Abstract 5942: Association of microsatellite instability status with pathologic complete response and tumor downstaging in locally advanced rectal cancer

Abstract Background: Two primary genomic instability pathways contribute to rectal carcinogenesis: microsatellite instability (MSI) and chromosomal instability, known as microsatellite stable (MSS). MSI rectal cancers generally have a better prognosis—attributed to enhanced immunogenicity, distinct molecular pathways, and reduced metastatic potential. This study assesses the impact of MSI status on pathologic complete response (pCR) and tumor downstaging after neoadjuvant treatment. We hypothesized that MSI rectal cancers are associated with higher odds of achieving pCR and tumor downstaging. Methods: A retrospective analysis was performed using the National Cancer Database, including patients aged ≥20 years diagnosed with stage II-III rectal cancer between 2004 and 2020 with documented MSI status. All patients underwent surgical resection, chemotherapy, and radiotherapy. Collected data encompassed demographics, tumor size and grade, TN stage, lymphovascular invasion, perineural invasion, and immunotherapy. MSI status was categorized as MSS, MSI-low (MSI-L), and MSI-high (MSI-H). The primary outcome is pCR, defined as the absence of tumor in the pathological specimen (T0/x, N0/x). Tumor downstaging was assessed by comparing pathological T or N stage with clinical staging. Multivariable binary logistic regression analyzed the impact of MSI status on pCR and tumor downstaging, adjusting for significant covariates. Results: Of the 5, 124 patients included, 93.5% were MSS, 3.1% MSI-L, and 3.4% MSI-H. Immunotherapy was administered to 1.1% of MSS, 1.9% of MSI-L, and 3.5% of MSI-H patients. MSI tumors were less likely to achieve pCR compared to MSS tumors (OR = 0.62; P = 0.023). Specifically, MSI-L tumors had significantly lower odds of pCR (OR = 0.40; P = 0.011), whereas MSI-H tumors did not differ significantly from MSS tumors. For T downstaging, MSI tumors were less likely to have a reduced pathological T stage (OR = 0.72; P = 0.009). MSI-H tumors were associated with lower odds of T downstaging (OR = 0.69; P = 0.027), while MSI-L tumors showed no significant impact. Neither MSI-L nor MSI-H status significantly affected N downstaging. Conclusion: Despite a better overall prognosis of MSI tumors, they are less likely to achieve pathologic complete response and T downstaging following neoadjuvant treatment. Additionally, MSI-L and MSI-H tumors exhibit distinct clinical outcomes in rectal cancer, indicating they should be considered separate entities in clinical management. Citation Format: Mohyeddine El Sayed, Sassine Youssef, Raymond Dubois. Association of microsatellite instability status with pathologic complete response and tumor downstaging in 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 5942.