Oncotarget

Research Papers:

Evaluation of the genomic alterations in the androgen receptor gene during treatment with high-dose testosterone for metastatic castrate-resistant prostate cancer

Marcus Moses, Ulkuhan Koksal, Elisa Ledet, Charlotte Manogue, Patrick Cotogno, Brian Lewis, Jodi Layton, A. Oliver Sartor _ and Pedro Barata _

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Oncotarget. 2020; 11:15-21. https://doi.org/10.18632/oncotarget.27408

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Abstract

Marcus Moses1, Ulkuhan Koksal1, Elisa Ledet1, Charlotte Manogue1, Patrick Cotogno1, Brian Lewis1, Jodi Layton1, A. Oliver Sartor1 and Pedro Barata1

1 Tulane Cancer Center, School of Medicine, Tulane University, New Orleans, LA, USA

Correspondence to:

Pedro Barata,email: pbarata@tulane.edu
A. Oliver Sartor,email: osartor@tulane.edu

Keywords: castration-resistant prostate cancer; high-dose testosterone; next-generation sequencing; androgen receptor

Received: October 29, 2019     Accepted: December 16, 2019     Published: January 07, 2020

ABSTRACT

Introduction: Castration resistant prostate cancer (CRPC) has been characterized by a reactivation of the androgen receptor (AR) signaling pathway via alterations in androgen metabolism and AR aberrations. High-dose testosterone (HDT) is emerging as an active treatment in metastatic CRPC, however, biomarkers of response are unknown. We hypothesized that responses to HDT might impact the genomic expression of AR alterations found in circulating-tumor DNA (ctDNA).

Methods: Retrospective analysis of mCRPC patients treated with HDT (testosterone cypionate q 2–4 weeks) with available clinical and somatic genomic data using a commercially available assay (Guardant360, Redwood City, CA). Clinical outcomes included PSA response (PSA50), time to PSA progression (TPP) and safety.

Results: A total of 33 mCRPC patients were treated with ≥2 testosterone cypionate injections. ctDNA testing revealed alterations in AR (39%), TP53 (48%), and DNA repair genes (12%). HDT was given for median of 4.0 months (95% CI, 2.6–5.3) with 24% of PSA50. Twenty patients were re-challenged with abiraterone (n = 2) or enzalutamide (n = 18) with 30% PSA50. Significant (grade ≥3) adverse events were observed in 5% of patients (grade 4 thrombocytopenia and asthenia). Patients with median baseline ctDNA% of ≥1.10 had numerically worse TPP outcomes and all patients with AR alterations exhibited decreased AR expression post-HDT (n = 9), yet no association between clinical outcomes and ctDNA findings was observed.

Conclusions: HDT led to a decrease in AR copy number and mutations which was independent from responses to therapy. Further understanding of the genomic alterations as potential predictor of response to HDT is needed.


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