Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer

William S Chen; Rahul Aggarwal; Li Zhang; Shuang G Zhao; George V Thomas; Tomasz M Beer; David A Quigley; Adam Foye; Denise Playdle; Jiaoti Huang; Paul Lloyd; Eric Lu; Duanchen Sun; Xiangnan Guan; Matthew Rettig; Martin Gleave; Christopher P Evans; Jack Youngren; Lawrence True; Primo Lara; Vishal Kothari; Zheng Xia; Kim N Chi; Robert E Reiter; Christopher A Maher; Felix Y Feng; Eric J Small; Joshi J Alumkal; West Coast Prostate Cancer Dream Team

doi:10.1016/j.eururo.2019.03.020

Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer

Eur Urol. 2019 Nov;76(5):562-571. doi: 10.1016/j.eururo.2019.03.020. Epub 2019 Mar 28.

Authors

William S Chen¹, Rahul Aggarwal², Li Zhang³, Shuang G Zhao⁴, George V Thomas⁵, Tomasz M Beer⁵, David A Quigley⁶, Adam Foye², Denise Playdle², Jiaoti Huang⁷, Paul Lloyd², Eric Lu⁵, Duanchen Sun⁵, Xiangnan Guan⁵, Matthew Rettig⁸, Martin Gleave⁹, Christopher P Evans¹⁰, Jack Youngren², Lawrence True¹¹, Primo Lara¹⁰, Vishal Kothari⁶, Zheng Xia⁵, Kim N Chi⁹, Robert E Reiter¹², Christopher A Maher¹³, Felix Y Feng¹⁴, Eric J Small¹⁵, Joshi J Alumkal⁵; West Coast Prostate Cancer Dream Team

Affiliations

¹ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; Yale School of Medicine, New Haven, CT, USA.
² Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
³ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.
⁴ University of Michigan, Ann Arbor, MI, USA.
⁵ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
⁶ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
⁷ Duke University, Durham, NC, USA.
⁸ University of California Los Angeles, Los Angeles, CA, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
⁹ University of British Columbia, Vancouver, Canada.
¹⁰ University of California Davis, Davis, CA, USA.
¹¹ University of Washington, Seattle, WA, USA.
¹² University of California Los Angeles, Los Angeles, CA, USA.
¹³ Washington University in St. Louis, St. Louis, MO, USA.
¹⁴ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, CA, USA.
¹⁵ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; Department of Medicine, University of California San Francisco, San Francisco, CA, USA. Electronic address: eric.small@ucsf.edu.

Abstract

Background: Metastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these genomic alterations have not been fully elucidated.

Objective: To use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance.

Design, setting, and participants: We performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients.

Outcome measurements and statistical analysis: OS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test.

Results and limitations: Harboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0mo; p=0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p=0.01) and independently predictive of poor OS (median 13.6 vs 41.7mo; p=0.025).

Conclusions: The presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort.

Patient summary: We observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC.

Keywords: Advanced prostate cancer; Castration-resistant; Clinical outcomes; Enzalutamide; Genomics; Metastatic prostate cancer; Prognostic factors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / adverse effects
Benzamides
Biomarkers, Tumor / blood
Drug Resistance, Neoplasm / genetics*
Humans
Male
Middle Aged
Neoplasm Metastasis* / drug therapy
Neoplasm Staging
Nitriles
Outcome Assessment, Health Care
Phenylthiohydantoin / administration & dosage
Phenylthiohydantoin / adverse effects
Phenylthiohydantoin / analogs & derivatives*
Predictive Value of Tests
Prognosis
Prostate / pathology*
Prostate-Specific Antigen / blood
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Prostatic Neoplasms, Castration-Resistant* / pathology
Whole Genome Sequencing / methods

Substances

Antineoplastic Agents
Benzamides
Biomarkers, Tumor
Nitriles
Phenylthiohydantoin
enzalutamide
Prostate-Specific Antigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding