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Objectives: To compare the results of Gleason Grade Group (GGG) classification following central pathology review with previous local pathology assessment, and to examine the difference between using overall and worst GGG in a large patient cohort treated with radiotherapy and short‐course hormone therapy. Patients and Methods: Patients with low‐ to high‐risk localized prostate cancer were randomized into the multicentre CHHiP fractionation trial between 2002 and 2011. Patients received short‐course hormone therapy (≤6 month) and radical intensity‐modulated radiotherapy (IMRT). Of 2749 consented patients, 1875 had adequate diagnostic biopsy tissue for blinded central pathology review. The median follow‐up was 9.3 years. Agreement between local pathology and central pathology‐derived GGG and between central pathology‐derived overall and worst GGG was assessed using kappa (κ) statistics. Multivariate Cox regression and Kaplan–Meier methods were used to compare the biochemical/clinical failure (BCF) and distant metastases (DM) outcomes of patients with GGG 1–5. Results: There was poor agreement between local pathology‐ and central pathology‐derived GGG (κ = 0.19) but good agreement between overall and worst GGG on central pathology review (κ = 0.89). Central pathology‐derived GGG stratified BCF and DM outcomes better than local pathology, while overall and worst GGG on central pathology review performed similarly. GGG 3 segregated with GGG 4 for BCF, with BCF‐free rates of 90%, 82%, 74%, 71% and 58% for GGGs 1–5, respectively, at 8 years when assessed using overall GGG. There was a progressive decrease in DM‐free rates from 98%, 96%, 92%, 88% and 83% for GGGs 1–5, respectively, at 8 years with overall GGG. Patients (n = 57) who were upgraded from GGG 2–3 using worst GS had BCF‐free and DM‐free rates of 74% and 92% at 8 years. CHHiP eligibility criteria limit the interpretation of these results. Conclusion: Contemporary review of International Society of Urological Pathology GGG successfully stratified patients treated with short‐course hormone therapy and IMRT with regard to both BCF‐free and DM‐free outcomes. Patients upgraded from GGG 2 to GGG 3 using worst biopsy GS segregate with GGG 3 on long‐term follow‐up. We recommend that both overall and worst GS be used to derive GGG. [ABSTRACT FROM AUTHOR]

Cancer evolution lays the groundwork for predictive oncology. Testing evolutionary metrics requires quantitative measurements in controlled clinical trials. We mapped genomic intratumor heterogeneity in locally advanced prostate cancer using 642 samples from 114 individuals enrolled in clinical trials with a 12-year median follow-up. We concomitantly assessed morphological heterogeneity using deep learning in 1,923 histological sections from 250 individuals. Genetic and morphological (Gleason) diversity were independent predictors of recurrence (hazard ratio (HR) = 3.12 and 95% confidence interval (95% CI) = 1.34-7.3; HR = 2.24 and 95% CI = 1.28-3.92). Combined, they identified a group with half the median time to recurrence. Spatial segregation of clones was also an independent marker of recurrence (HR = 2.3 and 95% CI = 1.11-4.8). We identified copy number changes associated with Gleason grade and found that chromosome 6p loss correlated with reduced immune infiltration. Matched profiling of relapse, decades after diagnosis, confirmed that genomic instability is a driving force in prostate cancer progression. This study shows that combining genomics with artificial intelligence-aided histopathology leads to the identification of clinical biomarkers of evolution., (© 2024. The Author(s).)