FGFR2-amplified gastroesophageal adenocarcinoma is a distinct genomic class: Lessons learned from a liquid biopsy platform.

Abstract

429 Background: Gastroesophageal cancers (GECs) are the 2nd highest cause of cancer mortality globally. Biomarkers such as MMR, PD-L1, and HER2 are critical for treatment strategies. Emerging biomarkers in late-stage clinical development include FGFR2b. Approximately 30% of GECs express FGFR2b, which is associated with a poor prognosis. FGFR2 amplification ( FGFR2amp) is seen in a subset of patients and may be particularly responsive to FGFR2-targeted approaches. We sought to elucidate the genomic landscape of FGFR2ampGECs using a ctDNA platform. Methods: We retrospectively queried the Guardant Health database from 2017-2022 for patients with advanced GECs who had ctDNA NGS (Guardant360, Redwood City, CA) performed as part of clinical care. Co-alterations were evaluated for patients who harbor FGFR2amp vs those without FGFR2amp detected via ctDNA. Fisher’s exact test was used for group comparisons. Results: Approximately 7100 patients met the diagnosis criteria. FGFR2amp was detected in 263 patients (3.7%). The majority were males (66 and median age in the cohort of FGFR2amp patients was 66 years (range 22-81 yrs). Most amps were high (+++) in gastric and GEJ (plasma CN≥4) and more frequently observed in patients who are tested at diagnosis (44%) vs progression (19%) (p=0.0147). The mean VAF across samples with high-level FGFR2amp is 22.42%. Patients with FGFR2amp were enriched for EGFR co-occuring amplifications and cell cycle pathway alterations. CDH1 was frequently mutated in pts under 50 who harbor FGFR2amp (p=0.0028). Thirty nine percent of patients with FGFR2amp were also found to harbor a gene fusion and 14% of patients with FGFR2amps harbored an activating fusion in FGFR1/2/3. Conclusions: FGFR2 is a validated target in GECs, and the contexture of FGFR2amp will be important to defining patient subgroups with responses to FGFR2-directed therapy. Here we define the FGFR2amp landscape which may help inform future combination strategies for this emerging biomarker.[Table: see text]