Purpose: Recent clinical trials suggest a survival advantage for adjuvant chemotherapy in non-small cell lung cancer (NSCLC). This study’s aim is to identify genes associated with NSCLC recurrence in patients not receiving adjuvant chemotherapy. Experimental design: Banked NSCLC tumors of patients who underwent resection of stage Ia-IIIb disease were identified. Patients were stratified into two groups: recurrent (R, n=11) or non-recurrent (NR, n=16) at two years following surgery. Microarray profiling and Cox multivariate analysis were performed. Results: Unsupervised clustering analysis using 51 probe sets separated the R and NR tumors. The CYP3A5 gene exhibited the greatest differential expression and was increased 18.7-fold in Group R (P=0.00013). Risk of NSCLC recurrence was highly associated with the ln of CYP3A5 gene expression (hazard ratio [HR] 2.80; 95% CI 1.58, 4.95; P=0.0004) and higher CYP3A5 was associated with a shorter time to recurrence (TTR). Older age at the time of surgery was marginally associated with decreased recurrence (HR 0.96; 95% CI 0.92, 1.00; P=0.033), while smoking history, race and sex were not significant. CYP3A5 was predominantly expressed in the NSCLC tumor epithelium. siRNA knock down of CYP3A5 in the A549 and H358 NSCLC lines inhibits proliferation. A potential mechanism of CYP3A5 in NSCLC progression involves CYP3A5 conversion of arachidonate to epoxyeicosatrienoic acids (EET’s), which are mitogenic for NSCLC lines under conditions of hypoxia. Conclusion: CYP3A5 gene expression is correlated with NSCLC recurrence and synthesizes EET, which promotes NSCLC growth. While the mechanisms of CYP3A5 in NSCLC recurrence remain to be identified, they may involve, in part, its epoxygenase activity.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA