R Minari1, P Bordi1, M Del Re2, F Facchinetti1, F Mazzoni3, F Barbieri4, A Camerini5, C E Comin6, L Gnetti7, C Azzoni7, R Nizzoli1, B Bortesi1, E Rofi2, P Petreni3, N Campanini7, G Rossi8, R Danesi2, M Tiseo9. 1. Medical Oncology Unit, University Hospital of Parma, Italy. 2. Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy. 3. Department of Medical Oncology, Careggi Hospital of Firenze, Firenze, Italy. 4. Department of Oncology, University Hospital Policlinico of Modena, Modena, Italy. 5. Medical Oncology, Versilia Hospital, Lido di Camaiore, Italy. 6. Department of Experimental and Clinical Medicine, Section of Surgery, Histopathology and Molecular Pathology, University of Florence, Italy. 7. Pathology Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy. 8. Pathology Unit, Azienda USL Valle d'Aosta, Regional Hospital "Parini", Aosta, Italy. 9. Medical Oncology Unit, University Hospital of Parma, Italy. Electronic address: mtiseo@ao.pr.it.
Abstract
OBJECTIVES: EGFR T790M mutation is the most common mechanism of resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) and could be overcome by third-generation EGFR-TKIs, such as osimertinib. Liquid biopsy, a non-invasive technique used to test the presence of the resistant mutation, may help avoiding tissue re-biopsy. However, analysing only circulating-free DNA, information about other less frequent and coexisting resistance mechanisms may remain unrevealed. MATERIALS AND METHODS: All patients reported in this series participated in the ASTRIS trial, a real world treatment study testing the efficacy of osimertinib (80mg os die) in advanced T790M-positive NSCLC progressed to prior EGFR-TKI. Patients were considered eligible to osimertinib if T790M positive on tissue or plasma samples. In our patients, EGFR molecular testing on blood sample was conducted with digital droplet PCR (ddPCR). RESULTS: We report our experience of five patients treated with osimertinib after T790M detection on liquid biopsy that presented a disease progression at first tumor assessment mediated by SCLC transformation, as evidenced at tissue re-biopsies. All patients showed low ratio T790M/activating mutation in the blood before osimertinib (lower than 0.03). For three patients, EGFR mutational analysis was T790M-negative when re-assessed by using a less sensitive method (therascreen®) on the same liquid biopsy sample analysed by ddPCR before osimertinib therapy. CONCLUSION: Although liquid biopsy is a relevant tool to diagnose T790M presence in NSCLC patients resistant to EGFR-TKI, in case of a low ratio T790M/activating mutation, tissue biopsy should be considered to exclude the presence of SCLC transformation and/or other concomitant resistance mechanisms.
OBJECTIVES: EGFR T790M mutation is the most common mechanism of resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) and could be overcome by third-generation EGFR-TKIs, such as osimertinib. Liquid biopsy, a non-invasive technique used to test the presence of the resistant mutation, may help avoiding tissue re-biopsy. However, analysing only circulating-free DNA, information about other less frequent and coexisting resistance mechanisms may remain unrevealed. MATERIALS AND METHODS: All patients reported in this series participated in the ASTRIS trial, a real world treatment study testing the efficacy of osimertinib (80mg os die) in advanced T790M-positive NSCLC progressed to prior EGFR-TKI. Patients were considered eligible to osimertinib if T790M positive on tissue or plasma samples. In our patients, EGFR molecular testing on blood sample was conducted with digital droplet PCR (ddPCR). RESULTS: We report our experience of five patients treated with osimertinib after T790M detection on liquid biopsy that presented a disease progression at first tumor assessment mediated by SCLC transformation, as evidenced at tissue re-biopsies. All patients showed low ratio T790M/activating mutation in the blood before osimertinib (lower than 0.03). For three patients, EGFR mutational analysis was T790M-negative when re-assessed by using a less sensitive method (therascreen®) on the same liquid biopsy sample analysed by ddPCR before osimertinib therapy. CONCLUSION: Although liquid biopsy is a relevant tool to diagnose T790M presence in NSCLC patients resistant to EGFR-TKI, in case of a low ratio T790M/activating mutation, tissue biopsy should be considered to exclude the presence of SCLC transformation and/or other concomitant resistance mechanisms.
Authors: Anna Buder; Ellen Heitzer; Julie Waldispühl-Geigl; Sabrina Weber; Tina Moser; Maximilian J Hochmair; Klaus Hackner; Peter Errhalt; Ulrike Setinek; Martin Filipits Journal: Biomolecules Date: 2021-04-21