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Preclinical Studies and Early Drug Development: Predicting Tumor Response to Cytotoxic Therapy

In vitro chemosensitivity testing in invasive breast cancer: Increased sensitivity of the basal subtype is not independent of the tumor proliferation rate

Department of Gynecology, University Hospital Muenster, Muenster, Germany, Institute of Pathology, Klinikum Osnabrück, Osnabrück, Germany, Institute of Pathology, University of Muenster, Muenster, Germany, Institute of Tumour Biology, University of Hamburg, Hamburg, Germany

Abstract

B15

Background:Advances in adjuvant breast cancer treatment have contributed to decreasing numbers of breast cancer deaths in developed countries. However, decision making on whether to opt for adjuvant chemotherapy regimens in a given patient and on which regimen to choose has long been restricted to evidence derived from clinical trials as well to single prognostic and predictive markers. A putative relationship between different molecular and phenotypic breast cancer subgroups and neoadjuvant chemotherapy response has recently been proposed. In vitro chemotherapy sensitivity and resistance assays (CSRAs) as a means to directly evaluate a tumors response to a given drug have been proposed repeatedly as a novel important tool in a more patient-tailored chemotherapeutic approach.Materials and Methods:In order to reveal correlations between in vitro chemosensitivity and different phenotypic breast cancer subgroups, tissue microarrays of 550 invasive breast cancers were composed and investigated for the expression of the estrogen receptor (ER), the progesterone receptor (PR), bcl-2, Cyclin D1, Epithelial Membrane Antigen (EMA), p53, EGFR, vimentin, Ck 5, Ck 14, Ck 19, erbB2 and Mib-1. All carcinomas have been subjected to 4 different in vitro chemotherapy protocols (DOCET, EC, MIT, PAEP) and sensivity had been established based on adenosine triphosphate bioluminescence assay technique.Results:Our results show that the expression of EGFR, Ck 5, vimentin and to a lesser degree of p53 and Ck 14 were significantly associated with a clearly increased in vitro chemosensitivity. In contrast, proteins described to characterize the luminal subtype, including ER and bcl-2 were inversely correlated with in vitro chemosensitivity. However, a more detailed analysis showed that these results were not independent of the proliferation rate i.e. increased Mib-1 expression.DISCUSSION:Other groups have already found evidence for an altered sensitivity towards various chemotherapy regimens based on luminal or basal tumor features. In our approach we could make the same observation, however, differences in response to chemotherapy were not independent of Mib-1 expression levels. We see these results as an important indicator, that the increased chemosensitivity in basal and the reduced chemosensitivity in luminal breast cancers, respectively, are mainly determined by the differing proliferation rate rather than to the phenotypic subtypes.