scholarly journals Development and Validation of a Novel Integrated Clinical-Genomic Risk Group Classification for Localized Prostate Cancer

2018 ◽  
Vol 36 (6) ◽  
pp. 581-590 ◽  
Author(s):  
Daniel E. Spratt ◽  
Jingbin Zhang ◽  
María Santiago-Jiménez ◽  
Robert T. Dess ◽  
John W. Davis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Distant Metastasis ◽  
Treatment Guidelines ◽  
Risk Groups ◽  
Localized Prostate Cancer ◽  
Tier System ◽  
Genomic Risk ◽  
Clinical Genomic ◽  
Risk Grouping

Purpose It is clinically challenging to integrate genomic-classifier results that report a numeric risk of recurrence into treatment recommendations for localized prostate cancer, which are founded in the framework of risk groups. We aimed to develop a novel clinical-genomic risk grouping system that can readily be incorporated into treatment guidelines for localized prostate cancer. Materials and Methods Two multicenter cohorts (n = 991) were used for training and validation of the clinical-genomic risk groups, and two additional cohorts (n = 5,937) were used for reclassification analyses. Competing risks analysis was used to estimate the risk of distant metastasis. Time-dependent c-indices were constructed to compare clinicopathologic risk models with the clinical-genomic risk groups. Results With a median follow-up of 8 years for patients in the training cohort, 10-year distant metastasis rates for National Comprehensive Cancer Network (NCCN) low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.3%, 9.2%, 38.0%, and 39.5%, respectively. In contrast, the three-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.5%, 29.4%, and 54.6%, for low-, intermediate-, and high-risk, respectively, which were consistent in the validation cohort (0%, 25.9%, and 55.2%, respectively). C-indices for the clinical-genomic risk grouping system (0.84; 95% CI, 0.61 to 0.93) were improved over NCCN (0.73; 95% CI, 0.60 to 0.86) and Cancer of the Prostate Risk Assessment (0.74; 95% CI, 0.65 to 0.84), and 30% of patients using NCCN low/intermediate/high would be reclassified by the new three-tier system and 67% of patients would be reclassified from NCCN six-tier (very-low– to very-high–risk) by the new six-tier system. Conclusion A commercially available genomic classifier in combination with standard clinicopathologic variables can generate a simple-to-use clinical-genomic risk grouping that more accurately identifies patients at low, intermediate, and high risk for metastasis and can be easily incorporated into current guidelines to better risk-stratify patients.

Development and validation of a novel clinical-genomic risk group classification for prostate cancer incorporating genomic and clinicopathologic risk.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5000-5000 ◽  
Author(s):  
Daniel Eidelberg Spratt ◽  
Jingbin Zhang ◽  
Maria Santiago-Jimenez ◽  
John W. Davis ◽  
Robert Benjamin Den ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Distant Metastasis ◽  
Treatment Guidelines ◽  
Risk Groups ◽  
Treatment Decisions ◽  
Pre Treatment ◽  
Genomic Risk ◽  
Clinical Genomic

5000 Background: It is clinically challenging to integrate genomic classifier results that report a continuous numerical risk of recurrence into treatment decisions for prostate cancer (PCa). We aimed to develop a novel clinical-genomic risk system that can readily be incorporated into treatment guidelines for localized PCa. Methods: Four multi-center cohorts (n = 6928 men; 5937 prospective samples and 991 retrospective samples with long-term follow-up) were utilized to identify and validate our clinical-genomic risk system in radical prostatectomy (RP) samples and subsequently in pre-treatment biopsy samples. All patients’ FFPE tissue underwent microarray analysis, and the expression values for 22 prespecified biomarkers that constitute Decipher were extracted. Cumulative incidence curves were constructed to estimate metastasis risk. C-indices were calculated to compare NCCN and CAPRA score to our clinical-genomic system. Results: With a median follow-up of 8 years for men in our RP cohort, the 10-year distant metastasis rates for NCCN low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.8%, 9.4%, 40.1%, and 41.4%, respectively. Our 3-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.7%, 30.7%, and 57.7%, for low, intermediate, and high-risk, which were validated in our pre-treatment biopsy cohort with 10-year rate of distant metastasis of 0%, 30.3%, and 63.2%, respectively. C-indices for the clinical-genomic system (0.84, 95%CI 0.62-0.92) were significantly improved over NCCN (0.71, 95%CI 0.59-0.84) and CAPRA (0.71, 95%CI 0.60-0.81) score. A total of 33.4% of men would be reclassified by the clinical-genomic system, and specifically 17.1%, 41.3%, and 19.4% of men in NCCN low, intermediate and high risk groups would be reclassified by our new system. Conclusions: The use of a readily available genomic classifier in combination with clinicopathologic variables can generate a simple to use 3-tier clinical-genomic risk system that is highly prognostic for distant metastasis, is more accurate than clinical risk, and can be easily incorporated into NCCN guidelines to inform treatment decisions.

