Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status.
AMP-Activated Protein Kinase Kinases
/ genetics
Adenocarcinoma of Lung
/ drug therapy
Adult
Aged
Aged, 80 and over
Female
Humans
Immune Checkpoint Inhibitors
/ therapeutic use
Kelch-Like ECH-Associated Protein 1
/ genetics
Ligands
Lung Neoplasms
/ drug therapy
Male
Middle Aged
Mutation
NF-E2-Related Factor 2
/ genetics
Proto-Oncogene Proteins p21(ras)
/ genetics
Young Adult
KEAP1
KRAS
NSCLC
PD-(L)1 blockade
STK11
Journal
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
ISSN: 1556-1380
Titre abrégé: J Thorac Oncol
Pays: United States
ID NLM: 101274235
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
17
09
2021
revised:
15
10
2021
accepted:
21
10
2021
pubmed:
7
11
2021
medline:
30
4
2022
entrez:
6
11
2021
Statut:
ppublish
Résumé
STK11 and KEAP1 mutations (STK11 mutant [STK11 Clinicopathologic and genomic data were collected from September 2013 to September 2020 from patients with advanced LUAD at the Dana-Farber Cancer Institute/Massachusetts General Hospital cohort and the Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center cohort. Clinical outcomes to PD-(L)1 inhibition were analyzed according to KRAS, STK11, and KEAP1 mutation status in two independent cohorts. The Cancer Genome Atlas transcriptomic data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 comutation status. In the combined cohort (Dana-Farber Cancer Institute/Massachusetts General Hospital + Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center) of 1261 patients (median age = 61 y [range: 22-92], 708 women [56.1%], 1065 smokers [84.4%]), KRAS mutations were detected in 536 cases (42.5%), and deleterious STK11 and KEAP1 mutations were found in 20.6% (260 of 1261) and 19.2% (231 of 1202) of assessable cases, respectively. In each independent cohort and in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free (STK11 hazard ratio [HR] = 2.04, p < 0.0001; KEAP1 HR = 2.05, p < 0.0001) and overall (STK11 HR = 2.09, p < 0.0001; KEAP1 HR = 2.24, p < 0.0001) survival to immunotherapy uniquely among KRAS STK11 and KEAP1 mutations confer worse outcomes to immunotherapy among patients with KRAS
Identifiants
pubmed: 34740862
pii: S1556-0864(21)03284-6
doi: 10.1016/j.jtho.2021.10.013
pmc: PMC10980559
mid: NIHMS1977099
pii:
doi:
Substances chimiques
Immune Checkpoint Inhibitors
0
KEAP1 protein, human
0
KRAS protein, human
0
Kelch-Like ECH-Associated Protein 1
0
Ligands
0
NF-E2-Related Factor 2
0
STK11 protein, human
EC 2.7.11.1
AMP-Activated Protein Kinase Kinases
EC 2.7.11.3
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
399-410Subventions
Organisme : NCI NIH HHS
ID : R01 CA203636
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009172
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA209414
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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