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Introduction: Chemotherapy resistance is a major obstacle in effective neoadjuvant treatment for estrogen receptor-positive breast cancer. The ability to predict tumour response would allow chemotherapy administration to be directed towards only those patients who would benefit, thus maximising treatment efficiency. We aimed to identify putative protein biomarkers associated with chemotherapy resistance, using fresh tumour samples with antibody microarray analysis and then to perform pilot clinical validation experiments., Materials and Methods: Chemotherapy resistant and chemotherapy sensitive tumour samples were collected from breast cancer patients who had received anthracycline based neoadjuvant therapy consisting of epirubicin with cyclophosphamide followed by docetaxel. A total of 5 comparative proteomics experiments were performed using invasive ductal carcinomas which demonstrated estrogen receptor positivity (luminal subtype). Protein expression was compared between chemotherapy resistant and chemotherapy sensitive tumour samples using the Panorama XPRESS Profiler725 antibody microarray containing 725 antibodies from a wide variety of cell signalling and apoptosis pathways. A pilot series of archival samples was used for clinical validation of putative predictive biomarkers., Results: AbMA analysis revealed 38 differentially expressed proteins which demonstrated at least 1.8 fold difference in expression in chemotherapy resistant tumours and 7 of these proteins (Zyxin, 14-3-3 theta/tau, tBID, Pinin, Bcl-xL, RIP and MyD88) were found in at least 2 experiments. Clinical validation in a pilot series of archival samples revealed 14-3-3 theta/tau and tBID to be significantly associated with chemotherapy resistance., Conclusions: For the first time, antibody microarrays have been used to identify proteins associated with chemotherapy resistance using fresh breast cancer tissue. We propose a potential role for 14-3-3 theta/tau and tBID as predictive biomarkers of neoadjuvant chemotherapy resistance in breast cancer. Further validation in a larger sample series is now required., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Breast conserving therapy is a currently accepted method for managing patients with early stage breast cancer. However, approximately 7% of patients may develop loco-regional tumour recurrence within 5 years. We previously reported that expression of the 26S proteasome may be associated with radio-resistance. Here we aimed to analyse the 26S proteasome in a pilot series of early breast cancers and correlate the findings with loco-regional recurrence. Fourteen patients with early breast cancer who developed loco-regional recurrence within 4 years of completing breast conserving therapy were selected according to strict criteria and compared with those from 14 patients who were disease-free at 10 years. Decreased expression of the 26S proteasome was significantly associated with radio-resistance, manifested as the development of a loco-regional recurrence within 4 years of breast conserving therapy (p = 0.018). This small pilot study provides further suggestion that the 26S proteasome may be associated with response to radiotherapy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Neoadjuvant therapy results in a significant increase in breast-conserving surgery. However, traditional imaging methods are unable to accurately predict the extent of viable residual disease leading to uncertainty in surgical planning and some previous studies have shown a disproportionately high incidence of locoregional recurrence. Dynamic contrast enhanced-MRI (DCE-MRI) has been shown to provide a potentially more accurate prediction of residual disease., Results: Patients undergoing neoadjuvant chemotherapy for breast cancer in our unit are staged with the DCE-MRI of the breast performed at 1.5 T before, during and after treatment and the final result was used to plan surgery. Two hundred and four patients with breast cancer were treated with neoadjuvant chemotherapy between 1996 and April 2005. Eighteen of these patients had distant metastases at the time of initial diagnosis and so were excluded from the present study. Following neoadjuvant chemotherapy, 186 patients underwent surgical treatment. Of these, 68 patients had breast-conserving surgery. At a median follow up of 30 months (range: 5.6-72 months) 21 patients in this group developed subsequent recurrence (21/68 - 30%) of whom 9 (9/68 - 13%) had locoregional recurrence, 7 had local recurrence (7/68 - 10%), and 17 (17/68 - 25%) had distant recurrence. Logistic regression analysis revealed only vascular invasion (p=0.006) of the tumour to be significantly associated with overall recurrence. None of the pathological factors (ER, PR status, vascular invasion, lymph node metastases, pathological complete response to neoadjuvant chemotherapy) showed a significant association with locoregional recurrence., Conclusion: Breast-conserving surgery with DCE-MRI planning after neoadjuvant chemotherapy provides an acceptable level of local recurrence without the need for mastectomy.