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Prognostic utility of a multi-gene signature (the cell cycle proliferation score) in patients with renal cell carcinoma (RCC) after radical nephrectomy: analysis in testing and validation cohorts
Adam S. Feldman, MD, MPH1, Rohit Mehra, MD2, Placede Fosso, MS3, J. Stuart Wolf, MD2, Brian Orr, MD2, Shulin Wu, PhD1, Zaina Sangale, MD3, Steven Stone, PhD3, Chin-Lee Wu, MD, PhD1, Todd Morgan, MD2.
1Massachusetts General Hospital, Boston, MA, USA, 2University of Michigan, Ann Arbor, MI, USA, 3Myriad Genetics, Inc, Salt Lake City, UT, USA.

BACKGROUND: There are currently no RCC biomarkers being routinely used in the clinic, and prognostic nomograms rely almost entirely on tumor size, stage and age. There is a critical need for improved prognostic discrimination given the increasing awareness that some patients may be managed with active surveillance, while others with higher risk disease might benefit from adjuvant therapy following surgery. We hypothesized that a previously developed multi-gene proliferation signature would predict long-term oncologic outcomes in surgically resected RCC. METHODS: The cell cycle proliferation (CCP) score was derived after radical nephrectomy in 305 patients who were treated at a single institution from 2000 to 2007 for clear cell, papillary or chromophobe RCC with localized disease (N0M0). Sixty-four percent of the cohort had stage I disease. The primary endpoint was disease specific survival (DSS), and disease recurrence (local or metastatic) was a secondary endpoint. Association with outcomes was evaluated by CoxPH survival analysis and likelihood ratio tests. Hazard ratios (HR) are given for one-unit increase in CCP score (equivalent to a doubling of gene expression). CCP score was then compared with current clinical nomograms for prediction of recurrence and survival. A second cohort of 262 patients with similar baseline characteristics, and from a separate institution was used as a validation cohort. RESULTS: Patient data were censored at 5-years of follow-up, by which time 68 patients (12%) recurred and 32 (6%) died of disease. In the development cohort, the median CCP score was 0.095 (IQR -0.50 to 0.60). In univariable analysis, CCP score was a significant prognostic variable for recurrence (p < 0.0001) and DSS (p < 0.0001). After adjusting for clinical variables including tumor size, stage, and grade, the CCP score HR for recurrence was 1.74 (95% CI (1.14, 2.65)), and for DSS was 2.59 (95% CI (1.43, 4.67)). There was no interaction between CCP and any clinical variable. Comparative bivariate analysis demonstrated that CCP score added significant predictive value to the Karakiewicz nomogram for DSS. The validation cohort demonstrated a consistent and significant prediction of recurrence and DSS, with the strongest association being for DSS. Kaplan-Meier analyses for DSS in both cohorts are shown in Figure 1. CONCLUSIONS: The CCP score appears to be a significant and independent predictor of key long-term oncologic outcomes in patients who have undergone nephrectomy for RCC, providing prognostic information beyond what is available from clinical parameters. With further validation, the CCP score may have utility in the clinical management of patients with RCC.


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