WNT Pathway Mutations in Metachronous Oligometastatic Castration-Sensitive Prostate Cancer

Philip Sutera, Matthew P. Deek, Kim Van der Eecken, Amol C. Shetty, Jin Hee Chang, Theresa Hodges, Yang Song, Sofie Verbeke, Jo Van Dorpe, Valérie Fonteyne, Bram De Laere, Mark Mishra, Zaker Rana, Jason Molitoris, Matthew Ferris, Ashley Ross, Edward Schaeffer, Nicholas Roberts, Daniel Y. Song, Theodore DeWeeseKenneth J. Pienta, Emmanuel S. Antonarakis, Piet Ost, Phuoc T. Tran

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Purpose: WNT signaling is a cellular pathway that has been implicated in the development and progression of prostate cancer. Oligometastatic castration-sensitive prostate cancer (omCSPC) represents a unique state of disease in which metastasis-directed therapy (MDT) has demonstrated improvement in progression-free survival. Herein, we investigate the clinical implications of genomic alterations in the WNT signaling cascade in men with omCSPC. Methods and Materials: We performed an international multi-institutional retrospective study of 277 men with metachronous omCSPC who underwent targeted DNA sequencing of their primary/metastatic tumor. Patients were classified by presence or absence of pathogenic WNT pathway mutations (in the genes APC, RNF43, and CTNNB1). Pearson χ2 and Mann-Whitney U tests were used to determine differences in clinical factors between genomic strata. Kaplan-Meier survival curves were generated for radiographic progression-free survival and overall survival, stratified according to WNT pathway mutation status. Results: A pathogenic WNT pathway mutation was detected in 11.2% of patients. Patients with WNT pathway mutations were more likely to have visceral metastases (22.6% vs 2.8%; P < .01) and less likely to have regional lymph node metastases (29.0% vs 50.4%; P = .02). At time of oligometastasis, these patients were treated with MDT alone (33.9%), MDT + limited course of systemic therapy (20.6%), systemic therapy alone (22.4%), or observation (defined as no treatment for ≥6 months after metastatic diagnosis). Multivariable cox regression demonstrated WNT pathway mutations associated with significantly worse overall survival (hazard ratio, 3.87; 95% confidence interval, 1.25-12.00). Conclusions: Somatic WNT pathway alterations are present in approximately 11% of patients with omCSPC and are associated with an increased likelihood of visceral metastases. Although these patients have a worse natural history, they may benefit from MDT.

Original languageEnglish (US)
Pages (from-to)1095-1101
Number of pages7
JournalInternational Journal of Radiation Oncology Biology Physics
Issue number5
StatePublished - Apr 1 2023

Bibliographical note

Funding Information:
P.T.T. was funded by an anonymous donor, Movember Foundation-Distinguished Gentlemen's Ride-Prostate Cancer Foundation, Babara's Fund, National Capitol Cancer Research Fund, and the National Institutes of Health/National Cancer Institute (U01CA212007, U01CA231776, and U54CA273956) and Department of Defense (W81XWH-21-1-0296), and the STOMP trial was supported by Kom op tegen Kanker, a Belgian nonprofit organization.

Publisher Copyright:
© 2022 Elsevier Inc.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.


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