Primär systemische Therapie des primären Mammakarzinom mit einer Kombination aus Docetaxel/Epirubicin/Cyclophosphamid (TEC) und begleitender Genexpressionsanalyse mittels cDNA micro array Analysen

Background: Currently there are no tests to assist in selecting the optimal preoperative chemotherapy (Primary Systemic Therapy, PST) regimens for breast cancer patients. Primary study goals of this prospective, single-armed multicentric investigation are pathologically confirmed tumour response and the rate of breast conserving therapy (BCT). Secondary study goals are to find histopathologic and gene profiling patterns best correlating with tumour remission in a taxane- anthracycline based neoadjuvant setting as well as to evaluate cytostatic toxicity and quality of life.

Patients and methods: In this neoadjuvant phase-II-study of totally 40 eligible patients with histologically confirmed invasive breast cancer Human Genome Survey Microarray (HGSM) expression profiling is preformed on jet-biopsy sample basis. The protocol was elaborated for the treatment of breast cancer patients suffering from a primary tumour greater than 1.5cm or inflammatory breast cancer with 6 cycles of Docetaxel / Epirubicin / Cyclophosphamide (TEC, 3-weekly) prior to the surgical treatment. The selection and validation of predictor genes was done with BRB-ArrayTools Version 3.3 using a model based the Compound Covariate Predictor, Diagonal Linear Discriminant Analysis, Nearest Neighbor Classification, and Support Vector Machines with linear kernel. The models incorporated genes that were differentially expressed among genes at the 0.001 significance level as assessed by the random variance t-test. We estimated the prediction error of each model using leave-one-out cross-validation (LOOCV) as described by Simon R et al. 2000 random permutations were used. Clustering was done using Cluster 3.0 and Java TreeView 1.0.12.

Results:Tumour response (pCR, pPR) of more than 70% can be achieved using neoadjuvant TEC-regimen. 22% of pCR (pT0; pN0) in this ongoing study is comparable with data of other published neoadjuvant trails.The rate of breast conserving therapy of more than 90% is high. The preliminary expression profiling results shown here indicate a subset of 148 genes that classifies all patients with a complete remission (pCR, no detectable tumor at the end of chemotherapy), in one cluster with a very closely related gene expression pattern (n=5; PPV=100%). Furthermore the 10 patients indicated as responders due to the selected Mib1-expression based criteria (expressing cells in the residual tumor ≤5% and a Δ Mib1-expression ≥20%) were correctly classified in 9 of 10 cases. A comparable separation of the groups could not achieved by established tumor factors, e.g. ER, PgR, HER2, uPA etc. which are measured simultaneously on the HGSM and also statistically evaluated.

Conclusion: HGSM semi-quantitative expression profiling is promising to have the potential to figure out genes that are related to cancer progression and chemotherapy resistance, especially in primary systemic chemotherapy.