BACKGROUND: Clinical prognostic groupings for @entity263 are imprecise, with 30-50% of @entity1 recurring after image-guided radiotherapy or radical prostatectomy. We aimed to test combined genomic and microenvironmental indices in @entity263 to improve risk stratification and complement clinical prognostic factors. METHODS: We used DNA-based indices alone or in combination with intra-prostatic @entity519 measurements to develop four prognostic indices in 126 low-risk to intermediate-risk @entity1 (Toronto cohort) who will receive image-guided radiotherapy. We validated these indices in two independent cohorts of 154 (Memorial Sloan Kettering @entity5 Center cohort [MSKCC] cohort) and 117 (Cambridge cohort) radical prostatectomy specimens from low-risk to high-risk @entity1 . We applied unsupervised and supervised machine learning techniques to the copy-number profiles of 126 pre-image-guided radiotherapy diagnostic biopsies to develop prognostic signatures. Our primary endpoint was the development of a set of prognostic measures capable of stratifying @entity1 for risk of biochemical relapse 5 years after primary treatment. FINDINGS: Biochemical relapse was associated with indices of @entity5 , genomic instability, and genomic subtypes based on multivariate analyses. We identified four genomic subtypes for @entity263 , which had different 5-year biochemical relapse-free survival. Genomic instability is prognostic for relapse in both image-guided radiotherapy (multivariate analysis hazard ratio [HR] 4  5 [95% CI 2  1-9  8]; p=0  00013; area under the receiver operator curve [AUC] 0  70 [95% CI 0  65-0  76]) and radical prostatectomy (4  0 [1  6-9  7]; p=0  0024; AUC 0  57 [0  52-0  61]) @entity1 with @entity263 , and its effect is magnified by intratumoral @entity519 (3  8 [1  2-12]; p=0  019; AUC 0  67 [0  61-0  73]). A novel 100-loci DNA signature accurately classified treatment outcome in the MSKCC low-risk to intermediate-risk cohort (multivariate analysis HR 6  1 [95% CI 2  0-19]; p=0  0015; AUC 0  74 [95% CI 0  65-0  83]). In the independent MSKCC and Cambridge cohorts, this signature identified low-risk to high-risk @entity1 who were most likely to fail treatment within 18 months (combined cohorts multivariate analysis HR 2  9 [95% CI 1  4-6  0]; p=0  0039; AUC 0  68 [95% CI 0  63-0  73]), and was better at predicting biochemical relapse than 23 previously published RNA signatures. INTERPRETATION: This is the first study of @entity5 outcome to integrate DNA-based and microenvironment-based failure indices to predict @entity1 outcome. @entity1 exhibiting these aggressive features after biopsy should be entered into treatment intensification trials. FUNDING: Movember Foundation, @entity263 Canada, Ontario Institute for @entity5 Research, Canadian Institute for Health Research, NIHR Cambridge Biomedical Research Centre, The University of Cambridge, @entity5 Research UK, Cambridge @entity5 Charity, @entity263 UK, Hutchison Whampoa Limited, Terry Fox Research Institute, Princess Margaret @entity5 Centre Foundation, PMH-Radiation Medicine Program Academic Enrichment Fund, Motorcycle Ride for Dad (Durham), Canadian @entity5 Society.

@entity5 genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of XXXX : a retrospective cohort study.

@entity1 :: ('9606', 'Species') :: ['Patients', 'patients', 'patient'] @entity519 :: ('MESH:D000860', 'Disease') :: ['hypoxia'] @entity263 :: ('MESH:D011471', 'Disease') :: ['localised prostate cancers', 'prostate cancer', 'Prostate Cancer'] @entity5 :: ('MESH:D009369', 'Disease') :: ['cancer', 'tumour hypoxia', 'Cancer']
@entity263 :: (MESH:D011471,Disease) :: ['prostate cancer']
