Plasma AR and abiraterone-resistant prostate cancer

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Androgen receptor (AR) gene aberrations are uncommon before initial hormone therapy for prostate cancer but frequently arise with castration resistance.
• Developing a minimally invasive assay to assess AR gene status has significant clinical potential for managing prostate cancer.
• Castration-resistant prostate cancer (CRPC) treatment often involves agents targeting the AR pathway, such as abiraterone.

Purpose of the Study:

• To establish a targeted next-generation sequencing (NGS) assay for detecting AR gene status in plasma DNA.
• To evaluate the clinical utility of plasma AR analysis for predicting abiraterone treatment response and survival in CRPC patients.

Main Methods:

• Developed a targeted NGS assay covering all AR coding bases and informative genomic regions for plasma DNA analysis.
• Sequenced 274 plasma samples from 97 CRPC patients treated with abiraterone.
• Quantified AR copy number and detected point mutations in circulating tumor DNA, controlling for normal DNA.

Main Results:

• Successfully quantified AR copy number in 80% of samples, enabling analysis of AR gene status.
• Observed an inverse correlation between AR copy number gain and point mutations in plasma DNA.
• Identified emergence of specific AR amino acid changes (T878A or L702H) in 13% of patients at progression on abiraterone.
• Patients with pre-existing AR gain or specific mutations showed significantly reduced PSA decline and worse overall and progression-free survival.

Conclusions:

• Plasma AR analysis using targeted NGS is a feasible and minimally invasive method to assess AR gene status in CRPC.
• Detection of AR gain or specific mutations in plasma DNA can identify patients with primary resistance to abiraterone.
• This approach could guide treatment decisions and improve patient outcomes by enabling personalized therapy selection.