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Article Open Access

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

  • Authors:
    • Junichi Soh
    • Hiromasa Yamamoto
    • Norihito Okumura
    • Hiroyuki Suzuki
    • Masao Nakata
    • Toshiya Fujiwara
    • Kenicehi Gemba
    • Isao Sano
    • Takuji Fujinaga
    • Masafumi Kataoka
    • Yasuhiro Terasaki
    • Nobukazu Fujimoto
    • Kazuhiko Kataoka
    • Shinji Kosaka
    • Motohiro Yamashita
    • Hidetoshi Inokawa
    • Masaaki Inoue
    • Hiroshige Nakamura
    • Yoshinori Yamashita
    • Yuta Takahashi
    • Hidejiro Torigoe
    • Hiroki Sato
    • Shuta Tomida
    • Katsuyuki Hotta
    • Hiroshige Yoshioka
    • Satoshi Morita
    • Keitaro Matsuo
    • Junichi Sakamoto
    • Hiroshi Date
    • Shinichi Toyooka
  • View Affiliations / Copyright

    Affiliations: Department of Thoracic Surgery, Okayama University Hospital, Okayama 700‑8558, Japan, Department of Thoracic Surgery, Kurashiki Central Hospital, Kurashiki, Okayama 710‑8602, Japan, Department of Chest Surgery, Fukushima Medical University Hospital, Fukushima 960‑1295, Japan, Department of General Thoracic Surgery, Kawasaki Medical School Hospital, Kurashiki, Okayama 701‑0192, Japan, Department of Thoracic Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima 730‑8518, Japan, Department of Respiratory Medicine, Chugoku Central Hospital, Fukuyama, Hiroshima 720‑0001, Japan, Department of Respiratory Surgery, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki 852‑8511, Japan, Department of General Thoracic Surgery, National Hospital Organization Nagara Medical Center, Gifu 502‑8558, Japan, Department of Surgery and Respiratory Center, Okayama Saiseikai General Hospital, Okayama 700‑8511, Japan, Department of Respiratory Surgery, Saga Medical Center Koseikan, Saga 840‑8571, Japan, Department of Medical Oncology and Respiratory Medicine, Okayama Rosai Hospital, Okayama 702‑8055, Japan, Department of Thoracic Surgery, National Hospital Organization Iwakuni Clinical Center, Iwakuni, Yamaguchi 740‑8510, Japan, Department of Thoracic Surgery, Shimane Prefectural Central Hospital, Izumo, Shimane 693‑8555, Japan, Department of Thoracic Surgery, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime 791‑0280, Japan, Department of Thoracic Surgery, National Hospital Organization Yamaguchi‑Ube Medical Center, Ube, Yamaguchi 755‑0241, Japan, Department of Thoracic Surgery, Shimonoseki City Hospital, Shimonoseki, Yamaguchi 750‑8520, Japan, Division of General Thoracic Surgery, Tottori University Hospital, Yonago, Tottori 683‑8504, Japan, Department of Thoracic Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima 737‑0023, Japan, Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama 700‑8558, Japan, Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700‑8558, Japan, Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata, Osaka 573‑1191, Japan, Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto 606‑8507, Japan, Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Aichi 464‑8681, Japan, Tokai Central Hospital, Kakamigahara, Gifu 504‑8601, Japan, Department of Thoracic Surgery, Kyoto University Hospital, Kyoto 606‑8507, Japan
    Copyright: © Soh et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 79
    |
    Published online on: July 3, 2025
       https://doi.org/10.3892/mco.2025.2874
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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.
View Figures

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.
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Copy and paste a formatted citation
Spandidos Publications style
Soh J, Yamamoto H, Okumura N, Suzuki H, Nakata M, Fujiwara T, Gemba K, Sano I, Fujinaga T, Kataoka M, Kataoka M, et al: 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. Mol Clin Oncol 23: 79, 2025.
APA
Soh, J., Yamamoto, H., Okumura, N., Suzuki, H., Nakata, M., Fujiwara, T. ... Toyooka, S. (2025). 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. Molecular and Clinical Oncology, 23, 79. https://doi.org/10.3892/mco.2025.2874
MLA
Soh, J., Yamamoto, H., Okumura, N., Suzuki, H., Nakata, M., Fujiwara, T., Gemba, K., Sano, I., Fujinaga, T., Kataoka, M., Terasaki, Y., Fujimoto, N., Kataoka, K., Kosaka, S., Yamashita, M., Inokawa, H., Inoue, M., Nakamura, H., Yamashita, Y., Takahashi, Y., Torigoe, H., Sato, H., Tomida, S., Hotta, K., Yoshioka, H., Morita, S., Matsuo, K., Sakamoto, J., Date, H., Toyooka, S."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". Molecular and Clinical Oncology 23.3 (2025): 79.
Chicago
Soh, J., Yamamoto, H., Okumura, N., Suzuki, H., Nakata, M., Fujiwara, T., Gemba, K., Sano, I., Fujinaga, T., Kataoka, M., Terasaki, Y., Fujimoto, N., Kataoka, K., Kosaka, S., Yamashita, M., Inokawa, H., Inoue, M., Nakamura, H., Yamashita, Y., Takahashi, Y., Torigoe, H., Sato, H., Tomida, S., Hotta, K., Yoshioka, H., Morita, S., Matsuo, K., Sakamoto, J., Date, H., Toyooka, S."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". Molecular and Clinical Oncology 23, no. 3 (2025): 79. https://doi.org/10.3892/mco.2025.2874
Copy and paste a formatted citation
x
Spandidos Publications style
Soh J, Yamamoto H, Okumura N, Suzuki H, Nakata M, Fujiwara T, Gemba K, Sano I, Fujinaga T, Kataoka M, Kataoka M, et al: 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. Mol Clin Oncol 23: 79, 2025.
APA
Soh, J., Yamamoto, H., Okumura, N., Suzuki, H., Nakata, M., Fujiwara, T. ... Toyooka, S. (2025). 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. Molecular and Clinical Oncology, 23, 79. https://doi.org/10.3892/mco.2025.2874
MLA
Soh, J., Yamamoto, H., Okumura, N., Suzuki, H., Nakata, M., Fujiwara, T., Gemba, K., Sano, I., Fujinaga, T., Kataoka, M., Terasaki, Y., Fujimoto, N., Kataoka, K., Kosaka, S., Yamashita, M., Inokawa, H., Inoue, M., Nakamura, H., Yamashita, Y., Takahashi, Y., Torigoe, H., Sato, H., Tomida, S., Hotta, K., Yoshioka, H., Morita, S., Matsuo, K., Sakamoto, J., Date, H., Toyooka, S."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". Molecular and Clinical Oncology 23.3 (2025): 79.
Chicago
Soh, J., Yamamoto, H., Okumura, N., Suzuki, H., Nakata, M., Fujiwara, T., Gemba, K., Sano, I., Fujinaga, T., Kataoka, M., Terasaki, Y., Fujimoto, N., Kataoka, K., Kosaka, S., Yamashita, M., Inokawa, H., Inoue, M., Nakamura, H., Yamashita, Y., Takahashi, Y., Torigoe, H., Sato, H., Tomida, S., Hotta, K., Yoshioka, H., Morita, S., Matsuo, K., Sakamoto, J., Date, H., Toyooka, S."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". Molecular and Clinical Oncology 23, no. 3 (2025): 79. https://doi.org/10.3892/mco.2025.2874
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