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

Franck Pagès, Bernhard Mlecnik, Florence Marliot, Gabriela Bindea, Fang Shu Ou, Carlo Bifulco, Alessandro Lugli, Inti Zlobec, Tilman T. Rau, Martin D. Berger, Iris D. Nagtegaal, Elisa Vink-Börger, Arndt Hartmann, Carol Geppert, Julie Kolwelter, Susanne Merkel, Robert Grützmann, Marc Van den Eynde, Anne Jouret-Mourin, Alex KartheuserDaniel Léonard, Christophe Remue, Julia Y. Wang, Prashant Bavi, Michael H.A. Roehrl, Pamela S. Ohashi, Linh T. Nguyen, Seong Jun Han, Heather L. MacGregor, Sara Hafezi-Bakhtiari, Bradly G. Wouters, Giuseppe V. Masucci, Emilia K. Andersson, Eva Zavadova, Michal Vocka, Jan Spacek, Lubos Petruzelka, Bohuslav Konopasek, Pavel Dundr, Helena Skalova, Kristyna Nemejcova, Gerardo Botti, Fabiana Tatangelo, Paolo Delrio, Gennaro Ciliberto, Michele Maio, Luigi Laghi, Fabio Grizzi, Tessa Fredriksen, Bénédicte Buttard, Mihaela Angelova, Angela Vasaturo, Pauline Maby, Sarah E. Church, Helen K. Angell, Lucie Lafontaine, Daniela Bruni, Carine El Sissy, Nacilla Haicheur, Amos Kirilovsky, Anne Berger, Christine Lagorce, Jeffrey P. Meyers, Christopher Paustian, Zipei Feng, Carmen Ballesteros-Merino, Jeroen Dijkstra, Carlijn van de Water, Shannon van Lent-van Vliet, Nikki Knijn, Ana Maria Mușină, Dragos Viorel Scripcariu, Boryana Popivanova, Mingli Xu, Tomonobu Fujita, Shoichi Hazama, Nobuaki Suzuki, Hiroaki Nagano, Kiyotaka Okuno, Toshihiko Torigoe, Noriyuki Sato, Tomohisa Furuhata, Ichiro Takemasa, Kyogo Itoh, Prabhu S. Patel, Hemangini H. Vora, Birva Shah, Jayendrakumar B. Patel, Kruti N. Rajvik, Shashank J. Pandya, Shilin N. Shukla, Yili Wang, Guanjun Zhang, Yutaka Kawakami, Francesco M. Marincola, Paolo A. Ascierto, Daniel J. Sargent, Bernard A. Fox, Jérôme Galon

Research output: Contribution to journalArticle

207 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2128-2139
Number of pages12
JournalThe Lancet
Volume391
Issue number10135
DOIs
Publication statusPublished - 2018 May 26

Fingerprint

Colonic Neoplasms
Neoplasms
Recurrence
Colon
Neoplasm Staging
T-Lymphocytes
Immunotherapy
Cell Count
Microsatellite Instability
Organized Financing
National Institutes of Health (U.S.)
Proportional Hazards Models
Quality Control
Paraffin
Biomedical Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pagès, 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. The Lancet, 391(10135), 2128-2139. https://doi.org/10.1016/S0140-6736(18)30789-X

