Abstract P2-01-09: Tumor cell emboli in the lung and transcriptional profiles of circulating tumor cells derived from different vascular compartments in patients with metastatic breast cancer.
Authors: Peeters DJ , Van den Eynden GG , Rutten A , Onstenk W , Sieuwerts AM , De Laere B , van Dam PA , Peeters M , Pauwels P , Van Laere SJ , Vermeulen PB , Dirix LY 
Published: August 2014

Background: We have shown that in up to 50% of patients with metastatic breast cancer (MBC) significantly higher numbers of circulating tumor cells (CTCs) can be detected in central venous blood (CVB) as compared to peripheral venous blood (PVB), suggesting that the lungs might retain a substantial number of CTCs from the blood stream (Peeters et al. Br J Cancer 2011). The aim of this study was 1) to investigate the relation between elevated numbers of CTCs and the presence of (intravascular) tumor cell emboli (TCE) in the lung in patients with advanced carcinomas, and 2) to investigate whether CTCs derived from CVB and PVB exhibit differential transcriptional characteristics.

Methods: Seven patients with MBC and 1 patient with metastatic cervical carcinoma, all suffering from end-stage disease, were included in the first part of this study. CTCs were isolated and enumerated with the CellSearch system (Veridex, Raritan, NJ, USA) in 7.5 ml blood obtained from the central venous access catheter (CVB) and/or a peripheral vein (PVB). All blood samples were obtained within 5 days prior to death. The presence of TCE was studied in lung tissue samples obtained at autopsy. For the second study aim, paired CVB and PVB CTC samples were collected from an additional 10 MBC and 2 LABC patients. Transcriptional profiles were obtained for 91 breast cancer related genes as described by Sieuwerts et al. (Clin Cancer Res 2011).

Results: Multiple TCE were observed in 4 out of 6 patients with highly elevated numbers of CTCs (&gt;100 CTC/7.5 ml blood). These TCE were located exclusively intravascularly in 2 patients, while the other 2 patients had a more diffuse infiltration pattern with perivascular and lymphovascular TCE. All 4 patients had a history of rapidly evolving respiratory distress in the last week of life although radiological examination of the lungs did not show significant interval changes. In another 2 MBC patients with &gt;100 CTCs and 2 MBC patients with &lt;5 CTCs, no TCE were observed. Of the 12 patients included for transcriptional CTC analysis, 8 patients had ≥5 CTCs in both blood samples. In line with our previous findings, 5/8 patients had at least a 15% higher CTC count in CVB than in PVB. Unsupervised hierarchical clustering of transcriptional profiles was primarily driven by the absence or presence of CTCs in the blood samples and revealed no significant differences between CTC samples derived from CVB or PVB from the same patient.

Conclusions: TCE were observed in 4 out of 6 patients with highly elevated numbers of CTCs. In these patients, cumulative entrapment of CTCs in the lung might have contributed to respiratory dysfunction. High numbers of CTC might therefore represent an oncological emergency. Transcriptional profiling of 91 breast cancer related genes revealed no substantial difference in gene expression of CTCs derived from CVB and PVB, suggesting that CTC entrapment by the lung is a rather passive process in advanced cancer patients. These findings will be further challenged by comparing the obtained profiles with gene expression profiles of 13 additionally selected homing markers in these samples.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-01-09.