Renal Cancer

Renal cell carcinoma accounts for about 3% of cancers and the incidence of the disease is rising steadily. Although removal of the kidney (nephrectomy) is curative for a significant proportion of patients, about 50% of patients with a diagnosis of kidney cancer will die of the disease. Metastatic renal cell carcinoma (RCC) generally is resistant to cytotoxic chemotherapy and despite the fact that there has been significant progress in the last 5 years in the treatment of advanced disease with the development of drugs targeting VEGF and mTOR signalling, no predictive biomarkers for these agents exist. This has enormous clinical and financial consequences.

Randomised trials reported since 2007 have demonstrated that a number of agents such as the monoclonal antibody bevacizumab and the kinase inhibitors everolimus, sorafenib, sunitinib and temsirolimus are active in advanced RCC. Bevacizumab is directed against vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGF and platelet-derived growth factor (PDGF) receptor tyrosine kinases. Everolimus and temsirolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitinib and temsirolimus have demonstrated efficacy in comparison with immunotherapy in the 1st line setting in patients with favourable and poor prognosis advanced disease respectively. Sorafenib has demonstrated efficacy in comparison with placebo in the 2nd line setting in patients with immunotherapy-refractory disease. Everolimus is active in patients that have progressed despite therapy with sorafenib or sunitinib. There are no predictive markers for any of these agents and as a consequence, a major unmet need exists.

Fit patients presenting with metastatic RCC routinely undergo palliative nephrectomy as a survival advantage has been shown in randomised studies. There is no standard pre-operative systemic therapy in metastatic RCC but pre-operative medical therapy is used widely in the treatment of cancer. The potential advantages of this approach are threefold. The first is disease down-staging, allowing less radical surgical approaches with possible benefits in terms of surgical morbidity and/or cosmesis (e.g. lumpectomy versus mastectomy for breast cancer). The second advantage is in terms of in vivo sensitivity testing i.e. is the cancer sensitive to the treatment? This may be important for the selection of post-operative adjuvant therapy inasmuch as tumours sensitive to a given therapy pre-operatively may logically be treated post-operatively with the same therapy. Conversely, tumours that are not sensitive to a given pre-operative therapy may better be treated post-operatively with an alternative therapy. Third, candidate markers of response and resistance may be assessed using pre-operative therapy i.e. a parameter may be measured both prior to and during treatment and correlated with clinical outcome either early (which markers correlate with response to a given pre-operative therapy?) or late (which markers correlate with overall survival or likelihood of relapse?). Such markers, after validation, may subsequently be used to tailor therapy to individual tumours or to individual patients in both adjuvant and metastatic settings and may give insight into in vivo mechanisms of drug action. The search for these markers is the aim of the PREDICT Consortium.