Cell Cycle Progression Score Research Articles

Discovery and Validation of a 15-Gene Prognostic Signature for Clear Cell Renal Cell Carcinoma.

Develop and validate gene expression-based biomarker associated with recurrent disease to facilitate risk stratification of clear cell renal cell carcinoma (ccRCC). We retrospectively identified 110 patients who underwent radical nephrectomy for ccRCC (discovery cohort). Patients who recurred were matched on the basis of grade/stage to patients without recurrence. Capture whole-transcriptome sequencing was performed on RNA isolated from archival tissue using the Illumina platform. We developed a gene-expression signature to predict recurrence-free survival/disease-free survival (DFS) using a 15-fold lasso and elastic-net regularized linear Cox model. We derived the 31-gene cell cycle progression (mxCCP) score using RNA-seq data for each patient. Kaplan-Meier (KM) curves and multivariable Cox proportional hazard testing were used to validate the independent prognostic impact of the gene-expression signature on DFS, disease-specific survival (DSS), and overall survival (OS) in two validation data sets (combined n = 761). After quality control, the discovery cohort comprised 50 patients with recurrence and 41 patients without, with a median follow-up of 26 and 36 months, respectively. We developed a 15-gene (15G) signature, which was independently associated with worse DFS and DSS (DFS: hazard ratio [HR], 11.08 [95% CI, 4.9 to 25.1]; DSS: HR, 9.67 [95% CI, 3.4 to 27.7]) in a multivariable model adjusting for clinicopathologic parameters (including stage, size, grade, and necrosis [SSIGN] score and Memorial Sloan Kettering Cancer Center nomogram) and mxCCP score. The 15G signature was also independently associated with worse DFS and DSS in both validation data sets (Validation A [n = 382], DFS: HR, 2.6 [95% CI, 1.6 to 4.3]; DSS: HR, 3 [95% CI, 1.4 to 6.1] and Validation B (n = 379), DFS: HR, 2.1 [95% CI, 1.2 to 3.6]; OS: HR, 3 [95% CI, 1.6 to 5.7]) adjusting for clinicopathologic variables and mxCCP score. We developed and validated a novel 15G prognostic signature to improve risk stratification of patients with ccRCC. Pending further validation, this signature has the potential to facilitate optimal treatment allocation.

Safety and clinical validity of tumor genomic testing for guiding active surveillance selection in men with NCCN intermediate-risk prostate cancer.

336 Background: Clinicopathologic features are considered the gold standard for predicting prostate cancer (PCa) disease severity and guiding decisions on the use of active surveillance (AS) or definitive treatment (DT). However, tumor genomic testing has been shown to provide valuable information as an addition to clinical risk stratification measures, allowing for more accurate identification of AS candidates. This study evaluated the safety of genomic testing for guiding AS selection in patients with National Comprehensive Cancer Network (NCCN) intermediate-risk PCa. Methods: In this retrospective observational cohort study, patients with NCCN intermediate-risk PCa underwent Prolaris testing at diagnosis from 9/2015–12/2018. The Prolaris test combines a molecular cell cycle progression score with clinicopathologic features (USCF Cancer of the Prostate Risk Assessment [CAPRA] score, inclusive of Gleason score), generating a Combined Clinical Risk (CCR) score to identify patients as candidates for AS or DT. Patients with a CCR-based 10-year disease-specific mortality (DSM) risk ≤3.2% were recommended to AS. Clinical follow up data, including initial treatment selection and time to metastasis, were retrospectively collected from the treating clinics. Kaplan-Meier estimates were used to evaluate the safety of AS in patients who initially selected AS. Cox proportional hazards models were used to evaluate CCR as a predictor of metastasis in all patients. Results: In total, 3204 patients were included in this analysis, with 1468 (46%) recommended to AS and 1736 (54%) recommended to DT. Among the 973 (30%) patients who initially selected AS, 613 (63%) were recommended to AS and 360 (37%) were recommended to DT. In patients who were recommended to AS and initially selected AS, the observed risk of metastasis within 5 years of diagnosis was 0.37% (95% confidence interval [CI], 0.09%–1.47%). Patients who were recommended to AS had a significantly lower rate of metastasis than patients who were recommended to DT after accounting for initial treatment decision (AS vs DT) and CAPRA score (hazard ratio 4.20 [95% CI, 1.41–18.04], P-value = 0.03). Conclusions: For patients with NCCN intermediate-risk PCa who were identified by genomic testing as candidates for AS, AS is safe based on the very low observed metastasis risk. The CCR score is a strong predictor of metastasis beyond clinicopathologic factors.

