Radiogenomic Profiling of Prostate Tumors prior to External Beam Radiotherapy Converges on a Transcriptomic Signature of TGF-β Activity Driving Tumor Recurrence

Abstract

Purpose: Clinical risk grouping based on PSA, tumor grade, and disease extent guides treatment intensity for localized prostate cancer. However, many patients with intermediate-or high-risk disease treated with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) still develop biochemical recurrence (BCR). Early identification of patients at high risk for BCR could enable personalized treatment strategies. Experimental Design: We prospectively enrolled 29 patients with intermediate-or high-risk prostate cancer undergoing EBRT and ADT. Pretreatment biopsies (n = 60) underwent whole-transcriptome microarray and whole-exome sequencing. Patients received multiparametric MRI at baseline and 6 months after treatment, with a median follow-up of 6 years. Gene expression differences between patients with and without BCR were analyzed using pathway tools and validated in external datasets. A novel TGF-β gene signature was derived and tested across multiple cohorts (median follow-up: 5–11 years). Results: TGF-β activity was significantly associated with BCR in the discovery cohort (P = 0.0081) and correlated with PTEN/ TP53 alterations (P = 0.0246) and baseline multiparametric MRI tumor volume (P = 0.026). TGF-β activity also predicted metastasis-free survival (P = 0.037) and, in an independent cohort (n = 265), was prognostic for BCR-free (P = 0.05), metastasis-free (P < 0.001), and overall survival (P < 0.001). Conclusions: TGF-β activity is a dominant feature of intermediateto unfavorable-risk prostate tumors prone to biochemical failure after EBRT with ADT and may serve as an independent prognostic biomarker beyond existing clinical criteria.