Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer

Adam Sharp, Jon C. Welti, Maryou B.K. Lambros, David Dolling, Daniel Nava Rodrigues, Lorna Pope, Caterina Aversa, Ines Figueiredo, Jennifer Fraser, Zai Ahmad, Changxue Lu, Pasquale Rescigno, Michael Kolinsky, Claudia Bertan, George Seed, Ruth Riisnaes, Susana Miranda, Mateus Crespo, Rita Pereira, Ana FerreiraGemma Fowler, Berni Ebbs, Penny Flohr, Antje Neeb, Diletta Bianchini, Antonella Petremolo, Semini Sumanasuriya, Alec Paschalis, Joaquin Mateo, Nina Tunariu, Wei Yuan, Suzanne Carreira, Stephen R. Plymate, Jun Luo, Johann S. de Bono

Research output: Contribution to journalArticle

Abstract

Background: Detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumour cells (CTCs) is associated with worse outcome in metastatic castration-resistant prostate cancer (mCRPC). However, studies rarely report comparisons with CTC counts and biopsy AR-V7 protein expression. Objective: To determine the reproducibility of AdnaTest CTC AR-V7 testing, and associations with clinical characteristics, CellSearch CTC counts, tumour biopsy AR-V7 protein expression and overall survival (OS). Design, setting, and participants: CTC AR-V7 status was determined for 227 peripheral blood samples, from 181 mCRPC patients with CTC counts (202 samples; 136 patients) and matched mCRPC biopsies (65 samples; 58 patients). Outcome measurements and statistical analysis: CTC AR-V7 status was associated with clinical characteristics, CTC counts, and tissue biopsy AR-V7 protein expression. The association of CTC AR-V7 status and other baseline variables with OS was determined. Results and limitations: Of the samples, 35% were CTC+/AR-V7+. CTC+/AR-V7+ samples had higher CellSearch CTC counts (median CTC; interquartile range [IQR]: 60, 19–184 vs 9, 2–64; Mann-Whitney test p < 0.001) and biopsy AR-V7 protein expression (median H-score, IQR: 100, 63–148 vs 15, 0–113; Mann-Whitney test p = 0.004) than CTC+/AR-V7− samples. However, both CTC− (63%) and CTC+/AR-V7− (62%) patients had detectable AR-V7 protein in contemporaneous biopsies. After accounting for baseline characteristics, there was shorter OS in CTC+/AR-V7+ patients than in CTC− patients (hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.23–3.71; p = 0.02); surprisingly, there was no evidence that CTC+/AR-V7+ patients had worse OS than CTC+/AR-V7− patients (HR 1.26; 95% CI 0.73–2.17; p = 0.4). A limitation of this study was the heterogeneity of treatment received. Conclusions: Studies reporting the prognostic relevance of CTC AR-V7 status must account for CTC counts. Discordant CTC AR-V7 results and AR-V7 protein expression in matched, same-patient biopsies are reported. Patient summary: Liquid biopsies that determine circulating tumour cell androgen receptor splice variant-7 status have the potential to impact treatment decisions in metastatic castration-resistant prostate cancer patients. Robust clinical qualification of these assays is required before their routine use.

Original languageEnglish (US)
Pages (from-to)676-685
Number of pages10
JournalEuropean Urology
Volume76
Issue number5
DOIs
StatePublished - Nov 2019

Keywords

  • Androgen receptor
  • Androgen receptor splice variant-7
  • Biomarker
  • Liquid biopsy
  • Metastatic castration-resistant prostate cancer
  • Prognostic

ASJC Scopus subject areas

  • Urology

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