PMID- 37125965
OWN - NLM
STAT- MEDLINE
DCOM- 20230717
LR  - 20240314
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 29
IP  - 14
DP  - 2023 Jul 14
TI  - Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in 
      Patients with Cancer.
PG  - 2714-2724
LID - 10.1158/1078-0432.CCR-22-3116 [doi]
AB  - 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.
CI  - (c)2023 American Association for Cancer Research.
FAU - Cortellini, Alessio
AU  - Cortellini A
AUID- ORCID: 0000-0002-1209-5735
AD  - Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario 
      Campus Bio-Medico, Roma, Italy.
AD  - Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital 
      Campus, London, United Kingdom.
FAU - D'Alessio, Antonio
AU  - D'Alessio A
AUID- ORCID: 0000-0002-9164-3671
AD  - Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital 
      Campus, London, United Kingdom.
AD  - Division of Oncology, Department of Translational Medicine, University of 
      Piemonte Orientale, Novara, Italy.
FAU - Cleary, Siobhan
AU  - Cleary S
AUID- ORCID: 0000-0003-1741-478X
AD  - Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital 
      Campus, London, United Kingdom.
FAU - Buti, Sebastiano
AU  - Buti S
AUID- ORCID: 0000-0003-0876-0226
AD  - Division of Oncology, Department of Translational Medicine, University of 
      Piemonte Orientale, Novara, Italy.
AD  - Department of Medicine and Surgery, University of Parma, Parma, Italy.
FAU - Bersanelli, Melissa
AU  - Bersanelli M
AUID- ORCID: 0000-0002-6527-6281
AD  - Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
FAU - Bordi, Paola
AU  - Bordi P
AUID- ORCID: 0000-0001-6994-7399
AD  - Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
FAU - Tonini, Giuseppe
AU  - Tonini G
AUID- ORCID: 0000-0003-4442-8677
AD  - Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario 
      Campus Bio-Medico, Roma, Italy.
FAU - Vincenzi, Bruno
AU  - Vincenzi B
AUID- ORCID: 0000-0001-8222-9025
AD  - Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario 
      Campus Bio-Medico, Roma, Italy.
FAU - Tucci, Marco
AU  - Tucci M
AUID- ORCID: 0000-0003-4008-4897
AD  - Department of Interdisciplinary Medicine (DIM), University of Bari "Aldo Moro", 
      Italy.
AD  - Medical Oncology Unit, Policlinico Hospital of Bari, Bari, Italy.
FAU - Russo, Alessandro
AU  - Russo A
AUID- ORCID: 0000-0002-3365-1972
AD  - Medical Oncology, A.O. Papardo & Department of Human Pathology, University of 
      Messina, Messina, Italy.
FAU - Pantano, Francesco
AU  - Pantano F
AUID- ORCID: 0000-0002-2894-9686
AD  - Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario 
      Campus Bio-Medico, Roma, Italy.
FAU - Russano, Marco
AU  - Russano M
AUID- ORCID: 0000-0002-6963-3864
AD  - Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario 
      Campus Bio-Medico, Roma, Italy.
FAU - Stucci, Luigia Stefania
AU  - Stucci LS
AUID- ORCID: 0000-0003-2063-1435
AD  - Medical Oncology Unit, Policlinico Hospital of Bari, Bari, Italy.
FAU - Sergi, Maria Chiara
AU  - Sergi MC
AUID- ORCID: 0000-0002-3093-6841
AD  - Medical Oncology Unit, Policlinico Hospital of Bari, Bari, Italy.
FAU - Falconi, Martina
AU  - Falconi M
AUID- ORCID: 0009-0005-3263-9030
AD  - Medical Oncology, A.O. Papardo & Department of Human Pathology, University of 
      Messina, Messina, Italy.
FAU - Zarzana, Maria Antonietta
AU  - Zarzana MA
AUID- ORCID: 0009-0008-0557-9142
AD  - Medical Oncology, A.O. Papardo & Department of Human Pathology, University of 
      Messina, Messina, Italy.
FAU - Santini, Daniele
AU  - Santini D
AUID- ORCID: 0000-0002-9118-3337
AD  - UOC Oncologia Medica territoriale, La Sapienza University, Polo Pontino, Rome, 
      Italy.
FAU - Spagnolo, Francesco
AU  - Spagnolo F
AUID- ORCID: 0000-0003-3287-1225
AD  - IRCCS Ospedale Policlinico San Martino, Genova, Italy.
FAU - Tanda, Enrica T
AU  - Tanda ET
AUID- ORCID: 0000-0002-1552-9826
AD  - IRCCS Ospedale Policlinico San Martino, Genova, Italy.
AD  - Genetics of Rare Cancers, Department of Internal Medicine and Medical 
      Specialties, University of Genoa, Genoa, Italy.
FAU - Rastelli, Francesca
AU  - Rastelli F
AUID- ORCID: 0000-0002-0546-3288
AD  - UOC Oncologia Ascoli Piceno - San Benedetto del Tronto, Ascoli Piceno, Italy.
