Prognostic Biomarkers and Immunotherapeutic Insights of Circulating Tumor DNA Analysis in Advanced Esophageal Squamous Cell Carcinoma From SCRUM-MONSTAR GOZILA Substudy.

Abstract

Advanced esophageal squamous cell carcinoma (ESCC) has a poor prognosis, and current treatments provide limited survival benefits. This study aimed to identify prognostic biomarkers and therapeutic targets by genomic profiling of advanced ESCC using circulating tumor DNA (ctDNA). The SCRUM-MONSTAR GOZILA study is a nationwide, plasma-based molecular profiling project using Guardant360, involving 31 core cancer institutions in Japan. We evaluated the genomic landscape of advanced ESCC and investigated associations between specific alterations and overall survival (OS). The correlation between blood tumor mutation burden (bTMB) and clinical outcomes in patients with PD-1 inhibitors was also assessed using multiple cutoff values (2, 4, 6, 8, and 10 mutations/Mb). Among 313 patients, alterations predominantly consisted of single nucleotide variants (SNVs, 68.9%) and copy number alterations (20.7%). <i>TP</i>53 was the most frequent alterations (88.5%), followed by <i>PIK3CA</i> (36.4%), <i>NFE2L2</i> (24.3%), <i>CCND1</i> (22.4%), and <i>EGFR</i> (20.1%). Amplifications in <i>PIK3CA</i>, <i>FGFR1</i>, <i>CCND1</i>, and <i>EGFR</i>, as well as mutations in <i>NFE2L2</i>, <i>FGFR1</i>, and <i>RB1</i> were associated with worse OS (any <i>P</i> < .05). Multivariable analysis confirmed mutations in <i>NFE2L2</i> or <i>FGFR1</i> and amplifications in <i>EGFR</i> or <i>PIK3CA</i> as independent poor prognostic factors (all <i>P</i> < .05). In 142 patients treated with PD-1 inhibitors, no significant differences in objective response rate or progression-free survival were observed at different bTMB cutoff values (all <i>P</i> > .1). ctDNA analysis identified key genomic alterations linked to poor outcomes in advanced ESCC, revealing potential prognostic biomarkers and therapeutic targets. In contrast, bTMB did not show predictive value for the efficacy of PD-1 inhibitors in this study.