Cell Cycle Progression Score, but Not Phosphatase and Tensin Homolog Loss, Is an Independent Prognostic Factor for Metastasis in Intermediate- and High-risk Prostate Cancer in Men Treated With and Without Salvage Radiotherapy.

PURPOSE: The prognostic value for metastasis of the cell-cycle progression score and phosphatase and tensin homolog haven't been evaluated jointly in contemporary men with exclusively intermediate- or high-risk prostate cancer. We evaluated associations of cell-cycle progression and phosphatase and tensin homolog with metastasis-free survival in contemporary intermediate/high-risk prostate cancer patients overall, and intermediate/high-risk men receiving salvage radiotherapy. MATERIALS AND METHODS: In a case-cohort of 209 prostatectomy patients with intermediate/high-risk prostate cancer, and a cohort of 172 such men who received salvage radiotherapy, cell-cycle progression score was calculated from RNA expression, and phosphatase and tensin homolog was analyzed by immunohistochemistry. Proportional hazards regression, weighted for case-cohort design or unweighted for the salvage radiotherapy cohort, was used to evaluate associations of cell-cycle progression, phosphatase and tensin homolog with metastasis-free survival. Improvement in model discrimination was evaluated with the concordance index. RESULTS: In the case-cohort 41 men had metastasis, and 17 developed metastasis in the salvage radiotherapy cohort, at median follow-up of 3 and 4 years, respectively. For both case-cohort and salvage radiotherapy cohort, cell-cycle progression was independently associated with metastasis-free survival after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical: hazard ratio (95% confidence interval) = 3.11 (1.70-5.69) and 1.85 (1.19-2.85), respectively. Adding cell-cycle progression to Cancer of the Prostate Risk Assessment Post-Surgical increased the concordance index from 0.861 to 0.899 (case-cohort), and 0.745 to 0.819 (salvage radiotherapy cohort). Although statistically significant in univariate analyses, phosphatase and tensin homolog was no longer significant after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical. Analysis of interaction with National Comprehensive Cancer Network risk group showed that cell-cycle progression had the strongest effect among unfavorable intermediate-risk men. CONCLUSIONS: In the first study to evaluate metastasis risk associated with cell-cycle progression and phosphatase and tensin homolog in exclusively intermediate/high-risk prostate cancer, and in such men with salvage radiotherapy, cell-cycle progression but not phosphatase and tensin homolog was associated with significantly increased 2- to 3-fold risk of metastasis after Cancer of the Prostate Risk Assessment Post-Surgical adjustment.

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.

PURPOSE: 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). METHODS AND MATERIALS: 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. RESULTS: 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%. CONCLUSIONS: 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.

Validation of the cell cycle progression score to differentiate indolent from aggressive prostate cancer in men diagnosed through transurethral resection of the prostate biopsy.

BACKGROUND: Validation of biomarker-based prognostic models to improve risk stratification in men with localized prostate cancer (PrCa) remains a clinical need. It has previously been shown that the cell cycle progression (CCP) test provides significant, independent prognostic information for men who were incidentally diagnosed with PrCa after transurethral resection of the prostate (TURP) and were conservatively managed. AIM: The results have been extended in a newly analyzed retrospective cohort of UK men diagnosed through TURP biopsy (TURP1B; N = 305). METHODS AND RESULTS: The CCP score was derived from TURP biopsy tissue and combined with a modified UCSF Cancer of the Prostate Risk Assessment score (CAPRA) to generate the clinical cell-cycle risk score (CCR). The primary endpoint was PrCa-specific mortality (PSM). Hazard ratios (HR) were calculated for a one-unit change in score. Median follow-up was 9.6 (IQR: 5.4, 14.1) years, and 67 (22%) men died from PrCa within 10 years of diagnosis. The median CCP score was 1.1 (IQR: 0.6, 1.7). In univariate analyses, CCR proved a significant prognosticator of PSM (HR per unit score change = 2.28; 95% CI: 1.89, 2.74; P = 1.0 × 10-19 ). In multivariate analyses, CCR remained a significant prognosticator of PSM after adjusting for CAPRA (HR per unit score change = 4.36; 95% CI: 2.65, 7.16; P = 1.3 × 10-8 ), indicating that its molecular component, CCP, provides significant, independent prognostic information. CONCLUSION: These findings validate a combined clinicopathologic and molecular prognostic model for conservatively managed men who are diagnosed through TURP, supporting the use of CCR to inform clinical management.

Personalizing Localized Prostate Cancer: Validation of a Combined Clinical Cell-cycle Risk (CCR) Score Threshold for Prognosticating Benefit From Multimodality Therapy.