Dynamic Changes of Molecular Subtype Classification and Genomic Classifier Scores in High-Risk Prostate Cancer Patients Undergoing Pre-Operative Stereotactic Body Radiation Therapy

The radiobiology of irradiated human prostate cancer (PCa) remains poorly understood as irradiated tissues often remain in situ. PREPARE-SBRT (NCT03663218) is a clinical trial testing the safety of neoadjuvant MRI-guided stereotactic body radiation therapy (SBRT) for men with high-risk PCa. We leveraged paired samples from pre-treatment biopsy and irradiated prostatectomy (RP) specimens to evaluate transcriptomic changes in irradiated tumors at acute timepoints following SBRT. Tumor RNA expression profiles were generated using Decipher GRID by Veracyte on 12 subjects enrolled on NCT03663218 with paired pre/post-SBRT tissues (n = 24). Descriptive statistics using Decipher Genomic Classifier (GC) Score [0-1] and GC risk group (low/int/high) were generated from a validated 22-gene GC. Tumor biology signatures reported as dichotomous variables evaluated changes in androgen receptor (AR) activity [higher v lower] and cell cycle progression (CCP) [lower v higher]. Decipher prostate subtype classifier [PSC, luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), basal neuroendocrine like (BN)] classification and PAM50 molecular subtype [luminal A (lumA), luminal B (lumB), basal] at pre/post-SBRT timepoints were reported. A control cohort of transcriptomic profiles of 803 matched untreated biopsy and RP samples from the same patients were used to control for signature differences attributable to sample type. The median pre- and post-SBRT GC scores were 0.55 and 0.72 (Δ+0.17), respectively. By comparison, median GC scores in a control cohort (n = 803) of biopsy and RP specimens were 0.50 and 0.56 (Δ+0.06), respectively. SBRT increased GC score in 9/12 subjects (75%) with a median increase of 0.3. Changes in GC score resulted in reclassification of baseline GC risk in 7 of 12 subjects with 71% of reclassified subjects (5/7) transitioning to a higher genomic risk. 92% of subjects (11/12) had higher AR activity scores at baseline. Of this subgroup, 5/11 (45%) converted to lower AR activity score after SBRT. CCP signatures remained stable in 9 of 12 subjects (75%) with 7/12 subjects exhibiting lower CCP score at baseline and only 1 subject transitioning from lower to higher CCP score. Distribution of PAM50 molecular subtype at baseline and after SBRT was lumA (33>53%), lumB (25>17%), basal (42>25%) resulting in 83% of subjects (10/12) annotated to a different PAM50 molecular subtype at pre/post-SBRT assessment. PSC subtype distribution at baseline was LD (33%), LP (25%), BI (33%) and BN (8%). Strikingly, after SBRT, 92% (11/12) of subjects were classified as BI molecular subtype with several immune activation signatures also increased after SBRT. A majority of subjects demonstrate a post-SBRT increase in GC score with reclassification of genomic-prognostic risk group in 58%. An enrichment of the basal-immune molecular subtype was observed following SBRT suggesting a convergence towards this biology in irradiated tumors.

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

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. 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. 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. 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.

Transcriptome-wide prediction of prostate cancer gene expression from histopathology images using co-expression-based convolutional neural networks.

