We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

The current role of circulating tumor cells in the diagnosis and management of bone metastases in advanced prostate cancer

    Fred Saad

    * Author for correspondence

    Department of Surgery, Université de Montréal, Centre Hospitalier de l’Université de Montréal (CHUM), Montréal, Canada and Institut du Cancer de Montréal, 1560 Sherbrooke Est, Montréal, Quebéc H2L 2W5, Canada.

    &
    Klaus Pantel

    Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany

    Published Online:https://doi.org/10.2217/fon.12.3

    Prostate-specific antigen (PSA) has been used for over two decades as a serum marker for adenocarcinoma of the prostate. Although PSA screening remains an important part of disease screening and monitoring in early prostate cancer (PC), its utility in monitoring disease progression in advanced PC is undetermined. Furthermore, the role of PSA monitoring in the management of patients with PC and bone metastases appears limited. The purpose of this review is to evaluate the role of circulating tumor cells (CTCs) as potential novel biomarkers in advanced PC. We present a review of CTC testing and the clinical data supporting the prognostic potential of CTCs in this setting. We propose that combination of CTCs and PSA velocity or doubling-time assessments may offer insights into the prognosis and management of advanced PC.

    Papers of special note have been highlighted as: ▪▪ of considerable interest

    References

    • Haas GP, Delongchamps N, Brawley OW, Wang CY, de la Roza G. The worldwide epidemiology of prostate cancer: perspectives from autopsy studies. Can. J. Urol.15(1),3866–3871 (2008).
    • Ross RK, Bernstein L, Lobo RA et al. 5-alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet339(8798),887–889 (1992).
    • Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N. Engl. J. Med.317(15),909–916 (1987).
    • Constantinou J, Feneley MR. PSA testing: an evolving relationship with prostate cancer screening. Prostate Cancer Prostatic Dis.9(1),6–13 (2006).
    • Etzioni R, Feuer E. Studies of prostate-cancer mortality: caution advised. Lancet Oncol.9(5),407–409 (2008).
    • Collette L, Burzykowski T, Carroll KJ, Newling D, Morris T, Schroder FH. Is prostate-specific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer? Joint research of the European Organisation for Research and Treatment of Cancer, the Limburgs Universitair Centrum, and AstraZeneca Pharmaceuticals. J. Clin. Oncol.23(25),6139–6148 (2005).
    • Scher HI, Warren M, Heller G. The association between measures of progression and survival in castrate-metastatic prostate cancer. Clin. Cancer Res.13(5),1488–1492 (2007).
    • Leman ES, Getzenberg RH. Biomarkers for prostate cancer. J. Cell. Biochem.108(1),3–9 (2009).
    • Thompson IM, Pauler DK, Goodman PJ et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or = 4.0 ng per mililiter. N. Engl. J. Med.350(22),2239–2246 (2004); erratum: 351(14),1470 (2004).
    • 10  Bunting PS. A guide to the interpretation of serum prostate specific antigen levels. Clin. Biochem.28(3),221–241 (1995).
    • 11  Loeb S, Cataona WJ. Prostate-specific antigen in clinical practice. Cancer Lett.249(1),30–39 (2007).
    • 12  Carter HB, Pearson JD, Metter EJ et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA267(16),2215–2220 (1992).
    • 13  Lembessis P, Msaouel P, Halapas A et al. Combined androgen therapy blockade can convert RT-PCR detection of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts from positive to negative in the peripheral blood of patients with clinically localized prostate cancer and increase biochemical failure-free survival after curative therapy. Clin. Chem. Lab. Med.45(11),1488–1494 (2007).
    • 14  Saad F, Perez J, Cook R, Segal S. Evaluation of prostate-specific antigen kinetics during zoledronic acid therapy for bone metastases in patients with castration-resistant prostate cancer. Presented at: AUA Annual Meeting. Washington DC, USA, 14–19 May 2011 (Abstract 717).
    • 15  Bubendorf L, Schopfer A, Wagner U et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum. Pathol.31(5),578–583 (2000).
    • 16  Noguchi M, Kikuchi H, Ishibashi M, Noda S. Percentage of the positive area of bone metastasis is an independent predictor of disease death in advanced prostate cancer. Br. J. Cancer88(2),195–201 (2003).
    • 17  Parker C. Overall survival benefit of radium-223 chloride (alpharadin) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer: a Phase III randomized trial (ALSYMPCA). Presented at: ECCO-ESMO. Stockholm, Sweden, 23–27 September 2011 (Abstract 1LBA).