International validation of the consensus Immunoscore for the classification of colon cancer : a prognostic and accuracy study. / Pagès, Franck; Mlecnik, Bernhard; Marliot, Florence; Bindea, Gabriela; Ou, Fang Shu; Bifulco, Carlo; Lugli, Alessandro; Zlobec, Inti; Rau, Tilman T.; Berger, Martin D.; Nagtegaal, Iris D.; Vink-Börger, Elisa; Hartmann, Arndt; Geppert, Carol; Kolwelter, Julie; Merkel, Susanne; Grützmann, Robert; Van den Eynde, Marc; Jouret-Mourin, Anne; Kartheuser, Alex; Léonard, Daniel; Remue, Christophe; Wang, Julia Y.; Bavi, Prashant; Roehrl, Michael H.A.; Ohashi, Pamela S.; Nguyen, Linh T.; Han, Seong Jun; MacGregor, Heather L.; Hafezi-Bakhtiari, Sara; Wouters, Bradly G.; Masucci, Giuseppe V.; Andersson, Emilia K.; Zavadova, Eva; Vocka, Michal; Spacek, Jan; Petruzelka, Lubos; Konopasek, Bohuslav; Dundr, Pavel; Skalova, Helena; Nemejcova, Kristyna; Botti, Gerardo; Tatangelo, Fabiana; Delrio, Paolo; Ciliberto, Gennaro; Maio, Michele; Laghi, Luigi; Grizzi, Fabio; Fredriksen, Tessa; Buttard, Bénédicte; Angelova, Mihaela; Vasaturo, Angela; Maby, Pauline; Church, Sarah E.; Angell, Helen K.; Lafontaine, Lucie; Bruni, Daniela; El Sissy, Carine; Haicheur, Nacilla; Kirilovsky, Amos; Berger, Anne; Lagorce, Christine; Meyers, Jeffrey P.; Paustian, Christopher; Feng, Zipei; Ballesteros-Merino, Carmen; Dijkstra, Jeroen; van de Water, Carlijn; van Lent-van Vliet, Shannon; Knijn, Nikki; Mușină, Ana Maria; Scripcariu, Dragos Viorel; Popivanova, Boryana; Xu, Mingli; Fujita, Tomonobu; Hazama, Shoichi; Suzuki, Nobuaki; Nagano, Hiroaki; Okuno, Kiyotaka; Torigoe, Toshihiko; Sato, Noriyuki; Furuhata, Tomohisa; Takemasa, Ichiro; Itoh, Kyogo; Patel, Prabhu S.; Vora, Hemangini H.; Shah, Birva; Patel, Jayendrakumar B.; Rajvik, Kruti N.; Pandya, Shashank J.; Shukla, Shilin N.; Wang, Yili; Zhang, Guanjun; Kawakami, Yutaka; Marincola, Francesco M.; Ascierto, Paolo A.; Sargent, Daniel J.; Fox, Bernard A.; Galon, Jérôme.

In: The Lancet, Vol. 391, No. 10135, 26.05.2018, p. 2128-2139.

