A circulating tumor cell RNA assay for dynamic assessment of androgen receptor signaling inhibitors sensitivity in metastatic castration-resistant prostate cancer.

157 Background: Tissue-based gene signatures can predict clinical behavior in prostate cancer (PC). Our objective was to extend their application to circulating tumor cells (CTCs) and to show that changes in the signature were associated with changes in clinical behavior. Methods: Our approach combined the Thermoresponsive(TR)-NanoVelcro CTC purification system with the Nanostring nCounter system for cellular purification and transcriptomic analysis. The Prostate Cancer Classification System (PCS) panel was modified for use in CTCs. We selected 31 blood samples from 23 PC patients receiving androgen receptor signaling inhibitors (ARSI) and measured the PCS1 Z score (probability). These findings were compared with clinical outcome data (responsiveness/resistance). Results: A modified, 16-gene PCS1 signature was established and validated through a rigorous bioinformatics process. We performed analytical validation of our combined CTC-RNA system to ensure reproducibility and specificity. In patient bloods, ARSI-resistant samples (ARSI-R, n = 14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n = 17) (Rank-sum test, P = 0.003). The analyzed bloods contained samples from 8 patients who developed resistance to an ARSI allowing for dynamic measurement of gene expression. Our analysis found that the PCS1 Z score increased at the time that ARSI-resistance emerged (Pairwise T-test, P = 0.016). Conclusions: Using this new methodology, contemporary, clinically-relevant gene signatures such as PCS could be measured non-invasively in CTCs. These findings can be used to relate gene expression to clinical drug response. This approach also allowed for measurement of dynamic variations of gene expression in individual patients over time that correlated to ARSI sensitivity.

Download Full-text

Assessment of immunohistochemical testing for androgen receptor splice variant 7 as a biomarker to predict resistance to androgen receptor signaling inhibitors in metastatic prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.308 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 308-308

Author(s):

Ojas Harihar Vyas ◽

Matthew James Butler ◽

Elizabeth Ann Bowhay-Carnes ◽

Muhammad Pathan ◽

Paromita Datta

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Splice Variant ◽

Receptor Signaling ◽

Health Administration ◽

Primary Resistance ◽

Androgen Receptor Signaling ◽

Signaling Inhibitors ◽

Psa Response ◽

Androgen Receptor Splice Variant

308 Background: Androgen receptor splice variant 7 (AR-V7) has been shown to confer resistance to androgen receptor signaling inhibitors (ARS-I) such as enzalutamide (enza) and abiraterone (abi). Resistance can be observed at the time of initial treatment, or may be acquired later in the disease course. Prior research has primarily focused on AR-V7 expression in circulating tumor cells (CTCs) but the utility of more affordable immunohistochemical (IHC) testing to predict for primary resistance to ARS-I remains unknown, which is of particular relevance as ARS-I gain use as initial therapy. Methods: We identified patients in the South Texas Veterans Health Administration Tumor Registry with metastatic, castrate-resistant prostate cancer who received ARS-I since 2011. IHC for AR-V7 staining was validated on controls and performed on tissue from the most recent tissue specimen (diagnostic biopsy, prostatectomy, or biopsy of a metastatic site) on all identified patients with adequate tissue available. Results: 25 of 42 (60%) patients receiving abi had PSA response with median duration of response (DOR) of 231 days. 14 of 26 (54%) of patients receiving enza experienced PSA response with a median DOR of 165 days. IHC is currently being interpreted on stored tissue specimens to assess predictive efficacy of AR-V7 staining. The de-novo rate of AR-V7 expression and correlation with response to ARS-I in the veteran population will be reported with final results. Conclusions: IHC testing for AR-V7 may provide a cost-effective biomarker to identify patients resistant to ARS-I, thus avoiding thus avoiding time-consuming and costly treatment with ineffective therapy. Further study is warranted to assess cost-effectiveness and reduction in unnecessary toxicity by the use of IHC testing for AR-V7 in the front-line setting to predict primary resistance for patients that would otherwise qualify for ARS-I.

Download Full-text