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

Prostate Cancer and Prostatic Diseases volume 28, pages 419–426 (2025)Cite this article

Subjects

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.

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Fig. 1: Co-occurring selected genetic alterations for Wnt altered vs Wnt non-altered patients.
Fig. 2: Oncoprint displaying Wnt alterations, co-occurring and mutually exclusive genetic alterations, and pre-sequencing treatment.
Fig. 3: Sites of metastatic disease for Wnt altered vs non-altered patients.
Fig. 4: Survival outcomes for Wnt altered vs Wnt non-altered patients.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request and per PROMISE consortium guidelines.

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Author information

Author notes

  1. Twitter: @AarmstrongDuke.

Authors and Affiliations

  1. Duke Cancer Institute Center for Prostate and Urologic Cancers, Division of Medical Oncology, Department of Medicine, Duke University, Durham, NC, USA

    Amanda Broderick, Matthew Labriola & Andrew J. Armstrong

  2. Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

    Elizabeth Pan & Rana R. McKay

  3. Rogel Cancer Center, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    Jinju Li

  4. Pathology Department, University of Michigan, Ann Arbor, MI, USA

    Alec Chu

  5. Division of Hematology/Oncology, Department of Internal Medicine, Henry Ford Cancer Institute, Detroit, MI, USA

    Clara Hwang

  6. Department of Internal Medicine, University Hospitals Seidman Cancer Center, Cleveland, OH, USA

    Pedro C. Barata

  7. Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Frank Cameron Cackowski

  8. Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA

    Alyssa Ghose & Ajjai Shivaram Alva

  9. Winship Cancer Institute of Emory University, Atlanta, GA, USA

    Mehmet Asim Bilen

  10. Department of Medicine, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA

    Deepak Kilari, Bicky Thapa & Michael Piero

  11. University of Colorado Cancer Center Anschutz Medical Campus, Aurora, CO, USA

    Laura Graham

  12. Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Abhishek Tripathi & Tanya B. Dorff

  13. Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA

    Rohan Garje

  14. University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA

    Vadim S. Koshkin & Erik Hernandez

  15. University of Washington, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Michael Thomas Schweizer

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  1. Amanda Broderick
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Contributions

Concept and design: Andrew J. Armstrong, Rana R. McKay, Elizabeth Pan, Amanda Broderick. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Andrew J. Armstrong, Rana R. McKay, Elizabeth Pan, Amanda Broderick, Alec Chu, Jinju Li. Critical review of the manuscript for important intellectual content: All authors. Statistical analysis: Jinju Li, Alec Chu.

Corresponding authors

Correspondence to Rana R. McKay or Andrew J. Armstrong.

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Competing interests

AJA has received support (to Duke) from the NIH/NCI, PCF/Movember, DOD, Astellas, Pfizer, Bayer, Janssen, Dendreon, BMS, AstraZeneca, Merck, Forma, Celgene, Amgen, Novartis and has consulting or advising relationships with Astellas, Pfizer, Bayer, Janssen, BMS, AstraZeneca, Merck, Forma, Celgene, Myovant, Exelixis, GoodRx, Novartis, Medscape, MJH, Z Alpha, Telix outside the submitted work. CH reported owning stock in Johnson and Johnson; receiving personal fees from Tempus, Genzyme, EMD Sorono, OncLive/MJH Life Sciences, Merck, and grants from Merck, Bausch Health, Genentech, Bayer, and AstraZeneca outside the submitted work. TBD reported consulting/advisory relationships with AstraZeneca, Bayer, Janssen, Sanofi. DK reported consulting/Honoraria for Exelixis, Pfizer. MJH life science; Advisory board for Eisai, Exelixis; institutional funding from Genetech, Exelixis; and speakers bureau for Aveo, Jannsen, Astellas. VSK reported consulting or advisory role for AstraZeneca, Janssen, Pfizer, EMD Serono, Seagen, Astellas, Guidepoint, GLG and ExpertConnect; has received research funding for the institution from Endocyte/Novartis, Nektar, Gilead, Janssen, Taiho, Merck and Seagen, individual research funding from Eli Lilly and is supported by the Prostate Cancer Foundation. MTS reported being a consultant and/or received Honoria from Sanofi, AstraZeneca, Janssen, Fibrogen, and Pfizer. He has received research funding to his institution from Novartis, Zenith Epigenetics, Eli Lilly, Bristol Myers Squibb, Merck, Immunomedics, Janssen, AstraZeneca, Pfizer, Hoffmann-La Roche, Tmunity, SignalOne Bio, Epigenetix, Xencor, Incyte and Ambrx, Inc. RRM reported consulting or advisory board for Ambrx, AstraZeneca, Aveo, Bayer, Bristol-Myers Squibb, Calithera, Caris, Dendreon, Exelixis, Eisai, Johnson & Johnson, Lilly, Merck, Myovant, Novartis, Pfizer, Sanofi, Seagen, Sorrento, Telix, Tempus. She has received istitutional research support Exelixis, BMS, AstraZeneca, Oncternal, Artera, Tempus. RG has received institutional research funding from Endocyte/Advanced Accelerator Applications, Pfizer, Amgen, Immunomedics, and Xencor outside the submitted work. MAB reported receiving personal fees from Exelixis, Bayer, Bristol Myers Squibb, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi and grants from Merck, Xencor, Bayer, Bristol Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, and Pfizer outside the submitted work. AT reported receiving personal fees from Genzyme, Exelixis, Seattle Genetics, Deka Biosciences, and Aldi Biosciences and grants from EMD Serono and Aravive outside the submitted work. PCB reported receiving personal fees from AVEO Oncology, Bayer, Pfizer, Caris Life Sciences, AstraZeneca, Myovant, Curio Science, Targeted Oncology, Bristol Myers Squibb, MJH Life Sciences, Seagen, and Vaniam Group and grants from EMD Serono outside the submitted work ASA reported serving as an advisor to AstraZeneca, Bristol-Myers Squibb, Merck, and Pfizer. He has previously received institutional research funding from Arcus Biosciences, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Genentech, Merck Sharp & Dohme, Janssen, Mirati Therapeutics, Progenics, Prometheus Laboratories, and Roche. He has also received travel and accommodation from Bristol-Myers Squibb and Merck.

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Broderick, A., Pan, E., Li, J. et al. Clinical implications of Wnt pathway genetic alterations in men with advanced prostate cancer. Prostate Cancer Prostatic Dis 28, 419–426 (2025). https://doi.org/10.1038/s41391-024-00869-1

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