Yoshiya Matsumoto1, Kenji Sawa2, Mitsuru Fukui3, Jun Oyanagi4, Naoki Yoshimoto5, Tomohiro Suzumura5, Tetsuya Watanabe2, Hiroyasu Kaneda5, Shigeki Mitsuoka5, Kazuhisa Asai2, Tatsuo Kimura6, Nobuyuki Yamamoto4, Kazuto Hirata2, Yasuhiro Koh7, Tomoya Kawaguchi8. 1. Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan; Internal Medicine III, Wakayama Medical University, Wakayama, Japan. 2. Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan. 3. Laboratory of Statistics, Graduate School of Medicine, Osaka City University, Osaka, Japan. 4. Internal Medicine III, Wakayama Medical University, Wakayama, Japan. 5. Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan. 6. Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan. 7. Internal Medicine III, Wakayama Medical University, Wakayama, Japan. Electronic address: ykoh@wakayama-med.ac.jp. 8. Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan; Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Abstract
OBJECTIVES: Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancer (NSCLC). However, the impact of pretreatment T790M (preT790M) on the efficacy of EGFR-TKIs and on resistance remains unclear. MATERIALS AND METHODS: Two independent cohorts consisting of advanced EGFR-mutated NSCLC patients treated with first-line EGFR-TKIs, a derivation cohort that started treatment between August 2013 and July 2016 (cohort A, n = 44) and a validation cohort between August 2016 and December 2017 (cohort B, n = 22), were examined in this study. Among these, 28 patients underwent re-biopsy at disease progression. DNAs from pretreatment tumor biopsy samples and re-biopsy samples were assessed to detect T790M by the Cobas EGFR Mutation Test v2 (Cobas) and for quantitating T790M by droplet digital polymerase chain reaction (ddPCR). RESULTS: Detection rates of preT790M were 40.9% (18/44) in cohort A and 45.5% (10/22) in cohort B by ddPCR, and none by Cobas. A cutoff value of 0.3% for dividing into high- vs. low-preT790M allele frequency was determined by receiver operating characteristic curve analysis in cohort A. Progression-free survival (PFS) was significantly shorter in the high- preT790M group (n = 12) than in the low-preT790M (n = 6) and negative (n = 26) groups (combined low-preT790M) (median: 6.9 vs. 13.8 months, P = 0.00073). These observations were validated in cohort B [median: 6.2 (n = 5) vs. 15.3 months (n = 17), P = 0.0029]. In 28 paired biopsies, Cobas detected post-progression T790M in 60% (3/5) of the high-preT790M, in 57% (4/7) of the low-preT790M, and in 56% (9/16) of the negative-preT790M groups. CONCLUSION: EGFR-mutated NSCLC with high preT790M had significantly shorter PFS on EGFR-TKIs. However, preT790M abundance may not necessarily confer post-TKI T790M resistance.
OBJECTIVES: Low-frequency epidermal growth factor receptor (EGFR) T790M mutation could be detected by ultrasensitive methods in EGFR tyrosine kinase inhibitor (TKI)-naïve non-small cell lung cancer (NSCLC). However, the impact of pretreatment T790M (preT790M) on the efficacy of EGFR-TKIs and on resistance remains unclear. MATERIALS AND METHODS: Two independent cohorts consisting of advanced EGFR-mutated NSCLCpatients treated with first-line EGFR-TKIs, a derivation cohort that started treatment between August 2013 and July 2016 (cohort A, n = 44) and a validation cohort between August 2016 and December 2017 (cohort B, n = 22), were examined in this study. Among these, 28 patients underwent re-biopsy at disease progression. DNAs from pretreatment tumor biopsy samples and re-biopsy samples were assessed to detect T790M by the Cobas EGFR Mutation Test v2 (Cobas) and for quantitating T790M by droplet digital polymerase chain reaction (ddPCR). RESULTS: Detection rates of preT790M were 40.9% (18/44) in cohort A and 45.5% (10/22) in cohort B by ddPCR, and none by Cobas. A cutoff value of 0.3% for dividing into high- vs. low-preT790M allele frequency was determined by receiver operating characteristic curve analysis in cohort A. Progression-free survival (PFS) was significantly shorter in the high- preT790M group (n = 12) than in the low-preT790M (n = 6) and negative (n = 26) groups (combined low-preT790M) (median: 6.9 vs. 13.8 months, P = 0.00073). These observations were validated in cohort B [median: 6.2 (n = 5) vs. 15.3 months (n = 17), P = 0.0029]. In 28 paired biopsies, Cobas detected post-progression T790M in 60% (3/5) of the high-preT790M, in 57% (4/7) of the low-preT790M, and in 56% (9/16) of the negative-preT790M groups. CONCLUSION:EGFR-mutated NSCLC with high preT790M had significantly shorter PFS on EGFR-TKIs. However, preT790M abundance may not necessarily confer post-TKI T790M resistance.
Authors: Marzia Del Re; Federico Cucchiara; Iacopo Petrini; Stefano Fogli; Antonio Passaro; Stefania Crucitta; Ilaria Attili; Filippo De Marinis; Antonio Chella; Romano Danesi Journal: ESMO Open Date: 2020-08
Authors: Weiting Li; Klaas Kok; Geok Wee Tan; Pei Meng; Mirjam Mastik; Naomi Rifaela; Frank Scherpen; T Jeroen N Hiltermann; Harry J M Groen; Anthonie J van der Wekken; Anke van den Berg Journal: Cancers (Basel) Date: 2022-07-19 Impact factor: 6.575