Evaluation and significance of circulating epithelial cells in patients with hormone‐refractory prostate cancer

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Purpose: Recent developments in rare-cell technology have led to improved blood-based assays that allow for the reliable detection, enumeration, and more recently, genomic profiling of circulating tumor cells (CTC). We evaluated two different approaches for enumeration of CTCs in a prospective therapeutic study of patients with metastatic triple-negative breast cancer (TNBC).Experimental Design: The CellSearch system, a commercially available and U.S. Food and Drug Administration (FDA)-cleared assay for CTC enumeration, and IE/FC, an alternative method using EPCAM-based immunomagnetic enrichment and flow cytometry that maintains cell viability, were used to enumerate CTCs in the blood of patients with metastatic TNBC. CTC numbers were assessed at baseline and 7 to 14 days after initiation of therapy with cetuximab AE carboplatin in a phase II multicenter clinical trial (TBCRC 001).Results: CTC numbers from two methods were significantly correlated at baseline (r ¼ 0.62) and at 7 to 14 days (r ¼ 0.53). Baseline CTCs showed no association with time-to-progression (TTP), whereas CTCs at 7 to 14 days were significantly correlated with TTP (CellSearch P ¼ 0.02; IE/FC P ¼ 0.03). CTCs at both time points were significantly associated with overall survival (OS) [CellSearch: baseline (P ¼ 0.0001) and 7 to 14 days (P < 0.0001); IE/FC: baseline (P ¼ 0.0009) and 7 to 14 days (P ¼ 0.0086)].Conclusions: Our findings demonstrate that CTC enumeration by two different assays was highly concordant. In addition, results of both assays were significantly correlated with TTP and OS in patients with TNBC. The IE/FC method is also easily adapted to isolation of pure populations of CTCs for genomic profiling.

“…Approximately 10 mL of blood was subjected to IE/FC as previously described (11,13,(16)(17)(18). All IE/FC samples were processed within 36 hours.…”

Section: Ctc Enumeration With Ie/fcmentioning

confidence: 99%

Circulating Tumor Cell Analysis in Metastatic Triple-Negative Breast Cancers

Magbanua

Carey

DeLuca

et al. 2015

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“…Previous work by others in breast (6,9) and colorectal (5) cancers and by ourselves and others in castration-resistant prostate cancer (8,10,23) have shown its prognostic importance without quantitation of its predictive strength. Although it is a factor in a prognostic nomogram (13), baseline Gleason score was not predictive of overall survival in our study.…”

Section: Discussionmentioning

confidence: 99%

Circulating Tumor Cell Number and Prognosis in Progressive Castration-Resistant Prostate Cancer

Danila

Heller

Gignac

et al. 2007

612

456

Purpose: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. Experimental Design: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We estimated the probability of survival over time by the Kaplan-Meier method. The concordance probability estimate was used to gauge the discriminatory strength of the informative prognostic factors. Results: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. Conclusions: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.

“…By using reverse transcription-PCR and prostate-specific membrane antigen as mRNA marker for monitoring CTCs in clinically localized PCa patients during radical prostatectomy, a previous report also showed significant correlations of CTCs with advanced tumor stages and increasing Gleason scores (28). Furthermore, the isolation of CTCs by immunomagnetic capture and flow cytometry fluorescenceactivated cell sorting showed that the CTC counts were strongly associated with survival of patients with progressive castrationresistant or hormone-refractory PCa (5,10). The use of a diagnostic antibody targeting the insulin-like growth factor-IR epitope showed that insulin-like growth factor-IR -positive CTCs were most common in advanced hormone-refractory PCa (29).…”

Section: Discussionmentioning

confidence: 99%

“…However, bone marrow aspiration is an invasive procedure, and therefore, many groups have focused on the detection of circulating tumor cells (CTC) in the peripheral blood of PCa patients (5 -13). The clinical utility of CTC counts in PCa is under active investigation with some promising clinical data from single institutions (5,7,8,10). The possibility of detecting tumor cell dissemination years before the onset of metastasis may allow an early curable therapeutic intervention and improve the clinical management of PCa patients.…”

mentioning

confidence: 99%

Cell-free Tumor DNA in Blood Plasma As a Marker for Circulating Tumor Cells in Prostate Cancer

Schwarzenbach

Alix‐Panabières

Müller

et al. 2009

221

141

Purpose: Circulating cell-free DNA in the blood of cancer patients harbors tumor-specific aberrations. Here, we investigated whether this DNA might also reflect the presence of circulating tumor cells (CTC). Experimental Design: To identify the source of cell-free DNA in blood, plasma derived from 81 patients with prostate cancer was examined for CTCs and cell-free DNA. An epithelial immunospot assay was applied for detection of CTCs, and a PCR-based fluorescence microsatellite analysis with a panel of 14 polymorphic markers was used for detection of allelic imbalances (AI). Results: The plasma DNA levels significantly correlated with the diagnosis subgroups of localized (stage M0, n = 69) and metastasized prostate cancer (stage M1, n = 12; P = 0.03) and with the tumor stage of these patients (P < 0.005). AI was found on cell-free DNA in plasma from 45.0% and 58.5% of M0 and M1 patients, respectively. Detection of CTCs showed that 71.0% or 92.0% of the M0 and M1 patients harbored 1 to 40 CTCs in their blood, respectively.The occurrence of CTCs correlated with tumor stage (P < 0.03) and increasing Gleason scores (P = 0.04). Notably, significant associations of the number of CTCs with the AI frequencies at the markers D8S137 (P = 0.03), D9S171 (P = 0.04), and D17S855 (P = 0.02) encoding the cytoskeletal protein dematin, the inhibitor of the cyclin-dependent kinase CDKN2/p16 and BRCA1, respectively, were observed. Conclusions: These findings show, for the first time, a relationship between the occurrence of CTCs and circulating tumor-associated DNA in blood, which, therefore, might become a valuable new source for monitoring metastatic progression in cancer patients.