Molecular markers of prognosis in renal cell carcinoma: Insight into tumor biology helps define risk and provides targets for therapy

The annual incidence of renal cell carcinoma in the United States is approximately 31,500, with 220,000 cases reported worldwide per annum [1]. Furthermore, the incidence of renal cell carcinoma is increasing, and thus will only further tax the limited resources spent on health care in the future. Roughly 50% of patients either present with or develop metastases as a consequence of the natural history of their disease. The median survival for patients with metastatic disease is 12 months [2]. These sobering facts emphasize both the need for increased detection of renal cell carcinoma at the earliest stages of disease and the need for the development of more effective systemic therapy for patients with metastatic progression. The ‘‘holy grail’’ of translational research in renal cell carcinoma remains the identification of molecular markers that predict prognosis. Until recently, molecular markers of any utility for renal cell carcinoma did not exist, probably based, in large part, on a lack of knowledge at the molecular level regarding the biology of renal cell carcinogenesis and progression. In addition, there was no real impetus to identify molecular markers of prognosis as there were no significant effective systemic therapies for metastatic disease and the prognosis for the overwhelming majority of patients was, indeed, grim. Now, with the development of targeted therapies such as sunitinib (tyrosine kinase inhibitor), sorafenib (tyrosine kinase inhibitor), bevacizumab (monoclonal antibody targeting vascular endothelial growth factor), and temsirolimus (m-TOR inhibitor) that appear to show real promise in the treatment of renal cell carcinoma, molecular markers are being actively sought to both assess risk, predict response to therapy, and to identify other novel molecular pathways worthy of targeting [3]. Currently, prognosis for patients with renal cell carcinoma has in large part been derived from the evaluation of clinical parameters such as TNM staging, tumor grade, performance status, tumor histology, and other histologic criteria such as the presence of coagulative necrosis or the presence of lymphovascular invasion. Nomograms and scoring systems have been developed based on these clinical parameters that can accurately assess risk of recurrence for a given patient, as well as recommend appropriate strategies for postoperative surveillance for tumor recurrence [4]. New trends in research have been directed primarily at identifying molecular markers for renal cell carcinoma that better predict and allow the stratification of risk as well as serve as potential novel targets for therapeutic intervention, based in large part on clinical advances in therapy that have occurred as a consequence of better understanding the molecular pathways important in renal cell carcinoma biology. Two excellent examples of molecular markers for renal cell carcinoma that are currently the subject of intensive translational research include carbonic anhydrase IX (CAIX) and the cell surface glycoprotein, B7-H1 [5,6]. CAIX is a transmembrane protein that is not expressed on normal renal tissue but is expressed on a variety of cancers, including renal cell carcinoma, where 95% of clear cell kidney cancers as well as 50% of papillary subtypes demonstrate expression. G250 is a monoclonal antibody that targets CAIX and has been used as a therapy for metastatic renal cell carcinoma with some reported responses. G250 is currently being tested in the adjuvant setting for locally advanced disease in a phase III multi-center randomized trial. Expression of CAIX inversely correlates with survival in metastatic renal cell carcinoma and use of this marker may also help better