The Clinical Cell-Cycle Risk (CCR) Score Is Associated With Metastasis After Radiation Therapy and Provides Guidance on When to Forgo Combined Androgen Deprivation Therapy With Dose-Escalated Radiation

Jonathan D Tward ,Michael K Brawer,Tatjana Antic,Paul L Nguyen,David T Marshall,David Raben,Arthur Hung,Steve P Lee,Steven Stone,Deepak A Kapoor,Lauren Lenz,Jonathan Henderson,Saradha Rajamani,Todd Cohen,Darl D Flake,Daniel J Albertson ,Carl A Olsson ,Jeff M Michalski ,Neal D Shore ,Michael Lewis ,Isla P Garraway ,S Liauw ,C.a Mantz

doi:10.1016/j.ijrobp.2021.09.034

Abstract

The clinical cell-cycle risk (CCR) score, which combines the University of California, San Francisco's Cancer of the Prostate Risk Assessment (CAPRA) and the cell cycle progression (CCP) molecular score, has been validated to be prognostic of disease progression for men with prostate cancer. This study evaluated the ability of the CCR score to prognosticate the risk of metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). This retrospective, multi-institutional cohort study included men with localized National Comprehensive Cancer Network (NCCN) intermediate-, high-, and very high-risk prostate cancer (N=741). Patients were treated with dose-escalated RT with or without ADT. The primary outcome was time to metastasis. The CCR score prognosticated metastasis with a hazard ratio (HR) per unit score of 2.22 (95% confidence interval [CI], 1.71-2.89; P < .001). The CCR score better prognosticated metastasis than NCCN risk group (CCR, P < .001; NCCN, P=.46), CAPRA score (CCR, P=.002; CAPRA, P=.59), or CCP score (CCR, P < .001; CCP, P=.59) alone. In bivariable analyses, CCR score remained highly prognostic when accounting for ADT versus no ADT (HR, 2.18; 95% CI, 1.61-2.96; P < .001), ADT duration as a continuous variable (HR, 2.11; 95% CI, 1.59-2.79; P < .001), or ADT given at or below the recommended duration for each NCCN risk group (HR, 2.19; 95% CI, 1.69-2.86; P < .001). Men with CCR scores below or above the multimodality threshold (CCR score, 2.112) had a 10-year risk of metastasis of 3.7% and 21.24%, respectively. Men with below-threshold scores receiving RT alone had a 10-year risk of metastasis of 3.7%, and for men receiving RT plus ADT, the 10-year risk of metastasis was also 3.7%. The CCR score accurately and precisely prognosticates metastasis and adds clinically actionable information relative to guideline-recommended therapies based on NCCN risk in men undergoing dose-escalated RT with or without ADT. For men with scores below the multimodality threshold, adding ADT may not significantly reduce their 10-year risk of metastasis.

Highlights

The Prolaris gene expression classifier test combines the University of California, San Francisco’s Cancer of the Prostate Risk Assessment (CAPRA)[1] score with a cell cycle progression (CCP) score derived from a tumor RNA expression profile to produce a personalized metastasis risk score after definitive treatment for localized prostate cancer
We sought to validate that the cycle risk (CCR) score multimodality threshold may identify National Comprehensive Cancer Network (NCCN) unfavorable intermediate- and high-risk men who might consider treatment with radiation therapy (RT) alone instead of the guideline-recommended androgen deprivation therapy (ADT) plus RT and potentially avoid the significant toxicities and quality-of-life impairment associated with ADT therapy
CCR testing is currently supported by NCCN guidelines and is a highly precise and accurate prognosticator of metastasis in men undergoing dose-escalated RT plus ADT

Summary

Introduction

The Prolaris gene expression classifier test combines the University of California, San Francisco’s Cancer of the Prostate Risk Assessment (CAPRA)[1] score with a cell cycle progression (CCP) score derived from a tumor RNA expression profile to produce a personalized metastasis risk score after definitive treatment for localized prostate cancer This combined clinical cell-cycle risk (CCR) score can prognosticate an individual’s risk of metastasis with single-modality or multimodality therapies.[2] A CCR score threshold has been developed, under which using multimodality therapies in men with National Comprehensive Cancer Network (NCCN) intermediate- or high-risk prostate cancer may not be warranted, given that the absolute risk reduction for 10year risk of metastasis would not exceed 5% compared with monotherapy.[2,3]. We sought to validate that the CCR score multimodality threshold may identify NCCN unfavorable intermediate- and high-risk men who might consider treatment with RT alone instead of the guideline-recommended ADT plus RT and potentially avoid the significant toxicities and quality-of-life impairment associated with ADT therapy

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