MotivationMolecular phenotyping by gene expression profiling is central in contemporary cancer research and in molecular diagnostics but remains resource intense to implement. Changes in gene expression occurring in tumours cause morphological changes in tissue, which can be observed on the microscopic level. The relationship between morphological patterns and some of the molecular phenotypes can be exploited to predict molecular phenotypes from routine haematoxylin and eosin-stained whole slide images (WSIs) using convolutional neural networks (CNNs). In this study, we propose a new, computationally efficient approach to model relationships between morphology and gene expression.ResultsWe conducted the first transcriptome-wide analysis in prostate cancer, using CNNs to predict bulk RNA-sequencing estimates from WSIs for 370 patients from the TCGA PRAD study. Out of 15 586 protein coding transcripts, 6618 had predicted expression significantly associated with RNA-seq estimates (FDR-adjusted P-value <1×10−4) in a cross-validation and 5419 (81.9%) of these associations were subsequently validated in a held-out test set. We furthermore predicted the prognostic cell-cycle progression score directly from WSIs. These findings suggest that contemporary computer vision models offer an inexpensive and scalable solution for prediction of gene expression phenotypes directly from WSIs, providing opportunity for cost-effective large-scale research studies and molecular diagnostics.Availability and implementationA self-contained example is available from http://github.com/phiwei/prostate_coexpression. Model predictions and metrics are available from doi.org/10.5281/zenodo.4739097.Supplementary information Supplementary data are available at Bioinformatics online.

Development and validation of a cell cycle progression signature for decentralized testing of men with prostate cancer.

Aim: The 46-gene Prolaris® cell cycle progression test provides information on the risk of prostate cancer progression. Here we developed and validated a 16-gene kit-based version. Methods: RNA was extracted from prostate cancer biopsy tissue. Amplification efficiency, minimum tumor content, repeatability, reproducibility and equivalence with the 46-gene test were evaluated. Results: Amplification efficiencies for all genes were within the acceptable range (90-110%), and samples with ≥50% tumor content were appropriate for the 16-gene test. Results were repeatable (standard deviation: 0.085) and reproducible (standard deviation: 0.115). Instrument, operator and kit lot had minimal impact on results. Cell cycle progression scores from the 46- and 16-gene tests were highly correlated (r=0.969; bias=0.217). Conclusion: The 16-gene test performs consistently and similarly to the 46-gene test.

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

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.

Radiology- and gene-based risk stratification in small renal cell carcinoma: A preliminary study.

PurposeMost small renal cell carcinomas (small RCCs) will remain indolent after detection, but some stage I RCCs still metastasize. There are no risk-stratification imaging factors that could be used to identify poor-prognosis patients based on genomic profiling. Here, we evaluated the relationships between imaging parameters and RNA expressions in small RCC and attempted to identify imaging factors that could be used as effective biomarkers.MethodsWe acquired biopsy specimens of 18 clear cell carcinomas that had undergone perfusion CT (pCT) and MRI between April 2018 and March 2019. We performed RNA sequencing, assessed RNA expressions, and calculated each tumor’s cell-cycle progression (CCP) score, which has prognostic value in predicting metastatic progression. We classified the tumors into two groups: clear cell type A (ccA) and type B (ccB). CcA has better survival compared to ccB. We evaluated the following characteristics of each tumor: tumor size, presence of pseudocapsule, and fat. We used the pCT and MRI to measure each tumor’s volume transfer constant (Ktrans), rate constant (Kep), extracellular extravascular volume fraction (VE), fractional plasma volume (VP), and apparent diffusion coefficient (ADC). The correlations between these small RCC imaging parameters and the tumor size and RNA expressions were determined.ResultsThe tumor size was significantly correlated with Kep and inversely correlated with VE, VP, ADC, and hallmark angiogenesis. The CCP score was significantly inversely correlated with Ktrans and Kep. The ccA tumors tended to show a pseudocapsule on MRI.ConclusionTumor size was correlated with low perfusion, but not with prognostic factors based on genomic profiling. Imaging parameters (e.g., Ktrans and Kep) and tumor characteristics (e.g., pseudocapsule) may enable gene-based risk stratification in small RCC.