INTRODUCTION: The combined clinical cell-cycle risk (CCR) score is a validated model that combines the cell-cycle progression (CCP) score with the University of California San Francisco Cancer of the Prostate Risk Assessment (CAPRA) score. This score determines the risk of progressive disease for men with prostate cancer. Here, we further validate the prognostic ability of the CCR score and evaluate its ability to help determine which patients may safely forgo multimodality therapy. PATIENTS AND METHODS: We evaluated the CCR and a CCR-based multimodality threshold (2.112) in a retrospective, multi-institutional cohort of men with National Comprehensive Cancer Network intermediate- or high-risk localized disease (N = 718). These men received single or multimodality therapy (androgen deprivation with radiation [RT], or surgery with adjuvant RT or hormones). RESULTS: CCR score prognosticated metastasis for single-modality therapy, as a continuous variable (hazard ratio, 3.97; 95% confidence interval [CI], 2.61-6.06) and when dichotomized at the threshold (hazard ratio, 15.90; 95% CI, 5.43-46.52). The 10-year Kaplan-Meier risk for those receiving single-modality (RT or surgical) therapy with CCR scores below and above the threshold for single-modality treatment was 4.3% (95% CI, 1.0%-17.1%) and 20.4% (95% CI, 13.2%-30.7%), respectively. Using the threshold, 27% of men with newly diagnosed high-risk and 73% with unfavorable intermediate-risk disease could avoid multimodality therapy. CONCLUSIONS: Patients with CCR scores below the multimodality threshold (2.112) may safely forgo multimodality therapy. The CCR score can be used as a decision aid to counsel men whether or not single-modality therapy would be sufficient for their intermediate- or high-risk prostate cancer.

Clinical outcomes in men with prostate cancer who selected active surveillance using a clinical cell cycle risk score.

Aim: To evaluate active surveillance (AS) selection, safety and durability among men with low-risk prostate cancer assessed using the clinical cell cycle risk (CCR) score, a combined clinical and molecular score. Patients & methods: Initial treatment selection (AS vs treatment) and duration of AS were evaluated for men with low-risk prostate cancer according to the CCR score and National Comprehensive Cancer Network guidelines. Adverse events included biochemical recurrence and metastasis. Results: 82.4% (547/664) of men initially selected AS (median follow-up: 2.2 years), 0.4% (2/547) of whom experienced an adverse event. Two-thirds of patients remained on AS for more than 3 years; patient choice was the most common reason for leaving AS. Conclusion: The CCR score may aid in the identification of men who can safely defer prostate cancer treatment.

Prognostic utility of biopsy-derived cell cycle progression score in patients with National Comprehensive Cancer Network low-risk prostate cancer undergoing radical prostatectomy: implications for treatment guidance.

OBJECTIVES: To determine the prognostic utility of the cell cycle progression (CCP) score in men with National Comprehensive Cancer Network (NCCN)-defined low-risk prostate cancer (PCa) undergoing radical prostatectomy (RP). PATIENTS AND METHODS: Men who underwent RP for Gleason score ≤6 PCa at three institutions (Martini Clinic [MC], Durham Veterans Affairs Medical Center [DVA] and Intermountain Healthcare [IH]) were identified. The CCP score was obtained from diagnostic (DVA, IH) or simulated biopsies (MC). The primary outcome was biochemical recurrence (BCR; prostate-specific antigen ≥0.2 ng/mL) after RP. The prognostic utility of the CCP score was assessed using Kaplan-Meier analysis and multivariable Cox proportional hazards models in the subset of men meeting NCCN low-risk criteria and in the overall cohort. RESULTS: Among the 236 men identified, 80% (188/236) met the NCCN low-risk criteria. Five-year BCR-free survival for the low (<0), intermediate (0-1) and high (>1) CCP score groups was 89.2%, 80.4%, 64.7%, respectively, in the low-risk cohort (P = 0.03), and 85.9%, 79.1%, 63.1%, respectively, in the overall cohort (P = 0.041). In multivariable models adjusting for clinical and pathological variables with the Cancer of the Prostate Risk Assessment (CAPRA) score, the CCP score was an independent predictor of BCR in the low-risk (hazard ratio [HR] 1.77 per unit score, 95% confidence interval [CI] 1.21, 2.58; P = 0.003) and overall cohorts (HR 1.41 per unit score, 95% CI 1.02, 1.96; P = 0.039). CONCLUSION: In a cohort of men with NCCN-defined low-risk PCa, the CCP score improved clinical risk stratification of men who were at increased risk of BCR, which suggests the CCP score could improve the assessment of candidacy for active surveillance and guide optimum treatment selection in these patients with otherwise similar clinical characteristics.