Polymorphism of the DNA repair enzyme XRCC1 is associated with treatment prediction in anthracycline and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of patients with primary invasive breast cancer.
OBJECTIVE
Outcome and survival in anthracycline-based and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of invasive breast cancer are unpredictable. Insights into treatment prediction are expected from studies searching for an association between genetic polymorphisms and treatment outcome effects. A common feature of treatment with chemoreagents is therapeutically induced DNA damage. Therefore, we tested the hypothesis of a relationship between event-free survival and genotype distributions of seven polymorphic DNA repair enzymes and four cell cycle regulators.


METHODS
This case-case comparison included 180 patients with primary invasive breast cancer diagnosed between 1986 and 2000 and subjected to adjuvant chemotherapy (anthracycline/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil). Ninety-two patients were reported without recurrence and 88 were reported with recurrences or dead. Median clinical follow-up was 61.7 months. Constitutional DNA isolated from archived tissues was genotyped at 19 loci by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Statistical analyses included adjusted risk estimates, Kaplan-Meier analyses, Cox proportional hazard model, and permutation testing.


RESULTS
Carriers of the XRCC1_1196_AA genotype had a reduced risk for recurrence/death (odds ratio adjusted 0.19; 95% confidence interval: 0.06-0.61), which was observed in survival analyses of all patients (P=0.003) and patients treated with chemotherapy but not radiotherapy (P=0.006). Multivariate analysis confirmed XRCC1 as a potential treatment predictor (hazard ratio 0.62; 95% confidence interval: 0.43-0.89). The result was stable upon permutation testing. No other significant associations were observed.


CONCLUSIONS
The DNA repair enzyme XRCC1 is a potential treatment predictor for the outcome and survival of anthracycline and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of invasive breast cancer.
Jaremko
Malgorzata
M
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
Justenhoven
Christina
C
Schroth
Werner
W
Abraham
Benny K
BK
Fritz
Peter
P
Vollmert
Caren
C
Illig
Thomas
T
Simon
Wolfgang
W
Schwab
Matthias
M
Brauch
Hiltrud
H
D018943:Anthracyclines / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006239:Haplotypes; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D000076105:X-ray Repair Cross Complementing Protein 1
D018943:Anthracyclines; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C095888:xeroderma pigmentosum group F protein; D005472:Fluorouracil; D008727:Methotrexate