3574 - Impact of HRD Status and DDR Pathway Genes on Chemoradiotherapy Effectiveness in Chinese Esophageal Cancer Patients

02:30pm - 03:45pm PT

Hall F

Screen: 12

POSTER

Presenter(s)

Jingping Yu, PhD, none - Changzhou Cancer Hospital, Changzhou, Jiangsu Province

J. Yu Sr¹, Y. Ding², Q. Gao³, N. Gao⁴, and E. Li⁴; ¹Radiotherapy Department, Changzhou Cancer Hospital, Changzhou, Jiangsu Province, 213032, China, Changzhou, Jiangsu Province, China, ²Radiotherapy Department, Changzhou Cancer Hospital, Changzhou, Jiangsu Province, 213032, China, Changzhou,, Jiangsu Province, China, ³Pathology Department, Changzhou Cancer Hospital, Changzhou, Jiangsu Province, 213032, China, Changzhou, Jiangsu Province, China, ⁴Department of Medical Affairs, 3D Medicines Inc., Shanghai, China, Shanghai, Shanghai, China

Purpose/Objective(s):

The DNA damage response (DDR) pathway plays a crucial role in maintaining genomic stability, and chemoradiotherapy can exerts its therapeutic effects by inducing DNA damage and subsequent apoptosis. However, the prognostic implications of homologous recombination deficiency (HRD) status, DDR-related genomic features, and their interplay with clinical factors remain underexplored in Chinese esophageal cancer (EC) patients. This study aimed to investigate these research questions

Materials/Methods:

Tumor tissue samples from 390 Chinese esophageal cancer patients (EC-HRD cohort) were genetically sequenced, covering 215 DDR-related genes. Survival analysis of high-frequency mutated DDR-related genes was conducted using the TCGA-ESCA cohort. Additionally, a prospective exploratory analysis included 10 Chinese esophageal cancer patients receiving definitive chemoradiotherapy to assess the survival correlations of HRD status and DDR-related genomic features

Results:

In the EC-HRD cohort, the median age was 64 years. Using a predefined cutoff (HRD score =22, median value), 209 patients(53.6%) were classified as HRD-positive. In HRD-positive patients, the 7 most frequently mutated DDR-related genes were: TP53 (53.6%), MSH2 (45.9%), MSH3 (45.9%), BLM (44.6%), POLD1 (44.6%), PRKDC (44.4%), and ERCC2 (44.1%). Kaplan-Meier survival analysis in TCGA-ESCA cohort revealed significantly that worse overall survival (OS) was in patients with BRIP1 (p=0.0329) or MSH2 (p<0.001) mutations. Among the 10 patients undergoing chemoradiotherapy, the median age was 77.5 years (range, 63-85). Meantime, 5 patients (50%) were HRD-positive and 2 patients (20%) had high tumor mutation burden (TMB-H; TMB =10 Muts/mb). The top 5 DDR-associated genes with the highest mutation frequencies were TP53 (80%), CHEK2 (30%), FANCM (30%), SETMAR (30%), and FANCD2 (20%). Kaplan-Meier analysis based on survival data show that HRD-positive patients had a trend toward longer progression-free survival (PFS) compared to HRD-negative cases (median PFS: 19 months vs. 11 months, p=0.26). TMB-H patients exhibited significantly shorter survival compared to those TMB-low patients (OS: 12.5 months vs. 28.5 months, p=0.029; PFS: 4.5 months vs. 13 months, p=0.031). Additionally, Patients with TP53 mutation had significantly shorter OS (18 months VS 37 months, p=0.045) than those without TP53 mutation, and patients with SETMAR mutation had significantly longer PFS (13 months VS 8 months, P=0.049) than those without SETMAR mutation.

Conclusion:

Our data provides a comprehensive analysis of HRD status and DDR-associated genomic features in Chinese patients with esophageal cancer. Notably, among those undergoing chemoradiotherapy, HRD positivity emerged as a potential favorable prognostic indicator.Besides, TMB-H, TP53 and SETMAR mutations were associated with prognosis.