Significance of druggable targets (PD-L1, KRAS, BRAF, PIK3CA, MSI, and HPV) on curatively resected esophageal squamous cell carcinoma
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, 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.
Methods: We 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.
Results: PD-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).
Conclusions: PIK3CA 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.
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Posted 18 Sep, 2020
On 14 Oct, 2020
On 04 Oct, 2020
Received 17 Sep, 2020
On 17 Sep, 2020
On 17 Sep, 2020
Received 17 Sep, 2020
Invitations sent on 16 Sep, 2020
On 15 Sep, 2020
On 14 Sep, 2020
On 14 Sep, 2020
On 07 Sep, 2020
Received 30 Aug, 2020
On 24 Aug, 2020
Received 12 Aug, 2020
On 29 Jul, 2020
Invitations sent on 27 Jul, 2020
On 20 Jul, 2020
On 19 Jul, 2020
On 15 Jul, 2020
On 13 Jul, 2020
Significance of druggable targets (PD-L1, KRAS, BRAF, PIK3CA, MSI, and HPV) on curatively resected esophageal squamous cell carcinoma
Posted 18 Sep, 2020
On 14 Oct, 2020
On 04 Oct, 2020
Received 17 Sep, 2020
On 17 Sep, 2020
On 17 Sep, 2020
Received 17 Sep, 2020
Invitations sent on 16 Sep, 2020
On 15 Sep, 2020
On 14 Sep, 2020
On 14 Sep, 2020
On 07 Sep, 2020
Received 30 Aug, 2020
On 24 Aug, 2020
Received 12 Aug, 2020
On 29 Jul, 2020
Invitations sent on 27 Jul, 2020
On 20 Jul, 2020
On 19 Jul, 2020
On 15 Jul, 2020
On 13 Jul, 2020
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, 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.
Methods: We 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.
Results: PD-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).
Conclusions: PIK3CA 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.
Figure 1
Figure 2
Figure 3