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AR-V7 Protein in Circulating Tumor Cells-The Decider for Therapy?

In this issue of JAMA Oncology, Scher et al 1 present additional evidence that the presence of the constitutively active androgen receptor variant 7 (AR-V7) is a marker for resistance to standard androgen deprivation or second line androgen receptor (AR) targeting agents in men with metastatic prostate cancer. Blood samples were drawn prior to therapy and nucleated cells analyzed for protein expression by immunofluorescence for AR-V7 protein. Results were not used for clinical decision making. Remarkably, no patients with circulating tumor cells (CTCs) positive for AR-V7 protein responded to AR-directed therapy (as defined by a >50% prostate-specific antigen decline), and they had significantly worse progression-free survival and overall survival (OS) compared with patients with AR-V7– negative CTCs. These findings are in agreement with those previously reported by Antonorakis et al 2 using a different messenger RNA (mRNA)-based CTC assay. 2 These 2 studies provide compelling evidence that AR-V7–positive CTCs are a predictive biomarker for failure to respond to AR-directed therapy (AR-DT). The studies by Scher et al 1 and Antonorakis et al 2 differ in several respects. First, there was a lower proportion of patients with AR-V7–positive CTCs at each line of therapy using the protein-based assay compared with the mRNAbased assay. Although the patient groups were not entirely identical, this difference in detection may reflect greater sensitivity provided by polymerase chain reaction (PCR) vs antibody detection systems. Second, the issues of specificity of antibodies vs PCR are clearly different. Work has been presented showing that AR-V7 antibodies can react with nonprostate tissue and cell lines such as PC-3, in which no AR-V7 message or N-terminal AR protein c an be identified. 3 In the study by Scher et al, AR-V7 immunofluorescence was identified in CTCs that were cytokeratin negative or where other presumed CTCs in the sample were negative for AR N-terminal staining that should detect AR-V7. Although relevant in only a small fraction of the patient samples, appropriate prospective and interinstitutional correlative studies should be done to confirm sensitivity and specificity of the assay before the current test can be applied broadly.