1. ¹Institute of Pathology, University Hospital of Basel, Schönbeinstrasse 40, Basel 4031, Switzerland
2. ²Department of Radiation Oncology, McGill University Health Centre, 1650 Cedar Avenue, Montreal, QC, Canada H3G 1A4
3. ³Office of Biorepositories and Biospecimen Research, National Cancer Institute, National Institutes of Health, 31 Center Drive, Bethesda, MD 20892, USA
4. ⁴Department of Pathology, McGill University, 3775 University Street, Montreal, QC, Canada H3A 2B4
5. ⁵Department of Pathology, Toyama University, 2630 Sugitani, Toyama 930-0194, Japan
6. ⁶Department of Cellular Pathology, St Mark's Hospital, Imperial College London, Watford Road, Middlesex HA1 3UJ, UK

Correspondence: Dr I Zlobec, E-mail: izlobec@uhbs.ch

Received 24 September 2007; Revised 29 November 2007; Accepted 29 November 2007; Published online 8 January 2008.

Abstract

The ability to predict complete pathologic response or sensitivity to radiation before treatment would have a significant impact on the selection of patients for preoperative radiotherapy or chemo-radiation therapy schedules. The aim of this study was to determine the value of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), p53, Bcl-2 and apoptosis protease-activating factor-1 (APAF-1) as predictors of complete pathologic tumour regression in patients undergoing preoperative radiotherapy for advanced rectal cancer. Pretreatment tumour biopsies from predominantly cT3 patients undergoing a preoperative high-dose-rate brachytherapy protocol were immunostained for EGFR, VEGF, p53, Bcl-2 and APAF-1. Immunoreactivity was evaluated by three pathologists. Cut-off scores for tumour marker positivity were obtained by receiver-operating characteristic (ROC) curve analysis. The association of marker expression with complete pathologic response was analysed in univariate and multivariable analysis. Multi-marker phenotypes of the independent protein markers were evaluated. In multivariable analysis, loss of VEGF (P-value=0.009; odds ratio (OR) (95% CI)=0.24 (0.08–0.69)) and positive EGFR (P-value=0.01; OR (95% CI)=3.82 (1.37–10.6)) both demonstrated independent predictive value for complete pathologic response. The odds of complete response were 12.8 for the multi-marker combination of VEGF-negative and EGFR-positive tumours. Of the 34 EGFR-negative- and VEGF-positive cases, 32 (94.1%) had no complete pathologic response. The combined analysis of VEGF and EGFR is predictive of complete pathologic response in patients undergoing preoperative radiotherapy. In addition, the findings of this study have identified a subgroup of simultaneous EGFR-negative and VEGF-positive patients who are highly resistant to radiotherapy and should perhaps be considered candidates for innovative neoadjuvant combined modalities.