BOSTONTaiwan-based researchers have defined and validated a set of five genes whose degree of expression in non-small-cell lung cancer (NSCLC) patients closely predicts their relapse-free and overall survival. Patients with low-risk expression signatures of the five genes had a median overall survival twice as long as those with high-risk expression signatures (N Engl J Med 356:11-20, 2007).
First author Hsuan-Yu Chen, MSc, of National Taiwan University in Taipei, and his colleagues emphasized the potential clinical benefits of the discovery, if their findings are confirmed by prospective, large-scale multicenter studies. "We propose that patients who have tumors with a high-risk gene signature could benefit from . . . adjuvant therapy, whereas those with a low-risk gene signature could be spared what may be unnecessary treatment," they wrote. And the five genes "may reveal targets for the development of therapy for lung cancer."
The team used computer-generated random numbers to assign frozen specimens from 185 consecutive NSCLC patients for microarray analysis. None of the patients had received adjuvant chemotherapy. They identified 16 genes that correlated with survival. After calculating risk scores, the researchers performed a real time RT-PCR analysis of the 16 genes and a control gene to confirm their levels of gene expression. From these 16 genes, they identified five that were significantly associated with survival: DUSP6, MMD, STAT1, ERBB3, and LCK. The team then validated its five-gene risk prediction model in a separate group of 60 Taiwanese NSCLC patients. The model was further validated using microarray data from 86 North American NSCLC patients.
Dr. Chen and his colleagues found significant correlation between their microarray and RT-PRC analyses of gene expression for the 5 genes in 101 of the initial 125 tumor samples they examined. The five-gene signature was strongly associated with overall survival: sensitivity, 98%; specificity, 93%; positive predictive value, 95%; negative predictive value, 98%; and overall accuracy, 96%.
Patients with low-risk signatures had a median overall survival of 40 months vs 20 months for those with high-risk signatures (P = .001). The median relapse-free survival was 29 months for low-risk vs 13 months for high-risk signature patients (P = .002). Among the patients with stage I or II disease in the original cohort, those with a low-risk signature had a significantly higher estimated overall survival (P = .001) and relapse-free survival (P = .005), compared with the high-risk signature group.
The low-risk group in the 60-patient independent cohort had a significant overall survival advantage over the high-risk arm (P = .006), as did cohort patients with stage I and II disease. Overall survival in the separate 86 patients just missed significance (P = .06).