Prognostic and Treatment-Associated Survival Effects of Microsatellite Instability Across Disease Stages in Colon...

Microsatellite instability (MSI) is an established molecular biomarker in colorectal cancer (CRC). However, its stage-specific prognostic value and treatment-modifying role in colon cancer remain incompletely defined, particularly across contemporary multimodality treatment strategies.

We conducted a retrospective cohort study using the National Cancer Database, including patients aged ≥ 20 years diagnosed with colon cancer between 2004 and 2020 with documented tumor stage and MSI status. MSI was categorized as microsatellite stable (MSS), MSI-low (MSI-L), or MSI-high (MSI-H). Multivariable Cox proportional hazards regression models were used to evaluate the association between MSI status and overall survival (OS), stratified by disease stage and treatment combinations. Patients who died within 90 days of diagnosis were excluded to minimize immortal-time bias.

A total of 129,484 patients met inclusion criteria. MSI-H tumors comprised 16.8% of cases. The prognostic impact of MSI status varied by stage. MSI-H was not associated with OS in stage 0-I disease but conferred a significant survival advantage in stage II (HR 0.86, P < 0.001), stage III (HR 0.71, P < 0.001), and stage IV disease (HR 0.65, P < 0.001). MSI-L tumors demonstrated no consistent survival benefit, with a modest association observed only in stage IV (HR 0.89, P = 0.015). Treatment-stratified analyses revealed that in stage II disease, MSI-H was associated with improved survival only among patients treated with surgery alone (HR 0.83, P < 0.001). In contrast, MSI-H tumors demonstrated substantial survival benefit across multiple treatment pathways in stage III and IV disease, including surgery plus chemotherapy (stage III HR 0.72; stage IV HR 0.70) and immunotherapy-containing regimens (stage III HR 0.28; stage IV HR 0.47; all P < 0.01).

MSI status demonstrates a stage-dependent role in colon cancer, serving as a prognostic biomarker in early-stage disease and a predictive marker for immunotherapy-associated survival benefit in advanced stages.