Clinical Significance of Mesenchymal Circulating Tumor Cells in Patients With Oligometastatic Hormone-Sensitive Prostate Cancer Who Underwent Cytoreductive Radical Prostatectomy

Abstract

PurposeGrowing evidence shows that circulating tumor cells (CTCs) become more aggressive after the epithelial–mesenchymal transition (EMT), though the clinical significance of CTCs undergoing EMT in oligometastatic hormone-sensitive prostate cancer (omHSPC) patients has not yet been reported. Accordingly, the aim of this study was to detect the CTC level and investigate the clinical significance of mesenchymal CTCs in omHSPC patients who underwent cytoreductive radical prostatectomy (CRP).Materials and MethodsBlood samples were drawn from 54 omHSPC patients who underwent CRP. The CanPatrol CTC enrichment technique was applied to isolate and identify different phenotypes of CTCs, which were classified as epithelial (E-CTCs), mesenchymal (M-CTCs), or biphenotypic epithelial/mesenchymal (Bi-CTCs). Univariable and multivariable Cox regression analyses were employed to investigate potential prognostic factors for metastatic castration-resistant prostate cancer (mCRPC)-free survival and cancer-specific survival (CSS). The prognostic value of CTCs for CSS and mCRPC-free survival was assessed using time-dependent receiver operating characteristic (ROC) curves and Kaplan–Meier analysis.ResultsCTCs were detected in 51 of 54 patients (94%). E-CTC, M-CTC, and Bi-CTC detection rates were 56%, 67%, and 85%, respectively. A positive correlation was found between the M-CTC count and number of bone metastases (p = 0.012). Time-dependent ROC analysis showed that the M-CTC count had higher predictive power than E-CTC or Bi-CTC for mCRPC-free survival (3-year area under the curve [AUC] values: 0.64, 0.60, and 0.61) and CSS (3-year AUC: 0.86, 0.58, and 0.67). Additionally, time-dependent ROC analysis revealed total CTCs (T-CTCs) ≥5 and M-CTCs ≥2 to be the cutoff points with optimal specificity and sensitivity. Based on multivariable Cox regression, T-CTC and M-CTC counts were both independently associated with CSS and mCRPC-free survival (all p < 0.05), though E-CTCs and Bi-CTCs had no significant prognostic value (all p > 0.05). Patients with T-CTC ≥5 or M-CTC ≥2 had significantly worse mCRPC-free survival and CSS than those with T-CTC<5 or M-CTC<2 (all p < 0.05) after CRP.ConclusionCTC quantification and phenotype characterization provide prognostic information, and M-CTCs can be used as a novel biomarker for omHSPC patients who undergo CRP. The results need to be validated in prospective studies.

Automated Image Analysis for Characterization of Circulating Tumor Cells and Clusters Sorted by Magnetic Levitation

“…[46,47] In addition, vimentin is also present at the extracellular surface of endothelial cells and macrophages, [48][49][50] which could potentially appear in the blood and exhibit CD45staining. The definition of mesenchymal CTCs in our study is based on the current literature, which suggests that VIM expression is associated with mesenchymal-like properties in cancer cells, [29,[51][52][53][54][55][56][57][58] including increased motility, invasiveness, and resistance to apoptosis. However, we understand that this definition may not be specific to CTCs, as other rare circulating cells in the blood may also express VIM.…”

“…Additionally, we utilized shape‐based features to identify elongated or irregularly shaped cells, which are more likely to represent CTCs rather than other blood cells. In addition to this image‐based analysis, the mesenchymal identity of the detected CTCs and CTCCs can be further differentiated by using other immunofluorescent mesenchymal markers in addition to Vim, such as N‐cadherin [ 29 ] and TWIST‐1, [ 57,58 ] as described in the literature. Thus, in addition to the accuracy and the time savings, our approach enables the capture of CTC and CTCC heterogeneity, ranging from epithelial to mesenchymal phenotypes.…”

Identification of epithelial and mesenchymal circulating tumor cells in clonal lineage of an aggressive prostate cancer case

“…We hypothesized the reasons to be that genetic defects of EMT-related genes could cause mesenchymal transformation in clade4/5 subclone or loss of cell state transition ability in clade2 subclone, e.g., copy number gains of PDGFRA, PIK3CA , etc in the clade4/5 subclone while copy number loss of TWIST2, JAK2, etc in the clade2 subclone. In addition to 4 subtypes of CTCs, we also included “VIM + only” classification of cells to represent the full spectrum of rare cells detected and to further investigate the potential of CTCs that completed the EMT and lost epithelial biomarker, e.g., cytokeratin 30 , 31 . Single cell copy number profiling showed those cells did not carry the cancer cell genomic architecture (the main clone) which is consistent with our observation in the previous publication 9 , demonstrating clonality in CK + cell groups in metastatic prostate cancer (mPC).…”

Gibt es eine Indikation zur Lokaltherapie des mHSPC?

“…Neben dem PSA-Wert gibt es immer wieder Bestrebungen weitere Marker für eine optimale Patientenselektion zu etablieren: So korrelieren bspw. die Last an zirkulierenden Tumorzellen, ein verringerter HALP-Score, welcher die Parameter Hämoglobin, Albumin, Lymphozyten und Thrombozyten berücksichtigt sowiemit Albumin assoziiertein Malnutrition [17,18,19,20]. Nichtsdestotrotz bleibt der PSA-Wert mit seinem Ansprechen zurzeit der klinisch am weitesten etablierte Marker [9].…”