Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in Patients with Cancer-Reference-Cited by-同舟云学术

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

Published:2023-06-01 Issue:14 Volume:29 Page:2714-2724
ISSN:1078-0432
Container-title:Clinical Cancer Research
language:en
Short-container-title:

Author:

Cortellini Alessio¹²^ORCID,D'Alessio Antonio²³^ORCID,Cleary Siobhan²^ORCID,Buti Sebastiano³⁴^ORCID,Bersanelli Melissa⁵^ORCID,Bordi Paola⁵^ORCID,Tonini Giuseppe¹^ORCID,Vincenzi Bruno¹^ORCID,Tucci Marco⁶⁷^ORCID,Russo Alessandro⁸^ORCID,Pantano Francesco¹^ORCID,Russano Marco¹^ORCID,Stucci Luigia Stefania⁷^ORCID,Sergi Maria Chiara⁷^ORCID,Falconi Martina⁸^ORCID,Zarzana Maria Antonietta⁸^ORCID,Santini Daniele⁹^ORCID,Spagnolo Francesco¹⁰^ORCID,Tanda Enrica T.¹⁰¹¹^ORCID,Rastelli Francesca¹²^ORCID,Giorgi Francesca Chiara¹²^ORCID,Pergolesi Federica¹²^ORCID,Giusti Raffaele¹³^ORCID,Filetti Marco¹⁴¹⁵^ORCID,Lo Bianco Francesca¹³^ORCID,Marchetti Paolo¹⁶^ORCID,Botticelli Andrea¹⁷^ORCID,Gelibter Alain¹⁷^ORCID,Siringo Marco¹⁷^ORCID,Ferrari Marco¹⁸^ORCID,Marconcini Riccardo¹⁸^ORCID,Vitale Maria Giuseppa¹⁹^ORCID,Nicolardi Linda²⁰^ORCID,Chiari Rita²¹^ORCID,Ghidini Michele²²^ORCID,Nigro Olga²³^ORCID,Grossi Francesco²³²⁴^ORCID,De Tursi Michele²⁵^ORCID,Di Marino Pietro²⁶^ORCID,Queirolo Paola²⁷^ORCID,Bracarda Sergio²⁸^ORCID,Macrini Serena²⁸^ORCID,Inno Alessandro²⁹^ORCID,Zoratto Federica³⁰^ORCID,Veltri Enzo³⁰^ORCID,Spoto Chiara³⁰^ORCID,Vitale Maria Grazia³¹^ORCID,Cannita Katia³²^ORCID,Gennari Alessandra³^ORCID,Morganstein Daniel L.³³³⁴^ORCID,Mallardo Domenico³¹^ORCID,Nibid Lorenzo³⁵^ORCID,Sabarese Giovanna³⁵^ORCID,Brunetti Leonardo¹^ORCID,Perrone Giuseppe³⁵^ORCID,Ascierto Paolo A.³¹^ORCID,Ficorella Corrado³⁶^ORCID,Pinato David J.²³^ORCID

Affiliation:

1. 1Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy.

2. 2Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.

3. 3Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

4. 4Department of Medicine and Surgery, University of Parma, Parma, Italy.

5. 5Medical Oncology Unit, University Hospital of Parma, Parma, Italy.

6. 6Department of Interdisciplinary Medicine (DIM), University of Bari “Aldo Moro”, Italy.

7. 7Medical Oncology Unit, Policlinico Hospital of Bari, Bari, Italy.

8. 8Medical Oncology, A.O. Papardo & Department of Human Pathology, University of Messina, Messina, Italy.

9. 9UOC Oncologia Medica territoriale, La Sapienza University, Polo Pontino, Rome, Italy.

10. 10IRCCS Ospedale Policlinico San Martino, Genova, Italy.

11. 11Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.

12. 12UOC Oncologia Ascoli Piceno – San Benedetto del Tronto, Ascoli Piceno, Italy.

13. 13Azienda Ospedaliera Sant'Andrea, Sapienza University of Rome, Rome, Italy.

14. 14Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

15. 15Early Phase Trials, Policlinico Agostino Gemelli IRCCS, Rome, Italy.

16. 16Istituto Dermopatico dell'Immacolata: IDI IRCCS, Rome, Italy.

17. 17Department of Clinical and Molecular Oncology, “Sapienza” University of Rome, Rome, Italy.

18. 18Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.

19. 19Medical Oncology, University Hospital of Modena, Modena, Italy.

20. 20UOC Oncologia Padova Sud - AULSS6 Euganea, Padova, Italy.

21. 21UOC Oncologia, Azienda Ospedaliera Marche Nord, Pesaro, Italy.

22. 22Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

23. 23Medical Oncology, ASST Sette Laghi, Ospedale di Circolo e Fondazione Macchi, Varese, Italy.

24. 24Division of Medical Oncology, University of Insubria, Varese, Italy.

25. 25Department of Innovative Technologies in Medicine & Dentistry, University G. D'Annunzio, Chieti-Pescara, Italy.

26. 26Oncology, SS. Annunziata Hospital, Chieti, Italy.

27. 27Division of Medical Oncology for Melanoma, Sarcoma, and Rare Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy.

28. 28S.C. Medical Oncology, Azienda Ospedaliera S. Maria, Terni, Italy.

29. 29Oncology Unit, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, Verona, Italy.

30. 30Medical Oncology, Santa Maria Goretti Hospital, Latina, Italy.

31. 31Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy.

32. 32Medical Oncology Unit, Department of Oncology, Teramo, Italy.

33. 33Skin Unit, Royal Marsden Hospital, London, United Kingdom.

34. 34Department of Endocrinology, Chelsea and Westminster Hospital, London, United Kingdom.

35. 35Pathology Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy.

36. 36Department of Biotechnology and Applied Clinical Science, University of L'Aquila, L'Aquila, Italy.

Abstract

Abstract Purpose: No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors. Experimental Design: 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. Results: 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. Conclusions: 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.

Funder

Wellcome Trust

Associazione Italiana per la Ricerca sul Cancro

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Link

https://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-22-3116/3327933/ccr-22-3116.pdf

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