Pre-treatment plasma-informed circulating tumor DNA detection as an early identification of therapeutic benefit for patients with untreated advanced lung squamous cell carcinoma.

Abstract

9041 Background: Circulating tumor DNA (ctDNA) detection as a promising prognostic factor to assess treatment response has been widely studied with customized tumor-informed strategies, the application of which was limited by the inaccessibility for tumor biopsies in a substantial proportion of patients. To overcome this challenge, we presented a proof-of-concept study for the development of a novel personalized pre-treatment plasma-informed next generation sequencing (NGS) panel and investigated its prognostic value for first line treatment in patients with advanced lung squamous cell carcinoma (LUSC). Methods: Paired plasma and white blood cell (WBC) samples were collected from 227 of stage IIIB-IV LUSC patients who were treated with first line either chemotherapy or chemotherapy plus PD-1 blockade at pre- and post-treatment. Somatic mutations in pre-treatment plasma were identified with a 769-gene based NGS panel (Genecast, Wuxi, China) followed with germline or clonal hematopoietic variants filtering by referring to the WBC samples. Positive variants detected in the pre-treatment plasma served as a basis for personalized variants tracking in post-treatment plasma. ctDNA kinetics was measured by plasmaDelta (Δgenevaf=((post-treatment genevaf – pre-treatment genevaf) / pre-treatment genevaf; genevaf was defined by variant allele frequency for each individual gene). Progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint were assessed. Results: ctDNA positivity was observed in 80% (182/227) of pre-treatment samples and subsequently 54% (99/182) of post-treatment samples. ctDNA positivity at post-treatment was shown to be a significant predictor for both PFS and OS in the whole group as well in the sub-treatment groups (Table). After adjusting for clinicopathologic variables, ctDNA positivity remained significantly associated with both worse PFS and OS (PFS: HR = 2.3, P <0.001 and OS: HR= 2.56, P <0.001). ctDNA kinetics further identified a worse treatment response group. Patients with high plasmaDelta had remarkably worse outcomes than patients with low plasmaDelta (PFS: HR =4.8; 95%CI=2.8-8.3; P < 0.001 and OS: HR=2.8; 95%CI=1.7-4.6; P <0.001). Conclusions: These results demonstrated the feasibility of pre-treatment plasma-informed ctDNA detection and kinetics for monitoring treatment response in LUSC patients whose tumor biopsies were unavailable. [Table: see text]