Adjuvant docetaxel for high-risk localized prostate cancer: Update of NRG Oncology/RTOG 0521.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 333-333
Author(s):  
Howard M. Sandler ◽  
Theodore Karrison ◽  
A. Oliver Sartor ◽  
Leonard G. Gomella ◽  
Mahul B. Amin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Proportional Hazards ◽  
Type I Error ◽  
Risk Group ◽  
Risk Groups ◽  
Localized Prostate Cancer ◽  
Type I ◽  
Group 1

333 Background: High-risk, localized prostate cancer has a poor prognosis. We hypothesized that adj docetaxel (D) and prednisone and long-term (24 mos) androgen suppression (AS) and radiation therapy (RT) would improve overall survival (OS) and tested this in NRG/RTOG 0521. Results with med follow-up of 5.7 yrs were reported (JCO 37:1159, 2019), showing a benefit of D (HR=0.69, 90% CI: 0.49-0.97, 1-sided p=0.034). Med follow-up is now 10.4 yrs and we report updated results for OS and metastasis (DM). Methods: NRG/RTOG 0521 opened 12/05 and closed 8/09 with targeted accrual of 600 and designed to detect a HR of 0.49, based on improvement in 4-yr OS from 86 to 93%. With 0.05 1-sided type I error and 90% power >78 deaths were required. Pts were stratified by predefined risk groups. Group 1: Gl 9-10, any T; Group 2: Gl 8, PSA<20, T≥T2; Group 3: Gl 8, PSA≥20, any T; Group 4: Gl 7, PSA≥20, any T. maxPSA ≤150. RT dose was 75.6 Gy. Chemo consisted of 6, 21-day cycles of D starting 28 days after RT. Results: Of 612 accrued, 563 were eligible/available for analysis. By risk group 1-4, there were 297, 116, 64, and 86 pts. Med PSA 15 ng/mL. 10-yr OS rates were 64% [95% CI: 58-70%] for AS+RT and 69% [95% CI: 63-75%] for AS+RT+CT (HR = 0.89, 90% CI: 0.70, 1.13, 1-sided p=0.22). However there was evidence of non-proportional hazards (Grambsch-Therneau test, p=0.016). Thus survival was alternatively evaluated with restricted mean survival time (RMST). The difference in RMST at 10 yrs was 0.42 yrs (90% CI: 0.07-0.77, 2-sided p=0.048). Cumulative incidence of DM at 10 yrs was 22% [95% CI: 17-27%] for AS+RT and 20% [95% CI: 15-25%] for AS+RT+CT (2-sided log-rank p=0.29). At 10 years most deaths occurred in risk group 1: 62 in AS+RT and 50 in AS+RT+CT (HR= 0.93, 95% CI: 0.66-1.32, 2-sided log-rank p=0.16). There was no new related Grade 5 toxicity. Conclusions: OS findings, reported after follow-up of 5.7 yrs, demonstrated a small beneficial effect of adding D to AS and RT. With longer follow-up the benefit of D remains, but the HR varies over time and the OS curves have converged. Support: U10CA180868 (NRG Operations), U10CA180822 (NRG SDMC), U24CA180803 (IROC) from the NCI and Sanofi-Synthelabo Int. Clinical trial information: NCT00288080.

Clinical-genomic sub-classification of high-risk prostate cancer: Implications for tailoring therapy and clinical trial design.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 337-337
Author(s):  
Vinayak Muralidhar ◽  
Mohammed Alshalalfa ◽  
Daniel Eidelberg Spratt ◽  
Yang Liu ◽  
R. Jeffrey Karnes ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Risk Stratification ◽  
High Risk Prostate Cancer ◽  
High Risk Disease ◽  
Risk Prostate Cancer ◽  
Risk Patients ◽  
Genomic Risk ◽  
Clinical Genomic ◽  
Very High