    • 18  Smith MR, Egerdie B, Hernandez N et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N. Engl. J. Med.361(8),745–755 (2009).
    • 19  Ryan CJ, Shah S, Efstathiou E et al. Phase II study of abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer displaying bone flare discordant with serologic response. Clin. Cancer Res.17(14),4854–4861 (2011).
    • 20  Saad F. Clinical benefit of zoledronic acid for the prevention of skeletal complications in advanced prostate cancer. Clin. Prostate Cancer4(1),31–37 (2005).
    • 21  Smith MR, Kabbinavar F, Saad F et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J. Clin. Oncol.23(13),2918–2925 (2005).
    • 22  Sutcliffe P, Hummel S, Simpson E et al. Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review. Health Technol. Assess.15(5),iii, xi–xiii 1–219 (2009).
    • 23  Coleman RE, Major P, Lipton A et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J. Clin. Oncol.23(22),4925–4935 (2005).
    • 24  Cook RJ, Coleman R, Brown J et al. Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin. Cancer Res.12(11 Pt 1),3361–3367 (2006).
    • 25  Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer110(8),1860–1867 (2007).
    • 26  Coleman RE. Metastatic bone disease: clinical features, pathophysiology, and treatment strategies. Cancer Treat. Rev.27(3),165–176 (2001).
    • 27  Weinfurt KP, Li Y, Castel LD et al. The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer. Ann. Oncol.16(4),579–584 (2005).
    • 28  Demers LM, Costa L, Lipton A. Biochemical markers and skeletal metastases. Cancer88(Suppl. 12),2919–2926 (2000).
    • 29  Kingsley LA, Fournier PG, Chirgwin JM, Guise TA. Molecular biology of bone metastasis. Mol. Cancer Ther.6(10),2609–2617 (2007).
    • 30  Thayer S, Cooke J, Kaura S. A retrospective database analysis to assess the impact of zoledronic acid (ZOL) on skeletal-related events (SREs) in solid tumor cancer and multiple myeloma (MM) patients (pts). Presented at: 2009 ASCO Annual Meeting. Orlando, FL, USA, 29 May–2 June 2009 (Abstract 9518).
    • 31  Saad F, Gleason DM, Murray R et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J. Natl Cancer Inst.96(11),879–882 (2004).
    • 32  Coleman RE. Skeletal complications of malignancy. Cancer80(8 Suppl.),1588–1594 (1997).
    • 33  Fizazi K, Carducci MA, Smith MR et al. A randomized Phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer. J. Clin. Oncol.28(Suppl. 18), Abstract LBA4507 (2010).
    • 34  Pantel K, Alix-Panabieres C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol. Med.16(9),398–406 (2010).▪▪ Proposes that detection and characterization of circulating tumor cells (CTCs) may provide both prognostic and predictive information that could aid physicians in identifying risk of disease progression and visceral metastases to better guide treatment decisions for patients with castration-resistant prostate cancer (CRPC).
    • 35  Ashworth TR. A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Aust. Med. J.14,146 (1869).
    • 36  Hugo H, Ackland ML, Blick T et al. Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J. Cell. Physiol.213(2),374–383 (2007).
    • 37  Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat. Rev. Cancer2(6),442–454 (2002).
    • 38  Steeg PS. Metastasis suppressors alter the signal transduction of cancer cells. Nat. Rev. Cancer3(1),55–63 (2003).
    • 39  Lafrenie R, Shaughnessy SG, Orr FW. Cancer cell interactions with injured or activated endothelium. Cancer Metastasis Rev.11(3–4),377–388 (1992).
    • 40  Riethdorf S, Fritsche H, Muller V et al. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin. Cancer Res.13(3),920–928 (2007).
    • 41  Dotan E, Cohen SJ, Alpaugh KR, Meropol NJ. Circulating tumor cells: evolving evidence and future challenges. Oncologist14(11),1070–1082 (2009).
    • 42  Stott SL, Lee RJ, Nagrath S et al. Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci. Transl Med.2(25),25ra23 (2010).
    • 43  Pelkey TJ, Frierson HF Jr, Bruns DE. Molecular and immunological detection of circulating tumor cells and micrometastases from solid tumors. Clin. Chem.42(9),1369–1381 (1996).
    • 44  Davis JW, Nakanishi H, Kumar V et al. Circulating tumor cells in peripheral blood samples from patients with increased serum prostate specific antigen: initial results in early prostate cancer. J. Urol.179(6),2187–2191 (2008).
    • 45  Kollerman J, Weikert S, Schostak M et al. Prognostic significance of disseminated tumor cells in the bone marrow of prostate cancer patients treated with neoadjuvant hormone treatment. J. Clin. Oncol.26(30),4928–4933 (2008).
    • 46  Weckermann D, Polzer B, Ragg T et al. Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. J. Clin. Oncol.27(10),1549–1556 (2009).
