Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer.
OBJECTIVE
Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy.


METHODS
We applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients.


RESULTS
In the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival (hazard ratio [HR] = 0.56; 95% CI, 0.35 to 0.89) in patients treated with fluorouracil (FU). The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26% and 46.43%, respectively. Joint analysis of five polymorphisms in three FU pathway genes showed a significant trend for reduced recurrence risk and longer recurrence-free survival as the number of adverse alleles decreased (P = .004). For patients receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk (HR = 0.25; 95% CI, 0.10 to 0.64) and improved survival (HR = 0.44; 95% CI, 0.23 to 0.85). In nucleotide excision repair genes, there was a significant trend for a decreasing risk of death with a decreasing number of high-risk alleles (P for trend = .0008). In base excision repair genes, the variant alleles of XRCC1 Arg399Gln were significantly associated with the absence of pathologic complete response (odds ratio = 2.75; 95% CI, 1.14 to 6.12) and poor survival (HR = 1.92; 95% CI, 1.00 to 3.72).


CONCLUSIONS
Several biologically plausible associations between individual single nucleotide polymorphisms and clinical outcomes were found. Our data also strongly suggest that combined pathway-based analysis may provide valuable prognostic markers of clinical outcomes.
Wu
Xifeng
X
Department of Epidemiology, Experimental Therapeutics, GI Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. xwu@mdanderson.org
Gu
Jian
J
Wu
Tsung-Teh
TT
Swisher
Stephen G
SG
Liao
Zhongxin
Z
Correa
Arlene M
AM
Liu
Jun
J
Etzel
Carol J
CJ
Amos
Christopher I
CI
Huang
Maosheng
M
Chiang
Silvia S
SS
Milas
Luke
L
Hittelman
Walter N
WN
Ajani
Jaffer A
JA
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D019091:Critical Pathways; D004268:DNA-Binding Proteins / Q000235:genetics; D019583:Dose Fractionation, Radiation; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D016629:Esophagectomy / Q000379:methods; D004943:Esophagogastric Junction; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D019450:Genes, MDR; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D016017:Odds Ratio; D017671:Platinum Compounds / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D018570:Risk Assessment; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D000076105:X-ray Repair Cross Complementing Protein 1
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D017671:Platinum Compounds; D043823:Taxoids; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D005472:Fluorouracil