WNT Pathway Mutations in Metachronous Oligometastatic Castration-Sensitive Prostate Cancer

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 impli-cations 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 metachro-nous omCSPC who underwent targeted DNA sequencing of their primary/metastatic tumor. Patients were classified by pres-ence or absence of pathogenic WNT pathway mutations (in the genes APC, RNF43, and CTNNB1). Pearson x2 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 meta-static diagnosis). Multivariable cox regression demonstrated WNT pathway mutations associated with significantly worse over-all 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 associ-ated with an increased likelihood of visceral metastases. Although these patients have a worse natural history, they may benefit from MDT.(c) 2022 Elsevier Inc. All rights reserved.