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Updated: Jun 18, 2026
Serum and Plasma Copy Number Detection Using Real-time PCR
Published on: December 15, 2017
Prevalence and Spectrum of AR Ligand-Binding Domain Mutations Detected in Circulating-Tumor DNA Across Disease States
Emmanuel S Antonarakis1, Nicole Zhang2, Jayati Saha2
1University of Minnesota Masonic Cancer Center, Minneapolis, MN.
Purpose:
Metastatic castration-resistant prostate cancer (mCRPC) is typically treated with agents directly or indirectly targeting the androgen receptor (AR) pathway. However, such treatment is limited by resistance mechanisms, including the development of activating mutations in the AR ligand-binding domain (AR-LBD).
Methods:
This study evaluated a database of over 15,000 patients with advanced prostate cancer (PC) undergoing comprehensive circulating-tumor DNA analysis (Guardant360, Redwood City, CA) between 2014 and 2021, with associated clinical information from administrative claims (GuardantINFORM database).
Results:
Of 15,705 patients with PC included, 54% had mCRPC at the time of their blood draw. Of those, 49% had previous treatment with an AR pathway inhibitor (ARPi). AR-LBD mutation prevalence was 15% in patients with mCRPC who were untreated with a next-generation ARPi, 22% in those after one line of ARPi therapy, and 24% in those after two lines of ARPi treatment. Next-generation ARPi treatment yielded an increase in AR L702H and T878A/S mutations after abiraterone, and an increase in AR L702H and F877L mutations after enzalutamide. AR-LBD+ patients demonstrated unique biology, including increased concurrent mutations in the cell-cycle, wingless-related integration site, homologous recombination repair, and phospho-inositide 3-kinase pathways (all P < .0005), and greater low-level (copy number <10) AR amplifications (P = .0041). AR-LBD+ patients exhibited worse overall survival (OS) relative to a matched cohort of AR-LBD- patients (50.1 v 60.7 months, unadjusted log-rank P = .013).
Conclusion:
This large database analysis demonstrates that AR-LBD mutation prevalence increases after next-generation ARPi use. AR-LBD+ tumors demonstrate unique biology (more oncogenic pathway mutations and low-level AR amplification) and reduced OS. These findings inform the development of novel therapies designed to circumvent AR-mediated therapeutic resistance.
Insights
Androgen receptor (AR) ligand-binding domain (LBD) mutations increase with next-generation AR pathway inhibitor (ARPi) use in metastatic castration-resistant prostate cancer (mCRPC). AR-LBD+ tumors show unique biology and worse overall survival, guiding new therapy development.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) treatment often targets the androgen receptor (AR) pathway.
- Therapeutic resistance can arise from activating mutations in the AR ligand-binding domain (AR-LBD).
- Understanding AR-LBD mutation prevalence and associated biology is crucial for improving mCRPC treatment strategies.
Purpose of the Study:
- To evaluate the prevalence of AR-LBD mutations in advanced prostate cancer (PC) patients.
- To investigate the association between AR-LBD mutations and prior AR pathway inhibitor (ARPi) treatment.
- To characterize the unique biological features and clinical outcomes of AR-LBD mutated tumors.
Main Methods:
- Analysis of a comprehensive circulating-tumor DNA database (Guardant360) from over 15,000 advanced PC patients (2014-2021).
- Integration of clinical information from administrative claims (GuardantINFORM database).
- Assessment of AR-LBD mutation prevalence across different lines of ARPi therapy and characterization of concurrent mutations and AR amplifications.
Main Results:
- AR-LBD mutation prevalence increased with successive lines of next-generation ARPi therapy (15% untreated, 22% after one line, 24% after two lines).
- Specific AR-LBD mutations (L702H, T878A/S, F877L) were associated with abiraterone or enzalutamide treatment.
- AR-LBD+ tumors exhibited increased mutations in cell-cycle, WNT, HRR, and PI3K pathways, along with low-level AR amplifications, and demonstrated worse overall survival (50.1 vs 60.7 months).
Conclusions:
- AR-LBD mutation prevalence escalates following next-generation ARPi treatment in mCRPC.
- AR-LBD+ tumors possess distinct oncogenic pathway alterations and low-level AR amplification, correlating with poorer survival.
- These findings highlight the need for novel therapeutic strategies to overcome AR-mediated resistance in mCRPC.
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