Chromosomal imbalances as biomarkers for recurrence and antiangiogenic resistance in clear cell renal cell carcinoma.

Abstract

e15012 Background: A key dilemma in the management of clear cell renal cell carcinoma (ccRCC) is the lack of reliable biomarkers for recurrence, prognosis, and prediction of resistance to anti-angiogenic therapy. Chromosome copy number alterations (CCNAs) by conventional cytogenetics have been shown to be associated with outcomes. In this study, the goal was to determine whether CCNAs identified with SNP arrays could be used as prognostic biomarkers for recurrence and predictors of antiangiogenic therapy response in ccRCC. Methods: We obtained archival formalin fixed paraffin embedded (FFPE) tumor samples from 32 patients with organ confined ccRCC, and 56 patients with metastatic ccRCC treated with sorafenib (after tumor removal, n=23) or bevacizumab (neoadjuvant treatment, n=33). DNA from the FFPE tissue sections was analyzed with Affymetrix 250K Nsp SNP microarrays to identify genomic CCNAs. Marker associations with tumor recurrence were evaluated using the Fisher's exact test. Logistic regression was used to evaluate the association between markers and response. Results: In the organ confined cohort, 14q loss showed a significant association with tumor recurrence (log rank P= 0.017), and a 3-locus model (gains of 1q or 12p or loss of 14q) showed a stronger association with recurrence (P= 0.0014). Gain of 5q was strongly associated with longer progression free survival (PFS) in both sorafenib and bevacizumab treated cohorts (HR = 0.25, 95% CI 0.08 to 0.81, P = 0.021 and HR = 0.82 95% CI 0.65- 1, P < 0.0001 respectively). In the bevacizumab cohort, 14q loss showed a significant association with worse response to treatment (CR or PR vs SD or PD, Fisher exact test, P = 0.0473). There was a nonsignificant trend toward a higher hazard of progression among patients who had loss of 9p or loss of 14q in the sorafenib cohort. Conclusions: Our results show that whole genome analysis with virtual karyotyping identifies genetic alterations associated with outcomes in ccRCC. These data suggest that genomic analysis of renal tumors with SNP arrays provides important prognostic information and may lead to a mechanistic understanding of progression and resistance to antiangiogenic therapy of ccRCC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer/Onyx, Genentech, iKaryos Diagnostics iKaryos Diagnostics Bayer/Onyx Genentech