Genomic Profiling Identified Prognostic Biomarkers of Definitive Chemo-Radiotherapy Response in Esophageal Carcinoma

Purpose/Objective(s) Esophageal cancer (EC), especially esophageal squamous cell carcinoma is one of the most aggressive tumors in China with a five-year survival rate of approximately 40%. While definitive chemo-radiotherapy (CRT) remains the main treatment modality for EC, its clinical efficacy is largely limited by variations in individuals’ radio-sensitivity. The ability to accurately and reliably identify poor CRT responders might be of great value for timely regimen adjustments. Materials/Methods In this retrospective study, targeted next-generation sequencing using a 474-gene panel was performed on baseline tumors of 190 inoperable EC patients treated with CRT. Baseline clinical characteristics, genomic alterations and canonical oncogenic pathways were investigated for their associations with clinical outcomes. Results In this cohort, alterations in TP53 (94.2%), CDKN2A (51.1%), CCND1 (45.3%), MYC (34.2%), FGF19 (34.2%), CDKN1C (33.2%), NOTCH1 (30.5%), NFE2L2 (30.0%), FAT1 (25.8%) and PIK3CA (24.2%) were frequently observed. We revealed distinct genomic profiles between patients who achieved complete or partial response (CR/PR) and those with stable or progressive disease (SD/PD). Specifically, deletion of CDKN2B [29.59% vs. 16.48%, fisher's exact P = 0.039] and amplification of CDK6 [10.2% vs. 0%, fisher's exact P = 0.002] were significantly enriched in the SD/PD group comparing to CR/PR. Pathway analyses demonstrated that genetic alterations in the cell cycle regulation pathway were also more commonly identified in SD/PD than CR/PR group [22.22% vs. 17.83%, fisher's exact P = 0.025]. At baseline, clinical stage, the best response and level of reported radiation toxicity were significantly associated with PFS following CRT. Additionally, mutations in CHEK2 [PFS HR 3.81 (1.89-7.67), P < 0.0001; OS HR 2.44 (1.06-5.64), P = 0.031] and deletion of CDKN1C [PFS HR 1.63 (1.12-2.36), P = 0.009; OS HR 1.57 (0.984-2.5), P = 0.057], among others, could predict poor PFS and OS following CRT and remained meaningful after adjusting for clinical factors. Conclusion We demonstrated here crucial prognostic factors and abnormal oncogenic pathways that were associated lesser clinical benefit of CRT-treated EC patients. Results from comprehensive pre-treatment genomic testing could provide guidance for future clinical management for inoperable EC patients.