Application of genetic features and serial ctDNA in estimating response and prognosis of immunotherapy-based total neoadjuvant therapy (iTNT) for microsatellite stable locally advanced rectal cancer: data from TORCH trial

Total neoadjuvant therapy (TNT) combined with immunotherapy (iTNT) has shown promising results for locally advanced rectal cancer (LARC) in microsatellite stable (MSS) patients. However, traditional clinical approaches often fail to accurately forecast clinical outcomes, and reliable methods to predict treatment response and recurrence risk are essential for optimizing treatment strategies and maximizing organ preservation. We analyzed clinical and genetic data from 63 patients from the prospectively registered TORCH clinical trial (NCT04518280) who received iTNT from May 1, 2021, to September 15, 2022. Baseline tissue mutations, magnetic resonance tumor regression grade (mrTRG), and circulating tumor DNA (ctDNA) positivity at different time points were collected and examined for their association with complete response (CR) and recurrence. Integrated models incorporating these features were developed to assess their accuracy in distinguishing CR from non-CR patients. Prognostic features were analyzed using Cox proportional hazards regression and Kaplan-Meier analyses. Baseline SMAD4 mutation was significantly associated with poor response to iTNT ( P = 0.007), while post-treatment mrTRG ( P < 0.0001), tumor mutational burden (TMB) ( P = 0.03) and latest ctDNA status ( P = 0.03) also correlated with CR rates. Integration of post-treatment mrTRG, SMAD4 mutation, TMB, and latest ctDNA status significantly improved CR discrimination accuracy compared with the mrTRG-only model (area under the curve (AUC) 0.92 vs. 0.75, P = 0.0098). Early integrated models incorporating mid-iTNT mrTRG and these genetic features showed better discriminative performance than the mrTRG-only model (AUC 0.89 vs. 0.76, P = 0.047). Furthermore, baseline SMAD4 mutations and ctDNA positivity at later time points correlated with an increased risk of disease progression, including local recurrence and distant metastasis. Our findings highlight the discriminative power of combining genetic features, particularly SMAD4 mutation and ctDNA, with clinical assessments like post-treatment mrTRG, for improving CR identification and early recurrence risk stratification over mrTRG alone in iTNT-treated LARC. These models could serve as complementary risk stratification tools to guide personalized treatment strategies, enabling early identification of patients requiring intensified therapy or nonoperative management. https://ClinicalTrials.gov identifier NCT04518280; Registration date August 15, 2020.