65. AR/enhancer alterations in metastatic castrate-resistant prostate cancer patient plasma predicts worse overall survival

Aly Abdelkareem

Pradeep Chauhan

My name is Pradeep Singh Chauhan. I did my Ph.D in cancer biology field from India. I am currently working as a Post-doctoral fellow in Dr. Aadel Chadhuri lab. My research in Dr. Chaudhuri’s lab focuses on the application of liquid biopsy in the detection of minimal residual disease in genitourinary cancer. In bladder cancer, we developed a urine biopsy that can measure tumor DNA in urine before surgery for muscle-invasive bladder cancer. We are also interested in the identifying the non-invasive biomarker that can predict resistance to androgen receptor-directed therapies in prostate cancer.


Pradeep Chauhana, Alexander Shianga, Ha Danga, Jace Webstera, Elisa Ledetb, Ramandeep Babbraa, Wenjia Fenga, Peter Harrisa, Faridi Qaiuma, Ellen Jaegerb, Patrick Millerb, Sydney Caputob, Giordano Santosa, Russell Pachynskia, A. Oliver Sartorb, Christopher Mahera, Aadel Chaudhuria

aWashington University School of Medicine, St. Louis, MO, USA; bTulane University School of Medicine, New Orleans, LA, USA

Androgen-receptor signaling inhibitors (ARSI) such abiraterone and enzalutamide have significantly improved clinical outcomes in patients with metastatic castrate-resistant prostate cancer (mCRPC). However, patients with genomic alterations in androgen receptor (AR) and its enhancer region do not respond well and acquire resistance to these inhibitors. We previously developed a cell-free DNA (cfDNA) liquid biopsy assay (EnhanceAR-Seq) that can detect alterations in AR locus including the upstream enhancer. Here, we applied this assay to detect AR/enhancer alterations in mCRPC patients prior to the administration of first-line AR-directed therapy and correlated with survival.

We applied EnhanceAR-Seq to plasma cfDNA isolated from 94 mCRPC patients enrolled independently from Washington University in St. Louis (n = 51) and Tulane University (n = 43). Plasma samples were collected prior to initiation of AR-targeted therapy (n = 60) and during treatment (n = 34).

EnhanceAR-Seq detected AR/enhancer alterations in 31% of all plasma samples analyzed. Presence of AR/enhancer alterations was highly prognostic for worse survival (PFS p = 0.0002; OS: p = 0.04). In subset analysis, AR/enhancer alterations detected in 37% of samples collected prior to first-line ARSI treatment correlated significantly with worse PFS (p = 0.02; HR = 2.23) and worse OS trending toward significance (p = 0.10). Furthermore, AR/enhancer alterations detected in 21% of samples collected during AR-directed therapy was also associated with worse PFS (p = 0.0005) and OS (p = 0.02). AR/enhancer alterations detected in pre-treatment and on-treatment plasma cfDNA predicted worse survival in mCRPC patients, which has important diagnostic and therapeutic implications.