Genomic alterations associated with response to neoadjuvant toripalimab plus chemotherapy in locally advanced esophageal squamous cell carcinoma.
4 affiliations
- 1Department of Cancer Center, Army Medical Center of PLA (Daping Hospital), Army Medical University, Chongqing, China.
- 2Radiobiology of Cancer Key Laboratory of Chongqing Education Commission of China, Chongqing, China.
- 3Department of Oncology, The 983rd Hospital of Joint Logistics Support Forces of the PLA, Tianjin, China.
- 4Genecast Biotechnology Co., Ltd., Wuxi, China.
Abstract
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. 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. 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. 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.
Related
- Efficacy and safety of neoadjuvant chemotherapy with toripalimab in locally advanced nasopharyngeal carcinoma: a phase II trial and biological correlate analysis
- Evaluation of the efficacy and safety of different cycles of neoadjuvant chemotherapy combined with immunotherapy in locally advanced esophageal squamous cell carcinoma: a multi-center, real-world study.
- Efficacy comparison of neoadjuvant chemotherapy, chemoradiotherapy, and chemoimmunotherapy in resectable esophageal squamous cell carcinoma: short- and long-term outcomes from a propensity score-matched analysis
- Impact of neoadjuvant chemotherapy on the association between key genetic alterations and tumor microenvironment in upper tract urothelial carcinoma
- Tumor Clusterin Expression at Diagnosis Is Associated with Residual Disease Burden After Neoadjuvant Chemotherapy in Breast Cancer
BibTeX
@article{yang2026genomic,
title = {{Genomic alterations associated with response to neoadjuvant toripalimab plus chemotherapy in locally advanced esophageal squamous cell carcinoma.}},
author = {Xiao Yang and Shuo Sun and He Xiao and Zhou Huang and Xiaoju Zhu and Xunjie Kuang and Mingfang Xu and Chun Liu and Lijia Wu and Xueqin Yang and Mengxia Li},
journal = {Journal of gastrointestinal oncology},
year = {2026},
month = aug,
doi = {10.21037/jgo-2026-0545},
url = {https://europepmc.org/article/MED/42996825},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Genomic alterations associated with response to neoadjuvant toripalimab plus chemotherapy in locally advanced esophageal squamous cell carcinoma.
AU - Xiao Yang
AU - Shuo Sun
AU - He Xiao
AU - Zhou Huang
AU - Xiaoju Zhu
AU - Xunjie Kuang
AU - Mingfang Xu
AU - Chun Liu
AU - Lijia Wu
AU - Xueqin Yang
AU - Mengxia Li
PY - 2026
DA - 2026/08/31
JO - Journal of gastrointestinal oncology
DO - 10.21037/jgo-2026-0545
UR - https://europepmc.org/article/MED/42996825
AB - 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. 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. 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. 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.
SN - 2078-6891
SN - 2219-679X
ER -