Cell-cycle Risk Score Research Articles

Using the Cell-Cycle Risk Score to Predict the Benefit of Androgen-Deprivation Therapy Added to Radiation Therapy in Patients With Newly Diagnosed Prostate Cancer.

Guidelines recommend adding androgen-deprivation therapy (ADT) to radiation therapy (RT) in certain patients with localized prostate cancer. Individualized genomic testing may improve the prognostic accuracy of risk assessments. Herein, we describe a mathematical model of the benefit of adding ADT to RT as a function of the personalized clinical cell-cycle risk (CCR) score to inform 10-year metastasis risk. A model of absolute risk reduction (ARR) was built using a retrospective cohort of men tested with Prolaris who received RT alone (N = 467). The relative benefit of ADT added to RT to reduce distant metastasis was estimated at 41% on the basis of a meta-analysis of randomized trials. The ARR and number needed to treat (NNT) were computationally derived in patients clinically tested with Prolaris between January 1, 2020, and October 31, 2022 (N = 56,485). Risks were predicted using a cause-specific Cox proportional hazards model with CCR score predicting time to metastasis. A CCR score of 2.112 represents the validated multimodal treatment (MMT) threshold. The ARR from ADT increased from almost zero at low CCR scores to 17.1% at CCR = 3.690 with the corresponding NNT = 6, indicating that adding ADT to RT would prevent metastasis within 10 years for one of every six treated individuals. In the clinical cohort, the average ARR was 0.86% in individuals under the MMT threshold (NNT = 116). The average ARR was 8.19% in individuals above the MMT threshold (NNT = 12). Broad ranges of ADT benefit were observed within National Comprehensive Cancer Network risk categories. The precise and personalized risk estimate of metastasis provided by the CCR score can help inform patients and physicians when considering treatment intensification.

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

BackgroundValidation 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.AimThe results have been extended in a newly analyzed retrospective cohort of UK men diagnosed through TURP biopsy (TURP1B; N = 305).Methods and ResultsThe 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.ConclusionThese 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.

Association of the clinical cell-cycle risk score with metastasis after radiation therapy and identification of men with prostate cancer who can forgo combined androgen deprivation therapy.

195 Background: This study evaluated the ability of the combined clinical cell-cycle risk score (CCR) to prognosticate the risk of prostate cancer metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). Methods: The CCR score is a validated model that combines the cell cycle progression score (CCP) with the UCSF Cancer of the Prostate Risk Assessment score (CAPRA). The CCR score and a CCR-based multimodality threshold score (2.112) were evaluated in a retrospective, multi-institutional cohort of men with National Comprehensive Cancer Center (NCCN) intermediate- or high-risk localized disease (N = 741) who received single (RT) or multimodality therapy (ADT with RT). Effects of prognostic variables were analyzed using Kaplan-Meier and Cox regression methods. Results: Median follow-up was 5.9 years. CCR predicted metastasis [hazard ratio (HR) 2.21, 95% Confidence Interval (CI) 1.70-2.87, p < 0.001]. The CCR score was a better prognosticator of metastasis (C-index 0.78) than either NCCN-risk group (C-index 0.70), CAPRA score (C-index 0.71), or CCP score (C-index 0.69) alone. In bivariate analyses, the CCR score remained highly prognostic for metastasis when comparing any ADT vs none (HR 2.19, 95% CI 1.62 to 2.97, p < 0.001), ADT duration as a continuous variable (HR 2.05, 95% CI 1.54-2.72, p < 0.001), or ADT use given as less than or at the recommended duration for each NCCN risk group (HR 2.22, 95% CI 1.71-2.88, p < 0.001). Men with CCR scores either below or above the threshold (2.112) had a 10-year risk of metastasis of 4.2% and 25.3%, respectively. For men below the threshold receiving RT alone versus RT+ADT, the 10-year risk of metastasis was 4.2% and 3.9%, respectively. Conclusions: CCR is a highly precise and accurate predictor of metastasis in men undergoing dose-escalated RT, with or without ADT. CCR adds clinically actionable information relative to guideline recommended therapies that are based on NCCN risk groups or CAPRA alone. Men with scores below the multimodality threshold may not significantly reduce their 10-year risk of metastasis with the addition of ADT.

