Genomic landscape and biomarker analyses utilizing circulating-tumor DNA in advanced esophageal squamous cell carcinoma: Sub-analysis of SCRUM-MONSTAR GOZILA.

4024 Background: Advanced esophageal squamous cell carcinoma (ESCC) is a cancer type with a poor prognosis, with limited survival benefits from current multimodal approaches. The incomplete understanding of molecular mechanisms in advanced ESCC has hindered the development of effective targeted therapies, emphasizing the critical need for identifying predictive biomarkers and novel therapeutic targets. Methods: SCRUM-MONSTAR GOZILA is a nationwide plasma-based genomic profiling study utilizing Guardant360 in Japan, which aimed to analyze circulating tumor DNA (ctDNA) genomic alterations in patients with advanced solid tumors, including ESCC. We evaluated the genomic landscape with advanced ESCC patients and investigated associations between genomic alterations and overall survival (OS) using the log-rank test. The correlation between progression-free survival (PFS) and blood tumor mutation burden (bTMB) in immune checkpoint inhibitor (ICI) monotherapy was also assessed using multiple cut-off values (2, 4, 6, 8, and 10 mutation/Mb). Results: The present study included 313 patients with available genomic and clinical data. The gene alteration spectrum comprised mutations (single nucleotide variants, 71.6%; and insertions/deletions, 10.7%), copy number alterations (CNAs, 17.3%), and fusions (0.48%). TP53 was the most frequently altered gene (88.5%), followed by PIK3CA (36.4%), NFE2L2 (24.3%), CCND1 (22.4%), EGFR (20.1%), ATM (16.3%), FGFR1 (10.2%), BRCA2 (10.2%), MET (9.6%) and ARID1A (9.6%). Regarding the survival outcomes, PIK3CA CNA was significantly associated with worse OS compared to those with PIK3CA wild type [hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.24–2.74; p-value, 0.0002], and PIK3CA mutation showed a trend toward shorter OS (HR, 1.43; 95%CI, 0.94–2.17; p-value, 0.06). Patients with both PIK3CA mutation and CNA exhibited significantly worse OS compared to those with PIK3CA wild type (HR, 1.94; 95%CI, 0.85–4.45; p-value, 0.03). Both FGFR1 CNA and mutation were associated with poorer OS (HR, 1.98; 95%CI, 1.03–3.79; p-value, 0.005; and HR, 2.84; 95%CI, 0.89–9.07; p-value, 0.002, respectively). CNA in CCND1 and EGFR , and mutation in NFE2L2 and RB1 also significantly correlated with worse OS (any p-value≤0.01). Among 142 patients treated with ICI monotherapy, no statistically significant differences in PFS were observed at any cut-off value of bTMB (any p-value > 0.1). Conclusions: This comprehensive analysis of ctDNA profiles revealed distinct genomic alterations with prognostic significance in advanced ESCC. Multiple alterations demonstrated significant associations with poor OS, meanwhile bTMB was not validated as an effective predictive biomarker for ICI efficacy. These findings provide insights into potential therapeutic targets and prognostic biomarkers in advanced ESCC. Clinical trial information: 2021-GB-009 .