Clinical Utility of Transcriptomic Signatures to Identify Androgen Receptor and Neuroendocrine Signaling in Prostate...

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Prostate cancer (PC) is heterogeneous, necessitating molecular classification for targeted therapies.
• Metastatic castration-resistant prostate cancer (mCRPC) presents therapeutic challenges due to evolving molecular landscapes.

Purpose of the Study:

• To define molecular subtypes of prostate cancer by integrating androgen receptor (AR) signaling, neuroendocrine prostate cancer (NEPC) transcriptional signatures, and genomic alterations.
• To inform biomarker-driven therapies in metastatic castration-resistant prostate cancer (mCRPC).

Main Methods:

• Analysis of 8,019 prostate tumors using DNA/RNA sequencing.
• Classification into four molecular subtypes: AR+/NE-, AR-/NE+, AR+/NE+, and AR-/NE-.
• Evaluation of genomic alterations, cell surface target expression (e.g., FOLH1, DLL3), and overall survival (OS).

Main Results:

• Identified four molecular subtypes: AR+/NE- (91%), AR-/NE+ (4.6%), AR+/NE+ (rare), and AR-/NE- (rare).
• TP53/PTEN alterations were enriched in AR-negative subtypes; SPOP mutations were frequent in AR+ tumors.
• High AR signaling correlated with longer OS (55.0 vs. 14.0 months), while NEPC signature correlated with shorter OS (16.1 vs. 54.3 months). AR+/NE- tumors had the most favorable OS (55.3 months), and AR-/NE+ tumors had the poorest (12.0 months).

Conclusions:

• Prostate cancer exhibits distinct molecular subtypes based on AR signaling, NEPC profiles, and genomic alterations.
• These subgroups offer a framework for precision oncology in mCRPC.
• Molecular subtyping can inform patient selection for biomarker-driven clinical trials, such as the PREDICT study (NCT06632977).