Clinical Implications of Circulating Tumor DNA Tumor Mutational Burden (ctDNA TMB) in Non-Small Cell Lung Cancer.
Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Immunological
/ pharmacology
B7-H1 Antigen
/ antagonists & inhibitors
Biomarkers, Tumor
/ blood
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Circulating Tumor DNA
/ blood
Drug Resistance, Neoplasm
/ genetics
Female
Follow-Up Studies
Humans
Kaplan-Meier Estimate
Lung Neoplasms
/ drug therapy
Male
Middle Aged
Mutation Rate
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
Progression-Free Survival
Response Evaluation Criteria in Solid Tumors
Retrospective Studies
Tumor Burden
Circulating tumor DNA (ctDNA)
NSCLC
PD‐1
PD‐L1
Tumor mutational burden (TMB)
Journal
The oncologist
ISSN: 1549-490X
Titre abrégé: Oncologist
Pays: England
ID NLM: 9607837
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
20
07
2018
accepted:
06
02
2019
pubmed:
15
3
2019
medline:
21
7
2020
entrez:
15
3
2019
Statut:
ppublish
Résumé
Tissue tumor mutational burden (TMB) has emerged as a potential biomarker predicting response to anti-programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) therapy, but few studies have explored using circulating tumor DNA (ctDNA) TMB in non-small cell lung cancer (NSCLC). A total of 136 patients with NSCLC with ctDNA testing were retrospectively evaluated from a single institution, along with a validation cohort from a second institution. ctDNA TMB was derived using the number of detected mutations over the DNA sequencing length. Higher ctDNA TMB was significantly correlated with smoking history ( The findings indicate that higher ctDNA TMB, at the current commercial sequencing length, reflects worse clinical outcomes. Biomarkers to identify patients who will respond to immune checkpoint blockade are critical. Tissue tumor mutational burden (TMB) has emerged as a viable biomarker to predict response to anti-PD-1/PD-L1 therapy, but few studies have explored the meaning and potential clinical significance of noninvasive, blood-based TMB. Here, we investigated circulating tumor DNA (ctDNA) TMB and present data demonstrating that current ctDNA TMB may reflect tumor burden and that ctDNA panels with a greater number of mutations may be necessary to more accurately reflect tissue TMB.
Sections du résumé
BACKGROUND
Tissue tumor mutational burden (TMB) has emerged as a potential biomarker predicting response to anti-programmed cell death-1 protein receptor (PD-1)/programmed cell death-1 protein ligand (PD-L1) therapy, but few studies have explored using circulating tumor DNA (ctDNA) TMB in non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS
A total of 136 patients with NSCLC with ctDNA testing were retrospectively evaluated from a single institution, along with a validation cohort from a second institution. ctDNA TMB was derived using the number of detected mutations over the DNA sequencing length.
RESULTS
Higher ctDNA TMB was significantly correlated with smoking history (
CONCLUSION
The findings indicate that higher ctDNA TMB, at the current commercial sequencing length, reflects worse clinical outcomes.
IMPLICATIONS FOR PRACTICE
Biomarkers to identify patients who will respond to immune checkpoint blockade are critical. Tissue tumor mutational burden (TMB) has emerged as a viable biomarker to predict response to anti-PD-1/PD-L1 therapy, but few studies have explored the meaning and potential clinical significance of noninvasive, blood-based TMB. Here, we investigated circulating tumor DNA (ctDNA) TMB and present data demonstrating that current ctDNA TMB may reflect tumor burden and that ctDNA panels with a greater number of mutations may be necessary to more accurately reflect tissue TMB.
Identifiants
pubmed: 30867242
pii: theoncologist.2018-0433
doi: 10.1634/theoncologist.2018-0433
pmc: PMC6656496
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
B7-H1 Antigen
0
Biomarkers, Tumor
0
CD274 protein, human
0
Circulating Tumor DNA
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
820-828Subventions
Organisme : NCI NIH HHS
ID : K12 CA090625
Pays : United States
Informations de copyright
© AlphaMed Press 2019.
Déclaration de conflit d'intérêts
Disclosures of potential conflicts of interest may be found at the end of this article.
