PMID- 34244291
OWN - NLM
STAT- MEDLINE
DCOM- 20220401
LR  - 20220401
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 27
IP  - 18
DP  - 2021 Sep 15
TI  - Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes 
      with PD-1 Blockade in Non-Small Cell Lung Cancer.
PG  - 5131-5140
LID - 10.1158/1078-0432.CCR-21-0921 [doi]
AB  - PURPOSE: Genetic differences in immunity may contribute to toxicity and outcomes 
      with immune checkpoint inhibitor (CPI) therapy, but these relationships are 
      poorly understood. We examined the genetics of thyroid immune-related adverse 
      events (irAE). EXPERIMENTAL DESIGN: In patients with non-small cell lung cancer 
      (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt 
      University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline 
      DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed 
      genotypes. Germline SNP imputation was also performed in an independent 
      Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic 
      risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC 
      BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in 
      patients with NSCLC at MSK, VUMC, and DFCI. RESULTS: Among 744 patients at MSK 
      and VUMC, thyroid irAEs occurred in 13% and were associated with improved 
      outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence 
      interval (CI), 0.52-0.88]. The PRS for hypothyroidism developed from UK Biobank 
      predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per 
      standard deviation (SD) = 1.33, 95% CI, 1.29-1.37; AUROC = 0.6]. The same PRS 
      also predicted development of thyroid irAEs in both independent cohorts of 
      patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08-1.66; AUROC = 0.6). 
      The results were similar in the DFCI cohort. However, PRS for hypothyroidism did 
      not predict CPI benefit. CONCLUSIONS: Thyroid irAEs were associated with response 
      to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of 
      developing thyroid irAEs. Additional studies are needed to determine whether 
      other irAEs also have shared genetic risk with known autoimmune disorders and the 
      association with treatment response.
CI  - (c)2021 American Association for Cancer Research.
FAU - Luo, Jia
AU  - Luo J
AUID- ORCID: 0000-0003-3606-827X
AD  - Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of 
      Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Martucci, Victoria L
AU  - Martucci VL
AD  - Department of Medicine, Division of Genetic Medicine, Vanderbilt University 
      Medical Center, Nashville, Tennessee.
FAU - Quandt, Zoe
AU  - Quandt Z
AUID- ORCID: 0000-0002-4568-4368
AD  - Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, 
      University of California, San Francisco, California.
AD  - Diabetes Center, University of California, San Francisco, California.
FAU - Groha, Stefan
AU  - Groha S
AD  - Dana-Farber Cancer Institute, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Boston, Massachusetts.
FAU - Murray, Megan H
AU  - Murray MH
AD  - Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, 
      Tennessee.
FAU - Lovly, Christine M
AU  - Lovly CM
AD  - Department of Medicine, Division of Hematology and Oncology, Vanderbilt 
      University Medical Center, Nashville, Tennessee.
AD  - Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, 
      Tennessee.
FAU - Rizvi, Hira
AU  - Rizvi H
AD  - Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer 
      Center, New York, New York.
FAU - Egger, Jacklynn V
AU  - Egger JV
AUID- ORCID: 0000-0002-2180-4169
AD  - Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer 
      Center, New York, New York.
FAU - Plodkowski, Andrew J
AU  - Plodkowski AJ
AUID- ORCID: 0000-0002-3772-370X
AD  - Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New 
      York.
FAU - Abu-Akeel, Mohsen
AU  - Abu-Akeel M
AD  - Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer 
      Center, New York, New York.
AD  - Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering 
      Cancer Center, New York, New York.
FAU - Schulze, Isabell
AU  - Schulze I
AD  - Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer 
      Center, New York, New York.
AD  - Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering 
      Cancer Center, New York, New York.
FAU - Merghoub, Taha
AU  - Merghoub T
AUID- ORCID: 0000-0002-1518-5111
AD  - Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer 
      Center, New York, New York.
AD  - Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering 
      Cancer Center, New York, New York.
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New 
      York.
FAU - Cardenas, Eduardo
AU  - Cardenas E
AUID- ORCID: 0000-0002-3025-4058
AD  - Department of Medicine, University of California San Francisco, San Francisco, 
      California.
FAU - Huntsman, Scott
AU  - Huntsman S
AD  - Department of Medicine, University of California San Francisco, San Francisco, 
      California.
