Abstract P4-01-07: Different prognostic value of circulating and disseminated tumor cells in primary breast cancer. Influence of bisphosphonate intake?
Authors: Kasimir-Bauer Sabine , Aktas Bahriye , Hauch Siegfried , Kimmig Rainer , Hoffmann Oliver 
Published: May 2015

Abstract
Background: Disseminated tumor cells (DTCs) in the bone marrow and circulating tumor cells (CTCs) in blood of breast cancer patients (pts) were shown to provide independent prognostic information and can be regarded as an early indicator of therapy failure. Here we demonstrate a different prognostic value of DTCs and CTCs and explain these findings by early bisphosphonate intake.
Patients and Methods: 10 ml blood and two bone marrow aspirates of 488 pts with first diagnosis of breast cancer between Aug 2006 and Dec 2010 were studied for DTCs and CTCs. CTCs were detected using the AdnaTest BreastCancer (AdnaGen AG, Hannover, Germany) for the detection of EpCAM, MUC-1 and HER2 transcripts. DTCs were analyzed by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. In addition to chemo-, radio- and anti-hormonal therapy, bisphosphonates were given to DTC-pos pts [clodronate (2×520 mg per day) for at least two years] and 69 DTC-neg, postmenopausal pts [zoledronic acid (4 mg, twice a year) for three years]. Results: After a median follow-up time of 48 months (range: 5 to 87 months), the overall survival rate was 93% (456/488 pts) and relapses occurred in 11% (56/488 pts) of cases. CTCs were detected in 109/488 pts (22%) and significantly correlated with reduced disease free survival (DFS; p=0.02). Negative prognostic relevance was predominantly related to the lobular subtype (p=0.0047), the ER-pos subtype, (pER+/Her2=0.01; pER+/Her2+=0.25; pER-/Her2+=0.5) and pts who had received chemotherapy (p=0.015) or radiation therapy (p=0.0083) but not to pts with anti-hormonal regimens (p=0.06). DTCs were detected in 162/488 pts (33%). In contrast to CTCs, no prognostic significance could be shown with regard to DFS (p=0.49), all clinical parameters as well as treatment regimens. In contrast, only in CTC-pos pts, the presence of DTCs significantly correlated with DFS (p=0.04). We further investigated whether this lack in prognostic significance was due to bisphosphonate intake in case of DTC-positivity. Predominantly, in the CTC-neg group, bisphosphonate treatment significantly influenced DFS in both histological subtypes (pCTC-/ductal=0.04; pCTC-/lobular=0.0021). However, in the CTC-pos group of pts, no such effect was observed (pCTC+/ductal=0.76; pCTC+/lobular=0.51).Conclusion: Here we show, that CTCs, rather than DTCs were significantly prognostic for early relapse. The ER-pos subtype was mostly affected which is in concordance with our previous studies, demonstrating that CTCs show EMT and tumor stem cell characteristics and, thus, down regulate ER which probably makes anti-hormonal treatment less effective. In addition, the presence of these CTC-subtypes might also explain the negative prognostic impact of CTCs in pts receiving chemo- or radiation therapy which we could verify in a subgroup of our pts (n=238) showing a significant correlation of CTCs and EMT/stem cell like CTCs (p=0.017; data not shown). The lack of prognostic significance of DTCs can be related to bisphosphonate intake in all DTC-pos pts, a subgroup of DTC-neg pts as well as in DTC-pos/CTC-neg pts, underlining our assumption that CTCs might be a high risk indicator for already ongoing metastasis not limited to bone metastasis.
Citation Format: Sabine Kasimir-Bauer, Bahriye Aktas, Siegfried Hauch, Rainer Kimmig, Oliver Hoffmann. Different prognostic value of circulating and disseminated tumor cells in primary breast cancer. Influence of bisphosphonate intake? [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-07.