Dynamics of circulating tumor cell subsets defined by PSMA and EpCAM predict survival in metastatic castration-resistant prostate cancer patients treated with 177 Lu-PSMA-617
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Background
177 Lu-PSMA-617 radioligand treatment represents a major advancement in the management of metastatic castration-resistant prostate cancer (mCRPC), but key questions remain about tumor-cell dynamics and evolution in patients who have received this drug. Here, we used a circulating tumor cell (CTC) capture assay to assess the prognostic capacity of CTC subset dynamics following 177 Lu-PSMA-617 treatment in a cohort of mCRPC patients.
Methods
Using an AI-empowered holographic imaging platform combined with in-flow protein marker analysis, we prospectively analyzed serial CTC samples from patients receiving 177 Lu-PSMA-617 therapy at pre-treatment and on-treatment time points (n=39 of 100 enrolled patients). PSMA and EpCAM proteins in CTCs were determined by immunofluorescence staining. Proportions and absolute counts of CTC subsets delineated by PSMA and EpCAM proteins were assessed in PSA50 responders (n=19) and non-responders (n=20). Within-patient changes in CTC subsets were compared using Wilcoxon signed-rank tests with Benjamini-Hochberg correction. Associations of CTC subset abundance and dynamics with overall survival were assessed using Kaplan-Meier estimates with log-rank tests and univariable Cox proportional hazards models.
Results
PSMA and EpCAM stratified CTCs into subsets, some of which were associated with survival outcomes following 177 Lu-PSMA-617. We observed an increase in the proportion of PSMA−/EpCAM+ CTCs following 177 Lu-PSMA-617, with a larger increase occurring in PSA50 responders (6.2% to 18.7%; p=0.041) than non-responders (7.9% to 15.4%; p=0.023). This corresponded to a decrease in the proportion of PSMA+/EpCAM-CTCs, whereas the proportion of PSMA+/EpCAM+ CTCs did not decline. On-treatment counts of >5 CTCs, relative to ≤5 CTCs, were associated with shorter overall survival in the PSMA+/EpCAM+ (HR 3.56, 95%CI 1.32-9.60, p=0.012) and PSMA+/EpCAM-(HR 7.50, 95%CI 0.96-52.99, p=0.054) subsets. Finally, on-treatment declines in PSMA+/EpCAM+ (HR 0.74, p=0.49) and PSMA+/EpCAM-(HR 0.61, p=0.215) CTC subsets were not significantly associated with overall survival relative to sustained high levels of these cells.
Conclusions
In mCRPC patients receiving 177 Lu-PSMA-617, dynamic changes in CTC subsets delineated by PSMA and EpCAM expression may have prognostic value, justifying additional evaluation.