FAU - Giorgi, Francesca Chiara
AU  - Giorgi FC
AUID- ORCID: 0009-0004-0514-1942
AD  - UOC Oncologia Ascoli Piceno - San Benedetto del Tronto, Ascoli Piceno, Italy.
FAU - Pergolesi, Federica
AU  - Pergolesi F
AUID- ORCID: 0009-0002-9637-8616
AD  - UOC Oncologia Ascoli Piceno - San Benedetto del Tronto, Ascoli Piceno, Italy.
FAU - Giusti, Raffaele
AU  - Giusti R
AUID- ORCID: 0000-0003-4592-8868
AD  - Azienda Ospedaliera Sant'Andrea, Sapienza University of Rome, Rome, Italy.
FAU - Filetti, Marco
AU  - Filetti M
AUID- ORCID: 0000-0002-4734-7541
AD  - Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
AD  - Early Phase Trials, Policlinico Agostino Gemelli IRCCS, Rome, Italy.
FAU - Lo Bianco, Francesca
AU  - Lo Bianco F
AUID- ORCID: 0000-0003-1905-4984
AD  - Azienda Ospedaliera Sant'Andrea, Sapienza University of Rome, Rome, Italy.
FAU - Marchetti, Paolo
AU  - Marchetti P
AUID- ORCID: 0000-0002-9064-8761
AD  - Istituto Dermopatico dell'Immacolata: IDI IRCCS, Rome, Italy.
FAU - Botticelli, Andrea
AU  - Botticelli A
AUID- ORCID: 0000-0002-6425-9893
AD  - Department of Clinical and Molecular Oncology, "Sapienza" University of Rome, 
      Rome, Italy.
FAU - Gelibter, Alain
AU  - Gelibter A
AUID- ORCID: 0000-0002-7832-5281
AD  - Department of Clinical and Molecular Oncology, "Sapienza" University of Rome, 
      Rome, Italy.
FAU - Siringo, Marco
AU  - Siringo M
AUID- ORCID: 0000-0002-0489-1790
AD  - Department of Clinical and Molecular Oncology, "Sapienza" University of Rome, 
      Rome, Italy.
FAU - Ferrari, Marco
AU  - Ferrari M
AUID- ORCID: 0000-0002-4023-0121
AD  - Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
FAU - Marconcini, Riccardo
AU  - Marconcini R
AUID- ORCID: 0000-0001-5120-911X
AD  - Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
FAU - Vitale, Maria Giuseppa
AU  - Vitale MG
AUID- ORCID: 0000-0001-8551-266X
AD  - Medical Oncology, University Hospital of Modena, Modena, Italy.
FAU - Nicolardi, Linda
AU  - Nicolardi L
AUID- ORCID: 0000-0001-7848-2650
AD  - UOC Oncologia Padova Sud - AULSS6 Euganea, Padova, Italy.
FAU - Chiari, Rita
AU  - Chiari R
AUID- ORCID: 0000-0002-7649-273X
AD  - UOC Oncologia, Azienda Ospedaliera Marche Nord, Pesaro, Italy.
FAU - Ghidini, Michele
AU  - Ghidini M
AUID- ORCID: 0000-0001-5435-1218
AD  - Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 
      Milan, Italy.
FAU - Nigro, Olga
AU  - Nigro O
AUID- ORCID: 0000-0002-1030-2809
AD  - Medical Oncology, ASST Sette Laghi, Ospedale di Circolo e Fondazione Macchi, 
      Varese, Italy.
FAU - Grossi, Francesco
AU  - Grossi F
AUID- ORCID: 0000-0001-8412-3136
AD  - Medical Oncology, ASST Sette Laghi, Ospedale di Circolo e Fondazione Macchi, 
      Varese, Italy.
AD  - Division of Medical Oncology, University of Insubria, Varese, Italy.
FAU - De Tursi, Michele
AU  - De Tursi M
AUID- ORCID: 0000-0002-1411-1946
AD  - Department of Innovative Technologies in Medicine & Dentistry, University G. 
      D'Annunzio, Chieti-Pescara, Italy.
FAU - Di Marino, Pietro
AU  - Di Marino P
AUID- ORCID: 0000-0002-1330-683X
AD  - Oncology, SS. Annunziata Hospital, Chieti, Italy.
FAU - Queirolo, Paola
AU  - Queirolo P
AUID- ORCID: 0000-0002-9917-6633
AD  - Division of Medical Oncology for Melanoma, Sarcoma, and Rare Tumors, IEO, 
      European Institute of Oncology IRCCS, Milan, Italy.
FAU - Bracarda, Sergio
AU  - Bracarda S
AUID- ORCID: 0000-0002-0703-2959
AD  - S.C. Medical Oncology, Azienda Ospedaliera S. Maria, Terni, Italy.
