Prognostic and Predictive Value of SARIFA-status Within Molecular Subgroups of Colorectal Cancer

We recently proposed Stroma AReactive Invasion Front Areas (SARIFA), defined as direct tumor-adipocyte interaction at the invasion front, as a novel hematoxylin-and-eosin (H&E)-based histopathological prognostic biomarker in various cancers. Given that microsatellite instability, BRAF , and RAS mutation status are routinely tested for colorectal cancers (CRC), studying SARIFA's additional prognostic value within these molecular subgroups is crucial. In addition, exploring whether the survival benefit from adjuvant therapy differs according to SARIFA-status may enhance patient treatment and outcome. SARIFA-status, BRAF , RAS , and DNA mismatch repair (MMR) status were available for 1726 CRC patients from the prospective Netherlands Cohort Study (NLCS, 1986-2006). In this study, we investigated (1) the relationship between SARIFA-status and CRC molecular characteristics, (2) the prognostic value of SARIFA-status within these molecular subgroups, and (3) whether SARIFA-status was associated with survival benefit from adjuvant therapy. SARIFA-positive CRCs more frequently showed a BRAF mutation compared to SARIFA-negative CRCs ( P <0.001). BRAF -mutant/MMR-proficient CRCs were enriched in SARIFA-positive cases. SARIFA-positivity was associated with poor CRC-specific (HR range : 1.47 to 1.78) and overall survival (HR range : 1.35 to 1.70) within all molecular subgroups except MMR-deficient CRCs. Patients with SARIFA-positive CRC showed a CRC-specific survival benefit from adjuvant therapy compared to surgery alone (HR CRC-specific : 0.59; 95% CI: 0.44-0.79), while no CRC-specific survival benefit was observed for patients with SARIFA-negative CRC. To conclude, our results indicate that SARIFA-positivity is more common in the aggressive subset of BRAF -mutant and BRAF -mutant/MMR-proficient CRCs. Moreover, SARIFA-positivity provides additional prognostic value within molecular subgroups based on BRAF , RAS , and MMR status, suggesting that it may enhance prognostic stratification of CRC patients.