Chinese Academy of Medical Sciences and Peking Union Medical College Beijing, Aisa/Beijing
L. R. Gao1, P. Yue2, Z. Zhou2, Z. Xiao1, Y. Jiao2, and W. Liu Jr1; 1Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, 2State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Purpose/Objective(s): For unresectable locally advanced esophageal squamous cell carcinoma (ESCC) patients, definitive concurrent chemoradiotherapy (dCRT) stands as the standard treatment. Despite recent advancements in radiotherapy (RT) techniques and therapeutic regimens, the overall prognosis remains unfavorable. Therefore, effective predictive methods hold promise in providing risk-stratified and response-adapted treatment plans for individuals. In this study, we aimed to assess the efficacy of circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection in predicting the therapeutic response and prognosis of patients with ESCC undergoing dCRT. Materials/
Methods: Fifty-one patients who underwent definitive radiotherapy (dRT) were included from a prospective real-world study on comprehensive treatment of ESCC (NCT05543057). Among the 51 patients, 8 patients exclusively underwent dRT, while 43 patients received a dRT-based comprehensive treatment. Tumor biopsies were collected before treatment. Blood samples for ctDNA analysis were collected after the whole dRT process. A tumor-informed MRD detection strategy was employed to analyze the cfDNA samples. Exome sequencing was performed on DNA from tumor biopsies and buffy coats to obtain a list of somatic mutations for each case. 40 mutations were selected for analysis in the matched cfDNA samples. We applied Mutation Capsule technology to profile the tumor-specific mutations in cfDNA. Plasma samples with two or more ctDNA mutations were defined as MRD positive. For the MRD positive samples, the sample-level ctDNA fraction was evaluated. Results: In the dRT cohort, 45% (23/51) of them exhibited disease progression during a median follow-up period of 19 months. A significant difference was observed in the ctDNA fractions between the disease progression group and the progression-free groups at the post-dRT time point (median, [IQR]: progression group, 0.213%, [0.035%-1.499%]; progression-free group, 0%, [0%-0%]; progression group versus progression-free group, Mann Whitney test P < 0.0001). Of the 51 cases, 26 (51%) were MRD positive and 25 (49%) were MRD negative in the post-dRT blood. Notably, none of the MRD negative patients (0/25) showed progression. Conversely, 88% (23/26) of the MRD-positive patients encountered disease progression. The post-dRT MRD status accurately forecasted prognosis by detecting residual cancer cells with a sensitivity of 100% (23/23) and a specificity of 89% (25/28). The post-dRT MRD negative patients demonstrated significantly better progression-free survival (PFS) compared to the MRD-positive patients (PFS, P < 0.0001). Conclusion: In summary, we present an MRD profiling solution that precisely identified a subgroup of ESCC patients who might progress after dRT. These findings highlight MRD profilings potential as an invaluable tool in predicting ESCC patient prognosis.
