Abstract 1675: Lung cancer chemotherapy: genetic variations in the transforming growth factor beta pathway as predictors of survival

Abstract

Abstract Treatments based on molecular determinants are likely to maximize therapeutic index for chemotherapy in non-small-cell lung cancer (NSCLC). The purpose of this study is to take a pathway-based approach to systematically evaluate the pharmacogenetic effects of transforming growth factor (TGF-β) pathway on lung cancer and identify potential genetic predictors of platinum-based chemotherapy. We genotyped 227 SNPS in 23 TGF-β pathways genes to evaluate their associations with overall survival in 598 late stage NSCLC patients receiving first-line platinum-based chemotherapy with or without radiotherapy. In individual analysis, 22 SNPs were significantly associated with overall survival, of which the strongest associations were found for BMP2:rs235756 (HR=1.45; 95%CI, 1.11-1.90; P=0.006) and SMAD3:rs4776342 (HR=1.25; 95%CI, 1.06-1.47; P=0.009). Cumulative effect analysis showed that individuals with multiple risk genotypes had a significant dose-dependent adverse affect on overall survival (Ptrend=2.44×10−15). Analysis stratified by treatment modality showed that SMAD3 haplotypes exhibited significant associations with outcomes of chemotherapy. Survival tree analysis categorized subgroups of patients with dramatically different survival pattern. The low-risk genetic profile group identified from patients treated with chemoradiation had a median survival time (MST) of 30.4 months. In comparison, the high-risk genetic profile group had a more than four-fold increased risk of death with MST of 6.8 months. The low-risk genetic profile group identified from patients treated with primary chemotherapy without definitive radiotherapy had a MST of 18.03 months, while the high-risk genetic profile group had a MST of 5.9 months and a four-fold increased risk of death. These results suggest that genetic variations in TGF-β pathway are potential predictors for clinical outcome in advanced NSCLC treated with platinum-based chemotherapy. We also found that genetic variations within the TGF-β signaling pathway may be able to identify potential subgroups of patients who will most benefit from platinum-based chemotherapy with or without radiotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1675.