Germline Predictors of Outcome in Non-small Cell Lung Cancer (2007)

PL07-02 Purpose: Genetic polymorphisms contribute to interindividual variation in drug response. Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. 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 (NSCLC). Methods: We genotyped 25 functional polymorphisms in 16 key genes involved in cisplatin metabolism and drug action and evaluated their associations with overall survival in 229 NSCLC patients receiving first-line cisplatin-based chemotherapy. The Cox proportional hazard model was used to assess the effect of individual polymorphisms on overall survival, Kaplan-Meier curves and log-rank tests were used to assess the differences in survival by individual polymorphisms. We then performed a pathway-based analysis by counting the number of putative unfavorable genotypes. Survival tree analyses using recursive-partitioning were also performed to investigate higher order gene-gene interactions and identify subgroups of individuals at higher risk of death. We finally constructed receiver operating characteristic (ROC) curves and calculated the area under the curve (AUC) to evaluate the specificity and sensitivity of predicting death and survival by clinical variables only, and by the combination of clinical, epidemiological, and genetic variables. Results: Several biologically plausible main effects were identified in individual analysis. Among nucleotide excision repair (NER) pathway genes, patients carrying the rare homozygous RAD23 Ala249Val genotype exhibited significantly poorer survival (HR= 2.08, 95% CI, 1.04 to 4.16). An ERCC1 3’ UTR SNP (rs3212986) variant-containing genotypes (GT+TT) exhibited significantly improved overall survival (HR=0.68, 95%CI, 0.48-0.95). Kaplan-Meier estimates demonstrated that the median survival time (MST) for individuals with the ERCC1 GT+TT genotypes was 15.8 months compared with MST for the wild-type GG genotype of 12.1 months. We then assumed an additive model and summed the unfavorable genotypes in the NER pathway. These unfavorable genotypes were XPA 5’ UTR A23G (AG/GG), XPC intron9 poly-AT (-), XPD Lys751Gln (AA/AC), CCNH Val270Ala (TT/TC), RAD23 (TT), and ERCC1 (GG). There was a trend of reduced risk of death with decreasing number of unfavorable genotypes. Compared with patients >4 unfavorable genotypes, the HRs for patients with 3-4, and 4, 3 to 4, and 1.2). Kaplan-Meier estimates were plotted for three representative nodes selected from each risk group. Terminal node 1 was in the low-risk group with a MST of 22.6 months, terminal node 3 was in the medium-risk group with a MST of 17.7 months, and terminal node 4 was in the high-risk group with a MST of 9.27 months (log rank P 4) and used Kaplan-Meier survival curves to plot three representative nodes from each risk group. The MST 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