Results from the UNITED study: a multicenter study validating the prognostic effect of the tumor–stroma ratio in colon cancer
ESMO Open, vol. 9, pp. 102988
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.
Authors 64
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Leiden University Medical Center
Affiliation as printed
Department of Surgery, Leiden University Medical Center, Leiden
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Leiden University Medical Center
Affiliation as printed
Department of Surgery, Leiden University Medical Center, Leiden
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Leiden University Medical Center
Affiliation as printed
Department of Surgery, Leiden University Medical Center, Leiden
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Annet G.H. Roodvoets Aachen Clinical Research Center Department of Surgery, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Clinical Research Center, Department of Surgery, Leiden University Medical Center, Leiden
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Elma Meershoek‐Klein Kranenbarg Aachen Clinical Research Center Department of Surgery, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Clinical Research Center, Department of Surgery, Leiden University Medical Center, Leiden
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Affiliation as printed
Department of Biomedical Data Sciences, Leiden
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Leiden University Medical Center
Affiliation as printed
Department of Medical Oncology, Leiden
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Leiden University Medical Center
Affiliation as printed
Department of Pathology, Leiden University Medical Center, Leiden
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Medisch Centrum Haaglanden · Stichting Haaglanden Medisch Centrum
Affiliation as printed
Department of Pathology, Haaglanden Medical Center, The Hague, The Netherlands
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Ss. Cyril and Methodius University in Skopje
Affiliation as printed
Department of Pathology, Medical Faculty of Ss. Cyril and Methodius University, Skopje, Republic of North Macedonia
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Institute of Oncology Ljubljana
Affiliation as printed
Department of Pathology, Onkološki inštitut-Institute of Oncology, Ljubljana, Slovenia
Department of Pathology, Onkološki inštitut—Institute of Oncology, Ljubljana, Slovenia
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Vejle Sygehus · Lillebaelt Hospital
Affiliation as printed
Department of Pathology, Vejle Sygehus-Sygehus Lillebælt, Vejle, Denmark
Department of Pathology, Vejle Sygehus–Sygehus Lillebælt, Vejle, Denmark
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Affiliation as printed
PATHAN Laboratories, Rotterdam, The Netherlands
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Affiliation as printed
Department of Pathology, Spaarne Gasthuis, Haarlem
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Utrecht University · University Medical Center Utrecht · Netherlands Comprehensive Cancer Organisation
Affiliation as printed
Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht; Department of Research and Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands
Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht
Department of Research and Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands
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Affiliation as printed
European Society of Pathology, Brussels, Belgium
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Leiden University Medical Center
Affiliation as printed
Department of Surgery, Leiden University Medical Center, Leiden
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Radboud University Medical Center
Affiliation as printed
Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Surgery, Leiden University Medical Center, Leiden. Electronic address: w.e.mesker@lumc.nl
Department of Surgery, Leiden University Medical Center, Leiden
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Leiden University Medical Center
Affiliation as printed
Department of Surgery, Leiden University Medical Center, Leiden
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Leiden University Medical Center
Affiliation as printed
Department of Surgery, Leiden University Medical Center, Leiden;
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