Disseminated tumor cells and their prognostic significance in nonmetastatic prostate cancer patients

Abstract

Detection of pretreatment disseminated cells (pre-DTC) reflecting its homing to bone marrow (BM) in prostate cancer (PCa) might improve the current model to predict recurrence or survival in men with nonmetastatic disease despite of primary treatment. Thereby, pre-DTC may serve as an early prognostic biomarker. Post-treatment DTCs (post-DTC) finding may supply the clinician with additional predictive information about the possible course of PCa. To assess the prognostic impact of DTCs in BM aspirates sampled before initiation of primary therapy (pre-DTC) and at least 2 years after (post-DTC) to established prognostic factors and survival in patients with PCa. Available BM of 129 long-term follow-up patients with T1-3N0M0 PCa was assessed in addition to 100 BM of those in whom a pretreatment BM was sampled. Patients received either combined therapy [n 5 81 (63%)], radiotherapy (RT) with different duration of hormone treatment (HT) or monotherapy with RT or HT alone [n 5 48 (37%)] adapted to the criteria of the SPCG-7 trial. Mononuclear cells were deposited on slides according to the cytospin methodology and DTCs were identified by immunocytochemistry using the pancytokeratin antibodies AE1/AE3. The median age of men at diagnosis was 64.5 years (range 49.5-73.4 years). The median long-term follow-up from first BM sampling to last observation was 11 years. Categorized clinically relevant factors in PCa showed only pre-DTC status as the statistically independent parameter for survival in the multivariate analysis. Pre-DTCs homing to BM are significantly associated with clinically relevant outcome independent to the patient's treatment at diagnosis with nonmetastatic PCa.Prostate cancer (PCa) is among the most commonly occuring malignancies in the world. It has a long natural course and its heterogeneous tumor biology leads to considerable underand overtreatment. In curatively treated patients up to 30% of men with localized PCa will encounter recurrence and metastatic deposits are preferred detected inbone. 1 Therefore, additional prognostic biomarkers are urgently needed to improve the standard clinical decision model used in routine [T-category, Gleason score, serum prostate-specific antigen (PSA) and bone scan 2 .The prevalence of disseminated tumor cells (DTCs) in bone marrow (BM) has shown clinical significant relevance when correlated to biochemically defined progression in PCa. 3,4 In one of our previous studies, Berg et al. 5 demonstrated a clinical correlation between presence pretreatment DTCs, dichotomized Gleason score and development of metastatic disease at follow up in nonmetastatic PCa.Several studies have also confirmed the potential of circulating tumor cells (CTC) detection as a monitoring method for treatment response in castration-resistance PCa. 6,7 In this study, we investigated the prognostic value of the prevalence of DTCs in BM of nonsurgical putatively curative treated men with a sufficient long-term follow-up. Methods and PatientsFor the current analysis, we included patients who had T1-3...

The role of the microenvironment-dormant prostate disseminated tumor cells in the bone marrow

“…The results correlating DTC and clinical outcomes have been largely inconclusive. Studies from Weckermann et al and Lilleby et al demonstrated that pre-operative or pre-treatment DTC predicted disease recurrence while our group did not observe such a correlation; in contrast our group reported the detection of post-operative DTC predicted poor prognosis but their results did not show such a trend [2;5;8]. Nevertheless, the bottom line is that if a PCa patient has DTC, it does not necessarily mean that he will develop an overt metastasis.…”

“…Alternatively, mononuclear cells are spun down onto a slide and then DTC are directly detected by positive pancytokeratin staining (e.g. A45B/B3 or AE1/AE3) [8;32]. …”

The Relationship Between Dormant Cancer Cells and Their Microenvironment

“…They therefore do not contribute to our understanding how the fate of solitary DTCs that enter a dormant state prior to their entry into proliferation is affected by MAMs or other immune cells. Clinical evidence shows that in the majority of patients, there is a significant lag between extravasation (that likely already occurred at the time of surgery) and proliferation into detectable metastasis (Hartkopf et al, 2014; Lilleby, Stensvold, Mills, & Nesland, 2013). Therefore, it seems that extravasation and activation of proliferation can be significantly uncoupled processes.…”

Cancer Cell Colonisation in the Bone Microenvironment

“…Similarly, DTCs were identified in the bone marrow for 90% of advanced-stage prostate cancer patients [54,55,56]. The processes that determine the fate of DTCs in the bone marrow remain unclear; however, the presence of DTCs is reported to be a negative prognostic indicator in breast and prostate cancer [53,57,58,59,60]. The influence of bone marrow niches on DTCs and the molecules that maintain dormancy will be discussed in the following sections.…”