Abstract 6403: Presence of Stroma AReactive Invasion Front Areas (SARIFA) - a potential novel histopathological tool for therapy response prediction in colorectal cancer

Abstract Background: Although many approaches based either on molecular investigations or on deep-learning algorithms applied to tissue sections have been proposed to stratify colorectal cancers (CRC) patients, clinical implementation of these novel cost-and time-consuming techniques is lacking, and conventional tumor-node-metastasis (TNM) staging remains one of the key factors to determine patient’s treatment. Hence, we developed a novel and solely Haematoxylin and Eosin (H&E) based histopathologic prognostic biomarker, called SARIFA (Stroma AReactive Invasion Front Areas, i.e., direct contact between tumor cells and fat cells). Materials/Methods: Based on a previous study, in which we could show that gene-expression based computational drug response prediction (oncoPredict) indicates a SARIFA-dependent differential drug sensitivity, we investigated whether SARIFA-status can predict which CRC patients might benefit from adjuvant therapy. SARIFA-status was established for 1,727 CRC patients from the prospective Netherlands Cohort Study. Multivariate-adjusted Cox regression analysis was performed (median follow-up: 4.79 years, with 1,463 deaths being observed in the first 10 years of follow-up [933, 63.8%, were CRC-related]). Only stages II to IV were included for further analysis regarding differential treatment response (n = 1,384). Results: In Multivariate-adjusted Cox regression analysis including patient age, sex, tumor location, pTNM stage, grade of differentiation, and mismatch repair status, SARIFA-positive CRC patients (n=496) benefitted significantly from adjuvant therapy (HRCRC-specific 0.59; 95% CI 0.44-0.78) compared to SARIFA-positive patients treated with surgery alone, which was not significant for SARIFA-negative CRC patients (HRCRC-specific 0.88; 95% CI 0.68-1.15). Regarding overall survival (OS), adjuvant therapy led to better OS outcomes regardless of SARIFA-status (HRoverall all patients 0.74; 95% CI 0.62-0.87). Conclusion: Our results suggest that SARIFA-positivity predicts a CRC-specific survival benefit from adjuvant therapy. As SARIFA-positivity is closely linked to an upregulation of lipid metabolism and an altered immune response, further studies are warranted to explore the potential benefit of not only conventional chemotherapy but also immunotherapy, targeted therapy as well novel drugs targeting lipid-metabolism. As SARIFA-status can be assessed fast and easily on for every cancer patient available H&E slides, SARIFA-status could serve as an ideal biomarker for a more detailed patient stratification in prospective clinical trials, and should be implemented into clinical routine if further validated. Citation Format: Nic G. Reitsam, Kelly Offermanns, Bianca Grosser, Jessica Zimmermann, Colinda Simons, Jakob N. Kather, Piet A. van den Brandt, Bruno Märkl, Heike I. Grabsch. Presence of Stroma AReactive Invasion Front Areas (SARIFA) - a potential novel histopathological tool for therapy response prediction in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6403.