PSMA-positive Circulating Tumor Cell Detection and Outcomes with Abiraterone or Enzalutamide Treatment in Men with Metastatic Castrate-resistant Prostate Cancer

Abstract

Background: In men with mCRPC, PSMA-targeted radioligand therapy has drastically improved clinical outcomes. A liquid biopsy characterizing PSMA expression could be useful in guiding optimal therapy. Methods: We conducted a retrospective analysis of the prospective multicenter PROPHECY trial of men with mCRPC (n=118) treated with abiraterone (abi) or enzalutamide (enza). CTCs were enriched (CTC/mL) and characterized for PSMA protein expression/heterogeneity at baseline and progression. We utilized proportional hazards modeling of the association between PSMA+ CTC enumeration with overall survival(OS) and progression free survival(PFS). Results: Overall, 97 men with mCRPC had evaluable blood samples for baseline CTC PSMA detection; 78 men (80%) had detectable CTCs. Of these, 55%(43/78) men had any PSMA CTC detection, 21%(16/78) had ≥2 PSMA+ CTCs/mL, and 19%(8/43) were 100% PSMA positive. At progression on abi/enza, 88%(50/57) of men had detectable CTCs, 68%(34/50) had any PSMA CTCs, and 12%(4/34) had 100% PSMA+ CTCs. Among paired cases (n=57), PSMA+ CTC detection increased slightly after abi/enza progression. Using an optimal cut-off of ≥2 PSMA+ CTCs/mL, median OS was 26, 21, and 11 mo for men without CTCs, PSMA- CTCs, and PSMA+ CTCs. Adjusting for prior abi/enza therapy, Halabi clinical risk-score, and CTC enumeration, the hazard ratios for OS and PFS for PSMA+ CTC+ were 3.0 (95% CI=1.1-7.8) and 2.3 (95%CI=0.9-5.8). Conclusions: We observed PSMA CTC heterogeneity between and within patients with mCRPC over time during abi/enza progression. CTC PSMA enumeration was adversely prognostic independent of clinical factors and disease burden. Further validation is warranted in the context of PSMA-targeted therapies.

Prognostic Role of Circulating Tumor Cells in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel: A Prospective Biomarker Study

“…However, in the past decade, emerging technologies for CTC isolation and characterization have permitted research on the biology of CTCs. These studies have identified distinct molecular subgroups of CTCs in patients with advanced PCa providing insights into inter-patient heterogeneity and subsequently potential targets for treatment [ 28 , 29 ]. The detection of epithelial–mesenchymal transition (EMT) markers on CTCs has been increasingly demonstrated to correlate with poor survival and resistance to treatment [ 30 ].…”

Dissemination of Circulating Tumor Cells in Breast and Prostate Cancer: Implications for Early Detection

“…This poses a challenge for size-based isolation methods, potentially leading to interference from leukocytes and failure in capturing smaller CTCs. The Epic Sciences CTC platform, a nonenrichment-based method, prevents the loss of any CTCs by depositing all nucleated cells from the blood onto slides for subsequent immunofluorescence or genomic analysis ( 100 , 101 ). This unique platform enables biobanking of unstained samples and analyzing plasma from the same sample; however, this assay does not allow for viable CTC collection.…”

“…In contrast, CTC counts have recently demonstrated greater predictive value for patient survival over traditional PSA levels in metastatic castration-resistant prostate cancer (mCRPC) ( 54 , 130 , 131 ), substantially contributing to disease monitoring and prognosis. Emerging technologies have enabled the isolation of CTCs in mCRPC patients and offer crucial insights into the molecular characteristics of these cells, signifying a paradigm shift ( 54 , 55 , 86 , 87 , 101 , 132 ). The solid clinical value of the presence of CTCs in mCRPC allows for expansion into the area of early-stage prostate cancer detection.…”

Can PSMA PET/CT help in dose-tailoring in post-prostatectomy radiotherapy?

“…Another possibility may be the use of PSMA as a biomarker on circulating tumor cells (CTCs). So far, in small studies, a high fraction of PSMA-negative CTCs has been shown to be a negative prognostic factor in metastatic hormone-resistant cancers ( 44 , 45 ).…”