FAU - Macrini, Serena
AU  - Macrini S
AUID- ORCID: 0009-0009-8262-1647
AD  - S.C. Medical Oncology, Azienda Ospedaliera S. Maria, Terni, Italy.
FAU - Inno, Alessandro
AU  - Inno A
AUID- ORCID: 0000-0001-6331-6908
AD  - Oncology Unit, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, Verona, Italy.
FAU - Zoratto, Federica
AU  - Zoratto F
AUID- ORCID: 0000-0001-8387-1968
AD  - Medical Oncology, Santa Maria Goretti Hospital, Latina, Italy.
FAU - Veltri, Enzo
AU  - Veltri E
AUID- ORCID: 0009-0007-8884-6850
AD  - Medical Oncology, Santa Maria Goretti Hospital, Latina, Italy.
FAU - Spoto, Chiara
AU  - Spoto C
AUID- ORCID: 0009-0007-6623-9312
AD  - Medical Oncology, Santa Maria Goretti Hospital, Latina, Italy.
FAU - Vitale, Maria Grazia
AU  - Vitale MG
AUID- ORCID: 0000-0003-2331-5315
AD  - Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto 
      Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy.
FAU - Cannita, Katia
AU  - Cannita K
AUID- ORCID: 0000-0002-9409-1171
AD  - Medical Oncology Unit, Department of Oncology, Teramo, Italy.
FAU - Gennari, Alessandra
AU  - Gennari A
AUID- ORCID: 0000-0002-0928-2281
AD  - Division of Oncology, Department of Translational Medicine, University of 
      Piemonte Orientale, Novara, Italy.
FAU - Morganstein, Daniel L
AU  - Morganstein DL
AUID- ORCID: 0000-0003-1565-8617
AD  - Skin Unit, Royal Marsden Hospital, London, United Kingdom.
AD  - Department of Endocrinology, Chelsea and Westminster Hospital, London, United 
      Kingdom.
FAU - Mallardo, Domenico
AU  - Mallardo D
AUID- ORCID: 0000-0002-1081-5313
AD  - Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto 
      Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy.
FAU - Nibid, Lorenzo
AU  - Nibid L
AUID- ORCID: 0000-0001-8583-0596
AD  - Pathology Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, 
      Italy.
FAU - Sabarese, Giovanna
AU  - Sabarese G
AUID- ORCID: 0000-0002-6841-1610
AD  - Pathology Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, 
      Italy.
FAU - Brunetti, Leonardo
AU  - Brunetti L
AUID- ORCID: 0000-0003-2639-4135
AD  - Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario 
      Campus Bio-Medico, Roma, Italy.
FAU - Perrone, Giuseppe
AU  - Perrone G
AUID- ORCID: 0000-0002-9538-5729
AD  - Pathology Unit, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, 
      Italy.
FAU - Ascierto, Paolo A
AU  - Ascierto PA
AUID- ORCID: 0000-0002-8322-475X
AD  - Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto 
      Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy.
FAU - Ficorella, Corrado
AU  - Ficorella C
AUID- ORCID: 0000-0003-0960-7127
AD  - Department of Biotechnology and Applied Clinical Science, University of L'Aquila, 
      L'Aquila, Italy.
FAU - Pinato, David J
AU  - Pinato DJ
AUID- ORCID: 0000-0002-3529-0103
AD  - Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital 
      Campus, London, United Kingdom.
AD  - Division of Oncology, Department of Translational Medicine, University of 
      Piemonte Orientale, Novara, Italy.
LA  - eng
GR  - PS3416/Wellcome Trust (WT)/
GR  - AIRC MFAG Grant ID 25697/Associazione Italiana per la Ricerca sul Cancro/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 9100L32L2N (Metformin)
SB  - IM
CIN - Clin Cancer Res. 2023 Oct 2;29(19):4017-4018. PMID: 37779446
CIN - Clin Cancer Res. 2023 Oct 2;29(19):4016. PMID: 37779447
MH  - Humans
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy
MH  - Immune Checkpoint Inhibitors/adverse effects
MH  - *Diabetes Mellitus, Type 2/drug therapy
MH  - *Lung Neoplasms/drug therapy/genetics
MH  - *Metformin/adverse effects
MH  - Disease Progression
MH  - Retrospective Studies
MH  - Tumor Microenvironment
EDAT- 2023/05/01 12:44
MHDA- 2023/07/17 06:42
CRDT- 2023/05/01 10:23
PHST- 2022/10/11 00:00 [received]
PHST- 2023/02/14 00:00 [revised]
PHST- 2023/04/25 00:00 [accepted]
PHST- 2023/07/17 06:42 [medline]
PHST- 2023/05/01 12:44 [pubmed]
PHST- 2023/05/01 10:23 [entrez]
AID - 726223 [pii]
AID - 10.1158/1078-0432.CCR-22-3116 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2023 Jul 14;29(14):2714-2724. doi: 
      10.1158/1078-0432.CCR-22-3116.