Abstract 722: Characterization and estimation of treatment response of immunotherapy-based total neoadjuvant therapy (iTNT) for microsatellite stable (MSS) locally advanced rectal cancer

Abstract Background: Total neoadjuvant therapy (TNT) combined with immunotherapy (iTNT) has shown promising results for locally advanced rectal cancer (LARC), especially in proficient mismatch repair (pMMR)/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. Methods: We analyzed clinical and genetic data from 63 patients in the TORCH clinical trial who received iTNT. Baseline tissue mutations, magnetic resonance tumor regression grade (mrTRG), and circulating tumor DNA (ctDNA) positivity at different time points were examined for their association with complete response (CR) and recurrence. Predictive models integrating these features were developed to assess their accuracy in distinguishing CR from non-CR patients. Prognostic features were analyzed using COX regression and Kaplan-Meier analyses. Results: 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 prediction accuracy compared with mrTRG-only model (area under the curve (AUC) 0.92 vs 0.75, P=0.0098). Early prediction models incorporating middle-iTNT mrTRG and these genetic features showed superior accuracy to predict CR than mrTRG-only model (AUC 0.89 vs 0.76, P=0.047). Furthermore, ctDNA positivity at later time points and SMAD4 mutations correlated with worse disease progression, including local recurrence and distant metastases. Conclusion: Our findings highlight the predictive power of combining genetic and clinical features, particularly ctDNA and SMAD4mutation, for improving CR prediction and early recurrence risk stratification in iTNT-treated LARC. These models could guide more personalized treatment strategies, enabling early identification of patients requiring intensified therapy or nonoperative management. Citation Format: Yaqi Wang, Yang Xu, Fan Xia, Juefeng Wan, Lijun Shen, Yan Wang, Hui Zhang, Hairong Bao, Haimeng Tang, Qiuxiang Ou, Hua Bao, Yang Shao, Sanjun Cai, Xinxiang Li, Zhen Zhang. Characterization and estimation of treatment response of immunotherapy-based total neoadjuvant therapy (iTNT) for microsatellite stable (MSS) locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 722.