RESUMO
Purpose: Noninvasive drug biomarkers for the early assessment of tumor response can enable adaptive therapeutic decision-making and proof-of-concept studies for investigational drugs. Circulating tumor DNA (ctDNA) is released into the circulation by tumor cell turnover and has been shown to be detectable in urine.Experimental Design: We tested the hypothesis that dynamic changes in EGFR activating (exon 19del and L858R) and resistance (T790M) mutation levels detected in urine could inform tumor response within days of therapy for advanced non-small cell lung cancer (NSCLC) patients receiving osimertinib, a second-line third-generation anti-EGFR tyrosine kinase inhibitor.Results: Eight of nine evaluable NSCLC patients had detectable T790M-mutant DNA fragments in pretreatment baseline samples. Daily monitoring of mutations in urine indicated a pattern of intermittent spikes throughout week 1, suggesting apoptosis with an overall decrease in fragment numbers from baselines to day 7 preceding radiographic response assessed at 6 to 12 weeks.Conclusions: These findings suggest drug-induced tumor apoptosis within days of initial dosing. Daily sampling of ctDNA may enable early assessment of patient response and proof-of-concept studies for drug development. The modeling of tumor lysis through the day-to-day kinetics of ctDNA released into the blood and then into the urine is demonstrated in this proof-of-concept study in lung cancer patients receiving anti-EGFR tyrosine kinase inhibitors. This strategy may determine the specific clonal populations of cells which undergo apoptosis within the first week of therapy. This has important implications for developing combinational strategies to address inter- and intralesional heterogeneity and characterizing residual disease after initial drug exposure. Clin Cancer Res; 23(16); 4716-23. ©2017 AACR.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , DNA Tumoral Circulante/urina , DNA de Neoplasias/urina , Neoplasias Pulmonares/tratamento farmacológico , Piperazinas/uso terapêutico , Acrilamidas , Idoso , Compostos de Anilina , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/urina , DNA Tumoral Circulante/genética , DNA de Neoplasias/genética , Monitoramento de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Éxons/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/urina , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
Targeted therapies have changed the treatment landscape of non-small cell lung cancer over the past decade. Analyses of cell free circulating tumor DNA (ctDNA) provide a non-invasive and robust approach for cancer diagnosis and prognosis, real-time monitoring of treatment response, and the identification of appropriate therapeutic targets based on the detection of tumor genetic aberrations. Recent improvements in the sensitivity, specificity, and feasibility of ctDNA detection assays allow the possibility for implementation into clinical practice. This review will focus on key studies using ctDNA analysis in early lung cancer detection, prediction of treatment response, monitoring minimal residual disease and disease relapse, and the identification of resistance mechanisms. We explore how ctDNA can be used as a surrogate for tissue biopsy and an integral biomarker in the clinical management of patients with non-small cell lung cancer.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , DNA Tumoral Circulante/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Mutação , Proteínas de Neoplasias/genética , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , DNA Tumoral Circulante/sangue , Detecção Precoce de Câncer/métodos , Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/metabolismo , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , RecidivaRESUMO
With the implementation of genomic technologies into clinical practice, we have examples of the predictive benefit of targeted therapy for oncogene-addicted cancer and identified molecular dependencies in non-small cell lung cancer. The clinical success of tyrosine kinase inhibitors against epidermal growth factor receptor and anaplastic lymphoma kinase activation has shifted treatment emphasize the separation of subsets of lung cancer and genotype-directed therapy. Advances have validated oncogenic driver genes and led to the development of targeted agents. This review highlights treatment options, including clinical trials for ROS1 rearrangement, RET fusions, NTRK1 fusions, MET exon skipping, BRAF mutations, and KRAS mutations.
