International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study

Journal article

Publication Details

Author(s): Pages F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, Lugli A, Zlobec I, Rau TT, Berger MD, Nagtegaal ID, Vink-Borger E, Hartmann A, Geppert C, Kolwelter J, Merkel S, Grützmann R, Van Den Eynde M, Jouret-Mourin A, Kartheuser A, Leonard D, Remue C, Wang JY, Bavi P, Roehrl MHA, Ohashi PS, Nguyen LT, Han S, Macgregor HL, Hafezi-Bakhtiari S, Wouters BG, Masucci GV, Andersson EK, Zavadova E, Vocka M, Spacek J, Petruzelka L, Konopasek B, Dundr P, Skalova H, Nemejcova K, Botti G, Tatangelo F, Delrio P, Ciliberto G, Maio M, Laghi L, Grizzi F, Fredriksen T, Buttard B, Angelova M, Vasaturo A, Maby P, Church SE, Angell HK, Lafontaine L, Bruni D, El Sissy C, Haicheur N, Kirilovsky A, Berger A, Lagorce C, Meyers JP, Paustian C, Feng Z, Ballesteros-Merino C, Dijkstra J, Van De Water C, Van Lent-Van Vliet S, Knijn N, Ina AMM, Scripcariu DV, Popivanova B, Xu M, Fujita T, Hazama S, Suzuki N, Nagano H, Okuno K, Torigoe T, Sato N, Furuhata T, Takemasa I, Itoh K, Patel PS, Vora HH, Shah B, Patel JB, Rajvik KN, Pandya SJ, Shukla SN, Wang Y, Zhang G, Kawakami Y, Marincola FM, Ascierto PA, Sargent DJ, Fox BA, Galon J
Journal: Lancet
Publication year: 2018
Volume: 391
Journal issue: 10135
Pages range: 2128-2139
ISSN: 0140-6736
eISSN: 1474-547X


BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer.
METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance.
FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system.
INTERPRETATION: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer.
FUNDING: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.

FAU Authors / FAU Editors

Geppert, Carol
Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie
Grützmann, Robert Prof. Dr.
Lehrstuhl für Allgemein- und Viszeralchirurgie
Hartmann, Arndt Prof. Dr. med.
Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie
Kolwelter, Julie
Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie
Merkel, Susanne Prof. Dr.
Medizinische Fakultät

External institutions with authors

Cliniques universitaires Saint-Luc (CHU St-Luc)
Curandis Laboratories LLC
Earle A. Chiles Research Institute at the Robert W. Franz Cancer Center
General University Hospital
Georges Pompidou European Hospital / Hôpital Européen Georges-Pompidou (HEGP)
Grigore T. Popa University of Medicine and Pharmacy / Universitatea de Medicină și Farmacie "Grigore T. Popa" (UMF Iași)
Gujarat Cancer & Research Institute
Inselspital, Universitätsspital Bern
Istituto Clinico Humanitas
Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"
Istituto Nazionale Tumori Regina Elena (IRE)
Karolinska Institute
Keio University / 慶應義塾大学
Kindai University / 近畿大学
Kurume University / 久留米大学
Mayo Clinic
National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM)
Providence Portland Medical Center
Radboud University Nijmegen
Sapporo Medical University / 札幌医科大学
Sidra Medical and Research Center
Università degli Studi di Siena (UNISI) / University of Siena
Universität Bern
Université Catholique de Louvain (UCL)
University Health Network (UHN)
University of Paris 5 - René Descartes / Université Paris V René Descartes
University of Toronto
Univerzita Karlova v Praze / Charles University in Prague
Xi'an Jiaotong University (XJTU) / 西安交通大学
Yamaguchi University

How to cite

Pages, F., Mlecnik, B., Marliot, F., Bindea, G., Ou, F.-S., Bifulco, C.,... Galon, J. (2018). International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet, 391(10135), 2128-2139.

Pages, Franck, et al. "International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study." Lancet 391.10135 (2018): 2128-2139.


Last updated on 2019-05-01 at 12:10