Genomic alterations associated with response to neoadjuvant toripalimab plus chemotherapy in locally advanced esophageal squamous cell carcinoma
Year: 2026
Type: article
Abstract: Background: Increasing evidence demonstrates the promising efficacy of neoadjuvant chemotherapy plus immunotherapy (NCIT) in locally advanced esophageal squamous cell carcinoma (ESCC). However, response-related genomic alterations remain poorly characterized. This exploratory study aims to identify potential genomic signatures associated with NCIT response.Methods: Seventeen ESCC patients who received NCIT before surgery were enrolled. An analysis of whole-exome sequencing (WES) and homologous recombination deficiency (HRD) score data from the biopsy samples before NCIT was performed. The biological relevance of identified mutations was further explored using The Cancer Genome Atlas (TCGA) ESCC dataset.Results: In ESCC patients with RYR3 or FSIP2 mutations, the efficacy of NCIT was nominally better than that in wild-type patients (P=0.02). Patients with a higher tumor mutation burden (TMB) (P=0.03) and tumor neoantigen burden (TNB) (P=0.04) tended to benefit from NCIT, while the amplification of chromosome 2q37.3, 8q24.3, and 19p13.3 was associated with poor NCIT efficacy. The HRD score (P=0.40) was only numerically higher in the pathological complete response (pCR) group than in the non-pCR group. In the TCGA-ESCC cohort, RYR3 or FSIP2 alterations were associated with an immune-active microenvironment, characterized by increased infiltration of exhausted T cells and B cells, and upregulation of major histocompatibility complex class II (MHC-II) and co-stimulatory pathways.Conclusions: Our pilot study suggests that RYR3 or FSIP2 mutations, TMB, TNB, and specific somatic copy number alterations may be associated with NCIT efficacy in ESCC. These hypothesis-generating findings warrant further validation in larger prospective cohorts.
Institutions: Army Medical University, Daping Hospital, Pingjin Hospital
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7224081420