Circulating Tumor Cells Are Detectable and Independent of PSA and PSMA-PET Metrics in Localized High-Risk and Biochemically Recurrent Prostate Cancer | medRxiv

Correlative study endpoint analyses schema:

Circulating tumor cells (CTCs) were isolated and quantified from blood samples collected from localized High Risk (HR) and Biochemical Recurrence (BCR) patients. CTC isolation was performed either using EpCAM-based capture or with magnetic CD45 depletion. The quantified CTC data were then systematically correlated with clinical information and PET imaging data to explore associations between CTC burden, imaging findings, and clinical outcomes.

Breaking New Ground: Circulating Tumor Cells as Independent Biomarkers in Localized High-Risk and Recurrent Prostate Cancer

A promising liquid biopsy approach offers new insights for prostate cancer monitoring, independent of PSA and PSMA-PET imaging

The Bottom Line

Researchers at the National Cancer Institute have demonstrated that circulating tumor cells (CTCs) can be successfully detected in men with localized high-risk prostate cancer and those experiencing biochemical recurrence—even when conventional imaging shows no evidence of disease. This groundbreaking study suggests that liquid biopsies could become a valuable tool for monitoring cancer activity independently of traditional markers like PSA levels and PSMA-PET scans.

What Are Circulating Tumor Cells?

Circulating tumor cells are cancer cells that have broken away from the primary tumor and entered the bloodstream. Think of them as "cellular scouts" that can potentially travel to distant parts of the body to establish new cancer sites. While CTCs have been known to exist for years, detecting them has been challenging because they're extremely rare—typically just 1-10 cells per milliliter of blood.

The significance of finding CTCs in men with localized disease cannot be overstated. As study co-author Dr. Peter Choyke from the National Cancer Institute explained, these findings suggest that even in apparently localized cancer, some tumor cells may already be circulating, providing important information about disease activity that current standard tests might miss.

The Study at a Glance

The research team analyzed blood samples from 105 prostate cancer patients enrolled in a clinical trial before they underwent PSMA-PET/CT imaging. The patients were divided into two groups:

  • 31 men with localized high-risk disease
  • 74 men with biochemical recurrence (rising PSA after treatment but no visible disease on conventional imaging)

Using two different detection methods—flow cytometry and droplet digital PCR (ddPCR)—the researchers successfully identified CTCs in both patient groups:

Flow Cytometry Results:

  • 14% of high-risk patients had detectable CTCs
  • 24% of biochemical recurrence patients had detectable CTCs

ddPCR Results (measuring EPCAM and PSMA gene expression):

  • 53% of high-risk patients showed elevated EPCAM expression
  • 29% of high-risk patients showed elevated PSMA expression
  • Both markers were found in biochemical recurrence patients, though at lower rates

Why This Matters for Patients

Independent Monitoring Tool

Perhaps most importantly, the study found no correlation between CTC levels and either PSA values or PSMA-PET scan results. This independence suggests that CTCs might provide unique information about cancer behavior that complement—rather than duplicate—existing tests.

Early Detection Potential

The ability to detect CTCs in localized disease opens exciting possibilities for earlier intervention. As liquid biopsy expert Dr. Catherine Alix-Panabières noted in recent research, "CTCs represent a real-time snapshot of the tumor's biology and could potentially identify aggressive disease before it becomes clinically apparent."

Minimally Invasive Monitoring

Unlike tissue biopsies or repeat imaging, CTC detection requires only a simple blood draw—making it an attractive option for regular monitoring without the discomfort, expense, or radiation exposure of other approaches.

The Broader Context: Liquid Biopsy Revolution

This study arrives at an exciting time in cancer care. The FDA has already approved several liquid biopsy tests, including the CellSearch® system for metastatic prostate cancer. Currently, CellSearch is the only FDA-approved CTC detection system for prostate cancer, but it's limited to men with advanced, castration-resistant disease.

