De novo EGFR T790M mutations in a community-based oncology practice.

Abstract

3146 Background: With the 2018 FDA approval of osimertinib for first-line treatment in EGFR-mutated lung cancers, the prevalence of acquired EGFR T790M mutations is expected to decrease, heightening the significance of de novo T790M mutations. Previous studies have reported a wide range of de novo T790M prevalence, and smaller retrospective studies have indicated that germline T790M may comprise the majority of de novo T790M mutations. Here, we assess the frequency of de novo T790M mutations in a community-based setting and report on germline T790M mutations occurring within this population. Methods: Patients with T790M-positive lung cancer were identified using Sarah Cannon’s clinicogenomics database containing information for patients treated within the Sarah Cannon research network. All T790M mutations were detected on tissue- and plasma-based NGS tests delivered as part of routine care. De novo and germline EGFR T790M status was determined via manual electronic health record chart review. When available, allele fraction and %cfDNA values were extracted from the structured NGS report and analyzed separately. Results: Of T790M-positive lung cancers with available pretreatment testing results, 36% (16/44) were confirmed to be T790M+ prior to EGFR TKI exposure; five of these patients received germline testing, and all five were confirmed to have originated in the germline. Two patients with germline T790M mutations detected on testing ordered by external providers were added to our de novo T790M+ patient analysis after chart review. Co-occurring EGFR mutations, including L858R, were detected in pre-TKI samples for 78% (14/18) of de novo T790M+ patients (Table). Co-occurring mutations in TP53, KRAS, PTEN, or RB1 were detected in pre-TKI samples of all patients without co-occurring EGFR mutations. EGFR C797S was observed after osimertinib treatment in one of four patients with post-TKI testing results. Of confirmed germline T790M+ cases with available allele frequencies, 100% (4/4) had allele fractions >0.5 (tissue) and/or %cfDNA values >50% (plasma). Average allele fraction and %cfDNA values were higher for de novo T790M mutations (allele fraction: 0.5 ± 0.2; %cfDNA: 40% ± 20%) than for acquired T790M mutations (allele fraction: 0.3 ± 0.2; %cfDNA: 2% ± 2%). Conclusions: Roughly one-third of T790M mutations detected in real-world settings occur before EGFR TKI exposure and may be associated with germline inheritance. Allele frequency may be a potential indicator of de novo T790M mutations in scenarios where pre-treatment data is not available. Future studies will investigate the impact of de novo T790M mutations on treatment response and evolution of resistance mechanisms in osimertinib-treated patients. [Table: see text]