Whole transcriptome analysis to reveal epithelial-mesenchymal transition after neoadjuvant therapy with or without additional anti-EGFR treatment: Subgroup analysis of esophageal squamous cell carcinomas of the SAKK 75/08 and the EORTC AIO POWER study.

Abstract

4071 Background: In localized disease of esophageal squamous cell cancer (ESCC), a trend in higher pathological response rates and longer time to treatment failure was seen by addition of anti-EGFR treatment to radio-chemotherapy (RCTX) compared to RCTX alone (SAKK 75/08 trial and others). On the contrary, the effect of anti-EGFR treatment to chemotherapy (CTX) remains unclear as no survival benefit was detected within advanced patients (EORTC-AIO-POWER study). Since perfect discrimination and selection of subgroups with highest benefit for anti-EGFR treatment (AB) is missing, we investigated the predictive values of whole transcriptomic gene expression analysis (WTGE) applied on biopsy tissue. Methods: 50 pretherapeutic formalin fixed paraffin embedded specimens of ESCC patients from SAKK 75/08 study were analyzed for the effect of RCTX with and without anti-EGFR AB. As well as 26 historic controls of primary resected tumor stage equally distributed ESCC were analyzed. For the advanced setting, we analyzed 28 additional pretherapeutic biopsies and compared groups from CTX to CTX plus AB. The HTG EdgeSeq method was used for NGS-based WTGE. Response to treatment was assessed by histopathological tumor regression in localized disease and clinical courses. Response to treatment in the advanced tumor setting was assessed to the clinical course of stable disease and partial response versus non-responders. Results: Firstly, NGS-based WTGE failed to show significant differences in expression patterns between responding and non-responding ESCC patients, irrespective of treatment protocols and EGFR AB in the localized as well in advanced disease setting. Secondly however, comparison between pre-treatment biopsies and posttreatment residual tumor tissues detected 781 genes that were upregulated and 623 that were downregulated with gene sets associated with muscle processes and epithelial-mesenchymal transition (EMT) in the localized disease. EMT genes were also enriched in residual tumors after neoadjuvant RCTX compared to primary resection in an independent control cohort. Additionally performed immunohistochemical studies showed lower numbers of ZEB-1 positive ESCC in an independent collection of tumors treated by neoadjuvant RCTX compared to primary resection. Conclusions: Our Whole transcriptomic gene expression analyses suggest that EMT is involved in responses to neoadjuvant protocols including EGFR targeting therapies. Targeting EMT may be a molecular pathway to increase complete responses after neoadjuvant RCTX in ESCC.