Abstract
433 Background: Despite the availability of targeted therapy, effective management of advanced RCC is an unmet medical need as treatment is not personalized and is not guided by patient-specific genomic alterations (GAs). To assess the spectrum of clinically relevant GAs (CRGAs) in advanced RCC, comprehensive genomic profiling (CGP) of clinical RCC samples was performed with the goal of informing use of existing and novel targeted therapies. Methods: DNA was extracted from 40 microns of FFPE sections from 443 consecutive patients with relapsed/metastatic RCC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 646X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The CGP assay included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: There were 73% male and 27% female patients with a mean age of 56 years, and the majority of cases were advanced stage with 198/443 specimens (44.6%) from metastatic sites. 400/443 patients (89%) had at least 1 GA on CGP with a mean 3.1 GA/case. 396/400 RCC harboring GA had at least 1 CRGA involving 111 individual genes with a mean of 1.32 CRGA/UC. The most common novel CRGA in order of frequency were: CDKN2A (21%), BAP1 (12%), ATM (11%), PTEN(8.5%), TSC1(8.3%), mTOR (7%), MET (6.5%), AR (5.3%), DNMT3A (5%) and TSC2 (5%). Moreover, VHL harbored a diversity of GA’s in in 49% of cases. Collecting duct carcinomas harbored an enrichment of NF2 truncating alterations (>40%), distinct from renal medullary carcinoma which did not harbor such GA. Multiple clinical antitumor responses to targeted therapies will be presented. Conclusions: Using a CGP assay capable of detecting all classes of GA simultaneously, a high frequency of CRGA was identified in a large series of patients with advanced RCC. The diversity of CRGA suggests opportunities for the rational application of existing and investigational targeted therapies, and for possible deeper characterization of histological types of RCC.
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