The Role of the TP53 Pathway in Predicting Response to Neoadjuvant Therapy in Esophageal Adenocarcinoma

Abstract Purpose: In patients with locally advanced esophageal adenocarcinoma (EAC), response to neoadjuvant therapy strongly predicts survival, but robust molecular predictors of response have been lacking. We therefore sought to discover meaningful predictors of response in these patients. Experimental Design: We retrospectively identified all patients with adenocarcinoma of the lower esophagus or gastroesophageal junction who (1) were treated with multimodality therapy with curative intent at our institution from 2014 through 2020 and (2) underwent prospective sequencing by MSK-IMPACT. Clinicopathologic and genomic data were analyzed to identify potential genomic features, somatic alterations, and oncogenic pathways associated with treatment response. Results: In total, 237 patients were included. MDM2 amplification was independently associated with poor response to neoadjuvant therapy [OR 0.10 (95% CI 0.01, 0.55); p=0.032], when accounting for significant clinicopathologic variables, including clinical stage, tumor grade, and chemotherapy regimen. Moreover, TP53 pathway alterations, grouped according to inferred severity of TP53 dysfunction, were significantly associated with response to neoadjuvant therapy (p=0.004, q=0.07). Patients with MDM2 amplifications or truncating bi-allelic TP53 mutations had similar outcomes in terms of poor responses to neoadjuvant therapy and, consequently, shorter progression-free survival, compared with patients with TP53 pathway wild-type tumors. Thus, worsening TP53 dysfunction was directly correlated with worse outcomes. Conclusions: MDM2 amplification and TP53 status are associated with response to therapy in patients with EAC. Given the dearth of actionable targets in EAC, MDM2 inhibition, in combination with cytotoxic chemotherapy, may represent an important therapeutic strategy to overcome treatment resistance and improve outcomes in these patients.