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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, 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?

SUBMITTER: Lee HK

PROVIDER: S-EPMC7557072 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Lee Hong Kyu HK Kwon Mi Jung MJ Ra Yong Joon YJ Lee Hee Sung HS Kim Hyoung Soo HS Nam Eun Sook ES Cho Seong Jin SJ Park Hye-Rim HR Min Soo Kee SK Seo Jinwon J Choe Ji-Young JY Min Kyueng-Whan KW Kang So Young SY

Diagnostic pathology 20201014 1

<h4>Background</h4>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 ...[more]

PMID: 33054840

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Project description:The prognostic value of BRAF and KRAS mutations within microsatellite-unstable (MSI) and microsatellite-stable (MSS) subgroups of resected colon carcinoma patients remains controversial. We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials.Three groups were defined: BRAF Mutant, KRAS Mutant, and double wild-type. The analytic strategy involved estimation of study-specific effects, assessment of homogeneity of results, and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials. Associations of mutations with patient outcome were analyzed, and multivariable models were adjusted for treatment and relevant factors.Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status; 3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23 to 1.92, P < .001), KRAS codon 12 alterations, and p.G13D mutations (HR?=?1.60, 95% CI?=?1.40 to 1.83, P < .001) were associated with shorter time to recurrence (TTR) and shorter survival after relapse (SAR; HR?=?3.02 , 95% CI?=?2.32 to 3.93, P < .001, and HR?=?1.20, 95% CI?=?1.01 to 1.44, P = .04, respectively). Overall survival (OS) in MSS patients was poorer for BRAF-mutant patients (HR?=?2.01, 95% CI?=?1.56 to 2.57, P < .001) and KRAS-mutant patients (HR?=?1.62, 95% CI?=?1.38 to 1.91, P < .001) vs wild-type. No prognostic role of KRAS or BRAF mutations was seen in MSI patients. Furthermore, no interaction was found between treatment arm (with or without cetuximab) and KRAS and BRAF mutations for TTR or OS in MSS patients.In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations are independently associated with shorter TTR, SAR, and OS in patients with MSS, but not MSI, tumors. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.

Dataset Information

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

Publications

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

Similar Datasets

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