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Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to osimertinib in NSCLC.
Knebel, Franciele H; Bettoni, Fabiana; Shimada, Andrea K; Cruz, Manoel; Alessi, João Victor; Negrão, Marcelo V; Reis, Luiz Fernando L; Katz, Artur; Camargo, Anamaria A.
Afiliação
  • Knebel FH; Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, São Paulo, SP, Brazil.
  • Bettoni F; Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, São Paulo, SP, Brazil.
  • Shimada AK; Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, São Paulo, SP, Brazil.
  • Cruz M; Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, São Paulo, SP, Brazil.
  • Alessi JV; Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, São Paulo, SP, Brazil; Instituto do Câncer do Estado de São Paulo, ICESP, São Paulo, SP, Brazil.
  • Negrão MV; Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, São Paulo, SP, Brazil; Instituto do Câncer do Estado de São Paulo, ICESP, São Paulo, SP, Brazil.
  • Reis LFL; Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, São Paulo, SP, Brazil.
  • Katz A; Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, São Paulo, SP, Brazil.
  • Camargo AA; Sociedade Beneficiente de Senhoras Hospital Sírio Libanês, SBSHSL, São Paulo, SP, Brazil. Electronic address: aacamargo@mochsl.org.br.
Lung Cancer ; 108: 238-241, 2017 06.
Article em En | MEDLINE | ID: mdl-28625643
Osimertinib is an EGFR-T790M-specific TKI, which has demonstrated impressive response rates in NSCLC, after failure to first-line anti-EGFR TKIs. However, acquired resistance to osimertinib is also observed and the molecular mechanisms of resistance are not yet fully understood. Monitoring and managing NSCLC patients who progressed on osimertinib is, therefore, emerging as an important clinical challenge. Sequential liquid biopsies were used to monitor a patient with EGFR-exon19del positive NSCLC, who received erlotinib and progressed through the acquisition of the EGFR-T790M mutation. Erlotinib was discontinued and osimertinib was initiated. Blood samples were collected at erlotinib progression and during osimertinib treatment for the detection of the activating (EGFR-exon19del) and resistance mutations (EGFR-T790M, EGFR-C797S, BRAF-V600E, METamp and ERBB2amp) in the plasma DNA using digital droplet PCR. Plasma levels of the activating EGFR-exon19del accurately paralleled the clinical and radiological progression of disease and allowed early detection of AR to osimertinib. Resistance to osimertinib coincided with the emergence of a small tumor cell subpopulation carrying the known EGFR-C797S resistance mutation and an additional subpopulation carrying amplified copies of EGFR-exon19del. Given the existence of multiple AR mechanisms, quantification of the original EGFR activation mutation, instead of the resistance mutations, can be efficiently used to monitor response to osimertinib, allowing early detection of AR. Absolute quantification of both activation and resistance mutations can provide important information on tumor clonal evolution upon progression to osimertinib. Selective amplification of the EGFR-exon19del allele may represent a novel resistance mechanism to osimertinib.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperazinas / Amplificação de Genes / Carcinoma Pulmonar de Células não Pequenas / Resistencia a Medicamentos Antineoplásicos / Receptores ErbB / Neoplasias Pulmonares / Mutação Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Female / Humans / Middle aged Idioma: En Revista: Lung Cancer Assunto da revista: NEOPLASIAS Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Brasil País de publicação: Irlanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperazinas / Amplificação de Genes / Carcinoma Pulmonar de Células não Pequenas / Resistencia a Medicamentos Antineoplásicos / Receptores ErbB / Neoplasias Pulmonares / Mutação Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Female / Humans / Middle aged Idioma: En Revista: Lung Cancer Assunto da revista: NEOPLASIAS Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Brasil País de publicação: Irlanda