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Prognostic Utility of a Multi-Gene Signature After Radical Nephrectomy

Feldman, Adam S. MD, MPH; Morgan, Todd MD

doi: 10.1097/01.COT.0000493054.41441.59
multi-gene signature

multi-gene signature

Kidney cancer is the third most common genitourinary malignancy in the U.S., resulting in approximately 14,080 deaths and 61,560 new cancer diagnoses in 2015 (CA Cancer J Clin 2015;65:5-29).

Renal cell carcinoma (RCC) accounts for the vast majority of kidney cancer cases, and approximately one-third of new RCC patients present with metastatic disease, with 40 percent of patients dying of their disease.

With the increased utilization of abdominal imaging in the general population, we have seen a significant rise in the detection of the incidental small renal mass. While many of these small renal masses are relatively indolent in nature, our true understanding of the biologic phenotype and malignant potential of these tumors is poor.

An improved understanding of the biology of these small renal masses is particularly important given the increasing evidence that some patients with localized renal tumors may be managed non-operatively with active surveillance or with less-invasive focal therapies.

Conversely, there is more attention being given to adjuvant therapies in patients with high-risk localized RCC following nephrectomy (e.g. EVEREST trial [NCT01120249] and S-TRAC trial [NCT00375674]), and there is a need for better identification of patients who may benefit from these treatments.

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Biomarker Discovery

Pre- and post-operative nomograms for risk stratification and prediction of overall survival in these patients rely almost entirely on tumor size, histologic characteristics, and patient age. We currently lack dependable and clinically useful biomarkers for predicting tumor growth, aggressive pathologic features, or metastatic potential, and it is evident that there is a tremendous need for diagnostic, prognostic, and predictive biomarkers in RCC.

Advances in biomarker discovery have led to the identification of a number of molecular markers with possible importance in renal cell carcinoma. However, despite these advances, none of the molecular markers identified to date have been translated into a clinically useful tool.

The cell cycle progression score (CCP score) is an assay of the expression levels of 31 genes involved in cellular proliferation and is strongly correlated with biochemical recurrence and death following prostatectomy.

While specific individual markers of cell proliferation, such as Ki-67, are associated with adverse oncologic outcomes in patients with RCC, multi-gene signatures of cell proliferation have not been previously assessed in RCC.

We hypothesized that the CCP score would predict long-term oncologic outcomes—specifically, recurrence and disease specific survival (DSS)—in surgically resected RCC, adding value to currently available clinical nomograms for disease recurrence.

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Study of CCP Score

Our study investigated the CCP score in two separate cohorts of patients from two separate institutions: Massachusetts General Hospital (training set) and University of Michigan (validation set).

Inclusion criteria were patients who underwent open or laparoscopic radical nephrectomy from 2000 to 2009 for clear cell, papillary or chromophobe RCC with localized disease (pT1-3N0M0). Any patients who had neo-adjuvant therapy, stage pT4 disease, sarcomatoid or rhabdoid subtype, or bilateral RCC were excluded.

The primary endpoint was DSS, and disease recurrence (local or metastatic) was a secondary endpoint. Association with outcomes was evaluated by Kaplan-Meier survival analysis, Cox proportional hazards models, 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.

Formalin-fixed paraffin-embedded (FFPE) blocks derived from eligible patients were retrieved from their respective institutional tissue repositories and analyzed for tumor content. Total RNA was extracted from representative 10mm thick FFPE tumor sections and then converted to single stranded cDNA. CCP gene expression levels were then measured using standard (Reverse Transcriptase-Polymerase Chain Reaction) RT-PCR techniques.

Three-hundred five patients were included in the training set and 262 patients in the validation set. Fifty-eight percent of patients had stage pT1 disease, 42 percent were high grade, and 81 percent were clear cell. Across both cohorts there was a normal distribution of CCP scores, which persisted when stratified by tumor stage. In the training cohort, the median CCP score was 0.095 (IQR -0.50 to 0.60), and median CCP score was 0.034 (IQR -0.30 to 0.94) in the validation cohort.

Patient data were censored at 5 years of follow-up, by which time a total of 68 patients (12%) recurred and 32 (6%) died of disease. In the univariable analysis, CCP score was a significant prognostic variable for recurrence (p < 0.0001) and DSS (p < 0.0001) in both cohorts. 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)) in the training cohort. Results were similar in the validation cohort, and there was no interaction between CCP and any clinical variable.

In order to assess whether CCP scores add information on top of known clinicopathologic predicters, Karakiewicz nomogram scores were calculated and a combined Karakiewicz nomogram plus CCP score model was derived and analyzed.

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 using the combined score, with the strongest association being seen for DSS.

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Molecular Diagnostics & RCC

While the increasing use of molecular diagnostics has been felt across numerous cancers, there still remains a paucity of markers in RCC.

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.

Such a molecular-based determination of malignancy could improve the diagnostic accuracy and prognostic utility of renal mass biopsy, leading to greater use of renal mass biopsy in patients with small renal masses. Additionally, a prognostic biomarker could have a critical role in management decisions both following renal mass biopsy (e.g. surgery vs. surveillance) and following surgery (e.g. adjuvant targeted therapy).

With further validation, the CCP score may have utility in the clinical management of patients with RCC.

ADAM S. FELDMAN, MD, MPH, is a Urologist at Massachusetts General Hospital, Boston. TODD MORGAN, MD, is an Associate Professor in Urology at University of Michigan, Ann Arbor.

Adam S

Adam S

Todd Morgan, MD

Todd Morgan, MD

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