Molecular targeting and pharmacogenomics in the management of advanced bladder cancer

Bladder cancer is one of the malignancies for which considerable information is available regarding molecular pathogenesis and genetic predictors of natural history, as well as response to treatment. Loss of heterozygosity of chromosome 9 appears to be essential to the genesis of superficial bladder cancer, and mutation of the p53 suppressor gene frequently is associated with progression to invasive and metastatic disease. Many oncogenes, gene products, and suppressor gene mutations, including those of Ras, Myc, p53, Rb, p16, p21, thrombospondin-1, glutathione, and factors controlling expression and function of the epidermal growth factor receptor, have been shown to be involved in the biology of this disease. Retrospective studies have demonstrated that some of these factors have important roles as independent prognostic determinants or predictors of response to chemotherapy, and clinical trials have now been established to validate the utility of molecular prognostication in bladder cancer. Paradigms developed from the treatment of colorectal malignancy, in which the metabolism of cytotoxic agents is affected by genetic and racial factors, now are being applied to the management of bladder cancer. This review summarizes current knowledge in these evolving domains.