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

Abstract

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.

Fig 1.

(A) Flow diagram of the study cohort details and analyses performed by cohort and (B) schema of how to combine National Comprehensive Cancer Network (NCCN) risk groups with Decipher groups to develop the clinical-genomic point system and the resulting clinical-genomic risk groups. fav, favorable; int, intermediate; PSA, prostate-specific antigen; RP, radical prostatectomy; unfav, unfavorable.

Fig 2.

Cumulative incidence curves using the training cohort for (A) distant metastasis by National Comprehensive Cancer Network (NCCN) risk group, (B) prostate cancer-specific mortality (PCSM) by NCCN risk group, (C) distant metastasis by clinical-genomic risks, and (D) prostate cancer–specific mortality by clinical-genomic risk groups. fav, favorable; int, intermediate; RP, radical prostatectomy; unfav, unfavorable.

Fig 3.

(A) Cumulative incidence curves using the validation cohort for distant metastasis by the clinical-genomic risk groups. (B) Discriminatory analysis of c-indices over time for metastasis of the training and validation cohorts comparing National Comprehensive Cancer Network (NCCN) and clinical-genomic risk groups. AUC, area under the curve.

Fig 4.

Reclassification of National Comprehensive Cancer Network (NCCN) risk groups to clinical-genomic risk groups within (A) prospective cohort I using the NCCN four-tier system, (B) prospective cohort II using the NCCN four-tier system, and (C) prospective cohort II using the expanded NCCN six-tier system (very-low–, low-, favorable-intermediate–, unfavorable-intermediate–, high-, and very-high–risk groups). Bx, biopsy; fav, favorable; int, intermediate; RP, radical prostatectomy; unfav, unfavorable.

Fig A1.

Cumulative incidence curves using the training cohort for distant metastasis by six-tier clinical-genomic risk groups. RP, radical prostatectomy.

Fig A2.

C-indices of all risk grouping systems in the retrospective training cohort: (A) metastasis at 5 years and (B) metastasis at 10 years. CAPRA, Cancer of the Prostate Risk Assessment; NCCN, National Comprehensive Cancer Network.

Fig A3.

C-indices of clinical-genomic risk grouping systems in the retrospective validation cohort. (A) Metastasis at 5 years and (B) metastasis at 10 years.

Fig A4.

Reclassification of National Comprehensive Cancer Network (NCCN) risk groups to clinical-genomic risk groups within (A) prospective cohort I and (B) prospective cohort II. Bx, biopsy; fav, favorable; int, intermediate; RP, radical prostatectomy; unfav, unfavorable.