Abstract 4339: Prognostic significance of copy number alteration burden in unfavorable intermediate-risk prostate cancers harboring intraductal carcinoma and cribriform architecture
Authors: Chua Melvin Lee Kiang , Murgic Jure , Pintilie Melania , Lalonde Emilie , Kweldam Charlotte , Lo Winnie , Berlin Alejandro , Dal Pra Alan , Orain Michele , Picard Valerie , Hovington Helene , Begeron Alain , Fradet Yves , Tetu Bernard , Livingstone Julie , Meng Alice , Zhang Jun Yan , Zafarana Gaetano , Fleshner Neil , Fraser Mike , Boutros Paul , Bristow Robert , van der Kwast Theodorus 
Published: July 2016

Abstract
Aim: Men with intermediate-risk prostate cancer represent a heterogeneous group of patients with varying prognoses. Intraductal carcinoma (IDC), cribriform architecture (CA), and high copy number alteration burden are novel pathological and genomic indices that predict aggressive disease and inferior clinical outcomes in patients with localised prostate cancer. We aimed to test the independent prognostic effect of these indices in a cohort of intermediate-risk prostate cancers.
Experimental methods: We defined a set of clinical and genomic indices to test for their prognostic significance in a cohort of individuals with NCCN-defined intermediate-risk prostate cancer, who were treated with radical prostatectomy (RadP) or radiotherapy (RT) (N = 173, RadP; N = 358, RT). Clinical indices include primary T-category, pre-treatment PSA level, Gleason's score and pattern, and presence of IDC and/or CA. Pathological features were reviewed centrally by two expert pathologists. Copy number alteration burden was assessed in 215 tumours of the cohort using SNP array profiling (Affymetrix Oncoscan), and reported as percent genome aberration (PGA). Our primary endpoint was to test if a model incorporating IDC/CA and PGA stratifies patients with intermediate-risk disease for risk of biochemical relapse after primary treatment.
Results: Biochemical relapse was associated with PGA on univariable and multivariable analysis for the sub-cohort of 215 patients (HR of High vs Low PGA defined by median = 1.61, 95% CI = 1.04-2.49, Wald's p = 0.033). Based on modelling of the clinical indices, presence of IDC/CA was associated with biochemical relapse-free rate (bRFR) on univariable and multivariable analyses (HR = 1.90, 95% CI = 1.34-2.69, p = 0.00034), along with PSA level. Risk stratification considering both IDC/CA and PGA indicated an additive prognostic effect of IDC/CA to PGA for early biochemical relapse, with 18-month bRFR of 83% in High PGA, present IDC/CA vs 94% in Low PGA, absent IDC/CA subgroups (HR = 2.55, 95% CI = 1.49-4.39, p = 0.00069). A comparison of risk stratification models revealed that inclusion of PGA to IDC/CA yielded the strongest model for predicting 18-month bRFR in patients with intermediate-risk prostate cancer following treatment (area under the curve, AUC = 0.580, 95% CI = 0.456-0.675 [T-category, PSA, and IDC/CA] vs 0.649, 95% CI = 0.476-0.776 [T-category, PSA, IDC/CA, and PGA]).
Conclusions: We herein demonstrate for the first time a novel risk stratification model integrating pathological (IDC/CA) and genomic (PGA) indices to identify patients with unfavourable intermediate-risk prostate cancer, who may benefit from intensification to conventional definitive treatment.
Citation Format: Melvin Lee Kiang Chua, Jure Murgic, Melania Pintilie, Emilie Lalonde, Charlotte Kweldam, Winnie Lo, Alejandro Berlin, Alan Dal Pra, Michele Orain, Valerie Picard, Helene Hovington, Alain Begeron, Yves Fradet, Bernard Tetu, Julie Livingstone, Alice Meng, Jun Yan Zhang, Gaetano Zafarana, Neil Fleshner, Mike Fraser, Paul Boutros, Robert Bristow, Theodorus van der Kwast. Prognostic significance of copy number alteration burden in unfavorable intermediate-risk prostate cancers harboring intraductal carcinoma and cribriform architecture. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4339.