Significance of druggable targets (PD-L1, KRAS, BRAF, PIK3CA, MSI, and HPV) on curatively resected esophageal squamous cell carcinoma

Abstract

Background: Esophageal squamous cell carcinoma (ESCC) still remains intractable disease with few therapeutic options. Programmed death-ligand 1 (PD-L1), which is essential for immune evasion, is involved in the pathogenesis of ESCC and thus is a potential therapeutic target.PIK3CA,KRAS, andBRAFmutations, microsatellite instability (MSI) caused by deficient mismatch repair (dMMR), and human papillomavirus (HPV) can potentially upregulate PD-L1 expression, which might contribute to the clinical outcome of patients with ESCC.

Methods: We investigated the significance of the present druggable markers [PD-L1,PIK3CA,KRAS, andBRAFmutations, MSI caused by deficient dMMR, and HPV] in 64 curatively resected ESCCs, using immunohistochemistry (PD-L1 and MMR protein expression), direct sequencing (KRAS,BRAF, andPIK3CAmutations), real-time PCR (HPV infection), and MSI using quasi-monomorphic markers.

Results: PD-L1 expression,PIK3CAmutation, and MSI/dMMR were detected in 35.9, 12.5, and 17.2% of ESCCs, respectively. HPV was rarely detected (1.6%) (high-risk HPV68), whereasKRASandBRAFmutations were not detected in ESCCs. PD-L1-positive tumors were not correlated withPIK3CAmutation or MSI/dMMR (allP > 0.05). PD-L1,PIK3CAmutation, and MSI/dMMR characterized the patients associated with light smoking, female and younger age, and younger age and well-differentiated tumors, respectively (allP < 0.05). In multivariate analysis, only PD-L1-positivity was an independent favorable prognostic factor for overall survival (OS) and disease-free survival (DFS) (P = 0.023,P = 0.014). In the PD-L1-negative ESCCs,PIK3CAmutation had a poor prognostic impact on both OS and DFS (P = 0.006,P = 0.002).

Conclusions: PIK3CAmutation may be an alternative prognostic biomarker in PD-L1-negative curatively resected ESCCs that can be optional to identify high-risk patients with worse clinical outcome who require more intensive therapy and follow-up.