Impact of chemoradiotherapy on PD1/PDL1 expression and clinical outcomes in gastroesophageal cancers.

Abstract

4031 Background: Expression of the immune modulating proteins, programmed death receptor-1 (PD1) and its ligand (PDL1), in gastrointestinal malignancies is associated with poor prognosis. PD1/PDL1 expression levels have also been identified as predictors of response to checkpoint inhibition. Minimal data is available on how expression of PD1 and PDL1 is influenced by chemoradiotherapy (CRT). In this study, we investigated the relationship between PDL1/PD1 expression, CRT, and clinical outcomes in gastroesophageal (GE) cancer. Methods: With IRB approval, we identified 28 patients with gastric cardia or GE junction tumors who underwent neoadjuvant standard CRT followed by surgical resection. Pre-CRT biopsies and post-CRT surgical specimens were analyzed using quantitative immunohistochemistry for the expression of PDL1 and PD1. Samples were categorized as trace-low (TL) or moderate-high (MH) expressors of PDL1 and PD1. The impact of these and other clinical and pathologic variables on overall survival (OS) was assessed using multivariate cox proportional hazards modeling. Co-expression of PDL1 and PD1 in matched samples was determined by regression analysis. Results: Following CRT, PDL1 and PD1 expression increased in 54% and 32% of patients, respectively. On multivariate analysis, patients with MH expression of PD1 after CRT irrespective of pre-CRT expression levels had a significant decrease in OS compared to those with TL expression (median survival 23.1 vs 74.1 months; HR,3.31; CI,1.05-10.35; p = 0.039). In patients with gastric confined tumors, an increase in PD1 expression from TL to MH after CRT was associated with significantly lower OS rates (p = 0.003). Regression analysis of PD1 to PDL1 was significant (p < 0.01) both before and after CRT, with a correlation coefficient of 0.34 in pre-CRT and 0.49 in post-CRT specimens. Conclusions: Elevated expression of PD1 is associated with poor OS in patients with GE cancer. Neoadjuvant CRT upregulates both PDL1 and PD1. In gastric cancer patients, this led to significantly worse survival. These data identify potential mechanisms of resistance and suggest a role for checkpoint inhibitors in combination with CRT.