Serial ultra-deep sequencing of circulating tumor DNA reveals the clonal evolution in non-small cell lung cancer patients treated with anti-PD1 immunotherapy.
Cancer Med
; 8(18): 7669-7678, 2019 12.
Article
em En
| MEDLINE
| ID: mdl-31692284
ABSTRACT
BACKGROUND:
Immune-therapy with anti-PD1 inhibitors, such as pembrolizumab, is revolutionizing the treatment of non-small cell lung cancers (NSCLC). However, identifying patients for the potential therapeutic response and predicting therapy resistance and early relapse remains a challenge.METHODS:
Between 2016 and 2018, 60 patients were treated with pembrolizumab, among who 12 NSCLC patients had both baseline (before treatment) and serial (on treatment) periodical circulating tumor DNA (ctDNA) samples. Those samples were sequenced on a 329 pan cancer-related gene panel. Analyses of tumor burden, blood tumor mutational burden (bTMB), maximum somatic allele frequency (MSAF), and tumor clonal structure were performed in association with clinical response. Candidate resistance mutations involved in relapse and metastases were further investigated.RESULTS:
ctDNA was detected and mutational profiling was performed for each patient. Those with a high baseline bTMB level showed significantly improved progression-free survival (PFS) after pembrolizumab treatment. Tumor burden and therapeutic response significantly correlated with the MSAF instead of the bTMB. Clone analysis detected tumor progression about 2-4 months ahead of computed tomography (CT) scan. One mutation in gene PTCH1 (Protein patched homolog 1) and two acquired anti-PD1 candidate resistance mutations of gene B2M (ß2 microglobulin) were identified in association with distant metastasis. The evolutionary tree of a representative patient was also described.CONCLUSION:
This pilot study showed that MSAF could be another good indicator of therapeutic response, and clonal analysis could be clinically useful in monitoring clonal dynamics and detecting remote metastasis and early relapse.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Biomarcadores Tumorais
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Transformação Celular Neoplásica
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Carcinoma Pulmonar de Células não Pequenas
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Evolução Clonal
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DNA Tumoral Circulante
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Neoplasias Pulmonares
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Cancer Med
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China