Approximately 30 percent of patients with stage 1-3 renal cell carcinoma (RCC) will relapse. The lack of accurate methods for estimating the true risk of recurrence in RCC has made it difficult for clinicians and patients to make informed decisions regarding treatment options. Standard risk classification systems — tumor, node, metastasis (TNM) staging, Fuhrman grade and ECOG PS — which analyze clinicopathologic parameters only, have limited prognostic value. A new study validating a multigene assay hopes to change that landscape.
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In other tumor types, such as breast, prostate and colon, multigene assays that reveal unique tumor biology have been extensively validated and shown to provide prognostic, and sometimes predictive, information beyond traditional parameters that can guide the selection of adjuvant therapy.
Over the past decade, a 16-gene Recurrence Score (RS) assay, consisting of 11 cancer-specific and five reference genes, has been developed and validated in one study of RCC patients with stage 1-3 disease. Cleveland Clinic participated in a second study to confirm the assay’s validity and provide the required level 1B evidence needed for inclusion in treatment guidelines.
The first validation study was based on an observational cohort of untreated stage 1-3 RCC patients. The current study analyzed primary RCC tumor tissue from 212 participants, with a focus on 193 with stage 3 RCC, from the randomized prospective trial, S-TRAC (Sunitinib as Adjuvant Treatment for Patients at High Risk of Recurrence of Renal Cell Carcinoma Following Nephrectomy). In S-TRAC, one-year adjuvant treatment with sunitinib, a multitargeted kinase inhibitor, prolonged disease-free survival versus placebo in patients with locoregional, high-risk RCC following nephrectomy. Based on the trial results, the U.S. Food and Drug Administration (FDA) recently approved sunitinib for adjuvant treatment for this category of RCC patients.
With the introduction of kinase inhibitors like sunitinib and the immune checkpoint inhibitor nivolumab, the RCC treatment landscape has rapidly evolved over the past decade. Having a validated, multigene assay may enable more astute selection of adjuvant therapy for locoregional and metastatic RCC.
The study’s primary objectives were to validate the prognostic ability of the RS assay to differentiate recurrence risk in untreated RCC patients with locoregional, high-risk T3, and evaluate the potential association between RS result and benefit from sunitinib treatment.
The study showed that the RS assay was able to identify patients with low and high risk of recurrence, based on overexpression of certain genes, and provide independent prognostic information beyond the parameters of standard systems. The results were prognostic for time to recurrence (TTR), disease-free survival (DFS) and renal cancer-specific survival (RCSS) in both the placebo and sunitinib arms. The performance of the RS result in the placebo arm was similar to the first study with a hazard ratio (HR) for a 25-unit increase in RS result of 4.24 versus 3.91 for TTR and 7.21 versus 5.55 for RCSS. When the high versus low groups were compared, the HR for recurrence was 9.18 in the placebo arm; interaction with RS results and treatment was not significant.
The assay has now been validated in more than 830 patients across stages 1-3 RCC. “The study confirmed the prognostic value of the gene signature. Patients will have more useful information to understand the true risk of recurrence,” says Brian Rini, MD, lead study author and Leader, Genitourinary Program, Cleveland Clinic Cancer Center.
While the study showed that the RS assay was able to predict recurrence, it did not include enough samples to determine whether it could predict the benefit of sunitinib treatment. The next step is applying the RS assay to a larger data set; conducting another study is currently under consideration. “The data indicates that the gene signature might have predictive value,” says Dr. Rini.
The study will be published in an upcoming issue of Clinical Cancer Research.
Figure reprinted with permission from Elsevier (Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009;373[9669]:1119-1132).
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