Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration-resistant Prostate Cancer Reveals...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Androgen receptor splice variant 7 (AR-V7) expression correlates with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC).
• A significant number of nonresponding patients are AR-V7-negative, indicating other resistance mechanisms exist.

Purpose of the Study:

• To determine if a comprehensive liquid biopsy-based androgen receptor (AR) profile can improve patient stratification for second-line endocrine therapy in CRPC.
• To investigate novel AR alterations and their association with treatment response.

Main Methods:

• Collected peripheral blood from 30 CRPC patients before new systemic therapy.
• Performed circulating tumor DNA (ctDNA) profiling using low-pass whole-genome and targeted AR gene sequencing.
• Assessed AR splice variant (ARV) expression via targeted RNA sequencing on enriched circulating tumor cells.

Main Results:

• Any AR perturbation, including ARVs, was detected in 25/30 patients.
• Intra-AR structural variation was found in 15/30 patients, with 14 expressing ARVs; AR-V3 was the most abundant.
• The presence of any ARV was associated with progression-free survival (HR 4.53, p=0.0105).
• Six of 17 poor responders were AR-V7-negative but carried other AR perturbations.

Conclusions:

• Comprehensive AR profiling using liquid biopsies is feasible and essential for understanding endocrine treatment resistance mechanisms.
• Beyond AR-V7, diverse AR alterations detected in ctDNA and CTCs are crucial for accurate patient stratification.
• Further research is needed to elucidate the impact of these identified AR alterations on hormonal therapy outcomes.