Faculty Collaboration Database

Radiogenomic Profiling of Prostate Tumors prior to External Beam Radiotherapy Converges on a Transcriptomic Signature of TGF-β Activity Driving Tumor Recurrence. Clin Cancer Res 2025 Dec 15;31(24):5211-5224

Date

10/02/2025

Pubmed ID

41037000

Pubmed Central ID

PMC12703358

DOI

10.1158/1078-0432.CCR-25-2186

Scopus ID

2-s2.0-105025007831 (requires institutional sign-in at Scopus site)

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 intermediate- to unfavorable-risk prostate tumors prone to biochemical failure after EBRT with ADT and may serve as an independent prognostic biomarker beyond existing clinical criteria.

Author List

Ku AT, Shankavaram U, Trostel SY, Zhang H, Kartal S, Sater HA, Harmon SA, Carrabba NV, Liu Y, Ryu H, Proudfoot JA, Hong BH, Wood BJ, Pinto PA, Choyke PL, Roach M, Sandler HM, Pugh SL, Zeitzer KL, Mendez LC, Kapadia NS, Hall WA, Desai AB, Stoyanova RS, Pollack A, Davicioni E, Chua MLK, Turkbey B, Sowalsky AG, Citrin DE

Author

William Adrian Hall MD Chair, Professor in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Androgen Antagonists
Chemoradiotherapy
Follow-Up Studies
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Male
Middle Aged
Neoplasm Recurrence, Local
Prognosis
Prospective Studies
Prostate
Prostate-Specific Antigen
Prostatic Neoplasms
Risk Assessment
Transcriptome
Transforming Growth Factor beta