Intratumoral Predictive Markers in Metastatic Renal Cancer Patients

Sammanfattning: There is no established predictive marker for the treatment of metastatic renal cell cancer (mRCC) patients. With a predictive marker, patients unlikely to respond could be selected upfront and offered other therapy options. Thereby, unnecessary toxicity could be avoided and costs would be reduced. Tyrosine kinase inhibitors (TKI) are the cornerstone in the treatment of mRCC. The aim of the thesis was to evaluate and hopefully define tumoral predictive markers for treatment with the common TKIs sunitinib and sorafenib.The studies are based on immunohistochemical analyses of renal cancer tissues from 139 primary tumors sampled in a tissue microarray. Three proteins with a specific and differential expression in RCC were chosen in co-operation with the Human Protein Atlas project. Since TKIs block vascular endothelial growth factor receptors (VEGFR) on tumor vessels, angiogenesis associated proteins were also analysed as putative predictive biomarkers.In two studies, the renal proteins cubilin (CUBN) and pyruvate kinase L/R (PKLR) were investigated. Our results indicate that these membranous proteins are positive predictive factors for sunitinib and sorafenib therapies. Patients with high membranous expressions of CUBN and PKLR respectively experienced significantly longer progression free survivals (PFS) and overall survivals (OS) compared to the other patients. Combining CUBN and PKLR negative tumors, a patient group with a particularly short PFS could be defined, possibly consisting of patients not benefitting at all from treatment with sunitinib or sorafenib.Studies of tumoral annexin A1 (ANXA1) and epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) demonstrated predictive potential for sunitinib but not for sorafenib treatment. A low cytoplasmic expression of ANXA1 was significantly associated with longer PFS and OS in patients treated with sunitinib. A combined analysis with CUBN and ANXA1 expression indicated a higher predictive value than the expressions of either marker alone. We further observed that a high vascular endothelial expression of ELTD1 is predictive for a longer PFS and OS in sunitinib treated patients. The expressions of CD34 which is a marker of the number of vessels and the sunitinib target VEGFR2 failed to demonstrate significant associations with PFS.To conclude, our real world studies indicate that CUBN, PKLR, ANXA1 and ELTD1 are potential tumoral biomarkers, to predict benefit from treatment with sunitinib (all four proteins) and sorafenib (CUBN and PKLR) in patients suffering from mRCC.