MP60-16 CELL CYCLE PROGRESSION SCORE AND PTEN AS PROGNOSTIC FACTORS FOR METASTASIS IN INTERMEDIATE AND HIGH RISK PROSTATE CANCER OVERALL, AND IN THOSE WHO RECEIVED SALVAGE RADIOTHERAPY

INTRODUCTION AND OBJECTIVE:The cell cycle progression (CCP) score and PTEN have never been evaluated together for metastasis-free survival (MFS) in a prostatectomy (RP) cohort of men with intermedi...

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.

Cell cycle progression score and PTEN as prognostic factors for metastasis in intermediate- and high-risk prostate cancer overall, and in those who also received salvage radiotherapy.

247 Background: The cell cycle progression (CCP) score and PTEN have never been evaluated together as prognostic markers for risk of metastasis in a radical prostatectomy (RP) cohort of men with National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa), nor in such patients who also received salvage radiation (SRT) alone or with androgen deprivation (SRT+ADT). This study evaluated CCP score and PTEN in both settings. Methods: Participants were treated with RP at Johns Hopkins from 2007-2015. Paraffin-embedded RP tissue was analyzed blind to clinical outcome at Myriad Genetics, for CCP score using qRT-PCR, and PTEN by immunohistochemistry. For overall evaluation of CCP and PTEN in intermediate- and high-risk men a case-cohort sample was selected. Intermediate- and high-risk men with biochemical recurrence who received SRT or SRT+ADT were also sampled to provide a population at particularly high risk. Metastasis-free survival (MFS) was analyzed with the proportional hazards model, weighted for case-cohort design for the overall analysis, and adjusted for CAPRA-S. The clinical cell-cycle risk (CCR) score, a fixed algorithm combining CCP and CAPRA-S was also analyzed in both contexts. Data were analyzed independently by Johns Hopkins and Myriad Genetics. Results: The case-cohort consisted of 209 men, including 47% with Gleason score &gt;4+3, 48% extra-prostatic extension, and 18% with seminal vesicle or lymph node involvement; 42 (20%) developed metastasis. In univariate analyses CCP, CAPRA-S, and PTEN were all highly significant. In multivariable analysis, only CCP and CAPRA-S retained significance (Table section A). CCR was also strongly prognostic, HR=7.9 (95% CI 4.4, 14.5) per unit change, p&lt;0.00001. SRT (56%) or SRT+ADT (44%) were received by 172 men, of whom 78% had Gleason &gt;4+3, 48% extra-prostatic extension, and 34% seminal vesicle or lymph node involvement; 19 (11%) developed metastases. Again, CCP and CAPRA-S, but not PTEN, were statistically significant (Table section B). CCR was also statistically significant, HR=1.7 (95% CI 1.2, 2.4), p=0.002. Conclusions: This is the first comparison, in a recent cohort of intermediate- and high-risk men, of CCP score and PTEN as risk factors for metastasis, and first evaluation in such men receiving SRT. In both multivariable settings, CCP score, but not PTEN, was significantly associated with MFS, adjusted for CAPRA-S. CCR, a fixed algorithm that combines CCP and CAPRA-S was also significant in both settings. [Table: see text]

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 &lt; 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 &lt; 0.001), ADT duration as a continuous variable (HR 2.05, 95% CI 1.54-2.72, p &lt; 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 &lt; 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.

