Germline genetic variations in drug action pathways predict clinical outcomes in advanced lung cancer treated with platinum-based chemotherapy.
OBJECTIVE
Genetic polymorphisms contribute to interindividual variation in drug response. However, a single polymorphism is likely to exhibit a modest effect. Therefore, we applied a pathway-based approach to evaluate the cumulative effect of multiple polymorphisms on clinical outcome of patients with non-small cell lung cancer.


METHODS
We genotyped 25 functional polymorphisms in 16 key genes involved in cisplatin metabolism and action and evaluated their associations with overall survival in 229 non-small cell lung cancer patients receiving first-line cisplatin-based chemotherapy.


RESULTS
Several biologically plausible main effects were identified in individual analysis. More importantly, when six polymorphisms in nucleotide excision repair genes were analyzed jointly, a significant trend of reduced risk of death with decreasing number of putative unfavorable genotypes was observed (P for trend < 0.001 and log rank P < 0.001). Survival tree analysis revealed potential higher-order gene-gene interactions and categorized subgroups with dramatically different survival experiences, based on distinct genotype profiles. The median survival time was 78.5 months for terminal node 1 in the low-risk group, 15.1 months for terminal node 10 in the medium-risk group, and 6.7 months for terminal node 9 in the high-risk group (log rank P < 0.001). We also constructed a prediction hazard model. The area under the curve increased from 0.71 (using clinical variables only) to 0.84 (using clinical, epidemiological, and genetic variations from survival tree analysis).


CONCLUSIONS
Our results highlight the clinical potential of taking a pathway-based approach and using survival tree analytic approach to identify subgroups of patients with distinctly differing outcomes.
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. xwu@mdanderson.org
Xifeng
X
Wu
Charles
C
Lu
Yuanqing
Y
Ye
Joe
J
Chang
Hushan
H
Yang
Jie
J
Lin
Jian
J
Gu
Waun Ki
WK
Hong
David
D
Stewart
Margaret R
MR
Spitz
D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002945:Cisplatin / Q000627:therapeutic use*; D004260:DNA Repair / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005854:Germ Cells / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012372:ROC Curve; D016019:Survival Analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D002945:Cisplatin