Clinical utility of plasma-based digital next-generation sequencing in oncogene-driven non-small-cell lung cancer patients with tyrosine kinase inhibitor resistance.
Lung Cancer
; 134: 72-78, 2019 08.
Article
en En
| MEDLINE
| ID: mdl-31319999
ABSTRACT
OBJECTIVES:
Resistance to tyrosine-kinase inhibitors (TKIs) is a clinical challenge in patients with oncogene-driven non-small-cell lung cancers (NSCLC). We have analyzed the utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) to impact the clinical care of patients with TKI resistance. MATERIALS ANDMETHODS:
We conducted a multi-institutional prospective study including consecutive EGFR, ALK, or ROS1-altered NSCLC patients with TKI resistance from 12 Spanish institutions. Post-progression ctDNA NGS was performed by Guardant Health (Guardant360 assay).RESULTS:
We included 53 patients separated in 3 cohorts 31 EGFR-mutant NSCLCs with first/second-generation TKI resistance (cohort 1), 15 EGFR T790Mâ¯+â¯NSCLCs with osimertinib resistance (cohort 2), and 7 ALK/ROS1-rearranged NSCLCs with crizotinib and/or next-generation TKI resistance (cohort 3). Besides Guardant360, 22 patients from cohort 1 (71%) underwent post-progression tumor biopsies and/or alternative plasma-based genotyping. In the entire study population, 34 patients (64%) had reliable evidence of tumor-DNA shed for resistance assessment, and 24 patients (45%) had actionable alterations. Target-independent pathogenic alterations were frequently detected, particularly at osimertinib resistance. Eleven patients (20%) received subsequent molecular-guided therapies indicated by plasma NGS alone (nâ¯=â¯9, 17%), or plasma NGS and tissue sequencing (nâ¯=â¯2, 4%), deriving the expected clinical benefit. Of these, 9 had EGFR T790â¯M mutation and received osimertinib, 1 had ALK G1202R mutation and received lorlatinib, and 1 had ROS1 G2032R mutation and received cabozantinib. Two additional cases from cohort 1 (6%) had undetectable EGFR T790â¯M by Guardant360 but were T790Mâ¯+â¯by tissue and BEAMing digital PCR respectively, and also received osimertinib.CONCLUSION:
NGS of ctDNA detects actionable alterations in a large proportion of oncogene-driven NSCLC patients with TKI resistance, and can be used to guide subsequent treatments as a complement or alternative to tissue or PCR-based plasma genotyping in the real-world clinical setting.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oncogenes
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Carcinoma de Pulmón de Células no Pequeñas
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Resistencia a Antineoplásicos
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Inhibidores de Proteínas Quinasas
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Secuenciación de Nucleótidos de Alto Rendimiento
/
Neoplasias Pulmonares
Tipo de estudio:
Diagnostic_studies
/
Observational_studies
Límite:
Adult
/
Aged
/
Aged80
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Lung Cancer
Asunto de la revista:
NEOPLASIAS
Año:
2019
Tipo del documento:
Article
Pais de publicación:
IE
/
IRELAND
/
IRLANDA