British journal of cancer · 2025
Relative telomere length and senescence-associated inflammatory cytokines as blood-based prognostic markers in patients with advanced or resectable gastro-oesophageal adenocarcinoma.
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Bilsland Alan E, McCulloch Eilidh, Degerman Sofie, Landfors Mattias, Wadsley Jon, Wall Lucy, Thompson Catherine, Damyanova Iva, Samuel Leslie, Petty Russell, Jain Ankit, Lewsley Liz-Anne, MacMillan Antonia, MacLeod Martin, Walker Jennifer, McCormick Carol, McCartney Elaine, Roxburgh Patricia, Stobo Jamie, Thomson Fiona, Evans T R Jeffry, Keith W Nicol
Аннотация
BACKGROUND: Combination chemotherapy provides significant survival advantage in patients with advanced gastro-oesophageal adenocarcinoma compared with best supportive care. Peri-operative chemotherapy is standard of care for patients with operable disease. We hypothesised that biomarkers of genomic instability and inflammation may have clinical utility in these patients.
METHODS: We initiated open-label, non-randomised biomarker studies in patients with advanced disease due to receive Epirubicin, Cisplatin and Capecitabine (ECX)/Epirubicin, Cisplatin and Fluorouracil (ECF) or Epirubicin, Oxaliplatin and Capecitabine (EOX)/Epirubicin, Oxaliplatin and Fluorouracil (EOF) regimens (advanced study, n = 375), and in patients planned to receive perioperative chemotherapy with the same regimen (peri-operative study, n = 306). Relative telomere length (RTL) in peripheral blood mononuclear cells (PBMCs) and plasma levels of 10 inflammatory cytokines were analysed to determine association with progression-free and overall survival, and response. Blood samples were collected prior to treatment and on each treatment cycle. Both studies comprised biomarker discovery and validation cohorts. Here we report analysis of the discovery cohorts.
RESULTS: In advanced disease, high pre-treatment levels of IL8 and IL10 associated with poor Progression Free Survival (PFS) and Overall Survival (OS) in univariate analysis, and IL6 with poor OS. In multivariate analysis, IL6 and IL8 remained associated with OS, and IL8 with PFS. In the perioperative study, cytokine levels were significantly lower and no relationships were observed. There was no association between RTL and any endpoint in either study.
CONCLUSIONS: Pre-treatment RTL was not prognostic, although IL6/IL8 were negative prognostic factors in advanced disease. Levels of these were lower in patients with localised disease, suggesting an association with disease progression. Further analysis of systemic inflammatory status in gastro-oesophageal adenocarcinoma may be promising for development of future predictive biomarker signatures.
METHODS: We initiated open-label, non-randomised biomarker studies in patients with advanced disease due to receive Epirubicin, Cisplatin and Capecitabine (ECX)/Epirubicin, Cisplatin and Fluorouracil (ECF) or Epirubicin, Oxaliplatin and Capecitabine (EOX)/Epirubicin, Oxaliplatin and Fluorouracil (EOF) regimens (advanced study, n = 375), and in patients planned to receive perioperative chemotherapy with the same regimen (peri-operative study, n = 306). Relative telomere length (RTL) in peripheral blood mononuclear cells (PBMCs) and plasma levels of 10 inflammatory cytokines were analysed to determine association with progression-free and overall survival, and response. Blood samples were collected prior to treatment and on each treatment cycle. Both studies comprised biomarker discovery and validation cohorts. Here we report analysis of the discovery cohorts.
RESULTS: In advanced disease, high pre-treatment levels of IL8 and IL10 associated with poor Progression Free Survival (PFS) and Overall Survival (OS) in univariate analysis, and IL6 with poor OS. In multivariate analysis, IL6 and IL8 remained associated with OS, and IL8 with PFS. In the perioperative study, cytokine levels were significantly lower and no relationships were observed. There was no association between RTL and any endpoint in either study.
CONCLUSIONS: Pre-treatment RTL was not prognostic, although IL6/IL8 were negative prognostic factors in advanced disease. Levels of these were lower in patients with localised disease, suggesting an association with disease progression. Further analysis of systemic inflammatory status in gastro-oesophageal adenocarcinoma may be promising for development of future predictive biomarker signatures.