Longitudinal association of plasma cytokines with survival in advanced gastro-oesophageal adenocarcinoma


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Alan Bilsland1,Sofie Degerman2,Mattius Landfors2,Jennifer Walker3,Carol McCormick3,Eilidh McCulloch4,Liz-Anne Lewsley5,Antonia MacMillan5,Martin MacLeod3,Jamie Stobo5,Goran Roos2,James Paul5,Jeff Evans4,Fiona Thomson4,W.nicol Keith6
1Institute of Cancer Science, Wolfson Wohl Cancer Research Centre, University of Glasgow,2Umea University,3Glasgow ECMC, Institue of Cancer Science, University of Glasgow,4Glasgow ECMC, Institute of Cancer Science, University of Glasgow,5CRUK Clinical Trials Unit, Institute of Cancer Science, University of Glasgow,6Institute of Cancer Science, University of Glasgow



Advanced gastro-oesophageal adenocarcinoma patients treated with palliative ECX/ECF or EOX/EOF show median overall survival (OS) of 10 months. To identify novel prognostic/predictive markers, we are conducting a multi-centre study, longitudinally analysing multiple candidate circulating biomarkers in these patients at each chemotherapy cycle. Co-primary endpoints are OS, progression-free survival (PFS) and objective response rate (ORR). Analyses include relative telomere length (RTL) in peripheral blood and plasma inflammatory cytokines. We previously reported that high baseline (pre-chemotherapy) plasma IL6, IL8 and IL10 associated with reduced PFS and OS. Here, we extended this analysis to patients on day 1 of chemotherapy cycle 2 (C2D1).


Our power calculation was previously reported (Bilsland et al, NCRI, 2017). 92 events are required to detect hazard ratio of 2 with 80% power (1.7% 2-sided significance level). However, both RTL and cytokines are analysed continuously using fractional polynomials. IL1b, IL2, IL4, IL6, IL8, IL10, IL12, IL13, IFNg, and TNFa were measured by MSD multiplex ELISA. We examined C2D1 cytokine concentrations and fold-change from baseline.


In 114 patients (105/94 PFS/OS events), no significant relation with ORR, PFS or OS was observed for fold-change for any cytokine at the 10% 2-sided level. High C2D1 IL6 and IL8 but not IL10 continued to associate with reduced OS (false discovery rate (FDR) adjusted p=0.0284, p=0.0016 and p=0.1450). We previously observed no significant survival relation for TNFa at baseline. However, C2D1 levels corresponded with reduced OS (p=0.0334). High C2D1 Il10, IL6 and TNFa also associated with poorer PFS (FDR adjusted p=0.0306, p=0.0082 and p=0.0028). There were no significant associations with any C2D1 cytokines and ORR.


High plasma IL6 may be a longitudinally robust marker of poor PFS and OS, while the other cytokines analysed showed different associations between baseline and C2D1. We are currently verifying these results in a second cohort of patients.