Cell-cycle risk score more accurately determines the risk for metastases and death in prostatectomy patients compared with clinical features alone.

BackgroundProstate cancer treatment aims to prevent metastases and disease‐specific mortality. Pathologic parameters have limited ability to predict these outcomes, but biomarkers can improve risk discrimination. We evaluated the ability of cell‐cycle progression and combined cell‐cycle risk scores to predict metastases and disease‐specific mortality after prostatectomy.MethodsEligibility included (1) treatment with radical prostatectomy (1985–1997); (2) cell‐cycle progression score; (3) preoperative prostate‐specific antigen; (4) no neoadjuvant therapy; and (5) clinical follow‐up (N = 360). Cancer of the prostate risk assessment postsurgical score was combined with cell cycle progression into the prespecified combined cell‐cycle risk score. Hazard ratios (HRs) are reported per unit score.ResultsIn total, 11% (41/360) developed metastases and 9% (33/360) experienced disease‐specific mortality. Combined cell‐cycle risk score predicted metastases and disease‐specific mortality post‐radical prostatectomy (p < 1 × 10−8). Adjusting for cancer of the prostate risk assessment postsurgical score, the combined cell‐cycle risk score remained a predictor of metastases (HR = 3.03 [95% confidence interval (CI): 1.49, 6.20]; p = .003] and disease‐specific mortality (HR = 3.40 [95% CI: 1.52, 7.59]; p = .004). Of patients with biochemical recurrence, 25% (41/163) developed metastases. Cancer of the prostate risk assessment postsurgical score was predictive of metastases postbiochemical recurrence but was improved by the addition of cell cycle progression (HR = 1.70 [95% CI: 1.14, 2.53]; p = .012). The combined cell‐cycle risk was also prognostic of metastases post‐biochemical recurrence (HR = 1.56 [95% CI: 1.20, 2.03]; p = .001).ConclusionCombined cell‐cycle risk and cell cycle progression scores predict metastases and disease‐specific mortality post‐radical prostatectomy and should help identify patients at greatest risk of treatment failure who might benefit from earlier intervention.

Ability of cell-cycle progression score to predict risk for progression to metastatic disease and disease-specific mortality in prostate cancer patients after prostatectomy.

5524 Background: Prostate cancer treatment aims to prevent metastatic disease (METS) and disease-specific mortality (DSM). A major challenge is to identify those at highest risk so additional intervention can be initiated earlier when it has a better chance of success. Pathologic parameters alone have limited ability to predict METS and DSM, but data suggests biomarkers can improve risk discrimination. Methods: Eligible patients had: (1) prostate cancer treated with radical prostatectomy (RP; 1988-1995); (2) available tissue for cell-cycle progression (CCP) testing that resulted in a valid score; (3) preoperative prostate-specific antigen (PSA); (4) no neoadjuvant therapy; and (5) clinical follow-up (N = 360). Cancer of the prostate risk assessment post-surgical (CAPRA-S) was combined with CCP into a combined cell-cycle risk score (CCR = 0.38 × CAPRA-S + 0.57 × CCP). Results: Median follow-up was 23.5 years for patients alive at last follow-up. Overall, 11% (41/360) developed METS and 9% (33/360) had DSM. CCP score added significant information to CAPRA-S when predicting METS (p = 0.001) and DSM (p = 0.001). CCR score was also a significant predictor of METS and DSM (p-values &lt; 1×10−8). CCP and CCR scores were prognostic of METS in patients with rising post-RP PSA. Of patients with biochemical recurrence (BCR), 25% (41/163) developed METS. CAPRA-S alone was predictive of these events (p = 0.01) but was significantly improved with the addition of CCP (Hazard Ratio [HR] = 1.69 [95% Confidence Interval (CI) 1.13, 2.52], p = 0.014). CCR was also highly prognostic (HR = 1.56 [95% CI 1.20, 2.03], p = 0.001). CCR score discriminated risk of METS both post-RP and after post-RP BCR (Table). Conclusions: Overall, the CCR score significantly predicted METS and DSM in prostate cancer post-RP and was also highly prognostic in those with a post-RP rising PSA. It is therefore a useful tool for determining who is at greatest risk of treatment failure and may benefit from earlier intervention. [Table: see text]

Ability of the combined clinical cell-cycle risk score to identify patients that benefit from multi versus single modality therapy in NCCN intermediate and high-risk prostate cancer.

