Clinical implications of Wnt pathway genetic alterations in men with advanced prostate cancer

Amanda Broderick; Elizabeth Pan; Jinju Li; Alec Chu; Clara Hwang; Pedro C Barata; Frank Cameron Cackowski; Matthew Labriola; Alyssa Ghose; Mehmet Asim Bilen; Deepak Kilari; Bicky Thapa; Michael Piero; Laura Graham; Abhishek Tripathi; Rohan Garje; Vadim S Koshkin; Erik Hernandez; Tanya B Dorff; Michael Thomas Schweizer; Ajjai Shivaram Alva; Rana R McKay; Andrew J Armstrong

doi:10.1038/s41391-024-00869-1

Clinical implications of Wnt pathway genetic alterations in men with advanced prostate cancer

Prostate Cancer Prostatic Dis. 2024 Jul 17. doi: 10.1038/s41391-024-00869-1. Online ahead of print.

Authors

Amanda Broderick¹, Elizabeth Pan², Jinju Li³, Alec Chu⁴, Clara Hwang⁵, Pedro C Barata⁶, Frank Cameron Cackowski⁷, Matthew Labriola¹, Alyssa Ghose⁸, Mehmet Asim Bilen⁹, Deepak Kilari¹⁰, Bicky Thapa¹⁰, Michael Piero¹⁰, Laura Graham¹¹, Abhishek Tripathi¹², Rohan Garje¹³, Vadim S Koshkin¹⁴, Erik Hernandez¹⁴, Tanya B Dorff¹², Michael Thomas Schweizer¹⁵, Ajjai Shivaram Alva⁸, Rana R McKay¹⁶, Andrew J Armstrong¹⁷

Affiliations

¹ Duke Cancer Institute Center for Prostate and Urologic Cancers, Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA.
² Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
³ Rogel Cancer Center, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
⁴ Pathology Department, University of Michigan, Ann Arbor, MI, USA.
⁵ Division of Hematology/Oncology, Department of Internal Medicine, Henry Ford Cancer Institute, Detroit, MI, USA.
⁶ Department of Internal Medicine, University Hospitals Seidman Cancer Center, Cleveland, OH, USA.
⁷ Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
⁸ Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA.
⁹ Winship Cancer Institute of Emory University, Atlanta, GA, USA.
¹⁰ Department of Medicine, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
¹¹ University of Colorado Cancer Center Anschutz Medical Campus, Aurora, CO, USA.
¹² Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
¹³ Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
¹⁴ University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
¹⁵ University of Washington, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁶ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. mckay@ucsd.edu.
¹⁷ Duke Cancer Institute Center for Prostate and Urologic Cancers, Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA. andrew.armstrong@duke.edu.

PMID: 39019980
DOI: 10.1038/s41391-024-00869-1

Abstract

Background: Aberrant Wnt signaling has been implicated in prostate cancer tumorigenesis and metastasis in preclinical models but the impact of genetic alterations in Wnt signaling genes in men with advanced prostate cancer is unknown.

Methods: We utilized the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database for this retrospective analysis. Patients with activating mutations in CTNNB1 or RSPO2 or inactivating mutations in APC, RNF43, or ZNRF3 were defined as Wnt-altered, while those lacking such alterations were defined as Wnt non-altered. We compared patient characteristics and clinical outcomes as well as co-occurring genetic alterations according to Wnt alteration status.

Results: Of the 1498 patients included, 193 (12.9%) were Wnt-altered. These men had a statistically significant 2-fold increased prevalence of liver and lung metastases as compared with Wnt non-altered patients at the time of initial diagnosis, (4.66% v 2.15% ; 6.22% v 3.07%), first metastatic disease diagnosis (10.88% v 5.29%; 13.99% v 6.21%), and CRPC development (11.40% v 6.36%; 12.95% v 5.29%). Wnt alterations were associated with more co-occurring alterations in RB1 (10.4% v 6.2%), AR (38.9% vs 25.7%), SPOP (13.5% vs 4.1%), FOXA1 (6.7% vs 2.8%), and PIK3CA (10.9% vs 5.1%). We found no significant differences in overall survival or other clinical outcomes from initial diagnosis, first metastatic disease, diagnosis of CRPC, or with AR inhibition for mCRPC between the Wnt groups.

Conclusions: Wnt-altered patients with prostate cancer have a higher prevalence of visceral metastases and are enriched in RB1, AR, SPOP, FOXA1, and PIK3CA alterations. Despite these associations, Wnt alterations were not associated with worse survival or treatment outcomes in men with advanced prostate cancer.

Abstract

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