期刊
MOLECULAR ONCOLOGY
卷 15, 期 9, 页码 2363-2376出版社
WILEY
DOI: 10.1002/1878-0261.13033
关键词
ALK-TKI; EML4-ALK; liquid biopsy; NGS; NSCLC
类别
资金
- Instituto de Salud Carlos III (European Regional Development Fund/European Social Fund 'A way to make Europe'/'Investing in your future') [PI17/01977]
- European Union's Horizon 2020 research and innovation program [875160]
- Consejeria de Ciencia, Universidades e Innovacion of the Comunidad de Madrid [IND2019/BMD-17258]
- Consejeria de Educacion, Juventud y Deporte of the Comunidad de Madrid
- Fondo Social Europeo (Programa Operativo de Empleo Juvenil)
- Fondo Social Europeo (Iniciativa de Empleo Juvenil) [PEJD-2018-PRE/BMD-8640]
Despite durable responses, NSCLC patients treated with ALK inhibitors eventually develop resistance. Liquid biopsy NGS analysis upon disease progression identified diverse potential ALK-I-resistance mutations and may be a valuable tool for therapy decision-making.
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.
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