Prognosis following a diagnosis of primary lung cancer is very poor: The one-year survival rate is only 20-50 percent for advanced disease; the five-year survival rate ranges from 10-60 percent for early stage to under 3 percent for late stage disease. It is vital that survival be improved, because lung cancer will continue to be a significant medical and public health burden for many decades even if all cigarette smokers were to stop. Individualized prognostic predictors are needed. Recent basic science studies suggest that genetic variations in human glutathione (GSH) synthesis and GSH-dependent enzymes (GSH system) are promising candidates for predicting platinum-based treatment outcomes and survival, but their interaction with patient characteristics and disease features has not been examined. Platinum compounds (cis- or carboplatin) are used in at least two-thirds of late stage lung cancer patients. We propose to answer an important question: whether patients' genotypes in the GSH system significantly influence lung cancer survival over and above disease stage and treatment modalities. Our primary goal is to test whether genotypes for four important enzymes in the GSH system (gamma-GCS, GSTP1, GSTM1, and GSTT1) predict short-term survival, which is defined as death due to lung cancer occurring within three years of lung cancer diagnosis, among patients treated with platinum compounds. Our secondary goal is to examine multiple risk factors including, in addition to the genotypes stated above, cigarette smoking status, clinical features of lung cancer (disease stage, tumor histology) and treatment modality as modifiers for short-term survival. We will enroll 800 primary lung cancer patients (with stage III and IV disease and treated with platinum compound) and follow these patients for up to three years after their diagnosis at the Mayo Clinic. Histologic subtypes under study include adenocarcinoma, squamous cell, small cell and large cell carcinomas. At least 500 deaths due to lung cancer are anticipated within three years of diagnosis. Our analytic approach is hypothesis-driven, logically progresses from descriptive statistics to survival analysis, and to multiple regression models. From this pharmacogenetic-epidemiology study, we will confirm or refute whether genotypes indicative of deficient or absent enzyme activities in the OSH system predict better short-term survival and whether such a survival benefit is only manifested among platinum-treated patients. Our results may suggest a new direction to enhance lung cancer chemotherapy by suppressing or depleting the relevant enzymes. Our results may also assist clinicians in planning patient-specific therapy and more accurately predicting prognosis. Through this project, we will establish a valuable data resource and an infrastructure to study promising biological markers for short- and long-term prognosis of lung cancer patients.
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