FAU - Li, Min
AU  - Li M
AD  - Department of Medicine, University of California San Francisco, San Francisco, 
      California.
FAU - Hu, Donglei
AU  - Hu D
AUID- ORCID: 0000-0002-0351-001X
AD  - Department of Medicine, University of California San Francisco, San Francisco, 
      California.
FAU - Gubens, Matthew A
AU  - Gubens MA
AD  - Medical Oncology, University of California San Francisco, San Francisco, 
      California.
AD  - Department of Medicine, Weill Cornell Medical Center, New York, New York.
FAU - Gusev, Alexander
AU  - Gusev A
AD  - Dana-Farber Cancer Institute, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Boston, Massachusetts.
FAU - Aldrich, Melinda C
AU  - Aldrich MC
AUID- ORCID: 0000-0003-3833-8448
AD  - Department of Medicine, Division of Genetic Medicine, Vanderbilt University 
      Medical Center, Nashville, Tennessee.
AD  - Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, 
      Tennessee.
FAU - Hellmann, Matthew D
AU  - Hellmann MD
AUID- ORCID: 0000-0002-2670-9777
AD  - Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of 
      Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 
      hellmanm@mskcc.org elad.ziv@ucsf.edu.
AD  - Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer 
      Center, New York, New York.
AD  - Department of Medicine, Weill Cornell Medical Center, New York, New York.
FAU - Ziv, Elad
AU  - Ziv E
AUID- ORCID: 0000-0002-2324-2884
AD  - Department of Medicine, University of California San Francisco, San Francisco, 
      California. hellmanm@mskcc.org elad.ziv@ucsf.edu.
AD  - Helen Diller Family Comprehensive Cancer Center, Center for Genes, Environment 
      and Health and Institute for Human Genetics, University of California San 
      Francisco, San Francisco, California.
LA  - eng
GR  - MC_PC_17228/MRC_/Medical Research Council/United Kingdom
GR  - U01 CA224276/CA/NCI NIH HHS/United States
GR  - U54 CA217450/CA/NCI NIH HHS/United States
GR  - R01 CA227466/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - UL1 TR002243/TR/NCATS NIH HHS/United States
GR  - K24 CA169004/CA/NCI NIH HHS/United States
GR  - UL1 TR000457/TR/NCATS NIH HHS/United States
GR  - R01 CA244569/CA/NCI NIH HHS/United States
GR  - R01 CA227237/CA/NCI NIH HHS/United States
GR  - T32 CA009207/CA/NCI NIH HHS/United States
GR  - UG1 CA233259/CA/NCI NIH HHS/United States
GR  - F30 HL140756/HL/NHLBI NIH HHS/United States
GR  - T32 GM007347/GM/NIGMS NIH HHS/United States
GR  - P30 CA068485/CA/NCI NIH HHS/United States
GR  - MC_QA137853/MRC_/Medical Research Council/United Kingdom
GR  - U01 CA253560/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210708
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)
SB  - IM
MH  - Aged
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy
MH  - Female
MH  - Humans
MH  - Immune Checkpoint Inhibitors/*adverse effects/*therapeutic use
MH  - Immunotherapy/*adverse effects
MH  - Lung Neoplasms/*drug therapy
MH  - Male
MH  - Middle Aged
MH  - Retrospective Studies
MH  - Risk Assessment
MH  - Thyroid Diseases/*chemically induced/*genetics
MH  - Treatment Outcome
PMC - PMC8815444
MID - NIHMS1724678
EDAT- 2021/07/11 06:00
MHDA- 2022/04/02 06:00
PMCR- 2022/03/15
CRDT- 2021/07/10 05:40
PHST- 2021/03/17 00:00 [received]
PHST- 2021/05/28 00:00 [revised]
PHST- 2021/07/06 00:00 [accepted]
PHST- 2021/07/11 06:00 [pubmed]
PHST- 2022/04/02 06:00 [medline]
PHST- 2021/07/10 05:40 [entrez]
PHST- 2022/03/15 00:00 [pmc-release]
AID - 1078-0432.CCR-21-0921 [pii]
AID - 10.1158/1078-0432.CCR-21-0921 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2021 Sep 15;27(18):5131-5140. doi: 
      10.1158/1078-0432.CCR-21-0921. Epub 2021 Jul 8.