Elsevier

European Urology

Volume 73, Issue 6, June 2018, Pages 818-821
European Urology

Brief Correspondence
Expression of Androgen Receptor Splice Variant 7 or 9 in Whole Blood Does Not Predict Response to Androgen-Axis–targeting Agents in Metastatic Castration-resistant Prostate Cancer

https://doi.org/10.1016/j.eururo.2018.01.007Get rights and content

Abstract

In 2014, a landmark study was published demonstrating that the expression of androgen receptor splice variant (AR-V) 7 was a negative predictive biomarker for response to abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) patients. However, these results were not supported by the recently reported ARMOR3-SV phase III clinical trial, which employed an identical circulating tumour cell assay to assess AR-V7 expression. Therefore, the predictive utility of AR-V7 expression in mCRPC remains uncertain, as does any potential association between other AR-Vs and treatment response. To further investigate, we designed a highly sensitive and specific whole blood assay for detecting AR-V7 and AR-V9. We then examined for a correlation between baseline AR-V7/V9 status and treatment outcome in 37 mCRPC patients commencing abiraterone or enzalutamide. Of the patients, 24% (9/37) were AR-V–positive. Notably, prostate-specific antigen (PSA) response rates did not significantly differ between AR-V–positive (6/9) and AR-V–negative (18/28) patients (66% vs 64%, p = 0.9). Likewise, median PSA progression-free survival was not significantly different between AR-V–positive and AR-V–negative patients (9.2 mo vs not reached; p = 0.9). These data, which support the findings of the pivotal ARMOR3-SV clinical trial, suggest that baseline AR-V expression does not predict outcomes in mCRPC patients receiving abiraterone or enzalutamide.

Patient summary

Detection of androgen receptor splice variants (AR-Vs) in circulating tumour cells of advanced prostate cancer patients has been linked to resistance to abiraterone and enzalutamide. We designed a blood test to detect AR-Vs that can be performed more routinely than tests involving circulating tumour cells and found that patients with AR-Vs still benefit from these effective treatments.

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    In addition, Liu et al. (2016) explained that by eliminating the circulating tumor cell (CTC) selection process, they shortened the application time and increased the sensitivity of the test, thereby enabling more patients to benefit from these tests. However, To et al. (2018) suggested that the expression states of AR variant 7 or 9 in whole blood cannot predict response to agents targeting the androgen pathway in mCRPC. They also stated that progression-free survival rate did not differ significantly between variant positive and variant negative patients.

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    The TMPRSS2:ERG fusion transcript was included given its demonstrated value as a treatment biomarker [16]. Finally, we included our previously optimised, highly sensitive, and specific whole-blood assay for AR-V7 and AR-V9 [1]. Peripheral blood (2.5 ml) was collected in a PAXgene RNA blood tube (Qiagen, Hilden, Germany) and stored at −80 °C until batch sample processing.

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    Furthermore, when Efstathiou et al. [41] analyzed AR-V7 protein levels in 60 patients with bone metastatic CRPC before and 8 weeks after enzalutamide treatment, AR-V7 expression was found to be associated with primary resistance to enzalutamide. However, To et al. [22] were unable to correlate baseline AR-V7 or AR-V9 in whole blood to PSA response rate or PSA progression-free survival. Overall, the varying results from these studies suggest that the potential of AR-V7 as a predictive biomarker is still ambiguous and more study in this area is needed.

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These authors contributed equally to this work.

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