P4-06-05: Prognostic Impact of Disseminated and Circulating Tumor Cells in Patients Treated for Locally Advanced Breast Cancer.
Authors: Mathiesen RR , Nesland JM , Renolen A , Løkkevik E , Anker G , Østenstad B , Lundgren S , Riisberg T , Mjaaland I , Kvalheim G , Lønning PE , Naume B 
Published: June 2012

INTRODUCTION: Neoadjuvant systemic therapy (NST) in breast cancer patients is an established approach to reduce tumor size prior to surgery and to assess the clinical effect of therapy on the breast cancer disease. The current study was designed to identify primary tumor resistance factors to epirubicin and paclitaxel therapy in patients with locally advanced breast cancer (Chrisanthar et al PLoSOne 2008 and 2011). As a substudy, the incidence of disseminated tumor cells (DTCs) and circulating tumor cells (CTCs) before and after therapy, was investigated. The aim was to evaluate the prognostic impact of DTCs and CTCs as well as to evaluate the effect of NST on DTCs and CTCs.

PATIENTS AND METHODS: Patients with locally advanced non-inflammatory breast cancer (T3-4and/or N2) were included in the study. The patients were randomly allocated to primary treatment either with epirubicin 90mg/m2 or paclitaxel 200mg/m2, with cross-over design if no response/progression, followed by mastectomy and axillary dissection. Bone marrow (BM) aspiration and peripheral blood (PB) samples were collected before NST (BM1/PB1)(n=230), at the time of surgery (BM2/PB2)(n=69; logistic reasons caused reduced sampling) and 12 months after randomization (BM3/PB3)(n=162). Detection of DTCs/CTCs was performed by standard immunocytochemical analysis of 2×106 mononuclear cells stained for cytokeratin by AE1AE3 antibodies. Patient outcomes were evaluated over a 10-year follow-up period. Univariate and multivariable proportional hazards models were estimated to assess the prognostic significance of DTC for disease-free survival (DFS) and overall survival (OS).

RESULTS: Before NST (BM1) 21.3% were DTC positive, compared to 15.9% and 26.5% at BM2 and BM3, respectively. Of those that both had BM1 and BM3 performed, 68% concordance and 22% overlap among positive cases was observed. Presence of DTCs in BM3 predicted reduced DFS (HR 2.2; 95% CI 1.3−3.7; p=0.007) and OS (HR 3.0; 95% CI 1.8−5.2; p&gt;0.001). DTC status before NST had no impact on outcome. No difference in the results was observed after exclusion of patients with limited M1 status at diagnosis (25 and 13 of those analysed for BM1 and BM3, respectively). The incidence of CTCs before NST was 4.9 % compared to 1.4% and 4.3 % at PB2 and PB3, respectively. Presence of CTC before NST was associated with reduced overall survival (HR 2.4; 95% CI 1.2−5.0; p=0.018), but CTC status was not significant for DFS or at other time points. In the multivariable analysis, DTC status at BM3 remained as a prognostic factor for both DFS (HR 2.0; 95% CI 1.1−3.6) and OS (HR 2.1; 95% CI 1.04−4.2).

CONCLUSION: In patients with locally advanced breast cancer, the presence of CTCs at the time of diagnosis identified high risk patients. However, the sensitivity of the performed CTC analysis was too low for further interpretation. Presence of DTCs 12 months after neoadjuvant therapy increased the risk for relapse and death. The best clinical utility of DTC analysis appears to be as a monitoring tool during follow up, in a “window of opportunity” for selection of patients to secondary adjuvant treatment intervention within clinical trials.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-06-05.