Correlation of genetic variants and immunotherapy-combined modality with neoadjuvant therapy outcomes in microsatellite-stable rectal cancer.

e15640 Background: The variability in response to neoadjuvant therapy (NAT) challenges the implementation of non-operative strategies, such as the watch-and-wait (W&W) approach, for rectal cancer. This study aimed to evaluate clinical and genomic factors associated with NAT outcomes in microsatellite-stable (MSS) rectal cancer. Methods: This cross-sectional study retrospectively included 437 patients with rectal adenocarcinoma at Fudan University Shanghai Cancer Center between December 2019 and March 2023. Paired tumor and blood samples were sequenced using an 887-gene panel. Logistic and Cox regression analyses were performed to identify clinical and genetic risk factors associated with tumor response and long-term survival outcomes. Results: MSS patients accounted for 96·6% (422/437) of all enrolled patients. Among 335 evaluable MSS patients, 127 (37.9%) achieved a complete response (CR) after NAT. Multivariate analysis identified an immunotherapy-combined regimen (odds ratio [OR] = 4.0, 95% CI [2.22–7.38], p < 0.001), and mutation in SYNE1 (OR = 1.98, 95% CI [1.02–3.9], p = 0.04) as predictors of CR. Tumor location higher from the anal verge (OR = 0.51, 95% CI [1.02–3.9], p = 0.02) and mesorectal fascia involvement (OR = 0.34 95% CI [0.17,0.67], p = 0.001) were associated with lower CR rate. Alteration in SYNE1 were notably prevalent in CR patients treated with immunotherapy-combined NAT (). No clinical factors were associated with decreased overall survival (DFS) or overall survival (OS). Mutations in FAT1 and KRAS were associated with poorer long-term survival outcomes: FAT1 mutations were linked to decreased OS (OR = 9.61, 95% CI [1.91–48.41], p = 0.006), and KRAS mutations with decreased DFS (OR = 1.88, 95% CI [1.07–3.29], p = 0.03). Post-NAT metastases occurred in 20.2% of patients, with KRAS G12D mutation correlating with the lowest 2-year distant metastasis-free survival rate compared to other KRAS mutation subtypes and wild type ( p = 0.02). Conclusions: Our study demonstrates that an immunotherapy-combined regimen and specific genomic alterations significantly influence NAT outcomes in MSS rectal cancer, providing potential biomarkers to guide personalized treatment strategies.