Research output: Contribution to journalArticle

Pagès, F, Mlecnik, B, Marliot, F, Bindea, G, Ou, FS, Bifulco, C, Lugli, A, Zlobec, I, Rau, TT, Berger, MD, Nagtegaal, ID, Vink-Börger, E, Hartmann, A, Geppert, C, Kolwelter, J, Merkel, S, Grützmann, R, Van den Eynde, M, Jouret-Mourin, A, Kartheuser, A, Léonard, D, Remue, C, Wang, JY, Bavi, P, Roehrl, MHA, Ohashi, PS, Nguyen, LT, Han, SJ, 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, Mușină, AM, 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 2018, 'International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study', The Lancet, vol. 391, no. 10135, pp. 2128-2139. https://doi.org/10.1016/S0140-6736(18)30789-X
Pagès, Franck ; Mlecnik, Bernhard ; Marliot, Florence ; Bindea, Gabriela ; Ou, Fang Shu ; Bifulco, Carlo ; Lugli, Alessandro ; Zlobec, Inti ; Rau, Tilman T. ; Berger, Martin D. ; Nagtegaal, Iris D. ; Vink-Börger, Elisa ; Hartmann, Arndt ; Geppert, Carol ; Kolwelter, Julie ; Merkel, Susanne ; Grützmann, Robert ; Van den Eynde, Marc ; Jouret-Mourin, Anne ; Kartheuser, Alex ; Léonard, Daniel ; Remue, Christophe ; Wang, Julia Y. ; Bavi, Prashant ; Roehrl, Michael H.A. ; Ohashi, Pamela S. ; Nguyen, Linh T. ; Han, Seong Jun ; MacGregor, Heather L. ; Hafezi-Bakhtiari, Sara ; Wouters, Bradly G. ; Masucci, Giuseppe V. ; Andersson, Emilia K. ; Zavadova, Eva ; Vocka, Michal ; Spacek, Jan ; Petruzelka, Lubos ; Konopasek, Bohuslav ; Dundr, Pavel ; Skalova, Helena ; Nemejcova, Kristyna ; Botti, Gerardo ; Tatangelo, Fabiana ; Delrio, Paolo ; Ciliberto, Gennaro ; Maio, Michele ; Laghi, Luigi ; Grizzi, Fabio ; Fredriksen, Tessa ; Buttard, Bénédicte ; Angelova, Mihaela ; Vasaturo, Angela ; Maby, Pauline ; Church, Sarah E. ; Angell, Helen K. ; Lafontaine, Lucie ; Bruni, Daniela ; El Sissy, Carine ; Haicheur, Nacilla ; Kirilovsky, Amos ; Berger, Anne ; Lagorce, Christine ; Meyers, Jeffrey P. ; Paustian, Christopher ; Feng, Zipei ; Ballesteros-Merino, Carmen ; Dijkstra, Jeroen ; van de Water, Carlijn ; van Lent-van Vliet, Shannon ; Knijn, Nikki ; Mușină, Ana Maria ; Scripcariu, Dragos Viorel ; Popivanova, Boryana ; Xu, Mingli ; Fujita, Tomonobu ; Hazama, Shoichi ; Suzuki, Nobuaki ; Nagano, Hiroaki ; Okuno, Kiyotaka ; Torigoe, Toshihiko ; Sato, Noriyuki ; Furuhata, Tomohisa ; Takemasa, Ichiro ; Itoh, Kyogo ; Patel, Prabhu S. ; Vora, Hemangini H. ; Shah, Birva ; Patel, Jayendrakumar B. ; Rajvik, Kruti N. ; Pandya, Shashank J. ; Shukla, Shilin N. ; Wang, Yili ; Zhang, Guanjun ; Kawakami, Yutaka ; Marincola, Francesco M. ; Ascierto, Paolo A. ; Sargent, Daniel J. ; Fox, Bernard A. ; Galon, Jérôme. / International validation of the consensus Immunoscore for the classification of colon cancer : a prognostic and accuracy study. In: The Lancet. 2018 ; Vol. 391, No. 10135. pp. 2128-2139.
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title = "International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study",
abstract = "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.",
author = "Franck Pag{\`e}s and Bernhard Mlecnik and Florence Marliot and Gabriela Bindea and Ou, {Fang Shu} and Carlo Bifulco and Alessandro Lugli and Inti Zlobec and Rau, {Tilman T.} and Berger, {Martin D.} and Nagtegaal, {Iris D.} and Elisa Vink-B{\"o}rger and Arndt Hartmann and Carol Geppert and Julie Kolwelter and Susanne Merkel and Robert Gr{\"u}tzmann and {Van den Eynde}, Marc and Anne Jouret-Mourin and Alex Kartheuser and Daniel L{\'e}onard and Christophe Remue and Wang, {Julia Y.} and Prashant Bavi and Roehrl, {Michael H.A.} and Ohashi, {Pamela S.} and Nguyen, {Linh T.} and Han, {Seong Jun} and MacGregor, {Heather L.} and Sara Hafezi-Bakhtiari and Wouters, {Bradly G.} and Masucci, {Giuseppe V.} and Andersson, {Emilia K.} and Eva Zavadova and Michal Vocka and Jan Spacek and Lubos Petruzelka and Bohuslav Konopasek and Pavel Dundr and Helena Skalova and Kristyna Nemejcova and Gerardo Botti and Fabiana Tatangelo and Paolo Delrio and Gennaro Ciliberto and Michele Maio and Luigi Laghi and Fabio Grizzi and Tessa Fredriksen and B{\'e}n{\'e}dicte Buttard and Mihaela Angelova and Angela Vasaturo and Pauline Maby and Church, {Sarah E.} and Angell, {Helen K.} and Lucie Lafontaine and Daniela Bruni and {El Sissy}, Carine and Nacilla Haicheur and Amos Kirilovsky and Anne Berger and Christine Lagorce and Meyers, {Jeffrey P.} and Christopher Paustian and Zipei Feng and Carmen Ballesteros-Merino and Jeroen Dijkstra and {van de Water}, Carlijn and {van Lent-van Vliet}, Shannon and Nikki Knijn and Mușină, {Ana Maria} and Scripcariu, {Dragos Viorel} and Boryana Popivanova and Mingli Xu and Tomonobu Fujita and Shoichi Hazama and Nobuaki Suzuki and Hiroaki Nagano and Kiyotaka Okuno and Toshihiko Torigoe and Noriyuki Sato and Tomohisa Furuhata and Ichiro Takemasa and Kyogo Itoh and Patel, {Prabhu S.} and Vora, {Hemangini H.} and Birva Shah and Patel, {Jayendrakumar B.} and Rajvik, {Kruti N.} and Pandya, {Shashank J.} and Shukla, {Shilin N.} and Yili Wang and Guanjun Zhang and Yutaka Kawakami and Marincola, {Francesco M.} and Ascierto, {Paolo A.} and Sargent, {Daniel J.} and Fox, {Bernard A.} and J{\'e}r{\^o}me Galon",
year = "2018",
month = "5",
day = "26",
doi = "10.1016/S0140-6736(18)30789-X",
language = "English",
volume = "391",
pages = "2128--2139",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "10135",

