Evaluating the Prognostic Value of ERCC1 and Thymidylate Synthase Expression and the Epidermal Growth Factor Receptor Mutation Status in Adenocarcinoma Non-Small-Cell Lung Cancer

Abstract

The present study evaluated the prognostic value of the epidermal growth factor receptor (EGFR) mutation status, and excision repair cross-complementation group 1 (ERCC1) and thymidylate synthase (TS) expression following intercalated tyrosine kinase inhibitor (TKI) therapy and platinum- and pemetrexed-based chemotherapies (subsequent second-line treatment) for patients with adenocarcinoma non-small-cell lung cancer (AC-NSCLC). In total, 131 patients with AC-NSCLC were enrolled. The EGFR mutation status and ERCC1 and TS expression were evaluated through direct DNA sequencing and immunohistochemical analyses, respectively. The EGFR mutation status and ERCC1 and TS expression were the significant predictors of clinical outcomes. The EGFR mutation status was the main outcome predictor for overall survival (OS) benefits in the overall population. Further exploratory ERCC1 and TS expression analyses were conducted to provide additional insights. Low TS expression was predictive of improved OS of patients with negative EGFR-mutated advanced AC-NSCLC, whereas high ERCC1 expression resulted in poor OS in patients with positive EGFR-mutated advanced AC-NSCLC. TS and ERCC1 expression levels were effective prognostic factors for negative and positive EGFR-mutated AC-NSCLC, respectively. In conclusion, the present results indicate that the EGFR mutation status and TS and ERCC1 expression can be used as the predictors of OS after subsequent second-line treatments for AC-NSCLC.

Thymidylate synthase (TS) immunostaining in the diagnosis of the myoepithelial cells, basal cells, stratified epithelium cells, and associated tumors

“…TS is the critical enzyme that catalyzes the methylation of dUMP to dTMP with 5,10-methylenetetrahydrofolate as a cofactor. Therefore, it provides the intracellular de novo source of thymidylate, which is essentially required for DNA replication and repair ( 24 ). Studies have shown that overexpression of TS is believed to confer resistance to 5FU-based adjuvant chemotherapy, and has been considerably associated with the poor prognosis of the subset of aggressive solid tumors, including breast, lung, stomach, and colorectal cancer ( 25 , 26 ).…”

Correlation of E-cadherin gene polymorphisms and epidermal growth factor receptor mutation in lung adenocarcinoma

“…We selected two CDH1 SNPs, including rs16260 (-160, C/A) in the promoter region and the intron 2 variant rs9929218 based on their potential involvement in the various cancer types 16 - 20 . Different associating factors relating to the mutations in EGFR were considered and analyzed as previously described 21 , 22 . Data obtained from medical record of each patient included demographics (age, gender), tobacco smoking status, and tumor staging and differentiation.…”

Lung adenocarcinoma mimicking metastatic pancreatic cancer, a diagnostic dilemma

“…Based on the diagnosis of highly symptomatic metastatic lung adenocarcinoma with a high tumor burden leading to organ compromise, systemic cytoreductive treatment was clearly indicated. Loss of thymidylate synthase expression predicted a good response to pemetrexed or other anti-folate agents, while the high tumor mutational burden and high PDL-1 expression predicted an excellent response to anti-PDL-1 antibodies [10][11][12][13]. Indeed, the prognosis of Stage IV non-small cell lung cancer in the modern age of immunotherapy is improved with a quadrupling of the historical 4% five year overall survival rate to 16% with immunotherapy [14].…”