Lung cancer is responsible for approximately one-third of all cancer-related deaths in the U.S. each year. Chemotherapy has been largely ineffective in producing complete responses or cures in the advanced disease setting. Therefore, investigation of new paradigms, including novel therapeutic approaches and early detection, has become an urgent priority for the oncology community. Key to early detection is the development of biomarkers that are found in primary tumor and can be detected in biological fluids prior to advanced disease. These biomarkers may also be useful for predicting therapeutic response during clinical trials. In support of these critical needs, our laboratory has identified two excellent biomarkers, the p16 tumor suppressor gene and the O6-methylguanine-DNA methyltransferase (MGMT) repair gene, whose inactivations through aberrant CpG island promoter hypermethylation occur frequently and early in the development of NSCLC. Furthermore, inactivation of these genes has been detected in exfoliated cells from sputum and shown to precede clinical diagnosis of squamous cell carcinoma (SCC). Aberrant methylation of p16, MGMT, and death-associated protein (DAP) kinase has also been detected in serum from NSCLC patients irrespective of tumor stage. Utilizing specimens and patients on ECOG study E3598, """"""""A Phase III trial of Carboplatin, Paclitaxel and Radiotherapy, With or Without Thalidomide, in Patients With Stage III NSCLC,"""""""" these advances in cancer biology will be translated into the clinic to address several important questions. First, can the detection of gene dysfunction in critical genes through analysis of sputum and/or serum be used for screening or as prognostic factors? This question will be addressed by determining the predictive power of sputum and serum to detect NSCLC through analysis for aberrant methylation of the p16, MGMT, DAP-kinase, and TIMP-3 genes within these biological fluids. Second, does inactivation of genes such as p16, DAP-kinase, or TIMP-3 in NSCLCs affect survival? A recent study demonstrated that median survival was shorter for patients with adenocarcinoma in which the p16 gene was inactivated. Thus, this question will be addressed by determining whether inactivation of p16, DAP-kinase, or TIMP-3 genes can be used to predict survival for patients on E3598. Finally, can detection of methylation markers in serum be useful for cancer diagnosis and/or have predictive value for survival? This will be addressed with patients on E3598. Results could have a profound impact on defining the utility of sputum and serum for detecting NSCLC, predicting survival from these therapeutic regimens, and delineating whether the presence of these tumor markers in serum affect survival. The validation of these genes as biomarkers of lung cancer risk and their detection in sputum and/or serum could ultimately support chemoprevention trials for preventing lung cancer.
