ABSTRACT
BACKGROUNDS The management of elderly patients presents several challenges due to age-related declines; however recent recommendations advocate for age not being the sole determinant for adjuvant treatment decisions in patients with non-small cell lung cancer (NSCLC). Aging may alter expression levels of 5-fluorouracil (5-FU) biomarkers.
METHODS Expression changes with aging were explored using The Cancer Genome Atlas (TCGA) database. 5-FU-related biomarker expressions, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase, epidermal growth factor receptor (EGFR), and excision repair cross-complementation group-1 (ERCC1), were assessed by the quantitative reverse-transcription PCR assays in 89 NSCLCs elderly patients (≥ 75 years old) receiving adjuvant S-1, an oral fluoropyrimidine agent, therapy in a SLCG1201 trial. RESULTS: TCGA database analysis (n=955) indicated decreased TS expression with aging, particularly in those 75 or older. In the SCLG1201 trial, univariate analysis revealed that high EGFR and low TS expressions correlated with favorable recurrence-free survival (RFS)(p=0.0264) and overall survival (OS)(p=0.0365), respectively. Multivariable analysis confirmed pathological stage as an independent prognostic factor for both RFS and OS (p=0.0052 and 0.0352, respectively). EGFR mutant tumors (n=27) showed significantly higher DPD (p=0.0066) and EGFR (p<0.0001) expressions, and lower TS(p=0.0125) and ERCC1(p=0.0015) expressions.
CONCLUSION Despite pathological stage being an independent prognostic factor, high EGFR and low TS expressions may predict better clinical outcomes in elderly NSCLC patients using adjuvant S-1. The age-related decrease in TS expression supports the potential benefit of 5-FU-based therapy in them compared to younger patients. Further research is warranted to validate these clinical implications.
Competing Interest Statement
I have read the journal's policy and the authors of this manuscript have the following potential competing interests out of this work: Junichi Soh reports a relationship with Chugai Pharmaceutical Co Ltd, Johnson & Johnson MedTech, Medtronic Inc, Intuitive Surgical Inc, CSL Behring LLC, and Olympus Corporation that includes: funding grants and speaking and lecture fees. Hiromasa Yamamoto reports a relationship with Chugai Pharmaceutical Co Ltd that includes: funding grants. Nobukazu Fujimoto reports a relationship with Merck & Co Inc, Ono Pharmaceutical Co Ltd, Nippon Kayaku Co Ltd, Chugai Pharmaceutical Co Ltd, Taiho Pharmaceutical Co Ltd, and Nippon Boehringer Ingelheim Co Ltd that includes: speaking and lecture fees. Katsuyuki Hotta reports a relationship with AstraZeneca Pharmaceuticals LP, Chugai Pharmaceutical Co Ltd, Eli Lilly Japan KK, MSD, Bristol-Myers Squibb Company, Ono Pharmaceutical Co Ltd, Boehringer Ingelheim Pharmaceuticals Inc, Nippon Kayaku Co Ltd, Amgen Inc, Taiho Pharmaceutical Co Ltd, Merck & Co Inc, and AbbVie Inc that includes: consulting or advisory, funding grants, and speaking and lecture fees. Hiroshige Yoshioka reports a relationship with Amgen Inc, AstraZeneca, Bristol Myers Squibb Co, Chugai Pharmaceutical Co Ltd, Daiichi Sankyo Inc, Delta-Fly Pharma, Eli Lilly and Company, Kyowa Kirin Co Ltd, Merch Biopharma, MSD, Boehringer Ingelheim Co Ltd, Nippon Kayaku Co Ltd, Nipro Pharma Corporation, Novartis Pharmaceuticals, Ono Pharmaceutical Co Ltd, Otsuka Pharmaceutical Co Ltd, Pfizer, Taiho Pharmaceutical Co Ltd, and Takeda Pharmaceutical Company Limited that includes: consulting or advisory, and speaking and lecture fees. Hiroshi Date reports a relationship with Johnson and Johnson Ltd, AstraZeneca Pharmaceuticals LP, and TriMed Inc that includes: speaking and lecture fees and funding grants. Shinichi Toyooka reports a relationship with Chugai Pharma, Daiichi Sankyo, Astellas Pharma, Boehringer Ingelheim, Taiho Pharmaceutical, Ono Pharmaceutical, Bayer, Medtronic, Johnson & Johnson, Kyorin, Eli Lilly, Novartis, AstraZeneca, Merck & Co, Guardant Health, and Eli Lilly that includes: consulting or advisory, funding grants, and speaking and lecture fees.