346 Background: Prolaris combines RNA expression analysis of cell cycle progression genes with clinicopathologic information to create a combined clinical cell-cycle risk score (CCR). We evaluated the ability of CCR to predict metastasis (mets) in men for whom guidelines indicate that multimodality therapy (MTx) should be considered. Methods: A commercial cohort (N=15669) of National Comprehensive Cancer Network unfavorable intermediate-risk (UFI) and high-risk (HR) men revealed a distribution of 70.5% and 29.5% respectively. A CCR threshold of 2.112 was selected so that 29.5% of these men were above the threshold. MTx was defined as combined use of androgen deprivation therapy with radiation (RT) or surgery, or with adjuvant RT. Associations were evaluated in a 718-person retrospective, multi-institutional database of Prolaris-tested UFI and HR men. Kaplan-Meier (KM) analyses and Cox regressions were used to estimate the effects of prognostic covariates. Results: Median follow-up was 5.13 years. CCR predicted mets in the full cohort (HR =3.8 [2.7,5.2], p&lt;10−15) and after accounting for CAPRA (HR=4.3 [2.7,7.0], p&lt; 10−7). CCR also was a significant predictor of mets in patients who received STx, as a continuous predictor (HR=4.0 [2.6,6.1], p&lt;10−9) and when dichotomized at the threshold (HR=15.9 [5.4,46.5], p&lt; 10−9). The KM probability of mets by 10 years for those below and above the threshold was 4.3% and 20.4% respectively. MTx reduced patients’ risk of mets (HR=0.46 [0.22,0.97], p=0.04), and treatment benefit can be evaluated as a function of CCR score (Table). Conclusions: The CCR score prognosticates a clinically meaningful different risk of metastasis for those receiving MTx versus STx. Approximately 27% and 73% of people with HR or UFI risk cancer have CCR scores below the risk threshold and may consider STx after considering the difference in risk of mets.[Table: see text]

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.

Outcomes of men with prostate cancer managed with active surveillance and tested with clinical cell-cycle risk score.

e16566 Background: The indolent nature of many prostate cancers (PC) makes some men eligible to undergo active surveillance (AS) rather than immediate definitive treatment. Accurate risk classification is critical for selection of appropriate candidates for AS. The clinical cell-cycle risk (CCR) score, a combined clinical and molecular score, provides improved prognostic information about tumor aggressiveness over clinical parameters alone. This study aimed to evaluate the clinical outcomes of men with low-risk PC by NCCN guidelines and CCR score who selected AS. Methods: This study retrospectively reviewed men with localized PC who received CCR testing (2013-2017) and had low-risk disease according to NCCN guidelines and CCR score (N = 664). Low-risk by CCR score was defined as having a risk of disease-specific mortality &lt; 3.2%. Men selected AS (no definitive treatment within 6 months of diagnosis) or underwent immediate definitive treatment. Durability of AS was evaluated beginning from diagnosis. Clinical outcomes were determined by reporting adverse events (biochemical recurrence (BCR), progression to metastasis as confirmed by radiographic imaging, prostate cancer specific mortality). Results: In this study, 547 men (82%) selected AS (median follow-up time 2.2 years [1.5, 3.1]). Of those managed by AS, two (0.4%) men experienced an adverse event. One man experienced BCR 3.7 years after diagnosis, and the other experienced metastasis 0.9 years after diagnosis. There were no reported cases of disease-specific mortality. The probability of remaining on AS for 3 years was 69.6%. Common reasons for exiting AS were patient choice (27.1%), increase in Gleason score (23.3%), and change in prostate specific antigen (PSA) (10.5%). Of those patients that left AS due to change in PSA (N = 14), only 4 exhibited a clinically significant increase in PSA ( &gt; 10 ng/mL). Conclusions: The majority of men with molecularly-confirmed (CCR), NCCN low-risk PC selected AS in both academic and community settings. The incidence of metastatic disease or BCR after definitive treatment for disease progression was rare. The majority of men who selected AS remained on AS for the duration of the study.

