A Molecular Model for Predicting Overall Survival in Patients with Metastatic Clear Cell Renal Carcinoma: Results from CALGB 90206 (Alliance)

• Metastatic renal cell carcinomas have a wide range of prognoses.
• Pretreatment nephrectomy specimens from a randomized phase III trial were analyzed.
• A prognostic signature was developed with 8 genes and MSKCC clinical risk factors.
• The prognostic signature accurately predicted overall survival for metastatic RCC.Kidney cancer can have a wide range of survival outcomes. Tumors obtained from patients with metastatic kidney cancer who enrolled in a multicenter clinical trial of bevacizumab and interferon were used to develop a molecular signature for predicting survival. A total of 424 candidate genes were considered. A molecular signature was developed that included 8 gene levels and well-accepted clinical risk factors. The signature accurately predicted survival for metastatic kidney cancer. This signature can be further developed for clinical use, to help counsel patients, assist with treatment planning, and determine eligibility for clinical trials.

BackgroundPrognosis associated with metastatic renal cell carcinoma (mRCC) can vary widely.MethodsThis study used pretreatment nephrectomy specimens from a randomized phase III trial. Expression levels of candidate genes were determined from archival tumors using the OpenArray® platform for TaqMan® RT-qPCR. The dataset was randomly divided at 2:1 ratio into training (n = 221) and testing (n = 103) sets to develop a multigene prognostic signature.FindingsGene expressions were measured in 324 patients. In the training set, multiple models testing 424 candidate genes identified a prognostic signature containing 8 genes plus MSKCC clinical risk factors. In the testing set, the time dependent (td) AUC for a prognostic model containing the 8 genes with and without MSKCC risk factors were 0.72 and 0.69, respectively. The tdAUC for the clinical risk factors alone was 0.61. Additional primary mRCCs from patients with mRCC (n = 12) were sampled in multiple sites and standard deviations of gene expressions within a tumor were used as a measure of heterogeneity. All 8 genes in the final prognostic model met our criteria for minimal heterogeneity.ConclusionsA molecular prognostic signature based on 8 genes was developed and is ready for external validation in this patient population and other related settings such as nonmetastatic RCC.