Tumor size and genomic risk in localized prostate cancer

PurposeUnlike many other cancers, measurement of primary prostate tumor size has no defined role in the management of localized prostate cancer. Here, we assess whether prostate tumor size is associated with aggressive tumor biology using biomarkers of genomic risk. Materials and methodsWe abstracted or imputed tumor size from the primary pathology reports of prostate cancers incorporated in The Cancer Genome Atlas. We used transcriptomic data to estimate the Cell Cycle Progression Score (CCPS, Prolaris), the Genomic Classifier Score (GCS, Decipher) and the Genomic Prostate Score (GPS, OncotypeDx), SChLaP1 expression, and copy number alteration percentage (%CNA) as well as hallmark gene set enrichment analysis. ResultsTumor size and gene expression data was available for 267 men. On multivariable regression adjusted for Gleason Grade Group and tumor purity, tumor size was independently associated with the calculated (c)GCS, cGPS, SChLaP1 expression, and %CNA (P< 0.05), but not cCCPS. Gene set enrichment analysis demonstrated that tumors <5 cc, when adjusting for Gleason grade group, were enriched for androgen response genes, while tumors >5 cc were enriched for MYC targets and genes associated with epithelial mesenchymal transition. ConclusionsProstate tumor size is independently associated with established markers of genomic risk. This study nominates the size of a primary prostate cancer as candidate for inclusion in future novel risk scores seeking to quantify cancer aggressiveness.

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.

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

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. 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). 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. 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.

Prognostic capabilities and clinical utility of cell cycle progression testing, prostate imaging reporting and data system, version 2, and clinicopathologic data in management of localized prostate cancer

ObjectivesTo compare the prognostic capabilities and clinical utility of the cell cycle progression (CCP) gene expression classifier test, multiparametric magnetic resonance imaging (mpMRI) with Prostate Imaging Reporting and Data System (PI-RADS) scoring, and clinicopathologic data in select prostate cancer (PCa) medical management scenarios. Patients and methodsRetrospective, observational analysis of patients (N = 222) ascertained sequentially from a single urology practice from January 2015 to June 2018. Men were included if they had localized PCa, a CCP score, and an mpMRI PI-RADS v2 score. Cohort 1 (n = 156): men with newly diagnosed PCa, with or without a previous negative biopsy. Cohort 2 (n = 66): men who initiated active surveillance (AS) without CCP testing, but who received the test during AS. CCP was combined with the UCSF Cancer of the Prostate Risk Assessment (CAPRA) score to produce a clinical cell-cycle risk (CCR) score, which was reported in the context of a validated AS threshold. Spearman's rank correlation test was used to evaluate correlations between variables. Generalized linear models were used to predict binary Gleason score category and medical management selection (AS or curative therapy). Likelihood-ratio tests were used to determine predictor significance in both univariable and multivariable models. ResultsIn the combined cohorts, modest but significant correlations were observed between PI-RADS score and CCP (rs = 0.22, P = 8.1 × 10−4), CAPRA (rs= 0.36, P = 4.8 × 10−8), or CCR (rs = 0.37, P = 2.0 × 10−8), suggesting that much of the prognostic information captured by these measures is independent. When accounting for CAPRA and PI-RADS score, CCP was a significant predictor of higher-grade tumor after radical prostatectomy, with the resected tumor approximately 4 times more likely to harbor Gleason ≥4+3 per 1-unit increase in CCP in Cohort 1 (Odds Ratio [OR], 4.10 [95% confidence interval [CI], 1.46, 14.12], P = 0.006) and in the combined cohorts (OR, 3.72 [95% CI, 1.39, 11.88], P = 0.008). On multivariable analysis, PI-RADS score was not a significant predictor of post-radical prostatectomy Gleason score. Both CCP and CCR were significant and independent predictors of AS versus curative therapy in Cohort 1 on multivariable analysis, with each 1-unit increase in score corresponding to an approximately 2-fold greater likelihood of selecting curative therapy (CCP OR, 2.08 [95% CI, 1.16, 3.94], P = 0.014) (CCR OR, 2.33 [95% CI, 1.48, 3.87], P = 1.5 × 10−4). CCR at or below the AS threshold significantly reduced the probability of selecting curative therapy over AS (OR, 0.28 [95% CI, 0.13, 0.57], P = 4.4 × 10−4), further validating the clinical utility of the AS threshold. ConclusionCCP was a better predictor of both tumor grade and subsequent patient management than was PI-RADS. Even in the context of targeted biopsy, molecular information remains essential to ensure precise risk assessment for men with newly diagnosed PCa.

