Association of the expression of 5-FU biomarkers with aging and prognosis in elderly patients with lung cancer treated with S-1 adjuvant chemotherapy: Follow-up results of the Setouchi Lung Cancer Group Study 1201

Abstract

Managing elderly patients presents several challenges because of age-related declines; however, age should not be the sole determinant for adjuvant treatment decisions in patients with non-small cell lung cancer (NSCLC). Moreover, age may affect the expression of 5-fluorouracil (5-FU) biomarkers. The present study assessed: i) The effect of age on the expression levels of 5-FU biomarkers by analyzing a public database; and ii) the ability of these biomarkers to predict clinical outcomes in elderly patients with NSCLC who underwent complete resection in the Setouchi Lung Cancer Group Study 1201 (SCLG1201) followed by S-1 adjuvant chemotherapy. Changes in gene expression levels across age groups were assessed by analyzing The Cancer Genome Atlas (TCGA) database. The expression of 5-FU biomarkers, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase, epidermal growth factor receptor (EGFR) and excision repair cross-complementation group 1 (ERCC1), were assessed via quantitative reverse-transcription PCR assays in 89 elderly patients (≥75 years) with NSCLC who received adjuvant chemotherapy with oral fluoropyrimidine prodrug S-1 in the SLCG1201 trial. TCGA database analysis (n=955) showed that TS expression decreased significantly with aging, especially in the age group ≥75. In the SCLG1201 trial, univariate analysis revealed that EGFR upregulation and TS downregulation were correlated with favorable recurrence-free survival (RFS) and overall survival (OS), respectively. Multivariate analysis demonstrated that pathological stage was an independent prognostic factor for both RFS and OS. EGFR mutations were associated with upregulation of DPD and EGFR, and downregulation of TS and ERCC1. In conclusion, although pathological stage is an independent prognostic factor for survival, EGFR upregulation and TS downregulation may be a greater predictor of clinical outcomes in elderly patients with NSCLC treated with S-1 adjuvant chemotherapy. The age-related decrease in TS expression supports the potential benefit of 5-FU therapies in elderly patients. Nonetheless, further research is warranted to validate these results.

Keywords: DPD; EGFR; ERCC1; OPRT; S-1; TP; TS; adjuvant chemotherapy; elderly patients; non-small cell lung cancer.

Figure 1

Impact of age on mRNA expression levels of six genes. Data on RNA-sequencing expression profiles of TCGA samples were obtained from the Genomic Data Commons Portal (https://portal.gdc.cancer.gov). The datasets TCGA-LUAD and TCGA-LUSC were downloaded in March 2023. (A) The mean and standard deviation of the z-scores for the six genes are shown by age group based on 10-year increments. (B) Data from all 955 samples were plotted and compared between patients of <75 years old (n=776) and those ≥75 years old (n=179). The Mann-Whitney U test was used for comparison between the two groups. TCGA, The Cancer Genome Atlas; EGFR, epidermal growth factor receptor; DPD, dihydropyrimidine dehydrogenase; TP, thymidine phosphorylase; TS, thymidylate synthase; OPRT, orotate phosphoribosyl transferase; ERCC1, excision repair cross-complementation group 1.

Figure 2

Relative mRNA expression of six genes. The relative mRNA expression of each gene was plotted for each sample. EGFR, epidermal growth factor receptor; DPD, dihydropyrimidine dehydrogenase; TP, thymidine phosphorylase; TS, thymidylate synthase; OPRT, orotate phosphoribosyl transferase; ERCC1, excision repair cross-complementation group 1.

Figure 3

Recurrence-free survival. Survival curves of (A) Smoking status, (B) pathological stage and (C) relative mRNA expression of EGFR. EGFR, epidermal growth factor receptor.

Figure 4

Overall survival. Survival curves of (A) sex, (B) smoking status, (C) histology, (D) pathological stage and (E) relative mRNA expression of TS. TS, thymidylate synthase.