The Significance of Co-Expression of Epidermal Growth Factor Receptor (EGFR) and Ki67 on Clinical Outcome in Patients with Anal Cancer Treated with Chemoradiotherapy: An Analysis of Study XXXX

Abstract Purpose To measure co-expression of EGFR and Ki67 proteins in pre-treatment tumor biopsies of anal cancer patients enrolled on Study XXXX, a phase III trial comparing 5FU/MMC/RT (Arm A) vs. 5FU/cisplatin/RT (Arm B), and to correlate expression with clinical outcome. Materials/Methods EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis (AQUA). Ki67 score within EGFR high vs. low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles and as a continuous variable. Associations between the tumor markers and clinical endpoints [overall and disease-free survival (OS, DFS), loco-regional and colostomy failure (LRF, CF), and distant metastases (DM] were explored. Results 282 pre-treatment tumors were analyzed from Study XXXX. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥ median had worse OS (HR=2.41, 95% C.I. = [1.38, 4.19], p=0.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (HR=1.85, 95% C.I. = [1.18, 2.92], p=0.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. Conclusions High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on Study XXXX. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR targeted therapeutic agent.