Dataset Information

Programmed death-ligand 1 expression level as a predictor of EGFR tyrosine kinase inhibitor efficacy in lung adenocarcinoma.

ABSTRACT:

Background

The main objective of this study was to investigate the impact of programmed death-ligand 1 (PD-L1) expression on the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC).

Methods

This study analyzed 108 patients with NSCLC who had received EGFR-TKI as first-line systemic treatment at Seoul National University Bundang Hospital and Seoul National University Hospital between December 2012 and October 2018. The National Cancer Center Research Institute (NCCRI) and The Cancer Genome Atlas (TCGA) datasets were analyzed to investigate the mechanisms underlying EGFR-TKI-resistance in tumors with high PD-L1 expression.

Results

Among the 108 patients, 55, 37, and 16 had negative (PD-L1 Tumor proportion score <1%), weak (1-49%), and strong (?50%) PD-L1 expression, respectively. Patients with strong PD-L1 expression had significantly shorter median progression-free survival (PFS; 7.07 months) than patients with weak (14.73 months, P<0.001) or negative (12.70 months, P=0.001) PD-L1 expression. After adjustment for covariates by Cox regression, PD-L1 expression remained a significant indicator of adverse prognosis. In EGFR-TKI-refractory patients, the frequency of T790M mutation and the PFS following treatment with third-generation EGFR-TKI and PD-1 antibody were similar in the three groups. TCGA and NCCRI database analysis showed that high PD-L1 expression in EGFR-mutated NSCLCs correlated with IL-6/JAK/STAT3 signaling and high MUC16 mutation frequency.

Conclusions

Strong PD-L1 expression in tumors might be a surrogate indicator of poor response to first-line EGFR-TKIs in NSCLC patients with sensitizing EGFR mutations, and may reflect a de novo resistance mechanism involving JAK-STAT signaling.

SUBMITTER: Kang M

PROVIDER: S-EPMC7947423 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Programmed death-ligand 1 expression level as a predictor of EGFR tyrosine kinase inhibitor efficacy in lung adenocarcinoma.

Kang Minsu M Park Changhee C Kim Se Hyun SH Yoon Sock Won SW Suh Koung Jin KJ Kim Yu Jung YJ Ock Chan-Young CY Kim Miso M Keam Bhumsuk B Kim Tae Min TM Kim Dong-Wan DW Heo Dae Seog DS Lee Jong Seok JS

Translational lung cancer research 20210201 2

<h4>Background</h4>The main objective of this study was to investigate the impact of programmed death-ligand 1 (PD-L1) expression on the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC).<h4>Methods</h4>This study analyzed 108 patients with NSCLC who had received EGFR-TKI as first-line systemic treatment at Seoul National University Bundang Hospital and Seoul National University Hospital between Decem ...[more]

PMID: 33718015

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Project description:IntroductionEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with favorable response in EGFR mutant lung cancer. Acquired resistance to reversible EGFR TKIs remains a significant barrier, and acquired EGFR T790M-mutation is the major mechanism. Second-generation irreversible EGFR TKI, afatinib, had also been approved for treating EGFR mutant lung cancer patients, but the mechanism of acquired resistance to afatinib has not been well studied.ResultsForty-two patients had tissue specimens taken after acquiring resistance to afatinib. The sensitizing EGFR mutation were all consistent between pre- and post-afatinib tissues. Twenty patients (47.6%) had acquired T790M mutation. T790M rate was not different between first-generation EGFR TKI-naïve patients (50%) and first-generation EGFR TKI-treated patients (46.4%) (p = 0.827). No clinical characteristics or EGFR mutation types were associated with the development of acquired T790M. No other second-site EGFR mutations were detected. There were no small cell or squamous cell lung cancer transformation. Other genetic mutations were not identified in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2.MethodsAfatinib-prescription record of our department of pharmacy from January 2007 and December 2014 was retrieved. We investigated patients with tissue specimens available after acquiring resistance to afatinib. Enrolled patients should have partial response or durable stable disease of treatment response to afatinib. Various mechanisms of acquired resistance to first-generation EGFR TKIs were evaluated. Histology and cytology were reviewed. EGFR, PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2 genetic alterations were evaluated by sequencing. Statistical analysis was performed using Chi-square test and Kaplan-Meier method.ConclusionsT790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired resistance mechanism. First-generation EGFR TKI exposure did not influence the prevalence of T790M in lung cancer acquired resistance to afatinib.

