Usefulness of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients With Non-small Cell Lung Cancer.
Aged
Biomarkers, Tumor
/ genetics
Biopsy
/ methods
Carcinoma, Non-Small-Cell Lung
/ genetics
Circulating Tumor DNA
/ genetics
Class I Phosphatidylinositol 3-Kinases
/ genetics
ErbB Receptors
/ genetics
Female
Humans
Lung Neoplasms
/ genetics
Male
Molecular Targeted Therapy
/ methods
Mutation
Precision Medicine
/ methods
Progression-Free Survival
Proto-Oncogene Proteins B-raf
/ genetics
Proto-Oncogene Proteins p21(ras)
/ genetics
Quality Improvement
circulating tumor DNA
non-small cell lung cancer
overall survival
precision oncology
progression-free survival
Journal
Chest
ISSN: 1931-3543
Titre abrégé: Chest
Pays: United States
ID NLM: 0231335
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
18
08
2020
revised:
21
03
2021
accepted:
01
04
2021
pubmed:
21
4
2021
medline:
6
1
2022
entrez:
20
4
2021
Statut:
ppublish
Résumé
The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC). How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC? We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution. A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples. Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.
Sections du résumé
BACKGROUND
The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC).
RESEARCH QUESTION
How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC?
METHODS
We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution.
RESULTS
A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples.
INTERPRETATION
Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.
Identifiants
pubmed: 33878340
pii: S0012-3692(21)00705-4
doi: 10.1016/j.chest.2021.04.016
pmc: PMC8449001
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
Circulating Tumor DNA
0
KRAS protein, human
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
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
1095-1107Subventions
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218545
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA247471
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA209978
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Références
Eur J Cancer. 2018 Jan;88:1-9
pubmed: 29175734
Cancer Res. 2019 Mar 15;79(6):1204-1213
pubmed: 30573519
Pharmacol Ther. 2017 Jun;174:22-26
pubmed: 28167216
Nat Med. 2018 Sep;24(9):1441-1448
pubmed: 30082870
J Natl Cancer Inst. 2016 Apr 07;108(8):
pubmed: 27059373
Nature. 2012 Jun 28;486(7404):532-6
pubmed: 22722830
Oncotarget. 2016 Oct 11;7(41):66880-66891
pubmed: 27602770
N Engl J Med. 2013 Feb 28;368(9):842-51
pubmed: 23445095
Thorac Cancer. 2018 May;9(5):509-515
pubmed: 29528556
J Natl Cancer Inst. 2005 Mar 2;97(5):339-46
pubmed: 15741570
J Hematol Oncol. 2019 Dec 4;12(1):130
pubmed: 31801585
Lung Cancer. 2019 Apr;130:50-58
pubmed: 30885352
Sci Rep. 2016 Aug 24;6:31985
pubmed: 27555497
Oncotarget. 2017 Jan 10;8(2):2130-2140
pubmed: 27791985
Clin Cancer Res. 2018 Aug 1;24(15):3528-3538
pubmed: 29776953
Ann Oncol. 2019 Apr 1;30(4):597-603
pubmed: 30891595
Nat Med. 2019 May;25(5):738-743
pubmed: 31011204
Oncotarget. 2015 Nov 24;6(37):40360-9
pubmed: 26452027
Bioinformatics. 2016 Oct 1;32(19):3012-4
pubmed: 27288499
Clin Cancer Res. 2020 Jan 15;26(2):397-407
pubmed: 31666247
Genome Biol. 2016 Dec 16;17(1):261
pubmed: 27986087
Mol Cancer Ther. 2017 Jul;16(7):1412-1420
pubmed: 28446639
Lung Cancer. 2018 Jul;121:54-60
pubmed: 29858028
Oncotarget. 2016 Jul 12;7(28):44583-44595
pubmed: 27323821
J Clin Oncol. 2014 Feb 20;32(6):579-86
pubmed: 24449238
J Transl Med. 2018 Nov 6;16(1):300
pubmed: 30400802
CA Cancer J Clin. 2020 Jan;70(1):7-30
pubmed: 31912902
Clin Cancer Res. 2016 Feb 15;22(4):790-2
pubmed: 26671996
PLoS One. 2015 Oct 16;10(10):e0140712
pubmed: 26474073
J Natl Cancer Inst. 2017 Dec 1;109(12):
pubmed: 29206995
Eur Respir Rev. 2020 Feb 12;29(155):
pubmed: 32051167
J Mol Diagn. 2020 Feb;22(2):228-235
pubmed: 31837429
N Engl J Med. 2014 Dec 4;371(23):2167-77
pubmed: 25470694
Clin Transl Oncol. 2018 Oct;20(10):1261-1267
pubmed: 29623586
Clin Cancer Res. 2019 Aug 1;25(15):4691-4700
pubmed: 30988079
NPJ Precis Oncol. 2020 Jun 24;4:15
pubmed: 32596507
Bioinformatics. 2016 Sep 15;32(18):2847-9
pubmed: 27207943
Sci Transl Med. 2014 Feb 19;6(224):224ra24
pubmed: 24553385
CA Cancer J Clin. 2021 Mar;71(2):176-190
pubmed: 33165928
Cancer Res. 2004 Dec 15;64(24):8919-23
pubmed: 15604253
Nat Rev Clin Oncol. 2021 May;18(5):297-312
pubmed: 33473219
J Thorac Oncol. 2016 Oct;11(10):1690-700
pubmed: 27468937
Nat Commun. 2015 Nov 04;6:8760
pubmed: 26530965
Nat Med. 2008 Sep;14(9):985-90
pubmed: 18670422
Genes Chromosomes Cancer. 2018 Apr;57(4):211-220
pubmed: 29277949
JAMA Oncol. 2019 Feb 1;5(2):173-180
pubmed: 30325992
Lancet Oncol. 2015 Feb;16(2):141-51
pubmed: 25589191
J Natl Compr Canc Netw. 2019 Dec;17(12):1464-1472
pubmed: 31805526
Sci Transl Med. 2012 May 30;4(136):136ra68
pubmed: 22649089
Nat Med. 2014 Apr;20(4):430-5
pubmed: 24658074
Mol Cancer. 2018 Aug 28;17(1):131
pubmed: 30153823
Cancer. 2020 Jul 15;126(14):3219-3228
pubmed: 32365229
Oncotarget. 2015 Oct 13;6(31):30850-8
pubmed: 26334838