The detection of primary malignant circulating prostate cells; their significance and clinical utility: Beyond the Abstract

Early in the natural history of prostate cancer there is a dissemination of cancer cells firstly to the neurovascular structures and then into the circulation (1). However, the majority of these cells will not cause metastasis, destroyed by the immune system or shear forces in the circulation, failure to implant at distant sites or thrive in distant tissues (2).

Based on this hypothesis their detection would imply the presence of prostate cancer and if the majority of these cells are eliminated their presence as a  prognostic factor would be limited.

The only FDA approved system for the detection of circulating tumor cells (CTCs) is the EpCAM based CellSearch® system. However, in localized prostate cancer the detection rate was only between 11-25% (3-5), and unable to distinguish between healthy controls and cancer patients (4). It has further been reported that EpCAM positive cells are detected in benign disease, and may represent normal trafficking of cells or as a result of cytokine stimulation in inflammatory disease epitelial cells are able to enter the circulation (6). 

The frequency of CTC detection is method dependent, using anti-Ber4 and telomerase activity CTCs were detected in 80% of men with localised prostate cancer (7). 

We have used an immunocytochemical method to detect CTCs, called circulating prostate cells (CPCs) in our reports. We have a manual method, with differential gel centrifugation and standard immunocytochemical methods to detect CPCs. Recognising  the inherent deficiencies in such methodology, interobserver variability, the potential loss of CPCs during their isolation from peripheral blood and limits of the sensibility of immunocytochemistry there are advantages. Firstly in the real world the method can be performed in the routine immunocytochemical laborstory of a district general hospital, does not require expensive high technology equipment or reagents and thus could have widespread application when health resources are limited.

We have defined a circulating prostate cell as one that expresses PSA, however this does not define a malignant from a benign cell. To address this problem we used a second marker, P504S which in prostate biopsies is used to differentiare malignant from benign prostate tissue (8). Thus a maligant CPC is one that expresses PSA and P504S. To limit the effect of interobserver variation we defined a test as positive or negative, recognizing that the the variation in the absolute number of CPCs detected/sample may limit the validity of a determined cut-off value as used with the CellSearch® system.

Initial studies showed that the frequency of CPCs detected increased with age and serum PSA levels, and associated with a biopsy positive for cancer (9). With an increasing number of patients in the study population, we have reported that:

1) P504S negative CPCs are found in benign disease, being more frequently detected in inflammatory disease than in benign hyperplasia (10).

2) Are not detected in all cancers, those men with low grade small volumen tumors are often negative for CPCs  (11).

3) In comparison with total PSA, free PSA, PSA velocity and density proven to be superior in predicting the presence of prostate cancer at initial biopsy (12), and was superior to the Montreal nomogram (13).

4) Proved to be superior to the Chuns nomogram in predicting prostate cancer at the second biopsy (14).

From the clinical view point it is not a test for all men, it is designed to be used in a specific part of the diagnostic sequence, that is in men with suspicion of prostate cancer, based on an elevated PSA and/or abnormal digital rectal examination. In men CPC negative the inference that a biopsy could be avoided, but that the patient needs to be in a follow up program.

In terms of prognostic values, two recent publications that of Meyer et al (3) using the CellSearch® system and of our group comparing the presence of primary CPCs with the CAPRA score (15) both concluded that as a prognostic factor primary circulating prostate cells had limited value. The difference being that CTCs were detected by the CellSearch® method in 11% of cases, whereas using anti-PSA CPCs were detected in 76% of cases.

The evidence seems to support the concept that the detection of primary malignant CPCs is associated with the presence of clinically significant prostate cancer. If used as a sequential test may decrease the number of unnecessary prostate biopsies. That their presence does not imply the presence of distant disease (micrometastasis) and such as a prognostic factor has limited value.

What is important is that multicentre studies are warrented to prove or refute the application of this simple technology as a sequential test to indicate the presence of clinically important prostate cancer.

Written by: Nigel P. Murray, MD

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References:

1) Moreno JG, Croce CM, Fischer R, Monne M, Vikha P, Mulholland SG et al. Detection of hematogenous micrometastasis in patients with prostate cancer. Cancer 1992; 52: 6110-6112

2) Fidler IJ. Metastasis: Quantitative analysis of distribution and fate of tumor microemboli labelled with 125-I-5-iodo 2´deoxyuridine. J Natl Cancer Inst, 1970;  45: 773-782.

3) Meyer CP, Pantel K, Tennstedt P et al. Limited prognostic value of preoperating circulating tumor cells for early biochemical recurrence in patients with localized prostate cancer. Urol Onc 2016; 34: 11-16

4) Davis JW, Nakanishi H, Kumar VS et al. CTCs in peripheral blood samples from patients with increased serum PSA: initial results in early prostate cancer. J Urol 2008; 179: 2187-91

5) Eshwège P, Moutereau S, Droupy S et al. Prognostic value of prostate circulating tumor cell detection in prostate cancer patients. Br. J Cancer 2009; 100: 608-10.

6) Pantel K, Deneve E, D´Nocca D et al. Circulating epitelial cells in patients with benign colon disease. Clin Chem 2012; 58: 936-940.

7) Fizazi K, Morat L, Chauveinic L et al. High detection of CTCs in blood of patients with prostate cancer using telomerase activity. Ann Oncol 2007; 18: 518-521

8) Rubin MA, Zhou M, Dhanasekaran SM et al.  ?-methylacyl Coenzyme-A racemase as a tissue biomarker for prostate cancer, JAMA 2001;  287: 1662–1670.

9) Murray NP, Calaf GM, Badinez L et al. P504S excpressing circulating prostate cells as a marker for prostate cancer. Oncol Reports 2010; 24: 687-692

10) Murray NP, Reyes E, Badinez L et al. CPCs found in men with benign prostate disease are P504S negative: clinical implications. J Oncol 2013 doi: 10.1155/2013/165014

11) Murray NP, Reyes E, Fuentealba C et al. Primary CPCs are not detected in men with low grade small volume prostate cancer. J Oncol 2014 dx.doi.org/10.1155/2014/612674

12) Murray NP, Reyes E, Orellana N et al, (2014). A comparative performance analysis of Total PSA, percentage free PSA, PSA velocity, and PSA density versus the detection of primary circulating prostate cells in predicting initial prostate biopsy findings in Chilean men. BioMed Research International Volume 2014, Article ID 676572, 8 pages http://dx.doi.org/10.1155/2014/676572

13) Murray NP, Reyes E, Fuentealba C et al. Head to head comparison of the Montreal nomogram with the detection of primary malignant circulating prostate cells to predict cancer at initial biopsy in Chilean men with suspicion of prostate cancer. Urol Oncol, 2015 dx.doi.10.1016/j.urolonc/2015.01.021

14) Murray NP, Reyes E, Orellana O et al. Head to head comparison of the Chun nomogram, percentage free PSA and primary circulating prostate cells to predict the presence of prostate cancer at repeat biopsy. Asian Pac J Cancer Prevention 2016; 17: 2941-2946

15) Murray NP, Aedo S, Fuentealba C et al. Limited improvement of incorporating primary circulating prostate cells with the CAPRA score to predict biochemical failure free outcome of radical prostatectomy for prostate cancer. Urol Onc 2016;
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