}

TY - JOUR

T1 - International validation of the consensus Immunoscore for the classification of colon cancer

T2 - a prognostic and accuracy study

AU - Pagès, Franck

AU - Mlecnik, Bernhard

AU - Marliot, Florence

AU - Bindea, Gabriela

AU - Ou, Fang Shu

AU - Bifulco, Carlo

AU - Lugli, Alessandro

AU - Zlobec, Inti

AU - Rau, Tilman T.

AU - Berger, Martin D.

AU - Nagtegaal, Iris D.

AU - Vink-Börger, Elisa

AU - Hartmann, Arndt

AU - Geppert, Carol

AU - Kolwelter, Julie

AU - Merkel, Susanne

AU - Grützmann, Robert

AU - Van den Eynde, Marc

AU - Jouret-Mourin, Anne

AU - Kartheuser, Alex

AU - Léonard, Daniel

AU - Remue, Christophe

AU - Wang, Julia Y.

AU - Bavi, Prashant

AU - Roehrl, Michael H.A.

AU - Ohashi, Pamela S.

AU - Nguyen, Linh T.

AU - Han, Seong Jun

AU - MacGregor, Heather L.

AU - Hafezi-Bakhtiari, Sara

AU - Wouters, Bradly G.

AU - Masucci, Giuseppe V.

AU - Andersson, Emilia K.

AU - Zavadova, Eva

AU - Vocka, Michal

AU - Spacek, Jan

AU - Petruzelka, Lubos

AU - Konopasek, Bohuslav

AU - Dundr, Pavel

AU - Skalova, Helena

AU - Nemejcova, Kristyna

AU - Botti, Gerardo

AU - Tatangelo, Fabiana

AU - Delrio, Paolo

AU - Ciliberto, Gennaro

AU - Maio, Michele

AU - Laghi, Luigi

AU - Grizzi, Fabio

AU - Fredriksen, Tessa

AU - Buttard, Bénédicte

AU - Angelova, Mihaela

AU - Vasaturo, Angela

AU - Maby, Pauline

AU - Church, Sarah E.

AU - Angell, Helen K.

AU - Lafontaine, Lucie

AU - Bruni, Daniela

AU - El Sissy, Carine

AU - Haicheur, Nacilla

AU - Kirilovsky, Amos

AU - Berger, Anne

AU - Lagorce, Christine

AU - Meyers, Jeffrey P.

AU - Paustian, Christopher

AU - Feng, Zipei

AU - Ballesteros-Merino, Carmen

AU - Dijkstra, Jeroen

AU - van de Water, Carlijn

AU - van Lent-van Vliet, Shannon

AU - Knijn, Nikki

AU - Mușină, Ana Maria

AU - Scripcariu, Dragos Viorel

AU - Popivanova, Boryana

AU - Xu, Mingli

AU - Fujita, Tomonobu

AU - Hazama, Shoichi

AU - Suzuki, Nobuaki

AU - Nagano, Hiroaki

AU - Okuno, Kiyotaka

AU - Torigoe, Toshihiko

AU - Sato, Noriyuki

AU - Furuhata, Tomohisa

AU - Takemasa, Ichiro

AU - Itoh, Kyogo

AU - Patel, Prabhu S.

AU - Vora, Hemangini H.

AU - Shah, Birva

AU - Patel, Jayendrakumar B.

AU - Rajvik, Kruti N.

AU - Pandya, Shashank J.

AU - Shukla, Shilin N.

AU - Wang, Yili

AU - Zhang, Guanjun

AU - Kawakami, Yutaka

AU - Marincola, Francesco M.

AU - Ascierto, Paolo A.

AU - Sargent, Daniel J.

AU - Fox, Bernard A.

AU - Galon, Jérôme

PY - 2018/5/26

Y1 - 2018/5/26

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85046846915&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046846915&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(18)30789-X

DO - 10.1016/S0140-6736(18)30789-X

M3 - Article

C2 - 29754777

AN - SCOPUS:85046846915

VL - 391

SP - 2128

EP - 2139

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10135

ER -