Cell cycle progression score as a predictive biomarker for overall survival in patients with adrenocortical carcinoma

Cell cycle progression score as a predictive biomarker for overall survival in patients with adrenocortical carcinoma

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]

MP09-01 GENOMIC HETEROGENEITY IN TISSUE-BASED PROGNOSTIC SIGNATURES FROM PROSTATE BIOPSIES; RESULTS FROM TWO PROSPECTIVE TRIALS

INTRODUCTION AND OBJECTIVE: Tissue based prognostic signatures have been used in various stages of prostate cancer, including biopsy tissue from men who are deciding between active surveillance versus treatment. Recent studies have suggested that these tests may be affected by tumor heterogeneity impacting their performance for appropriate risk stratification. We evaluated the performance of tissue based prognostic signatures on biopsy tissue from two ongoing prospective trials in men with prostate cancer at the University of Miami. METHODS: The positive cancers cores in Miami Active Surveillance Trial (MAST) and diagnostic and targeted biopsies in BlastEM trial are sent for genomic sequencing.This study reports on preliminary results from both trials on men whose biopsy cores were sequenced at GenomeDx, and evaluated for three commercially available gene signatures (GenomeDx Decipher Genomic classifier, Oncotype Dx Genomic Prostate Score, and Myriad Prolaris Cell Cycle Progression Score). RESULTS: The current cohort consists of 78 men from the MAST (n=46) and BlastEM (n=32) trials whose 231 biopsy cores were sent to GenomeDX for genomic sequencing.We found that for each signature there was a trend toward higher scores with higher grade groups, however each signature displayed a significant degree of variation within each grade group (p<0.001)(Figure 1). When assessing genomic scores from different cores we found significant variability (figure 2) with the level of genomic risk within each biopsy session changing by 25-62% depending on which core was sequenced and which signature was used. Typically in clinical utility genomic score is used for highest grade of the tumor. But we found that on an average 80 % of the time the highest genomic score did not come from the highest grade group in all the three commercially available gene signatures. CONCLUSIONS: There exists a significant degree of genomic heterogeneity between biopsy cores .This may have implications when considering the reliability of these signatures in biopsy tissue.Source of Funding: None

Cell cycle progression score has potential prognostic value for stage T1 renal cell carcinomas

BackgroundThere is an ongoing effort to identify a biomarker which predicts metastatic progression of renal cell carcinoma (RCC). ObjectiveTo evaluate the utility of the cell cycle progression (CCP) score biomarker in predicting metastasis in RCC after local resection of pathologic T1 disease. Design, setting, and participantsPathologic T1 tumors at the University of Iowa were reviewed in patients who had a radical or partial nephrectomy between 1995 and 2010. Patients with known or suspected metastasis, who had received chemotherapy, or who developed metastasis within 60 days of surgery were excluded. Final analysis included 163 patients with RCC who developed metastasis or a new primary within 5 years after surgery or had been followed for 5 years without developing metastasis. Intervention(s)Expression levels of 31 cell cycle genes and 15 control genes from the tumor were measured and reported as a CCP score. Outcome measurements and statistical analysisThe sensitivity, specificity, positive predictive value, and negative predictive value for the development of a metastasis or new primary within 5 years of resection was calculated for varying CCP score cutoffs. Results and limitationsA total of 4 (2.5%) patients developed metastasis and 7 (4.3%) developed a new primary renal tumor. A CCP score of >−0.25 had a 100% sensitivity and 43% specificity for predicting metastatic progression. A CCP score of >−0.7 had a 100% sensitivity and 20% specificity for predicting the development of a new renal primary. ConclusionsThe CCP score has potential prognostic value in predicting metastatic progression and might be a useful tool for the management of patients with RCC. Patient summaryIn this study we looked at the utility of a particular gene expression profile from kidney tumors. We found that this gene expression test has the potential to identify tumors at risk of metastasis and thus could be a useful tool in the management of patients with kidney tumors.