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© 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Despite impressive and durable responses, nonsmall cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase (ALK) inhibitors (ALK‐Is) ultimately progress due to development of resistance. Here, we have evaluated the clinical utility of circulating tumor DNA (ctDNA) profiling by next‐generation sequencing (NGS) upon disease progression. We collected 26 plasma and two cerebrospinal fluid samples from 24 advanced ALK‐positive NSCLC patients at disease progression to an ALK‐I. These samples were analyzed by NGS and digital PCR. A tool to retrieve variants at the ALK locus was developed (VALK tool). We identified at least one resistance mutation in the ALK locus in ten (38.5%) plasma samples; the G1269A and G1202R mutations were the most prevalent among patients progressing to first‐ and second‐generation ALK‐Is, respectively. Overall, 61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1), FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3, and CCND1. Specifically, a deletion in exon 19 in EGFR, a non‐V600 BRAF mutation (G466V), and the F129L mutation in MAP2K1 were identified in four patients who showed no objective survival benefit from ALK‐Is. Potential ALK‐I‐resistance mutations were also found in PIK3CA and IDH2. Finally, a c‐MYC gain, along with a loss of CCND1 and FGFR3, was detected in a patient progressing on a first‐line treatment with crizotinib. We conclude that NGS analysis of liquid biopsies upon disease progression identified different putative ALK‐I‐resistance mutations in most cases and could be a valuable approach for therapy decision making.

Details

Title
NGS‐based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment
Author
Estela Sánchez‐Herrero 1 ; Roberto Serna‐Blasco 2 ; Ivanchuk, Vadym 2 ; Rosario García‐Campelo 3 ; Gómez, Manuel Dómine 4 ; Sánchez, José M 5 ; Massutí, Bartomeu 6 ; Reguart, Noemi 7 ; Camps, Carlos 8 ; Sandra Sanz‐Moreno 2 ; Silvia Calabuig‐Fariñas 9 ; Eloísa Jantus‐Lewintre 10 ; Arnal, Magdalena 11 ; Dietmar Fernández‐Orth 12   VIAFID ORCID Logo  ; Calvo, Virginia 13 ; Víctor González‐Rumayor 14 ; Provencio, Mariano 15 ; Romero, Atocha 15   VIAFID ORCID Logo 

 Liquid Biopsy Laboratory, Biomedical Sciences Research Institute Puerta de Hierro‐Majadahonda, Spain; Atrys Health, Barcelona, Spain 
 Liquid Biopsy Laboratory, Biomedical Sciences Research Institute Puerta de Hierro‐Majadahonda, Spain 
 Medical Oncology Department, Complejo Hospitalario Universitario A Coruña, Spain 
 Medical Oncology Department, Hospital Universitario Fundación Jiménez Díaz, Oncohealth Institute, Universidad Autónoma de Madrid, Spain 
 Medical Oncology Department, Hospital La Princesa, Madrid, Spain 
 Medical Oncology Department, Hospital Universitario de Alicante, ISABIAL, Alicante, Spain 
 Medical Oncology Department, Hospital Clinic of Barcelona, Spain 
 Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Spain; CIBERONC, Valencia, Spain; Department of Medical Oncology, Hospital General Universitario de Valencia, Spain; Department of Medicine, Universitat de València, Spain 
 Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Spain; CIBERONC, Valencia, Spain; Department of Pathology, Universitat de València, Spain 
10  Molecular Oncology Laboratory, Fundación Hospital General Universitario de Valencia, Spain; CIBERONC, Valencia, Spain; Department of Biotechnology, Universitat de València, Spain 
11  MARGenomics, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain 
12  European Genome‐phenome Archive, Centre for Genomic Regulation (CRG), Barcelona, Spain 
13  Medical Oncology Department, Hospital Universitario Puerta de Hierro‐Majadahonda, Spain 
14  Atrys Health, Barcelona, Spain 
15  Liquid Biopsy Laboratory, Biomedical Sciences Research Institute Puerta de Hierro‐Majadahonda, Spain; Medical Oncology Department, Hospital Universitario Puerta de Hierro‐Majadahonda, Spain 
Pages
2363-2376
Section
Research Articles
Publication year
2021
Publication date
Sep 2021
Publisher
John Wiley & Sons, Inc.
ISSN
15747891
e-ISSN
18780261
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2568094815
Copyright
© 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.