Molecular events in bronchogenic carcinoma and their implications for therapy

Lung cancer patients suffer a 15% overall survival despite advances in chemotherapy, radiation therapy and surgery. This unacceptably low survival rate is due to the usual finding of advanced disease at diagnosis. Detecting preneoplastic lesions and determining which invasive lesions are prone to metastasize or recur can be formidable tasks. Understanding the molecular events that occur during the multistep process of bronchogenic carcinogenesis may make these tasks more surmountable. Approaches leading to identification of patients susceptible to cancer formation include detection of poor metabolizers of carcinogens, those unable to repair genetic alterations, those with activated oncogenes or inactivated tumor suppressor genes, and those at risk of poor outcomes. Detection may be achieved at the cellular, chromosomal, genetic, or protein level. Novel therapies can then be developed that prevent tumor initiation into and promotion through the multistep carcinogenesis pathway, conversion from preneoplastic into invasive malignancies, and progression into metastasis or recurrences. Therapeutic success of chemoprevention can be followed by changes in molecular marker levels. Blockade of activated tumor-promoting oncogenes or replacement of inactivated tumor-suppressing or apoptosis-promoting genes can be achieved by gene therapy. Development of these novel molecular diagnostic and therapeutic strategies could result in prevention of cancer formation or at least prolongation of disease-free survival.