTR may be useful in predicting overall survival and time to progression of colorectal cancer in patients who receive 5-FU/oxaliplatin chemotherapy. These findings require independent prospective confirmation.
Stoehlmacher
J
J
Department of Hematology and Oncology, University of Hamburg, University Hospital, Hamburg 20247, Germany.
Park
D J
DJ
Zhang
W
W
Yang
D
D
Groshen
S
S
Zahedy
S
S
Lenz
H-J
HJ
D000217:Acyltransferases / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004265:DNA Helicases; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D018450:Disease Progression; D004720:Endonucleases / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011110:Polymorphism, Genetic / Q000235:genetics*; D011237:Predictive Value of Tests; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors; D016896:Treatment Outcome; D000076105:X-ray Repair Cross Complementing Protein 1; D051760:Xeroderma Pigmentosum Group A Protein; D051759:Xeroderma Pigmentosum Group D Protein
D000217:Acyltransferases; D014408:Biomarkers, Tumor; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005472:Fluorouracil; D005982:Glutathione Transferase; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011506:Proteins; D012333:RNA, Messenger; D013940:Thymidylate Synthase; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; D051760:Xeroderma Pigmentosum Group A Protein; D051759:Xeroderma Pigmentosum Group D Protein; C497314:XPA protein, human; C000619371:XRCC1 protein, human; C413545:glutathione S-transferase T1; C071447:ERCC1 protein, human; C043403:fatty acyl ethyl ester synthase; C497292:ERCC2 protein, human