PSMA‐heterogeneity in metastatic castration‐resistant prostate cancer: Circulating tumor cells, metastatic tumor burden, and response to targeted radioligand therapy

Abstract

AbstractBackgroundWe explored the interrelation between prostate‐specific membrane antigen (PSMA) expression on circulating tumor cells (CTCs) and that of solid metastatic lesions as determined by whole‐body PSMA‐targeted positron emission tomography (PET) to refine the prediction of response to subsequent PSMA‐targeted radioligand therapy (RLT).MethodsA prospective study was performed in 20 patients with advanced mCRPC. Of these, 16 underwent subsequent RLT with [177Lu]Lu‐PSMA‐617 at a dose of 7.4 GBq every 6–8 weeks. PSMA expression on CTCs using the CellSearch system was compared to clinical and serological results, and to marker expression in targeted imaging and available histological sections of prostatectomy specimens (19% of RLT patients). Clinical outcome was obtained after two cycles of RLT.ResultsMarked heterogeneity of PSMA expression was observed already at first diagnosis in available histological specimens. Targeted whole‐body imaging also showed heterogeneous inter‐ and intra‐patient PSMA expression between metastases. Heterogeneity of CTC PSMA expression was partially paralleled by heterogeneity of whole‐body tumor burden PSMA expression. Twenty percent of CTC samples showed no PSMA expression, despite unequivocal PSMA expression of solid metastases at PET. A high fraction of PSMA‐negative CTCs emerged as the sole predictor of poor RLT response (odds ratio [OR]: 0.9379 [95% confidence interval, CI, 0.8558–0.9902]; p = 0.0160), and was prognostic for both shorter progression‐free survival (OR: 1.236 [95% CI, 1.035–2.587]; p = 0.0043) and overall survival (OR: 1.056 [95% CI, 1.008–1.141]; p = 0.0182).ConclusionThis proof‐of‐principle study suggests that liquid biopsy for CTC PSMA expression is complementary to PET for individual PSMA phenotyping of mCRPC.