WNT Pathway Mutations in Metachronous Oligometastatic Castration-Sensitive Prostate Cancer

• DOI: 10.1016/j.ijrobp.2022.12.006
• Publication Date: 2023-01-26T08:50:02Z
• Authors: 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 DeWeese; Kenneth J. Pienta; Emmanuel S. Anton...; Piet Ost; Phuoc T. Tran
• Keywords: Male; 03 medical and health sciences; 0302 clinical medicine; Mutation; Humans; Prostatic Neoplasms; Castration; Wnt Signaling Pathway; 3. Good health; Retrospective Studies

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.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.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).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.