Changing Therapy as a Consequence of the Behaviour of CETC during Adjuvant Trastuzumab Treatment in Patients with Her2/Neu Positive Breast Cancer.
Authors: Hammer U. , Camara O. , Hekimian K. , Gellner A. , Runnebaum I. , Pachmann K. 
Published: December 2010

Abstract
Gene silencing, demethylation, translocations and amplifications crucially contribute to the growth potential and aggressiveness of malignant tumors. This has led to the development of compounds specifically targeting such alterations. Although parts of these compounds have led to an impressive improvement in relapse free survival such as trastuzumab in breast cancer treatment, a considerable part of patients carrying the alteration will not respond to this targeted treatment. Therefore, in addition to defining the subpopulation of patients with a high probability of responding to the targeted therapy only immediate control of the response to treatment will ultimately improve outcome.Epithelial tumor cells circulating in peripheral blood are easily accessible and have been shown to reflect the response of the tumor to therapy. They can, therefore, be used to monitor the effect of therapy.Here we report on the application of therapy monitoring using CETCs during adjuvant trastuzumab treatment and the consequences which may be deduced from these observations for individualized therapy.30 patients with either IHC3+ or FISH confirmed Her2/neu positive breast cancer were prospectively analysed for the number of CETC before therapy, before each new cycle of chemotherapy and during maintenance therapy with trastuzumab.1ml of blood was drawn into EDTA vials, red blood cells lysed and the white blood cell pellet stained with FITC-labelled anti-Epcam. Green fluorescent cells were detected by image analysis and dead cells excluded due to red PI fluorescence.Most patients showed the typical response of high risk patients upon chemotherapy with an initial decrease in cell numbers followed by a rapid reincrease still during chemotherapy. The subsequent maintenance therapy with trastuzumab led to a stabilization or a decrease in CETC numbers in 89% of patients all of which are in sustained complete remission whereas all of the 11% patients with increasing CETCs have suffered relapse. Thus CETC monitoring allowed an excellent discrimination of patients at risk of relapse also during trastuzumab treatment.To further investigate the reason for treatment failure in the patients with increasing CETCs the cells were additionally analysed for their status of Her2/neu amplification during treatment. At the end of chemotherapy cells with a low number of Her2/neu amplificates comprised between 80 and 100% whereas cells with more than 10 signals comprised between 0 and 20%. During the subsequent therapy with trastuzumab the fraction of cells with more than 10 signals continuously increased to between 50 and 60%. This indicates that in these patients trastuzumab was not capable of eliminating the cells with a high Her2/neu amplification probably because the concentration of trastuzumab is not sufficient to eliminate these cells. With regard to the high probability with which a relapse must be expected in these patients a trial using higher trastuzumab doses seems warranted in patients with increasing CETC during the conventional trastuzumab treatment. Alternatively lapatinib might be an option.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2088.