Evaluation of a predefined AS threshold in a large cohort of men with localized prostate cancer.

36 Background: Men with newly diagnosed, localized prostate cancer (PC) have historically been selected for active surveillance (AS) using clinicopathologic features. However, a clinical cell−cycle risk (CCR) score has been developed to include both molecular [cell cycle progression (CCP) RNA signature] and clinical [Cancer of the Prostate Risk Assessment (CAPRA)] features. Previous validations have demonstrated that this combined CCR score provides improved prognostic information relative to molecular or clinical features alone. As such, a CCR threshold score has been recently developed and validated to identify men with low−risk disease who may be candidates for AS. Here, we have evaluated the performance of the AS threshold in a contemporary cohort of men with newly diagnosed localized PC. Methods: Men with localized adenocarcinoma of the prostate who were treated at the Ochsner Clinic between 2006 and 2011 (4 patients were diagnosed in 2012−2014) were evaluated. Formalin−fixed paraffin embedded biopsy tissue and was analyzed for the RNA expression of 46 genes to obtain a CCP score. The CCR score was calculated as (0.57xCCP) + (0.39xCAPRA). A CCR score threshold of 0.8 has been previously validated in a cohort of conservatively managed men. Men with a CCR score equal to the threshold had an estimated 10−year disease−specific mortality risk of 3.3%, while men with scores below the threshold had a 2.7% risk. Results: Complete molecular and clinical information were available for 767 men with a median clinical follow−up time of 5.6 years measured from date of diagnosis. Overall, 217 men had CCR scores ≤ 0.8. Of these, 125 were treated by radical prostatectomy, 61 with radiation, 2 with radiation with hormones, 2 with hormones only, and 19 with watchful waiting. Treatment for eight men was unknown. One patient (0.5%) with a CCR score below the AS threshold progressed to metastatic disease, and was initially treated with radiation. Conclusions: We evaluated the performance of a previously validated AS threshold on a contemporary US cohort. Although the majority of the patients in this study were treated, the observed metastatic event rate of 0.5% supports that the CCR threshold can be safely used to identify candidates for AS.

Patient NCCN risk classification based on combined clinical cell cycle risk (CCR) score.

249 Background: Improved prognostic tools for newly diagnosed prostate cancer are needed to more appropriately match treatment to a patient’s risk of progression. The cell cycle progression (CCP) score is a highly validated prognostic RNA expression signature which has been combined with CAPRA (CCR, combined clinical cell cycle risk score) to generate an estimate of prostate cancer mortality (PCM) within 10-years of diagnosis. Here, we evaluate how the prognostic information from CCR can reclassify patients compared to their initial assignment to an NCCN risk category based on clinicopathologic features alone. Methods: The CCR score was previously validated and is calculated as a linear combination of CAPRA and CCP score (0.39 x CAPRA + 0.57 x CCP). A risk reclassification scheme was applied to patients tested by the Myriad Genetics commercial laboratory (N = 16,442). First, PCM risk was assigned based on the patient’s CCR score. Next, patients whose PCM risks were outside the interquartile range (IQR) of their NCCN risk category were reclassified according to whether their PCM risks fell within the IQR of another NCCN risk category. Finally, patients whose PCM risks were below (or above) the IQR of the NCCN low (or high) category were reclassified as low (or high). Results: Based on clinicopathologic features alone the commercial cohort was classified according to NCCN Guidelines as low (N = 8,695), favorable intermediate (N = 3,347), intermediate (N = 3,086), or high risk (N = 1,224). After calculating patient risk of PCM based on CCR, 25% of the NCCN low risk men were reclassified to favorable intermediate or intermediate risk; 47% of the NCCN favorable intermediate risk men were reclassified (24% lower and 23% higher); 49% of the NCCN intermediate risk men were reclassified (24% lower and 25% higher); and 25% of the NCCN high risk were reclassified to favorable intermediate or intermediate risk. There is no outcome data associated with commercial samples. Conclusions: The prognostic information in the CCR score results in significant amounts of risk reclassification for all patients with localized disease when compared to stratification based only on NCCN risk categories.