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

Authors

Anson T. Ku
Uma Shankavaram
Shana Y. Trostel
Hong Zhang
Sumeyra Kartal
Houssein A. Sater
Stephanie A. Harmon
Nicole V. Carrabba
Yang Liu
Hyunnam Ryu
James A. Proudfoot
Boon Hao Hong
Bradford J. Wood
Peter A. Pinto
Peter L. Choyke
Mack Roach
Howard M. Sandler
Stephanie L. Pugh
Kenneth L. Zeitzer, Thomas Jefferson UniversityFollow
Lucas C. Mendez
Nirav S. Kapadia
William A. Hall
Anand B. Desai
Radka S. Stoyanova
Alan Pollack
Elai Davicioni
Melvin L. K. Chua
Baris Turkbey
Adam G. Sowalsky
Deborah E. Citrin

Document Type

Article

Publication Date

12-15-2025

Comments

This article is the author’s final published version in Clinical Cancer Research, Volume 31, Issue 24, 2025, Pages 5211-5224.

The published version is available at https://doi.org/10.1158/1078-0432.CCR-25-2186. Copyright © 2025 The Authors.

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.

Recommended Citation

Ku, Anson T.; Shankavaram, Uma; Trostel, Shana Y.; Zhang, Hong; Kartal, Sumeyra; Sater, Houssein A.; Harmon, Stephanie A.; Carrabba, Nicole V.; Liu, Yang; Ryu, Hyunnam; Proudfoot, James A.; Hong, Boon Hao; Wood, Bradford J.; Pinto, Peter A.; Choyke, Peter L.; Roach, Mack; Sandler, Howard M.; Pugh, Stephanie L.; Zeitzer, Kenneth L.; Mendez, Lucas C.; Kapadia, Nirav S.; Hall, William A.; Desai, Anand B.; Stoyanova, Radka S.; Pollack, Alan; Davicioni, Elai; Chua, Melvin L. K.; Turkbey, Baris; Sowalsky, Adam G.; and Citrin, Deborah E., "Radiogenomic Profiling of Prostate Tumors prior to External Beam Radiotherapy Converges on a Transcriptomic Signature of TGF-β Activity Driving Tumor Recurrence" (2025). Einstein Health Papers. Paper 62.
https://jdc.jefferson.edu/einsteinfp/62

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Language

English