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Decoding the Evolutionary Response to Ensartinib in Patients With ALK-Positive NSCLC by Dynamic Circulating Tumor DNA Sequencing
- Source :
- Journal of Thoracic Oncology. 16:827-839
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC.In a multicenter phase 2 trial, patients with ALK-positive NSCLC who progressed on crizotinib were treated with ensartinib. Blood samples for ctDNA analysis were collected at baseline, cycle 3 day 1, and progression disease (PD) and analyzed with a 212-gene panel.A total of 440 samples were collected from 168 patients. Baseline TP53 mutations (20.2%) significantly correlated with inferior progression-free survival (4.2 mo versus 11.7 mo, p0.0001). Patients with TP53 mutations had higher mutation load than those without TP53 mutations at baseline (13.79 ± 3.72 versus 4.67 ± 0.39, p0.001). Although there was no significant difference in mutation load between these groups at cycle 3 day 1 (5.89 ± 2.25 versus 3.72 ± 0.62, p = 0.425), patients with mutated TP53 developed more mutations at PD (7.07 ± 1.25 versus 3.20 ± 0.33, p = 0.003). Frequency and abundance of secondary ALK mutations G1269A, G1202R, and E1210K increased markedly at PD than baseline. In patients without secondary ALK mutations, we identified ALK-independent resistance mechanisms including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation, and epigenetic dysregulation.Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib.
- Subjects :
- 0301 basic medicine
Pulmonary and Respiratory Medicine
Oncology
medicine.medical_specialty
Lung Neoplasms
Disease
Tp53 mutation
Piperazines
Circulating Tumor DNA
03 medical and health sciences
0302 clinical medicine
Genetic Evolution
Internal medicine
medicine
Humans
Anaplastic Lymphoma Kinase
In patient
Protein Kinase Inhibitors
Crizotinib
business.industry
ALK-Positive
Pyridazines
030104 developmental biology
Drug Resistance, Neoplasm
Circulating tumor DNA
030220 oncology & carcinogenesis
Mutation
business
medicine.drug
Subjects
Details
- ISSN :
- 15560864
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- Journal of Thoracic Oncology
- Accession number :
- edsair.doi.dedup.....22308602dda010f76fdbc6af21e732ed