TP53-centric ctDNA complements PET/CT for non-invasive assessment of pathological complete response and survival after neoadjuvant immunochemotherapy in esophageal squamous cell carcinoma: a prospective cohort study

BACKGROUND: Accurate assessment of pathologic complete response (pCR) after neoadjuvant immunochemotherapy (NICT) is crucial to implement active surveillance or tailor therapeutic strategies for esophageal squamous cell carcinoma (ESCC), while reliable non-invasive methods for pCR prediction are lacking. We aimed to evaluate the potential of integrating circulating tumor DNA (ctDNA) and PET/CT for predicting pCR to NICT for ESCC. METHODS: A total of 123 eligible patients were enrolled, including 68 patients from our prospective clinical trial (ChiCTR2000028900) and a real-world study (NCT04822103) that formed the discovery cohort, as well as 55 patients from another clinical trial (ChiCTR2100051763) comprising the validation cohort. Blood samples for ctDNA sequencing and PET/CT metrics were collected before and after NICT. RESULTS: The ctDNA status and PET/CT parameters at the post-NICT stage rather than the pre-NICT stage significantly differentiated pCR from non-pCR patients. ctDNA and PET/CT synergistically enhanced the prediction of pCR from perspectives of sensitivity and specificity, respectively. The model integrating ctDNA concentration and mean standardized uptake value (SUVmean) demonstrated area under curves (AUCs) of 0.860 in the discovery cohort and 0.798 in the validation cohort for pCR prediction and stratified patients into high- and low-risk groups with differential survival prospects. The key gene modules converged on TP53 as the core mutation for pCR prediction, among which those located in the exon regions contributed the most to its predictive capacity. The model constructed based on TP53 mutation and SUVmean differentiated pCR from non-pCR with comparable performance to the model based on PET/CT and the overall ctDNA concentration. CONCLUSION: The combination of post-treatment TP53 -centric ctDNA and PET/CT synergistically enhances the prediction of pCR following NICT in ESCC patients, indicating the potential to inform clinical decision-making for these patients.