Mechanisms of acquired resistance to afatinib clarified with liquid biopsy

• Published in: PloS one 2018-12, Vol.13 (12), p.e0209384-e0209384
• Main Authors: Nakamura, Tomomi, Nakashima, Chiho, Komiya, Kazutoshi, Kitera, Kazuki, Hirai, Mitsuharu, Kimura, Shinya, Aragane, Naoko
• Format: Article
• Language: English
• Subjects: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung - blood; Adenocarcinoma of Lung - drug therapy; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - mortality; Adult; Afatinib - pharmacology; Afatinib - therapeutic use; Aged; Aged, 80 and over; Alleles; Amplification; Aniline Compounds; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biology and Life Sciences; Biopsy; Care and treatment; Circulating Tumor DNA - genetics; Circulating Tumor DNA - isolation & purification; Data processing; Deoxyribonucleic acid; DNA; Drug Resistance, Neoplasm - genetics; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; Female; Gene Frequency; Hematology; Humans; Internal medicine; Kinases; Liquid Biopsy; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - blood; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Male; Medicine; Medicine and Health Sciences; Methods; Middle Aged; Mutation; Oncology; Patients; Piperazines - pharmacology; Piperazines - therapeutic use; Plasma; Polymerase Chain Reaction; Progression-Free Survival; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Research and Analysis Methods
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0209384

Although mechanisms of acquired resistance to 1st and 3rd generation EGFR-TKI continue to be elucidated, there have been few clinical investigations into the mechanisms of acquired resistance to the 2nd generation EGFR-TKI afatinib. We analyzed data from 20 patients with advanced lung adenocarcinoma who acquired resistance to afatinib, including resistance during EGFR-TKI re-challenge. We examined EGFR T790M and C797S mutations, BRAF V600E mutation, and MET amplification with the MBP-QP method and with droplet digital PCR using ctDNA and re-biopsy samples obtained before and after afatinib treatment. Just before afatinib treatment, 15 of the 20 patients were T790M negative and five were positive. Among the T790M negative patients, 40.0% (6/15) became positive at the time of PD under afatinib. In patients positive for T790M, changes in T790M allele frequency were correlated with afatinib treatment efficacy. C797S was not detected in any patients just before afatinib treatment, but it appeared after treatment in three patients, although with very low allele frequency. Two of these three patients, although positive for both C797S and T790M, achieved PR to osimertinib. However, PFS of these patients was somewhat shorter than that of patients positive for T790M only. BRAF V600E was detected in one patient at PD under afatinib. MET amplification was not detected in this study. T790M is associated with acquired resistance to afatinib, as with 1st generation EGFR-TKI, but with somewhat lower frequency. The influence of C797S on resistance to afatinib is less than that of T790M, but C797S might cause shorter PFS under osimertinib.