    • 47  Alix-Panabieres C, Vendrell JP, Pelle O et al. Detection and characterization of putative metastatic precursor cells in cancer patients. Clin. Chem.53(3),537–539 (2007).
    • 48  Allard WJ, Matera J, Miller MC et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin. Cancer Res.10(20),6897–6904 (2004).
    • 49  Mani SA, Guo W, Liao MJ et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell133(4),704–715 (2008).
    • 50  Alix-Panabieres C, Schwarzenback H, Pantel K. Circulating tumor cells and circulating tumor DNA. Annu. Rev. Med.63,199–215 (2012).
    • 51  Eschwege P, Moutereau S, Droupy S et al. Prognostic value of prostate circulating cells detection in prostate cancer patients: a prospective study. Br. J. Cancer100(4),608–610 (2009).
    • 52  de Bono JS, Scher HI, Montgomery RB et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin. Cancer Res.14(19),6302–6309 (2008).▪▪ This prospective study of 231 patients with CRPC and a prostate-specific antigen level of ≥5 ng/ml was designed to evaluate the relationship between post-treatment CTCs and overall survival (OS). CTC counts predicted OS better than prostate-specific antigen decrement algorithms at all time points. Ultimately, this study led to the US FDA approval of the CellSearch® System for the evaluation of CRPC.
    • 53  Scher HI, Jia X, de Bono JS et al. Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol.10(3),233–239 (2009).
    • 54  Olmos D, Arkenau HT, Ang JE et al. Circulating tumour cell (CTC) counts as intermediate end points in castration-resistant prostate cancer (CRPC): a single-centre experience. Ann. Oncol.20(1),27–33 (2009).▪▪ In this study of 119 patients with CRPC, higher CTC counts were associated with baseline characteristics of aggressive disease. Patients with baseline CTCs ≥5 had significantly shorter median OS than those patients with CTCs <5 (19.5 vs >30 months; p < 0.012) and patients with CTCs >50 had significantly shorter median OS than those with CTCs 5–50 (6.3 vs 21.1 months; p < 0.001).
    • 55  Danila DC, Heller G, Gignac GA et al. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin. Cancer Res.13(23),7053–7058 (2007).▪▪ Study of 120 patients with progressive CRPC evaluating the association between CTC number, clinical characteristics and survival. Higher CTC counts were observed in patients with bone metastases, as compared with patients with soft tissue disease. The authors concluded that CTCs are an intrinsic property of the tumor, distinct from extent of disease and may provide unique information relative to prognosis.
    • 56  Reid AH, Attard G, Danila DC et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J. Clin. Oncol.28(9),1489–1495 (2010).
    • 57  Scher HI, Heller G, Molina A et al. Evaluation of circulating tumor cell (CTC) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): planned final analysis of COU-AA-301, a randomized double-blind, placebo-controlled Phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. J. Clin. Oncol.29(Suppl.), Abstract LBA4517 (2011).▪▪ CTC testing in a Phase III trial of 1195 patients with metastatic CRPC who received abiraterone acetate and low-dose prednisone following docetaxel. As part of a biomarker panel, CTCs demonstrated surrogacy for OS by correlating with survival. Baseline CTCs and CTC conversion were both key predictors of OS.
    • 58  Aft R, Naughton M, Trinkaus K et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, Phase 2 trial. Lancet Oncol.11(5),421–428 (2010).
    • 59  Saad F, Eastham J. Zoledronic acid improves clinical outcomes when administered before onset of bone pain in patients with prostate cancer. Urology76(5),1175–1181 (2010).▪▪ Illustrates that early treatment of bone metastases in CRPC patients is especially effective at preventing resulting skeletal-related events, elevating the importance of early identification of bone metastases and evaluation of skeletal-related event and survival risk factors in patients with CRPC.
    • 60  Kraan J, Sleijfer S, Strijbos MH et al. External quality assurance of circulating tumor cell enumeration using the CellSearch® system: a feasibility study. Cytometry B Clin. Cytom.80(2),112–118 (2011).
    • 61  Doyen J, Alix-Panabieres C, Hofman P et al. Circulating tumor cells in prostate cancer: a potential surrogate marker of survival. Crit. Rev. Oncol. Hematol.81(3),241–256 (2011) (Epub ahead of print).
    • 101  GLOBOCAN. Age standardized incidence rates for prostate cancer (2008). http://globocan.iarc.fr/factsheets/cancers/prostate.asp
    • 102  US FDA. FDA public workshop on clinical trial endpoints in prostate cancer (2004). www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/CancerDrugs/ucm095039.pdf