20005 Background: Neoadjuvant chemotherapy is increasingly employed in operable breast cancer. Our initial studies on a cDNA array platform failed to identify gene expression patterns predicting response to neoadjuvant chemotherapy in breast cancer patients (J Clin Oncol 23:3331, 2005). Now we included more patients and used oligo microarrays. Methods: Patients with operable or locally advanced breast cancer were included in a randomized phase II study or received neoadjuvant chemotherapy off protocol. All except 7 patients began chemotherapy with 3 courses of dose-dense adriamycin and cyclophosphamide (ddAC) and response was evaluated by MRI. Patients with a response and a HER2-positive tumor were then randomized between either 3 additional courses of ddAC or six weekly courses of carboplatin, paclitaxel and trastuzumab (CPT). Patients without response were switched to CPT. Patients with HER2-negative tumors were randomized between 3 courses of either ddAC or capecitabine and docetaxel (CD). After evaluation, patients without response were switched to the alternative treatment arm. From all patients 14G core needle biopsies were taken before treatment and total RNA was isolated. Amplified mRNA was labeled and hybridized to 35k human oligo microarrays from our microarray facility. Results: So far, 77 patients have been included into the study. From 48 of these, good quality RNA from tissue with >50% tumor cells was isolated. 43 patients had received ddAC as initial chemotherapy; 32 of these had not been switched to another regimen. In a training set containing 11 pathological complete remissions (pCR) and 9 non-responders (NR) we could separate these groups by using 20 genes in a supervised classification and a 9-step cross validation. These results could be validated in an independent set of 11 samples (6 pCR, 5 NR). From 10 out of 11 samples, response status could be predicted correctly, independent from the treatment regimen. Although ER-positive tumors have a lower pCR rate than ER-negative ones, the steroid hormone receptors were not present in the classifier. Conclusions: We conclude that it should be possible to identify a reliable gene expression profile associated with response to adriamycin based neoadjuvant chemotherapy in breast cancer. No significant financial relationships to disclose.
Digital gene expression profiling analysis and its application in the identification of genes associated with improved response to neoadjuvant chemotherapy in breast cancer
