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

Abstract

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 stroma-high (>50%) or stroma-low (≤50%), was scored through standardized microscopic assessment by certified pathologists, and effect on disease-free survival (DFS) was evaluated with 3-year median follow-up. Secondary endpoints were benefit 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 significantly 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% confidence 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, confirming 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.

Keywords: colon cancer; disease-free survival; pathology; tumor microenvironment; tumor–stroma ratio.

Graphical abstract

Figure 1

CONSORT diagram of the UNITED cohort. CONSORT, Consolidated Standards of Reporting Trials; UNITED, Uniform Noting for International application of Tumor-stroma ratio as Easy Diagnostic tool.

Figure 2

Disease-free survival effect of TSR in the UNITED cohort and subgroup analyses. (A) Kaplan–Meier analysis and log-rank test showing worse 3-year disease-free survival rates for stroma-high patients in the whole UNITED cohort (70% versus 83%, respectively; P < 0.001). (B) Kaplan–Meier analysis with log-rank test in stage II patients receiving adjuvant chemotherapy, illustrating the worse 3-year survival rates for stroma-high patients despite treatment, indicating potential resistance to adjuvant chemotherapy (stroma-high 73% versus stroma-low 92%; P = 0.008). (C) Kaplan–Meier analysis with log-rank test in stage III patients receiving adjuvant chemotherapy, again illustrating the worse 3-year survival rates for stroma-high patients despite treatment (stroma-high 66% versus stroma-low 80%; P = 0.011). (D) The ASCO criteria (high risk versus low risk) not distinguishing any disease-free survival difference (high risk 91% versus low risk 90%; P = 0.529). (E) Kaplan–Meier analysis with log-rank test in stage II patients not receiving adjuvant chemotherapy, showing significant worse 3-year survival rates in stroma-high patients compared to stroma-low patients (stroma-high 80% versus stroma-low 93%; P < 0.001). (F) Kaplan–Meier analysis with log-rank test, showing overall worse survival in the stroma-high groups despite the short median follow-up of 3 years instead of 5 years, with the curves already diverging at 3 years. The 5-year overall survival rates are 74% versus 83%, respectively (P = 0.102). ASCO, American Society for Clinical Oncology; TNM, tumor–node–metastasis; TSR, tumor–stroma ratio; UNITED, Uniform Noting for International application of the Tumor-stroma ratio as Easy Diagnostic tool.^aFor disease-free survival, the number of patients starting can be lower due to missing data.