Circulating Tumor Cells for Prostate Cancer

Recent advances in technology have made it possible to locate circulating tumors cells (CTCs) in the blood of patients with metastatic cancer of the breast, colon and prostate.  Prior to CTCs, the only options for the diagnosis and monitoring of metastatic cancer were biopsy of metastatic deposits and inference from imaging like CT, MRI and PET scans.  CTCs offer a number of advantages to traditional biopsy or imaging:

• CTCs can be measured in blood, which is easy, cheap, have relatively little pain and risks associated with them.
• CTCs can be used as a biomarker; once isolated, viable CTCs can be processed and analyzed to identify:
• the type of CTC in circulation
• aggressiveness of the cancer
• potential response to specific treatments (like chemotherapy)
• CTCs can be measured over time, adding a new dimension to the ability to measure resistance or responsiveness to therapies.

CTCs are emerging as a promising prognositic factor in men with metastatic, castrate-resistant prostate cancer.  Here we review some the recent data regarding CTCs in prostate cancer.  

CTCs as a Biomarker

Through a variety of techniques, prostate cancer CTCs have been analyzed for a variety of markers that can define the aggressiveness of the prostate cancer and have the potential to predict clinical outcomes.  These markers encompass a number of established protein and genetic markers of prostate cancer aggressiveness including: chromosomal abnormalities, epidermal growth factor receptor (EGFR) expression,  androgen receptor (AR) gene amplification, telomerase activity and TMPRSS2-ERG status.[1-6]

CTCs as Predictors of Oncologic Outcomes

High CTC counts are associated with more advanced disease including higher PSA levels, bone metastases (compared to soft tissue metastases), volume of bone metastases by imaging and laboratory markers (lactate dehydrogenase and alkaline phosphatase).[7,8]

High CTC counts predict men who develop castrate-resistant prostate cancer, and the relative length of survival and response to chemotherapy for men who have already developed castrate-resistant prostate cancer.[7-10] In one study of men receiving chemotherapy for metastatic, castrate-resistant prostate cancer, low CTC counts (<5) were associated with a longer survival prior to initiating chemotherapy.  In the same study and others, men who's CTC counts dropped to <5 while on additional therapy also had a longer survival compared to men who had no response in CTC count.[9-11]

The best cutoff value for CTC has yet to be established, with most studies reporting the clinically important cutoff to be between 3-5 CTC.[8,9]

CTCs have demonstrated prognostic abilities in hormone-sensitive disease,[8] in mCRPC treated with a variety of first-line therapies,[9,11] and in mCRPC treated with second-line hormonal therapy.[10]

A recent, large, prospectively phase III trial was completed by SWOG (Southwest Oncology Group) evaluating CTCs in men with metastatic, castrate-resistant prostate cancer receiving docetaxel chemotherapy (standard first-line chemotherapy).  This study validated 5 CTC as a valuable cut-point in this population as men with <5 CTCs at enrollment had an improved overall survival (26 vs. 13 months) and that a rising CTC count while on chemotherapy was associated with worse overall survival.[12]

Summary

• CTCs have the opportunity to change the way we manage advanced prostate cancer and other malignancies.
• CTCs can serve as biomarkers to indicate the aggressiveness of prostate cancer cells.
• Increasing CTC counts are associated with worse oncologic outcomes in a number of trials for men with advanced prostate cancer - however the exact cutoff point for CTCs has yet to be determined.
• Future studies will help define the role of CTCs in prostate cancer.

[1] Shaffer DR, Leversha MA, Danila DC, et al. (2007) Circulating tumor cell analysis in patients with progressive castration-resistant prostate cancer. Clin Cancer Res 13:2023–2029.

[2] Danila DC, Anand A, Sung CC, et al. (2011) TMPRSS2-ERG status in circulating tumor cells as a predictive biomarker of sensitivity in castration-resistant prostate cancer patients treated with abiraterone acetate. Eur Urol 60:897–904.

[3] Jiang Y, Palma JF, Agus DB, et al. (2010) Detection of androgen receptor mutations in circulating tumor cells in castration-resistant prostate cancer. Clin Chem 56:1492–1495.

[4] Lin HK, Zheng S, Wiliams AJ, et al. (2010) Portable filter-based microdevice for detection and characterization of circulating tumor cells. Clin Cancer Res 16:1–8.

[5] Moreno JG, Miller MC, Gross S, et al. (2005) Circulating tumor cells predict survival in patients with metastatic prostate cancer. Urology 65:713–718

[6] Xu T, Lu B, Tai YC, et al. (2010) A cancer detection platform which measures telomerase activity from live circulating tumor cells captured on a microfilter. Cancer Res 70:6420–6426.

[7] Danila DC, Heller G, Gignac GA, et al. (2007) Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 13:7053–7058. Abstract/FREE Full Text
[8] Goodman OB Jr, Symanowski JT, Loudyi A, et al. (2011) Circulating tumor cells as a predictive biomarker in patients with hormone-sensitive prostate cancer. Clin Genitourin Cancer 9:31–38.

[9] de Bono JS, Scher HI, Montgomery RB, et al. (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14:6302–6309.
[10] Scher HI, Heller G, Molina A, et al. (2011) 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 (FA) 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):293s, abstr LBA4517.

[11] Scher HI, Jia X, de Bono JS, et al. (2009) Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: A reanalysis of IMMC38 trial data. Lancet Oncol 10:233–239.

[12] Goldkorn A, Ely B, Quinn DI, Tangen CM, Fink LM, Xu T, Twardowski P, Van Veldhuizen PJ, Agarwal N, Carducci MA, Monk JP 3rd, Datar RH, Garzotto M, Mack PC, Lara P Jr, Higano CS, Hussain M, Thompson IM Jr, Cote RJ, Vogelzang NJ.Circulating Tumor Cell Counts Are Prognostic of Overall Survival in SWOG S0421: A Phase III Trial of Docetaxel With or Without Atrasentan for Metastatic Castration-Resistant Prostate Cancer.J Clin Oncol. 2014 Apr 10;32(11):1136-42. doi: 10.1200/JCO.2013.51.7417. Epub 2014 Mar 10.