Recent advances in liquid biopsy technology have been remarkable:

FDA-Approved Tests

  • CellSearch® CTC Test: Approved for monitoring metastatic breast, colorectal, and prostate cancers
  • cobas® EGFR Mutation Test: Detects circulating tumor DNA for lung cancer treatment decisions
  • Guardant360® CDx: Multi-cancer genetic testing from blood samples
  • FoundationOne® Liquid CDx: Comprehensive genomic profiling from plasma

Emerging Technologies

Several new CTC detection methods are showing promise:

  • EPISPOT assay: Detects viable cancer cells based on protein secretion
  • CellCollector: An in-vivo device that captures CTCs directly from blood vessels
  • Microfluidic platforms: Advanced chip-based systems with improved sensitivity

PSMA-PET: The Current Gold Standard

While this study focused on CTCs, it's worth understanding how they relate to current best practices. PSMA-PET imaging has revolutionized prostate cancer care over the past decade. The FDA approved Gallium-68 PSMA-11 in 2020, followed by additional PSMA tracers in 2021 and 2023.

PSMA-PET Advantages:

  • Superior accuracy compared to conventional imaging (92% vs 65%)
  • Excellent detection of small metastases
  • Changes treatment plans in up to 28% of patients
  • Particularly effective for biochemical recurrence

However, PSMA-PET has limitations:

  • Expensive and not universally available
  • Requires specialized facilities and expertise
  • Can miss PSMA-negative cancer cells
  • May show false positives in certain conditions

Clinical Implications and Future Directions

For High-Risk Localized Disease

The detection of CTCs in men with apparently localized cancer raises important questions about treatment approaches. Should men with detectable CTCs receive more aggressive initial treatment? Could CTC monitoring help identify those who need earlier intervention?

For Biochemical Recurrence

In men with rising PSA but negative conventional imaging, CTC detection might help:

  • Identify those with active disease requiring treatment
  • Monitor treatment response more accurately than PSA alone
  • Guide timing of more expensive imaging studies

Treatment Monitoring

The study's finding that some CTCs express PSMA while others express EPCAM—and some express both—highlights cancer's heterogeneity. This information could potentially guide treatment selection, particularly for PSMA-targeted therapies like Lutetium-177 PSMA-617 (Pluvicto®), which was FDA-approved in 2022 for metastatic castration-resistant prostate cancer.

Challenges and Limitations

The researchers were careful to note several important limitations:

Technical Challenges:

  • CTCs are extremely rare, making detection difficult
  • Different detection methods showed varying results
  • Standardization across laboratories remains challenging

Clinical Limitations:

  • Limited follow-up data on patient outcomes
  • Small sample sizes in some subgroups
  • No direct comparison of detection methods

Biological Complexity:

  • Cancer cells can lose epithelial markers during metastasis (epithelial-to-mesenchymal transition)
  • PSMA expression can vary within tumors
  • The clinical significance of low CTC numbers remains unclear

Looking Ahead

Ongoing Research

Several exciting developments are on the horizon:

  1. Combination Approaches: Studies are testing whether combining multiple CTC detection methods improves sensitivity and clinical utility.
  2. Single-Cell Analysis: Advanced techniques allow researchers to study individual CTCs in detail, potentially revealing important information about cancer biology and drug resistance.
  3. Real-Time Monitoring: Newer technologies may enable continuous or frequent CTC monitoring to track disease progression and treatment response.
  4. Expanded Applications: Research is exploring CTC utility in earlier disease stages and for treatment selection.

Integration with Existing Care

Rather than replacing current approaches, CTCs will likely complement existing tools:

  • PSA monitoring for baseline disease activity
  • PSMA-PET for detailed anatomical assessment
  • CTC analysis for biological insights and treatment guidance
  • Traditional imaging for treatment planning

What This Means for Patients Today

While these findings are promising, patients should understand that CTC testing for localized or biochemically recurrent prostate cancer remains investigational. The CellSearch system is currently approved only for men with metastatic disease.

