Treatment with trastuzumab in recurrence free patients with early breast cancer and persistent disseminated tumor cells (DTC) in bone marrow.

Abstract

Abstract Abstract #3135 Background:
 Detection of DTC in bone marrow of breast cancer patients is correlated with both increased risk of recurrence and reduced survival. Cytological examination of DTC showed overexpression or amplification of Her2 disconcordantly to the HER2-status of the primary tumor in a subgroup of patients. Aim of the present study is to evaluate therapeutic effects of Trastuzumab on persistent HER2-positive DTC in bone marrow of early breast cancer patients having completed primary treatment.
 Patients and Methods:
 Detection of DTC was performed using the monoclonal pan-cytokeratin antibody A45-B/B3 and the APAAP technique for immunocytochemical staining. In 129 breast cancer patients without evidence for local or distant recurrence and detection of DTC in the bone marrow the HER2-status of these DTC was determined by chromogenic in situ hybridisation (CISH). Patients were followed prospectively for a median of 21 months (std 36,9) after the first bone marrow aspiration.
 12 of the patients with HER2 positive DTC received Trastuzumab at 6mg/kg q3w x 12mon (8mg/kg loading dose) as part of an interventional pilot trial. All patients had underwent surgery, leading to R0 resection of the tumor, and adjuvant chemotherapy was completed at least 6 month ago.
 Results:
 All of the 129 patients showed DTC at the first time of bone marrow aspiration. (range 1-256, median 2).
 Looking at primary histo-pathological findings, most of the patients' tumors were small (60,3% T1, 30,1% T2, 6,6% T3, 2,9% T4) but of intermediate or unfavourable grade (9,6% G1, 44,9% G2, 45,6% G3). 61% of the patients were node-negative (61,0% N0, 24,3% N1, 14,7% N2-3) and in 78,7% a positive hormone receptor status was seen. 26,4% of the tumors showed overexpression of Her2. 38.2% of the detected DTC showed a positive Her2-status at first bone marrow aspiration. The Her2-status of the primary tumor and of the DTC was concordant in 87 patients (67,6%, p=0.004), whereas 9.6% showed a positive status on the tumor but Her2-negative DTC. In 22.8% DTC were Her2-positive despite a negative Her2-status of the tumor. After Trastuzumab therapy in only 5 (41.7%) of the 12 treated patients DTC were present. The reduction in cell numbers between aspiration before and after Trastuzumab treatment showed a statistical trend (p= 0.51). Two (16.7%) of the treated patients developed distant metastases and 1 of them died for the disease .
 Trastuzumab treatment was generally well tolerated without severe cardiotoxicity.
 Conclusions:
 Identification of Her2-overexpressing DTC might proof as a useful objective for targeted therapies thus meliorating the prognosis of patients with DTC by eradicating these cells. If Trastuzumab shows a therapeutic effect in these patients, even if the Her2-Status of the primary tumor is negative, will have to be evaluated in further prospectively randomized studies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3135.