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Supplementary Figure S1 from Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in Patients with Cancer

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posted on 2023-06-01, 13:20 authored by Alessio Cortellini, Antonio D'Alessio, Siobhan Cleary, Sebastiano Buti, Melissa Bersanelli, Paola Bordi, Giuseppe Tonini, Bruno Vincenzi, Marco Tucci, Alessandro Russo, Francesco Pantano, Marco Russano, Luigia Stefania Stucci, Maria Chiara Sergi, Martina Falconi, Maria Antonietta Zarzana, Daniele Santini, Francesco Spagnolo, Enrica T. Tanda, Francesca Rastelli, Francesca Chiara Giorgi, Federica Pergolesi, Raffaele Giusti, Marco Filetti, Francesca Lo Bianco, Paolo Marchetti, Andrea Botticelli, Alain Gelibter, Marco Siringo, Marco Ferrari, Riccardo Marconcini, Maria Giuseppa Vitale, Linda Nicolardi, Rita Chiari, Michele Ghidini, Olga Nigro, Francesco Grossi, Michele De Tursi, Pietro Di Marino, Paola Queirolo, Sergio Bracarda, Serena Macrini, Alessandro Inno, Federica Zoratto, Enzo Veltri, Chiara Spoto, Maria Grazia Vitale, Katia Cannita, Alessandra Gennari, Daniel L. Morganstein, Domenico Mallardo, Lorenzo Nibid, Giovanna Sabarese, Leonardo Brunetti, Giuseppe Perrone, Paolo A. Ascierto, Corrado Ficorella, David J. Pinato

Kaplan-Meier survival estimates according to the receipt of any diabetes medication. A) Overall Survival NSCLC matched cohort; patients on any diabetes medication: 14.2 months (95%CI: 9.0 – 17.5; 99 events), patients not receiving diabetes medications: 17.5 months (95%CI: 14.2 – 26.6; 77 events). B) Progression Free Survival NSCLC matched cohort; patients on any diabetes medication: 7.9 months (95%CI: 5.4 – 10.8; 113 events), patients not receiving diabetes medications: 10.1 months (95%CI: 7.7 – 13.8; 99 events). C) Overall Survival Melanoma matched cohort; patients on any diabetes medication: 22.9 months (95%CI: 12.0 – NR; 25 events), patients not receiving diabetes medications: NR months (95%CI: 28.8 – NR; 52 events). D) Progression Free Survival Melanoma matched cohort; patients on any diabetes medication: 11.4 months (95%CI: 4.9 – 23.4; 37 events), patients not receiving diabetes medications: 13.8 months (95%CI: 8.7 – 26.0; 77 events). NR: not reached; PSM: propensity score matching.

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ARTICLE ABSTRACT

No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors. In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose-lowering medications (GLM) for T2DM had shorter overall survival (OS) and progression-free survival (PFS). We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment (TME) of patients with or without diabetes. A total of 1,395 patients were included. Primary tumors included non–small cell lung cancer (NSCLC; 54.7%), melanoma (24.7%), renal cell (15.0%), and other carcinomas (5.6%). After multivariable analysis, patients on GLM (n = 226, 16.2%) displayed an increased risk of death [HR, 1.29; 95% confidence interval (CI),1.07–1.56] and disease progression/death (HR, 1.21; 95% CI, 1.03–1.43) independent of number of GLM received. We matched 92 metformin-exposed patients with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM, was associated with an increased risk of death (HR, 1.53; 95% CI, 1.16–2.03) and disease progression/death (HR, 1.34; 95% CI, 1.04–1.72). Patients with T2DM with higher pretreatment glycemia had higher neutrophil-to-lymphocyte ratio (P = 0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n = 22) revealed differential regulation of innate and adaptive immune pathways in patients with T2DM. In this study, patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a preexisting diagnosis of T2DM in influencing poorer outcomes in this population.

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