Abstract
BackgroundEsophageal 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, and BRAF mutations, 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.MethodsWe investigated the significance of the present druggable markers [PD-L1, PIK3CA, KRAS, and BRAF mutations, MSI caused by deficient dMMR, and HPV] in 64 curatively resected ESCCs, using immunohistochemistry (PD-L1 and MMR protein expression), direct sequencing (KRAS, BRAF, and PIK3CA mutations), real-time PCR (HPV infection), and MSI using quasi-monomorphic markers.ResultsPD-L1 expression, PIK3CA mutation, 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), whereas KRAS and BRAF mutations were not detected in ESCCs. PD-L1-positive tumors were not correlated with PIK3CA mutation or MSI/dMMR (all P > 0.05). PD-L1, PIK3CA mutation, and MSI/dMMR characterized the patients associated with light smoking, female and younger age, and younger age and well-differentiated tumors, respectively (all P < 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, PIK3CA mutation had a poor prognostic impact on both OS and DFS (P = 0.006, P = 0.002).ConclusionsPIK3CA mutation 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.
Highlights
Esophageal cancer is the seventh most prevalent cancer and the sixth most common cause of cancerrelated mortality, representing one of the most aggressive malignant tumors that are very difficult to treat [1]
We investigated Programmed death-ligand 1 (PD-L1) expression in association with PIK3CA, KRAS, and BRAF mutations, microsatellite instability (MSI)/deficient mismatch repair (dMMR) status, and human papillomavirus (HPV) infection to determine their prognostic relevance for curatively resected Esophageal squamous cell carcinoma (ESCC)
The incidence of HPV was very rare, while the KRAS and BRAF mutations were not detected in ESCCs
Summary
Esophageal cancer is the seventh most prevalent cancer and the sixth most common cause of cancerrelated mortality, representing one of the most aggressive malignant tumors that are very difficult to treat [1]. Among the Korean population, esophageal cancer is the eighth most common cause of cancer-related mortality [3]. The incidence and mortality rates are high among Korean males with esophageal squamous cell carcinoma (ESCC), which is the most common histological form of esophageal cancer in Korea [3]. There have been rapid advances in surgical techniques and multimodal chemoradiation therapies for other cancers, ESCCs still remain intractable disease with few therapeutic options. The risk factors for ESCCs are less established in the Korean population. Esophageal squamous cell carcinoma (ESCC) still remains intractable disease with few therapeutic options. PIK3CA, KRAS, and BRAF mutations, 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
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