Predictive Potential Role of GSTT1 and GSTM1 Genes in the Overall Survival and Treatment Outcome of Lung Cancer Patients Treated with Platinum-Based Doublet Chemotherapy

Abstract

Some studies have evaluated the association of genetic polymorphisms in GST genes and survival in lung cancer patients based on smoking status, histological sub-types and performance status and many others report the relationship between genetic distribution of GSTT1 and GSTM1 and treatment outcomes of patients receiving platinum based chemotherapy. However, the results have been contradicting and have yet not been evaluated in North Indian population. The focus of this study is to find an association between GSTT1 and GSTM1, individually and in different combinations, with the overall survival and treatment outcome in patients receiving platinum-based chemotherapy. Methods: a total of 323 patients were evaluated for GSTT1 and GSTM1 polymorphisms. The genes were amplified using multiplex PCR. Results: the present study found no significant association of GSTT1 and GSTM1 with the overall survival in LC patients. Based on smoking status, a statistically significant association was observed between the GSTT1 null genotype and overall survival in case of non-smokers (HR’=2.72; 95%CI=1.09-6.79; p=0.03). Also, it was found that GSTT1 null genotype was associated with the performance status of patients under the KPS scale of 70-80, showing about 2.3 folds increased death risk as compared to the patients with wild GSTT1 genotype (HR’=2.34; 95%CI=1.44-3.82; p=0.0006) but no such statistically significant association was found with GSTM1. The study also investigated on various clinic-pathological parameters contributing in determining the susceptibility in lung cancer patients and it was found that the patients in stage IV, with null GSTT1 genotype had a 2.6 folds higher susceptibility to lung cancer as compared to the patients in clinical stage III (AOR=2.64; 95%CI=1.38-5.04; p=0.003). It was also seen that the patients with null GSTT1 genotype showed a 2-fold increased metastasis of lung cancer (AOR=2.12; 95%CI=1.13-3.98; p=0.019). On studying the combined effect of these genetic polymorphisms, it was seen that the SCLC patients with the genotypic combination of wild GSTT1 and null GSTM1 genotype had a higher death risk due to lung cancer (HR’=1.71; 95%CI=1.03-2.84; p=0.035). Further, the association of GSTM1 and GSTT1 polymorphisms and the outcomes of chemotherapy in patients with lung cancer were examined. The results suggested that null GSTM1 genotype was associated with poor response to chemotherapy in patients with lung cancer (AOR=2.00; 95%CI=1.04-3.84; p=0.018).