Whole blood androgen receptor variant expression and overall survival in metastatic castrate resistant prostate cancer

Chicago, IL (UroToday.com) The detection of full length androgen receptor (AR-FL) or AR variants (AR-Vs) in blood and association with outcomes in metastatic castrate resistant prostate cancer (mCRPC) is unknown. Dr. Giridhar presented a study comparing whole blood mRNA expression of AR-FL and AR-Vs to circulating tumor cells (CTCs) for predicting overall survival (OS) and time to treatment failure (TTF). 

Overall 92 men with mCRPC were enrolled in the PROMOTE study. After obtaining a pretreatment first blood test and metastatic site biopsy, patients were treated with Abiraterone and prednisone. Peripheral blood gene expression sequencing was available for 53 men. The authors also isolated RNA from whole blood collected in PAXgene RNA tubes. Whole transcriptome sequencing (RNAseq) was performed on blood samples and paired biopsies to detect AR-FL, ARV1, ARV3, ARV7, ARV8, AR12, ARV14, and ARV45. Reads were aligned to the GRCh38 reference genome with the spliced-alignment TopHat2 package. Lastly, CTCs were determined using the CELLSEARCH assay.

Median age was 75 (70-79) with a median PSA of 11.8 (5.4-41) at time of CRPC. The median follow up was 2.85 years, (range 0.27-3.45), and the median CTC count was 3 (range 0-372); 34/53 men were deceased. Blood based AR-FL or AR-Vs were detected in 50/53 patients with following distribution: AR-FL (41/53), ARV3 (9/53), ARV45 (8/53), ARV12 (4/53), ARV14 (4/53), ARV7 (2/53), and ARV8 (2/53). Whole blood AR-FL transcripts were highly correlated to paired bone biopsy (r2= 0.76). Elevated transcripts of either ARV12 or ARV14 were associated with decreased OS [hazard ratio (HR) 3.46, p = 0.006]. CTC count ≥5 was associated with poorer OS [HR 3.42, p = 0.02] and shorter TTF [HR 3.52, p = < 0.001]. Adjusting for CTC counts, in a multivariable model, blood AR12 and ARR14 expression was associated with poor OS [HR = 6.33, p = 0.009]. AR12 and CTCs trended toward improved AUC compared to CTC alone (0.78 vs 0.71, p = 0.07). 


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