Results from the UNITED study: a multicenter study validating the prognostic effect of the tumor-stroma ratio in colon cancer

Background: The TNM (tumor - node - metastasis) Evaluation Committee of Union for International Cancer Control (UICC) and College of American Pathologists (CAP) recommended to prospectively validate the cost-effective and robust tumor - stroma ratio (TSR) as an independent prognostic parameter, since high intratumor stromal percentages have previously predicted poor patient-related outcomes. Patients and methods: The ' Uniform Noting for International application of Tumor-stroma ratio as Easy Diagnostic tool ' (UNITED) study enrolled patients in 27 participating centers in 12 countries worldwide. The TSR, categorized as stromahigh ( > 50%) or stroma-low ( < 50%), was scored through standardized microscopic assessment by certi fi ed pathologists, and effect on disease-free survival (DFS) was evaluated with 3-year median follow-up. Secondary endpoints were bene fi t assessment of adjuvant chemotherapy (ACT) and overall survival (OS). Results: A total of 1537 patients were included, with 1388 eligible stage II/III patients curatively operated between 2015 and 2021. DFS was signi fi cantly shorter in stroma -high ( n = 428) than in stroma-low patients ( n = 960) (3-year rates 70% versus 83%; P < 0.001). In multivariate analysis, TSR remained an independent prognosticator for DFS ( P < 0.001, hazard ratio 1.49, 95% con fi dence interval 1.17-1.90). As secondary outcome, DFS was also worse in stage II and III stroma -high patients despite adjuvant treatment (3-year rates stage II 73% versus 92% and stage III 66% versus 80%; P = 0.008 and P = 0.011, respectively). In stage II patients not receiving ACT ( n = 322), the TSR outperformed the American Society of Clinical Oncology (ASCO) criteria in identifying patients at risk of events (event rate 21% versus 9%), with a higher discriminatory 3-year DFS rate (stroma -high 80% versus ASCO high risk 91%). A trend toward worse 5-year OS in stroma -high was noticeable (74% versus 83% stroma-low; P = 0.102). Conclusion: The multicenter UNITED study unequivocally validates the TSR as an independent prognosticator, con fi rming worse outcomes in stroma -high patients. The TSR improved current selection criteria for patients at risk of events, and stroma -high patients potentially experienced chemotherapy resistance. TSR implementation in pathology diagnostics and international guidelines is highly recommended as aid in personalized treatment.