Introduction

There is a continued need to develop liquid biomarkers that predict response to 2nd generation hormonal therapies. While circulating tumor cell (CTC)-based detection of AR-V7 has been shown to be one potential marker, the apparent rarity of AR-V7 positivity is indicative of the importance of other drivers of resistance in this setting. We sought to utilize a multiplex gene expression platform for assessing CTCs in order to determine other potential predictive biomarkers of response to abiraterone and enzalutamide.

Methods

Whole blood (~5mL) was obtained from 37 patients with metastatic castration resistant prostate cancer (mCRPC) starting enzalutamide (n=16) or abiraterone (n=21). CTCs were isolated using anti-EpCAM-conjugated magnetic beads, and following cell lysis, mRNA was extracted followed by multiplex qRT-PCR for 44 prostate cancer-related genes plus internal controls. Gene expression was normalized to controls, and samples were considered CTC-positive based on a previously established set of epithelial markers (EpCAM, EGFR, DSG2, KRT8, KRT18 and KRT19). The primary endpoint was PSA progression-free survival (PFS), with PSA progression defined as an increase of 25% or more above the nadir. Univariable Cox regression analyses were performed to assess for genes associated with PFS at false discovery rate (FDR) < 0.20.

Results

We identified 27 (73%) patients with detectable CTCs among the 37mCRPC patients. The median age of the cohort was 73 years (IQR 64-78), and patients were followed for a median of 7.4 months (IQR 3.8-18.5). A total of 22 (81.5%) patients suffered PSA progression at a median time of 3.3 months (IQR 1.5-6.8). In the Cox analysis, PSMA (HR 3.83, 95%CI 1.62-9.03, p=0.002), TSPAN8 (HR 2.04, 95%CI 1.21-3.46, p=0.008), BMP7 (HR 1.46, 95%CI 1.09-1.95, p=0.017), and GAS6 (HR 2.29, 95%CI 1.16-4.51, p=0.017) were independent predictors of shorter PFS.

Conclusions

We identified four prostate cancer-related genes that can be identified in CTCs and appear to predict short PFS in men with mCRPC being treated with enzalutamide or abiraterone. While this is a small cohort and prospective validation is needed, these findings highlight the potential role for this approach in helping guide therapy choice.

Funding

This work was supported by the Prostate Cancer Foundation and Department of Defense.