Références
J Clin Oncol. 2013 Jan 1;31(1):17-22
pubmed: 23129736
N Engl J Med. 2017 Jun 1;376(22):2109-2121
pubmed: 28445112
Clin Cancer Res. 2018 Aug 1;24(15):3539-3549
pubmed: 29691297
Mol Cancer Ther. 2017 Jul;16(7):1412-1420
pubmed: 28446639
Genome Med. 2017 Apr 19;9(1):34
pubmed: 28420421
Nat Med. 2018 Sep;24(9):1449-1458
pubmed: 30013197
Cancer Res. 2001 Feb 15;61(4):1659-65
pubmed: 11245480
Clin Cancer Res. 2009 Dec 1;15(23):7412-20
pubmed: 19934295
Clin Cancer Res. 2012 Feb 15;18(4):1177-85
pubmed: 22228631
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
J Immunother Cancer. 2014 Dec 16;2(1):42
pubmed: 25516806
Clin Cancer Res. 2015 Jul 15;21(14):3196-203
pubmed: 25829397
Clin Cancer Res. 2017 Jan 1;23(1):116-123
pubmed: 27993964
Oncotarget. 2016 Oct 4;7(40):65364-65373
pubmed: 27588476
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
N Engl J Med. 2014 Dec 4;371(23):2189-2199
pubmed: 25409260
Cell. 2012 Sep 14;150(6):1121-34
pubmed: 22980976
Science. 2015 Apr 3;348(6230):124-8
pubmed: 25765070
Science. 2015 Oct 9;350(6257):207-211
pubmed: 26359337
Oncotarget. 2016 Apr 26;7(17):23312-21
pubmed: 27004405
Oncotarget. 2015 Nov 24;6(37):40360-9
pubmed: 26452027
N Engl J Med. 2012 Jun 28;366(26):2455-65
pubmed: 22658128
J Immunother Cancer. 2016 Jan 19;4:3
pubmed: 26788324
Clin Cancer Res. 2017 Oct 1;23(19):5729-5736
pubmed: 28972084
Lancet. 2016 May 7;387(10031):1909-20
pubmed: 26952546
Oncotarget. 2015 Oct 27;6(33):34221-7
pubmed: 26439694
PLoS Med. 2016 Dec 20;13(12):e1002198
pubmed: 27997533
Nature. 2013 Sep 19;501(7467):338-45
pubmed: 24048066
Nature. 2013 May 2;497(7447):108-12
pubmed: 23563269
Cancer Discov. 2015 Oct;5(10):1040-8
pubmed: 26109333
N Engl J Med. 2012 Mar 8;366(10):883-892
pubmed: 22397650
N Engl J Med. 2012 Jun 28;366(26):2443-54
pubmed: 22658127
PLoS One. 2015 Oct 16;10(10):e0140712
pubmed: 26474073
Nature. 2012 May 09;485(7399):502-6
pubmed: 22622578
Cancer Immunol Res. 2016 Nov;4(11):959-967
pubmed: 27671167
Clin Cancer Res. 2016 Nov 15;22(22):5497-5505
pubmed: 27185373
Nat Med. 2018 Sep;24(9):1441-1448
pubmed: 30082870
Ann Oncol. 2015 Aug;26(8):1715-22
pubmed: 25851626
Sci Transl Med. 2014 Feb 19;6(224):224ra24
pubmed: 24553385
JAMA Oncol. 2017 Jul 1;3(7):996-998
pubmed: 27978570
Oncotarget. 2017 Feb 21;8(8):13195-13205
pubmed: 28061461
Breast Cancer Res Treat. 2017 Aug;164(3):627-638
pubmed: 28500398
Genome Res. 2014 May;24(5):743-50
pubmed: 24782321
Nature. 2017 May 4;545(7652):60-65
pubmed: 28397821
Clin Lung Cancer. 2016 Sep;17(5):350-361
pubmed: 27137346
Science. 2015 Apr 3;348(6230):69-74
pubmed: 25838375
Oncotarget. 2015 Dec 8;6(39):42008-18
pubmed: 26524482
Nat Med. 2008 Sep;14(9):985-90
pubmed: 18670422
Clin Cancer Res. 2016 Dec 1;22(23):5772-5782
pubmed: 27601595