Genomic differences and survival in African Americans with metastatic clear cell renal cell carcinoma in the targeted therapy era.

Abstract

504 Background: African American (AA) patients with RCC have historically had inferior survival relative to Caucasians. There is little data on racial differences in tumor biology between AA and Caucasians to explain this disparity. In addition, it is not known if racial differences may result in differential response to targeted therapy and if the disparity has changed over time. Our study aims to define racial differences in tumor biology between AA and Caucasians with clear cell RCC (ccRCC) and to evaluate if observed differences in tumor biology are reflected in survival rates in the era of targeted therapy. Methods: We identified AA and Caucasian patients with stage IV clear cell RCC (ccRCC) in the National Cancer Data Base (NCDB) and analyzed survival of AA and Caucasians in the pre- and post-targeted therapy eras (1998-2004 and 2006-2011). We then analyzed The Cancer Genome Atlas (TCGA): Renal Clear Cell Carcinoma dataset to determine differences in somatic mutation rate, molecular subtype, and RNA expression between AA and Caucasians. Results: Overall survival (OS) is significantly longer in Caucasians than AA (9.2 vs 6.5 months, p < 0.01). The adjusted HR for death for AA compared with Caucasian patients was 1.08 (95% CI 1.01-1.14) in the post-targeted therapy era, which was unchanged from the pre-targeted therapy era (HR 1.07, 95% CI 1.01-1.14). AA patients were less likely than Caucasians to have VHL mutations (17% vs 50%, p = 0.04) and were enriched in the ccB molecular subtype (79% in AA vs 45% in Caucasians, p < 0.01). RNA expression revealed upregulation of several HIF-associated pathways in Caucasian compared with AA patients. Conclusions: ccRCC in AA have less frequent VHL mutations, are enriched in the ccB molecular subtype, and have less upregulation of HIF-associated pathways than Caucasians. These molecular features predict for decreased responsiveness to VEGF-targeted therapy and inferior survival in AA compared to Caucasians. Data from a large national database confirm that AA patients maintain inferior survival compared to Caucasians in the era of targeted therapy, potentially related to underlying tumor biology.