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Updated: Nov 10, 2025
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Circulating Tumor Cell Chromosomal Instability and Neuroendocrine Phenotype by Immunomorphology and Poor Outcomes in
Landon C Brown1, Susan Halabi1,2, Joseph D Schonhoft3
1Department of Medicine, Duke Prostate and Urologic Cancer Center, Duke Cancer Institute, Duke University, Durham, North Carolina.
Purpose:
While the detection of AR-V7 in circulating tumor cells (CTC) is associated with resistance to abiraterone or enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC), it only accounts for a minority of this resistance. Neuroendocrine (NE) differentiation or chromosomal instability (CIN) may be additional mechanisms that mediate resistance.
Experimental Design:
PROPHECY was a multicenter prospective study of men with high-risk mCRPC starting abiraterone or enzalutamide. A secondary objective was to assess Epic CTC CIN and NE phenotypes before abiraterone or enzalutamide and at progression. The proportional hazards (PH) model was used to investigate the prognostic importance of CIN and NE in predicting progression-free survival and overall survival (OS) adjusting for CTC number (CellSearch), AR-V7, prior therapy, and clinical risk score. The PH model was utilized to validate this association of NE with OS in an external dataset of patients treated similarly at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY).
Results:
We enrolled 118 men with mCRPC starting on abiraterone or enzalutamide; 107 were evaluable on the Epic platform. Of these, 36.4% and 8.4% were CIN positive and NE positive, respectively. CIN and NE were independently associated with worse OS [HR, 2.2; 95% confidence interval (CI), 1.2-4.0 and HR 3.8; 95% CI, 1.2-12.3, respectively] when treated with abiraterone/enzalutamide. The prognostic significance of NE positivity for worse OS was confirmed in the MSKCC dataset (n = 173; HR, 5.7; 95% CI, 2.6-12.7).
Conclusions:
A high CIN and NE CTC phenotype is independently associated with worse survival in men with mCRPC treated with abiraterone/enzalutamide, warranting further prospective controlled predictive studies to inform treatment decisions.
Insights
Chromosomal instability (CIN) and neuroendocrine (NE) differentiation in circulating tumor cells (CTCs) predict poor survival in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. These findings suggest new therapeutic targets for mCRPC.
Area of Science:
- Oncology
- Cancer Biology
- Prostate Cancer Research
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) treatment resistance to abiraterone and enzalutamide is a significant clinical challenge.
- While AR-V7 detection in circulating tumor cells (CTCs) indicates resistance, it explains only a fraction of treatment failures.
- Alternative resistance mechanisms, including neuroendocrine (NE) differentiation and chromosomal instability (CIN), are hypothesized to play a role.
Purpose of the Study:
- To investigate the prognostic significance of CTC CIN and NE phenotypes in men with mCRPC receiving abiraterone or enzalutamide.
- To assess the association of these phenotypes with progression-free survival and overall survival (OS).
- To validate the prognostic value of NE differentiation for OS in an independent patient cohort.
Main Methods:
- The PROPHECY study prospectively enrolled men with high-risk mCRPC initiating abiraterone or enzalutamide.
- CTC CIN and NE phenotypes were assessed using the Epic platform before treatment and at progression.
- Proportional hazards models were used to analyze the association of CIN and NE with survival outcomes, adjusting for known prognostic factors.
Main Results:
- In the PROPHECY cohort (n=107), 36.4% of patients exhibited CIN and 8.4% showed NE phenotypes.
- Both CIN and NE positivity were independently associated with significantly worse overall survival (OS) (HR 2.2 and 3.8, respectively).
- The association between NE positivity and worse OS was confirmed in an external validation cohort from MSKCC (n=173; HR 5.7).
Conclusions:
- A high prevalence of CTC CIN and NE phenotypes is independently linked to poorer survival in mCRPC patients treated with abiraterone/enzalutamide.
- These CTC phenotypes represent critical mechanisms contributing to treatment resistance.
- Further prospective studies are warranted to confirm these findings and guide clinical treatment decisions.