Project description:BackgroundA subset of lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutations (mEGFR) is common in non-smokers and women, suggesting that mutational stressors other than smoking are involved.MethodsTargeted sequencing using a custom panel containing 70 cancer-related genes were performed from 73 cases of lung adenocarcinoma with mEGFR (study cohort). In parallel, publicly available data of 47 TCGA-LUAD cases with mEGFR (LUAD cohort) were extracted from the GDC data portal and analyzed by non-negative matrix factorization using the Maftools package.ResultsIn the study cohort, the C?>?A transversions accounted for 12.9% of all single nucleotide variations (SNVs), comprising the second smallest proportion among SNVs. The E19del-subgroup had a significantly lower mutational burden with significantly higher Ti/Tv ratio than the SNV-subgroup, which includes cases with L858R and other EGFR-TKI sensitizing SNVs. (P?=?0.0326 and 0.0002, respectively, Mann-Whitney U test). In the LUAD cohort, the mutational burden was substantially lower than in other TCGA cancer cohorts, and the frequency of C?>?A transversions was 30.3%, occupying the second frequency. The E19del-subgroup had a lower mutational burden overall and a higher Ti/Tv ratio than the SNV-subgroup (P?=?0.0497 and P?=?0.0055, respectively, Mann-Whitney U test). Smoking-related signature 4 was observed only in the L858R-subgroup, while ignature 30 and 5 was observed in both groups.ConclusionsLung adenocarcinoma with mEGFR(+) has a lower mutational burden and does not show a characteristic mutation pattern influenced by smoking. E19del and L858R, which are representative subtypes of mEGFR(+) lung adenocarcinoma, differ in terms of mutational spectrum, as the E19del-subgroup has a lower mutation burden and a higher Ti/Tv ratio than the SNV-subgroup. These findings could help explain the differences in the responses to EGFR-TKIs and in the clinical courses between the two lung adenocarcinoma subgroups.

Project description:Background: There is limited data on the relative survival rate of first-line therapy of gefitinib, erlotinib (first-generation epidermal growth factor receptor-tyrosine kinase inhibitor [EGFR-TKI]), and afatinib (second-generation EGFR-TKI) in patients with EGFR-mutated advanced lung adenocarcinoma in real-world data, especially in the Asian population. This study aimed to compare the relative survival rate of gefitinib, erlotinib, and afatinib in patients with EGFR-mutated advanced lung adenocarcinoma by real-world data in Taiwan. Methods: This retrospective cohort population-based study included untreated adult patients diagnosed with advanced lung adenocarcinoma who were identified in the Taiwan National Health Insurance Research Database between 2014 and 2017. The date of EGFR-mutated advanced lung adenocarcinoma diagnosis was referred as index date. This outcome evaluated overall survival (OS) and time to treatment failure (TTF) between gefitinib, erlotinib, and afatinib. Switching EGFR-TKIs or chemotherapy and new development of brain metastases were proxies of TTF. Estimated relative treatment effects on OS and TTF among EGFR-TKIs were adjusted by inverse probability of treatment weighting (IPTW) in Cox proportional hazards model. Propensity score (PS) matched pair analyses were performed as sensitivity analyses. Results: The study cohort included 3,695 patients initiated with gefitinib, 3,310 with erlotinib, and 3,041 with afatinib. The mean age among the three treatment groups was 70.4 (±11.6), 66.8 (±11.6), and 64.3 (±11.4) years, and the female percentage was 70.4, 58.6, and 57.7%, respectively. Afatinib showed longer median OS than gefitinib (23.9 vs. 21.3 months; adjusted hazard ratio (aHR), 0.87; p < 0.001) and erlotinib (23.9 vs. 21.8 months; aHR, 0.87; p = 0.001). Consistent results were observed with TTF outcomes. For patients with brain metastases at diagnosis, afatinib showed similar OS with erlotinib (p = 0.917) but superior to gefitinib (p = 0.028). PS matching had similar results with IPTW adjustment in the study population. Conclusion: Afatinib as first-line therapy had better survival outcomes for EGFR-mutated advanced lung adenocarcinoma than gefitinib and erlotinib in the Taiwan population. Both erlotinib and afatinib demonstrated superior treatment effect in patients with initial brain metastases than gefitinib.

Dataset Information

Programmed death-ligand 1 expression level as a predictor of EGFR tyrosine kinase inhibitor efficacy in lung adenocarcinoma.

Background

Methods

Results

Conclusions

Publications

Programmed death-ligand 1 expression level as a predictor of EGFR tyrosine kinase inhibitor efficacy in lung adenocarcinoma.

Similar Datasets

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