RESPONSE PREDICTION IN CLEAR CELL RENAL CELL CARCINOMA TREATED WITH ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR-TARGETED THERAPY

Based upon the knowledge that neo-angiogenesis plays a critical role inthe progression of locally advanced and metastatic clear cell Renal Cell Carcinoma (ccRCC), efficient drugs targeting the vascular endothelial growth factor (VEGF)-pro-angiogenic pathway were developed during the last decade. These drugs, mainly anti-VEGF-receptor-tyrosine kinase inhibitors (anti-VEGFR-TKIs), which are now increasingly used in clinical practice, allow to elicit responses and to prolong survival in metastatic ccRCC. Unfortunately they can induce severe side-effects and are very expensive. Our project was to identify/discover clinical factors, pathological and biochemical characteristics, and new molecular markers allowing to predict response and outcome in metastatic ccRCC patients treated with anti-VEGFR-TKIs. Additionally, independently of the systemic treatment used, we also investigated whether some of these factors were of prognostic value in metastatic ccRCC patients.We identified as clinically relevant for prognosis in metastatic ccRCC patients the following pathological and biochemical features: (A) The presence of bone metastases, with or without other metastatic localizations, generally indicatea poor prognosis. (B) Elevated baseline C-reactive protein-levels and (C) the presence of an important component of sarcomatoid dedifferentiation in the primary tumour and/or the metastasis are also associated with a more aggressive behaviour and worse outcome. We also found several biochemical markers with a (potential) predictive value, among them variants in the ABCB1-efflux pump and in the VEGF-receptor-1 and -3.These newly identified clinico-pathological and biological characteristics of metastatic ccRCC patients and of their tumors, as well as other markers described in the literature, allow us to predict more precisely the outcome in an individual patient treated with anti-VEGFR-TKIs. Metastatic ccRCC may respond to targeted anti-angiogenic therapy, but metastatic ccRCCs with an important sarcomatoid component are nearly always refractory. We showed that metastatic ccRCC patients with bone metastases benefit from agents blocking the osteoclastic activity like bisphosphonates. When the latter or newer agents like denosumab are combined to anti-VEGFR-TKIs, better results can probably be achieved, but caution and preventive measures are warranted in view of an increased risk of osteonecrosis of the jaw.Moreover, based on a multi-omics analysis using unsupervised clustering of expression data, we identified four molecular subgroups of ccRCCs, each of them displaying distinct and typical histologic, mutational, epigenetic, and cytogenetic characteristics. When treatedwith the anti-VEGFR-TKI sunitinib, these four subgroups behaved differently in terms of response rate, progression-free survival and overall survival: two subgroups displayed a good outcome with high response rates,while the two remainders had low response rates and very short survival. As a consequence, this new molecular ccRCC classification distinguishing these subgroups has certainly a prognostic value; further prospectivevalidation of its predictive interest is warranted and ongoing, in order to see whether anti-VEGF-targeted therapy could be selectively indicated or omitted in some of them. Finally, our findings are hypothesis-generating, contributing to a better understanding of the mechanisms of sensitivity or resistance of metastatic ccRCC to anti-VEGFR-TKIs. These drugs block further development of neo-angiogenesis, and restore normal vasculature in metastatic ccRCC, leading to better oxygenation of tumoral deposits, thereby interrupting the vicious circle of hypoxia-induced tumor progression. Therefor, induction of normoxia should be the target of therapy. Induction of normoxia is possible in slow growing tumors, but will be more difficult in aggressive tumors and sarcomatoid tumors, which are hypoxia resistent and generally display little or no neo-angiogenesis. We thus emit the hypothesis that response in metastatic ccRCCs treated with anti-VEGFR-TKIs is highly dependent of thebalance between neo-angiogenesis and hypoxia.nrpages: 175status: publishe