Immunocytochemical monitoring of micrometastatic disease: Reduction of prostate cancer cells in bone marrow by androgen deprivation

The purpose of this study was to explore whether detection of disseminated tumor cells (DTCs) in bone marrow (BM) of nonmetastatic prostate cancer (PC) was associated with other clinical or histopathological factors at diagnoses or clinical outcome subsequent to definitive radiotherapy (RT). We evaluated BM aspirates from 272 cT 1-4 pN 0 M 0 PC patients by immunocytochemistry employing anticytokeratin antibodies (AE1/AE3). BM-status was compared with clinical and histopathological parameters. Longterm clinical outcome was assessed in 131 of the patients who all had completed definitive RT with or without androgen deprivation (AD), initiating treatment >5 years before cut-off date June 1, 2005. They had at least 1 unfavorable prognostic feature defined as cT [3][4] or Gleason score (GS) ≥7B or PSA ≥10 lg/l. Overall death, cause-specific death, distant metastases (DM) as first clinical relapse, local failure as first clinical relapse and biochemical failure were defined as end-points. DTCs were detected in 18% of the patients and were associated with increasing GS (p 5 0.04) and percentage of Gleason pattern 4/5 (p 5 0.04). The 7-year cumulative risk of DM was 21% for BM-positive patients vs. 6% for BM-negative patients (p 5 0.07). In patients receiving RT without AD (n 5 75), the 7-year cumulative risk of DM for BM-positive patients was 28% vs. 9% for BM-negative patients (p 5 0.03). BM-status did not have impact on other end-points. In conclusion our study shows that presence of DTCs in BM at diagnosis was associated with the histological differentiation of the primary tumor and an increased risk of developing distant metastases after RT. ' 2007 Wiley-Liss, Inc.

Section: Discussionmentioning

confidence: 62%

Impact of disseminated tumor cells in bone marrow at diagnosis in patients with nonmetastatic prostate cancer treated by definitive radiotherapy

Berg

Berner

Lilleby

et al. 2007

“…DTC appear to survive hormonal therapy 183,184 and this might be one explanation for the well-known failure of neoadjuvant hormonal therapy. However, improved characterization of DTC and larger multicenter studies followed by nomogram testing against the established risk parameters are required to introduce DTC detection into the future clinical management of prostate cancer patients.…”

Section: Prostate Cancermentioning

confidence: 99%

Review: Biological relevance of disseminated tumor cells in cancer patients

Riethdorf

Wikman

Pantel

2008

Self Cite

289

236

The prognosis of cancer patients is largely determined by the occurrence of distant metastases. In patients with primary tumors, this relapse is mainly due to clinically occult micrometastasis present in secondary organs at primary diagnosis but not detectable even with high resolution imaging procedures. Sensitive and specific immunocytochemical and molecular assays enable the detection and characterization of disseminated tumor cells (DTC) at the single cell level in bone marrow (BM) as the common homing site of DTC and circulating tumor cells (CTC) in peripheral blood. Because of the high variability of results in DTC and CTC detection, there is an urgent need for standardized methods. In this review, we will focus on BM and present currently available methods for the detection and characterization of DTC. Furthermore, we will discuss data on the biology of DTC and the clinical relevance of DTC detection. While the prognostic impact of DTC in BM has clearly been shown for primary breast cancer patients, less is known about the clinical relevance of DTC in patients with other carcinomas. Current findings suggest that DTC are capable to survive chemotherapy and persist in a dormant nonproliferating state over years. To what extent these DTC have stem cell properties is subject of ongoing investigations. Further characterization is required to understand the biology of DTC and to identify new targets for improved risk prevention and tailoring of therapy. Our review will focus on breast, colon, lung, and prostate cancer as the main tumor entities in Europe and the United States.

“…The antibody is well evaluated and has already been applied for BM analysis to obtain clinical relevant information on patients with different solid tumor types including PCa. [3][4][5][6][7][8] Out of 57 PCa patients, we were able to investigate BM from 55 patients, and detected DTCs in 12 (22%) samples. A representative example of a CK-positive cell in the BM of a PCa patient is shown in Figure 5.…”

Section: Relationship Of the Detected Lohs In Bm Plasma And Tumor Tismentioning

confidence: 99%

“…1 Thus, several groups (including ours) have developed sensitive methods and were able to detect disseminated tumor cells (DTCs) in BM of 20-30% of PCa patients at the time of primary surgery years before the onset of overt metastases. [4][5][6][7][8] In particular, enrichment techniques and immunocytochemical assays based on monoclonal antibodies specific for epithelial cytokeratins (CK) allow now the detection of single DTCs in BM of patients with solid epithelial tumors including PCa. 2 Initiation and progression of PCa is accompanied by a multistep process with numerous genetic aberrations.…”

mentioning

confidence: 99%

Detection of tumor‐specific DNA in blood and bone marrow plasma from patients with prostate cancer

Schwarzenbach

Chun

Lange

et al. 2007

Self Cite

Tumor tissues, blood plasma and bone marrow (BM) aspirates of 57 prostate cancer patients (PCa) without clinical signs of overt metastases were assessed for LOH (loss of heterozygosity) by a PCRbased fluorescence microsatellite analysis, using a panel of 15 markers. Additionally, micrometastatic tumor cells in BM were monitored by an immunocytological cytokeratin assay. In total, 25 (44%), 32 (56%) and 41 (72%) of the patients had at least 1 LOH in their blood, BM and tumor samples, respectively. Among the informative cases, the frequency of LOH was highest in blood plasma for the markers D8S360 (18%) and D10S1765 (15%), and in BM plasma for THRB (24%) and D8S137 (22%). Comparison of blood plasma and BM with tumors showed discrepant results in 35% and 45% of patients, respectively. Whereas all LOHs at THRB in BM plasma were also detected in the autologous tumor tissues, LOHs at D6S474 and D11S898 in BM were not retrieved in the tumors. The comparison with established risk factors showed a correlation of borderline significance for LOH at D9S1748 in the BM aspirates (p 5 0.055) and a significant correlation in the tumor samples (p 5 0.004) with increasing pathologic Gleason scores. Interestingly, 22% of the PCa patients harbored tumor cells in their BM and tended (p 5 0.065) to have more frequent LOH (16%) in BM plasma compared to patients without tumor cells (9%). These data demonstrate, for the first time, the presence of free tumor-specific DNA in blood and BM of PCa patients and suggest a possible relationship to BM micrometastasis. ' 2007 Wiley-Liss, Inc.