The Role of Androgen Receptor (AR) in Liquid Biopsy to Predict Clinical Outcome to AR Signaling Inhibitors in Metastatic Castration Resistance Prostate Cancer Patients

The ability to predict clinical outcomes prior to starting therapy is the hallmark of precision oncology. The detection of the androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) has now been externally and prospectively validated in the multicenter PROPHECY study using both the Hopkins mRNA and the Epic Sciences nuclear protein assays, demonstrating strong and significant associations with worse progression free and overall survival (PFS and OS) and a lack of responses in men with mCRPC,¹ but such AR-V7 positive men can still have good outcomes with taxane chemotherapy.² However, a limitation of CTC AR-V7 detection is that CTCs are required to be present, and nearly half of men with mCRPC have low to absent CTCs despite disease progression. In addition, AR-V7 likely only explains about 20-30% of AR therapy cross-resistance, meaning that other resistance mechanisms such as AR indifference and neuroendocrine transformation/lineage plasticity are also important.

In this context, having novel assays to assess key resistance biomarkers could have a major impact on care. Del Re et al, writing in Prostate Cancer and Prostatic Diseases³ have now presented data suggesting that exosomal and plasma cell free AR biomarkers including AR-V7 and AR gain, respectively, can discriminate outcomes in a retrospective study of 84 men with CRPC starting enzalutamide or abiraterone. While ctDNA AR gain is well established to be prognostic in this setting, exosomal mRNA detection of AR-V7 was associated with inferior PFS of 5.4 vs. 24.3 (HR 4.9, p < 0.0001) and OS of not reached vs 16.2 months (HR 4.5, p = 0.0001). AR gain and AR-V7 mRNA were correlated and both associated with poor outcomes, likely related to the relationship between AR transcriptional activity and alternative splicing of AR into these AR variants.

Detection of AR-V7 by this exosomal method was more common (36%) than prior studies (<5%) in this first line mCRPC setting, suggesting that using exosomes may permit a greater ability to detect important biomarkers such as mRNA and splice variants than CTCs, and may permit detection of RNA biomarker missed in common ctDNA panels.

Limitations of this work include the retrospective nature of the study, the small sample size and inability to adjust for many common clinical variables, and the lack of an assessment of predictive utility to guide therapy, all of which merit future prospective studies, ideally utilizing exosomal mRNA to assess a range of resistance biomarkers including AR biomarkers. The authors are to be congratulated for moving the liquid biopsy field further along!

Written by: Andrew Armstrong, MD, MSc, Medical Oncologist, Professor of Medicine, Associate Professor in Pharmacology and Cancer Biology, Professor in Surgery, Duke Cancer Institute

References:

Armstrong A, Halabi S, Luo Jetal. "Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study" J Clin Oncol. 2019. 10.1200/JCO.18.01731.
Armstrong A, Luo J, Nanus D et al. "Prospective Multicenter Study of Circulating Tumor Cell AR-V7 and Taxane Versus Hormonal Treatment Outcomes in Metastatic Castration-Resistant Prostate Cancer" JCO Precis Oncol. 2020. 10.1200/PO.20.00200.
Del Re, M., Conteduca, V., Crucitta, S. et al. Androgen receptor gain in circulating free DNA and splicing variant 7 in exosomes predict clinical outcome in CRPC patients treated with abiraterone and enzalutamide. Prostate Cancer Prostatic Dis (2021). https://doi.org/10.1038/s41391-020-00309-w

Read the Full-Text Article: Androgen Receptor Gain in Circulating Free DNA and Splicing Variant 7 in Exosomes Predict Clinical Outcome in CRPC Patients Treated with Abiraterone and Enzalutamide - Full-Text Article

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