Current Recommendations:

  • Follow standard care guidelines for your disease stage
  • Discuss participation in clinical trials if interested in CTC testing
  • Stay informed about emerging liquid biopsy technologies
  • Maintain regular follow-up with your oncology team

Questions to Ask Your Doctor:

  • Could liquid biopsy testing be appropriate for my situation?
  • Are there clinical trials involving CTC analysis I might consider?
  • How might future CTC testing complement my current monitoring plan?
  • What new monitoring technologies are becoming available?

The Bigger Picture

This study represents an important step toward personalized cancer care. By potentially providing unique insights into cancer biology through a simple blood test, CTCs could help tailor treatment approaches to individual patients' needs.

As Dr. Roshan Shrestha, the study's co-corresponding author, noted, "These findings support the potential role of CTCs as a minimally invasive biomarker independent of serum PSA levels and PSMA-PET parameters." This independence is crucial—it suggests that CTCs might detect important cancer activity that other tests miss.

The ultimate goal is improving patient outcomes through better monitoring and treatment selection. While we're not there yet, studies like this one bring us closer to a future where a simple blood test could provide comprehensive information about cancer status, treatment response, and disease progression.

For now, the research continues, with larger studies and longer follow-up needed to fully understand the clinical utility of CTC testing in localized and biochemically recurrent prostate cancer. The early results, however, offer genuine hope for better, less invasive cancer monitoring in the years ahead.

Sources and References

  1. Rastogi, S., Sato, N., Lee, S., et al. (2025). "Circulating Tumor Cells Are Detectable and Independent of PSA and PSMA-PET Metrics in Localized High-Risk and Biochemically Recurrent Prostate Cancer." medRxiv. https://doi.org/10.1101/2025.07.09.25331014
  2. Harvard Health Publishing. (2025). "A liquid biopsy for metastatic prostate cancer." Harvard Health Blog. https://www.health.harvard.edu/blog/a-liquid-biopsy-for-metastatic-prostate-cancer-202501033085
  3. Cleveland Clinic. (2025). "Liquid Biopsy: What It Is & Procedure Details." https://my.clevelandclinic.org/health/diagnostics/23992-liquid-biopsy
  4. Casanova-Salas, I., et al. (2021). "Quantitative and Qualitative Analysis of Blood-based Liquid Biopsies to Inform Clinical Decision-making in Prostate Cancer." European Urology, 79(6), 762-771. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450827/
  5. Lin, D., et al. (2021). "Circulating tumor cells: biology and clinical significance." Signal Transduction and Targeted Therapy, 6(1), 404. https://www.nature.com/articles/s41392-024-02021-w
  6. Kuske, A., et al. (2016). "Improved detection of circulating tumor cells in non-metastatic high-risk prostate cancer patients." Scientific Reports, 6, 39736. https://www.nature.com/articles/srep39736
  7. OncoLive. (2023). "Emerging Uses for Circulating Tumor Cell Technology." https://www.onclive.com/view/emerging-uses-for-circulating-tumor-cell-technology
  8. CellSearch®. (2025). "CELLSEARCH® Circulating Tumor Cell Test." https://www.cellsearchctc.com/
  9. Hofman, M. S., et al. (2024). "Impact of PSMA PET on Prostate Cancer Management." Current Opinion in Urology, 34(2), 89-96. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11034977/
  10. UCSF Radiology. (2025). "Prostate Specific Membrane Antigen (PSMA) PET Imaging for Prostate Cancer." https://radiology.ucsf.edu/psma-pet-scan-for-prostate-cancer
  11. National Cancer Institute. (2020). "PSMA PET-CT Accurately Detects Prostate Cancer Spread." https://www.cancer.gov/news-events/cancer-currents-blog/2020/prostate-cancer-psma-pet-ct-metastasis
  12. Gupta, S., et al. (2023). "Performance of a blood-based liquid biopsy test to detect PSMA expression on circulating tumor cells in men with metastatic prostate cancer." Journal of Clinical Oncology, 41(6_suppl), 256. https://ascopubs.org/doi/10.1200/JCO.2023.41.6_suppl.256
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Circulating Tumor Cells Are Detectable and Independent of PSA and PSMA-PET Metrics in Localized High-Risk and Biochemically Recurrent Prostate Cancer | medRxiv

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