439O Tracking spatiotemporal T790M heterogeneity in patients with EGFR-mutant advanced NSCLC after acquired resistance to EGFR TKIs

Abstract

Background The evolution landscape of EGFR-mutant advanced NSCLC might be characterized by evolving traces of actionable EGFR mutations. With the approval of osimertinib, T790M has shifted from a resistant biomarker to an actionable biomarker for EGFR-mutant advanced NSCLC. However, T790M status might vary spatiotemporally and consequently hinder the initiation and clinical efficacy of third generation EGFR TKIs. Till now, the spatiotemporal traces of T790M under treatment pressure have not been fully elucidated. Methods We retrospectively reviewed T790M status and clinical courses of 114 patients who had multiple (>2) rebiopsies after acquired resistanceto EGFR TKIs from January 2010 to July 2016 in our institute. Tissue EGFR detection was performed by SNaPshot or ARMS. Plasma EGFR was detected by ARMS. Results The ratio of spatial T790M heterogeneity was 57%. In detail, 14 of 21 patients with synchronous rebiopsies at the same lesion and 20 of 39 patients with paired tissue and plasma rebiopsies showed T790M heterogeneity. 33% (10/30) of patients who had heterochronous rebiopsies at the same lesion revealed temporal T790M heterogeneity. Spatiotemporal T790M heterogeneity was observed in 53% (17/32) of patients who had heterochronous multiple sites rebiopsies. Of 24 patients with temporal or spatiotemporalT790Mheterogeneity(3withbothtypes),T790Mstatusin15switched from negative to positive after sequential treatments (7 first generation EGFR TKIs, 7 chemotherapy and 1 combined first generation EGFR TKIs and chemotherapy) and in 7 switchedfrompositivetonegativeaftersequentialtreatments(1thirdgenerationEGFR TKIs, 5 chemotherapy, 1 combined first generation EGFR TKIs and chemotherapy). 2 showed a cycle of T790M heterogeneity with a “positive-negative-positive” manner. Conclusions: T790M status could vary spatiotemporally at a ratio of 33-57% in patients with acquired resistance to previous EGFR TKIs, highlighting the necessity of repeated rebiopsies and dynamic monitor of T790M in this subpopulation. Moreover, this study provides a new insight of valuing actionable mutations when deciphering spatiotemporal genomic heterogeneity of lung cancer in clinical practice. Legal entity responsible for the study N/A Funding This study was supported by Guangzhou Science and Technology Bureau (No. 2014Y2-00050). Disclosure All authors have declared no conflicts of interest.