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 DeWeese; Kenneth J. Pienta; Emmanuel S. Antonarakis; Piet Ost; Phuoc T. Tran

doi:10.1016/j.ijrobp.2022.12.006

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

Medicine - Hematology, Oncology, Transplant

Research output: Contribution to journal › Article › peer-review

Abstract

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 language	English (US)
Pages (from-to)	1095-1101
Number of pages	7
Journal	International Journal of Radiation Oncology Biology Physics
Volume	115
Issue number	5
DOIs	https://doi.org/10.1016/j.ijrobp.2022.12.006
State	Published - 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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10.1016/j.ijrobp.2022.12.006

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Sutera, P., Deek, M. P., Van der Eecken, K., Shetty, A. C., Chang, J. H., Hodges, T., Song, Y., Verbeke, S., Van Dorpe, J., Fonteyne, V., De Laere, B., Mishra, M., Rana, Z., Molitoris, J., Ferris, M., Ross, A., Schaeffer, E., Roberts, N., Song, D. Y., ... Tran, P. T. (2023). WNT Pathway Mutations in Metachronous Oligometastatic Castration-Sensitive Prostate Cancer. International Journal of Radiation Oncology Biology Physics, 115(5), 1095-1101. https://doi.org/10.1016/j.ijrobp.2022.12.006

Sutera, P, Deek, MP, Van der Eecken, K, Shetty, AC, Chang, JH, Hodges, T, Song, Y, Verbeke, S, Van Dorpe, J, Fonteyne, V, De Laere, B, Mishra, M, Rana, Z, Molitoris, J, Ferris, M, Ross, A, Schaeffer, E, Roberts, N, Song, DY, DeWeese, T, Pienta, KJ, Antonarakis, ES, Ost, P & Tran, PT 2023, 'WNT Pathway Mutations in Metachronous Oligometastatic Castration-Sensitive Prostate Cancer', International Journal of Radiation Oncology Biology Physics, vol. 115, no. 5, pp. 1095-1101. https://doi.org/10.1016/j.ijrobp.2022.12.006

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title = "WNT Pathway Mutations in Metachronous Oligometastatic Castration-Sensitive Prostate Cancer",

abstract = "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.",

author = "Philip Sutera and Deek, {Matthew P.} and {Van der Eecken}, Kim and Shetty, {Amol C.} and Chang, {Jin Hee} and Theresa Hodges and Yang Song and Sofie Verbeke and {Van Dorpe}, Jo and Val{\'e}rie Fonteyne and {De Laere}, Bram and Mark Mishra and Zaker Rana and Jason Molitoris and Matthew Ferris and Ashley Ross and Edward Schaeffer and Nicholas Roberts and Song, {Daniel Y.} and Theodore DeWeese and Pienta, {Kenneth J.} and Antonarakis, {Emmanuel S.} and Piet Ost and Tran, {Phuoc T.}",

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: {\textcopyright} 2022 Elsevier Inc.",

year = "2023",

month = apr,

day = "1",

doi = "10.1016/j.ijrobp.2022.12.006",

language = "English (US)",

volume = "115",

pages = "1095--1101",

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TY - JOUR

T1 - WNT Pathway Mutations in Metachronous Oligometastatic Castration-Sensitive Prostate Cancer

AU - Sutera, Philip

AU - Deek, Matthew P.

AU - Van der Eecken, Kim

AU - Shetty, Amol C.

AU - Chang, Jin Hee

AU - Hodges, Theresa

AU - Song, Yang

AU - Verbeke, Sofie

AU - Van Dorpe, Jo

AU - Fonteyne, Valérie

AU - De Laere, Bram

AU - Mishra, Mark

AU - Rana, Zaker

AU - Molitoris, Jason

AU - Ferris, Matthew

AU - Ross, Ashley

AU - Schaeffer, Edward

AU - Roberts, Nicholas

AU - Song, Daniel Y.

AU - DeWeese, Theodore

AU - Pienta, Kenneth J.

AU - Antonarakis, Emmanuel S.

AU - Ost, Piet

AU - Tran, Phuoc T.

N1 - 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.

PY - 2023/4/1

Y1 - 2023/4/1

N2 - 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.

AB - 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.

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JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

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WNT Pathway Mutations in Metachronous Oligometastatic Castration-Sensitive Prostate Cancer

Abstract

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