A proprietary multianalyte test for predicting extreme resistance to neoadjuvant 5-FU based chemoradiation (CTRT) in esophageal adenocarcinoma (EC).

Abstract

51 Background: Standard of care for localized EC is neoadjuvant CTRT followed by surgery. Although 5-FU based regimens are still commonly used, other regimens (CROSS) are also prescribed. Published EC studies report 20-25% of patients exhibit extreme resistance (exCTRT) to 5-FU based neoadjuvant treatment (NT); these patients may benefit from alternative treatment regimens. We have developed a proprietary assay using a training set of 167 patients to accurately identify patients with exCTRT (ROC 0.96). The results presented herein constitute an independent clinical validation. Methods: Biopsy samples from 71 pts diagnosed to have EC and who had undergone surgical excision following NT were obtained. IHC detection of NF-kB, SHH, and Gli-1 proteins in FFPE sections was performed in a CLIA approved lab. A GI pathologist and an expert clinical scientist blindly evaluated resection specimens and assigned a labeling index (LI) score. The LI for each case was compared to the established training set and the predicted response determined using a logistic regression algorithm. Blinded pathology scoring for exCTRT vs. non-exCTRT was performed for all samples using both CAP Tumor Response Grade (TRG) and the Rohatgi research scale. Results: Of the 71 EC cases in the clinical validation cohort, 24 had an outcome of exCTRT (<50% reduction in tumor following neoadjuvant treatment; TRG 3) and 47 had an outcome of non-exCTRT (>50% reduction in tumor; TRG 0-2). ROC for the validation cohort was 0.85. The positive predictive value for the validation study was 83%, reflecting an assay that can accurately predict those likely to have some degree of response to chemotherapy / radiation. Conversely, a negative predictive value of 83% with specificity of 94% was achieved indicating accurate identification of those not likely to benefit from neoadjuvant treatment. Conclusions: The analysis of NF-kB, SHH, and Gli-1 in EC tissue can accurately identify patients unlikely to respond to 5-FU based NT. These results are now confirmed using a CLIA accredited lab and a multicenter independent validation cohort of esophageal adenocarcinoma biopsies.