Longitudinal therapy monitoring of ALK-positive lung cancer by combined copy number and targeted mutation profiling of cell-free DNA.
ALK
Liquid biopsy
Non-small cell lung cancer
Therapy monitoring
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
received:
05
06
2020
revised:
15
09
2020
accepted:
15
10
2020
pubmed:
9
11
2020
medline:
25
8
2021
entrez:
8
11
2020
Statut:
ppublish
Résumé
Targeted therapies (TKI) have improved the prognosis of ALK-rearranged lung cancer (ALK 271 longitudinal plasma DNA samples from 73 patients with TKI-treated metastatic ALK cfDNA mutations were identified in 58% of patients. They included several potentially actionable alterations, e.g. in the genes BRAF, ERBB2, and KIT. sWGS detected CNVs in 18% of samples, compared to 6% using targeted sequencing. Several of the CNVs included potentially druggable targets, such as regions harboring EGFR, ERBB2, and MET. Circulating tumour DNA (ctDNA) mutations and t-MAD scores increased during treatment, correlated with markers of higher molecular risk, such as the EML4-ALK variant 3 and/or TP53 mutations, and were associated with shorter patient survival. Importantly, t-MAD scores reflected the tumour remission status in serial samples similar to mutant ctDNA allele frequencies, and increased with disease progression in 79% (34/43) of cases, including those without detectable single nucleotide variant (SNV). Combined copy number and targeted mutation profiling could improve monitoring of ALK This work was supported by the German Center for Lung Research (DZL), by the German Cancer Consortium (DKTK), by the Heidelberg Center for Personalized Oncology at the German Cancer Research Center (DKFZ-HIPO), and by Roche Sequencing Solutions (Pleasanton, CA, USA).
Sections du résumé
BACKGROUND
BACKGROUND
Targeted therapies (TKI) have improved the prognosis of ALK-rearranged lung cancer (ALK
METHODS
METHODS
271 longitudinal plasma DNA samples from 73 patients with TKI-treated metastatic ALK
FINDINGS
RESULTS
cfDNA mutations were identified in 58% of patients. They included several potentially actionable alterations, e.g. in the genes BRAF, ERBB2, and KIT. sWGS detected CNVs in 18% of samples, compared to 6% using targeted sequencing. Several of the CNVs included potentially druggable targets, such as regions harboring EGFR, ERBB2, and MET. Circulating tumour DNA (ctDNA) mutations and t-MAD scores increased during treatment, correlated with markers of higher molecular risk, such as the EML4-ALK variant 3 and/or TP53 mutations, and were associated with shorter patient survival. Importantly, t-MAD scores reflected the tumour remission status in serial samples similar to mutant ctDNA allele frequencies, and increased with disease progression in 79% (34/43) of cases, including those without detectable single nucleotide variant (SNV).
INTERPRETATION
CONCLUSIONS
Combined copy number and targeted mutation profiling could improve monitoring of ALK
FUNDING
BACKGROUND
This work was supported by the German Center for Lung Research (DZL), by the German Cancer Consortium (DKTK), by the Heidelberg Center for Personalized Oncology at the German Cancer Research Center (DKFZ-HIPO), and by Roche Sequencing Solutions (Pleasanton, CA, USA).
Identifiants
pubmed: 33161228
pii: S2352-3964(20)30479-5
doi: 10.1016/j.ebiom.2020.103103
pmc: PMC7670098
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
Circulating Tumor DNA
0
Protein Kinase Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103103Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.