337 Background: Current risk stratification schema have limited prognostic performance in predicting outcome within National Comprehensive Cancer Network (NCCN) high-risk to very high-risk prostate cancer. Methods: Two multicenter high-risk cohorts were used for training (n = 214) and validation (n = 151) of a novel RNA microarray-based integrated clinical-genomic Classifier Optimized for Outcome in High-risk Prostate cancer (COOHP) to classify patients as COOHP favorable high-risk, standard high-risk, or very high-risk. Cox analysis was used to model metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Model performance was compared to prior sub-classification systems using time-dependent c-indices. Results: Among NCCN high/very high-risk patients in the training cohort, 11% were classified as COOHP favorable high-risk, 70% as COOHP standard high-risk, and 18% as COOHP very high-risk. Patients with COOHP favorable high-risk disease had better rates of 5-year MFS compared to those with COOHP standard high-risk disease (94% vs 76%, hazard ratio [HR] 0.10, p = 0.02), and patients with COOHP very high-risk disease had worse 5-year MFS compared to those with COOHP standard high-risk disease (34% vs 76%, HR 3.5, p < 0.0001). Similarly, patients with COOHP very high-risk disease had worse 10-year PCSS compared to those with COOHP standard high-risk disease (36% vs 82%, HR 4.4, p < 0.0001). The c-indices for 5-year MFS and 10-year PCSS in the training cohort were 0.80 and 0.74, significantly improved compared to prior clinical and clinical-genomic risk stratification systems (0.62-0.69 for 5-year MFS and 0.56-0.63 for 10-year PCSS). These results were consistent in the validation cohort, where 5-year MFS significantly varied among the three COOHP subgroups (100% vs 89% vs 79%, p = 0.020), as did 10-year OS (100% vs 71% vs 53%, p = .040). Conclusions: A clinical-genomic risk stratification system specifically designed to discriminate prognosis in high-risk prostate cancer better identified favorable high-risk and very high-risk subsets of disease compared to prior clinical and clinical-genomic stratification systems.

Prospective analysis of 4,474 prostate biopsies to evaluate potential treatment management impact of combined clinical-genomic risk classification.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 39-39
Author(s):  
Paul L. Nguyen ◽  
Jingbin Zhang ◽  
Kasra Yousefi ◽  
Elai Davicioni ◽  
Robert Benjamin Den ◽  
...  
Keyword(s):  
High Risk ◽  
Change Management ◽  
Risk Groups ◽  
Low Risk ◽  
Intermediate Risk ◽  
Prognostic Information ◽  
High Risk Patients ◽  
Risk Patients ◽  
Genomic Risk ◽  
Clinical Genomic

39 Background: Prior studies suggested integrated clinical-genomic risk grouping can more accurately prognosticate prostate cancer (PCa) outcome than NCCN clinical risk. We evaluated the potential for genomic testing to reclassify patients in a manner that could change management compared to NCCN risk groups. Methods: We evaluated 4,474 consecutive patients with PCa who received the Decipher Biopsy test between 01/2016-08/2017 and had information to determine NCCN risk. Genomic categorizations with the potential to change management were defined as NCCN very low/low to genomic intermediate or high (active surveillance to active treatment), NCCN favorable intermediate to genomic high (radiation therapy [RT] alone to RT plus androgen deprivation therapy [ADT]), NCCN unfavorable intermediate to genomic low (RT + ADT to RT alone), NCCN high risk to genomic low (RT + long term ADT to RT + short term ADT). Results: There were 927 NCCN low-risk, 2,427 intermediate, and 1,120 high-risk patients. Among NCCN low-risk, the incidence of genomic low, intermediate, and high risk was 58.7%, 25.0%, and 16.3% respectively, for NCCN intermediate it was 36.5%, 27.6%, and 35.8%, and for NCCN high risk it was 15.9%, 17.1%, and 67.1%. Management could have been changed in the 41.3% of NCCN low risk patients with intermediate or high genomic risk, 26.7% of favorable intermediate risk patients who had high genomic risk, 32.4% of unfavorable intermediate risk patients with low genomic risk, and 15.9% of high risk patients with low genomic risk. Conclusions: A slight majority (54%) of Decipher Biopsy users have NCCN intermediate-risk disease, likely reflecting a need for further prognostic information to refine recommendations in intermediate risk. Reclassification of NCCN groups by genomic risk was common and an integrated clinical-genomic risk system could have altered treatment recommendations in 41.3% of NCCN low, 26.7% of favorable intermediate, 32.4% of unfavorable intermediate risk, and 15.9% of high risk patients.

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