Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer

Bernhard Mlecnik; Alessandro Lugli; Gabriela Bindea; Florence Marliot; Carlo Bifulco; Jiun Kae Jack Lee; Inti Zlobec; Tilman T. Rau; Martin D. Berger; Iris D. Nagtegaal; Elisa Vink-Börger; Arndt Hartmann; Carol I. Geppert; Julie Kolwelter; Susanne Merkel; Robert Grützmann; Marc Van den Eynde; Anne Jouret-Mourin; Alex Kartheuser; Daniel Léonard; Christophe Remue; Julia 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; Lucie Lafontaine; Pauline Maby; Amine Majdi; Assia Hijazi; Carine El Sissy; Amos Kirilovsky; Anne Berger; Christine Lagorce; Christopher Paustian; 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; Prabhu 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; Bernard A. Fox; Franck Pagès; Jérôme Galon

doi:10.3390/cancers15020418

Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer

Bernhard Mlecnik, Alessandro Lugli, Gabriela Bindea, Florence Marliot, Carlo Bifulco, Jiun Kae Jack Lee, Inti Zlobec, Tilman T. Rau, Martin D. Berger, Iris D. Nagtegaal, Elisa Vink-Börger, Arndt Hartmann, Carol I. Geppert, Julie Kolwelter, Susanne Merkel, Robert Grützmann, Marc Van den Eynde, Anne Jouret-Mourin, Alex Kartheuser, Daniel LéonardChristophe Remue, Julia 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, Lucie Lafontaine, Pauline Maby, Amine Majdi, Assia Hijazi, Carine El Sissy, Amos Kirilovsky, Anne Berger, Christine Lagorce, Christopher Paustian, 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, Prabhu 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, Bernard A. Fox, Franck Pagès, Jérôme Galon

Biostatistics

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p < 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ² for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.

Original language	English (US)
Article number	418
Journal	Cancers
Volume	15
Issue number	2
DOIs	https://doi.org/10.3390/cancers15020418
State	Published - Jan 2023

Keywords

colon cancer
early-stage
Immunoscore
predictive biomarkers
prognosis
tumor microenvironment

ASJC Scopus subject areas

Oncology
Cancer Research

MD Anderson CCSG core facilities

Biostatistics Resource Group

Access to Document

10.3390/cancers15020418

Cite this

Mlecnik, B., Lugli, A., Bindea, G., Marliot, F., Bifulco, C., Lee, J. K. J., Zlobec, I., Rau, T. T., Berger, M. D., Nagtegaal, I. D., Vink-Börger, E., Hartmann, A., Geppert, C. I., Kolwelter, J., Merkel, S., Grützmann, R., Van den Eynde, M., Jouret-Mourin, A., Kartheuser, A., ... Galon, J. (2023). Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer. Cancers, 15(2), Article 418. https://doi.org/10.3390/cancers15020418

Mlecnik, B, Lugli, A, Bindea, G, Marliot, F, Bifulco, C, Lee, JKJ, Zlobec, I, Rau, TT, Berger, MD, Nagtegaal, ID, Vink-Börger, E, Hartmann, A, Geppert, CI, Kolwelter, J, Merkel, S, Grützmann, R, Van den Eynde, M, Jouret-Mourin, A, Kartheuser, A, Léonard, D, Remue, C, Wang, J, 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, Lafontaine, L, Maby, P, Majdi, A, Hijazi, A, El Sissy, C, Kirilovsky, A, Berger, A, Lagorce, C, Paustian, C, Ballesteros-Merino, C, Dijkstra, J, van de Water, C, Vliet, SVLV, 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, Patel, P, Vora, HH, Shah, B, Patel, JB, Rajvik, KN, Pandya, SJ, Shukla, SN, Wang, Y, Zhang, G, Kawakami, Y, Marincola, FM, Ascierto, PA, Fox, BA, Pagès, F & Galon, J 2023, 'Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer', Cancers, vol. 15, no. 2, 418. https://doi.org/10.3390/cancers15020418

@article{8ed04954fed84f149f226561255d32c3,

title = "Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer",

abstract = "Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p < 0.0001) of the patient{\textquoteright}s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.",

keywords = "colon cancer, early-stage, Immunoscore, predictive biomarkers, prognosis, tumor microenvironment",

author = "Bernhard Mlecnik and Alessandro Lugli and Gabriela Bindea and Florence Marliot and Carlo Bifulco and Lee, {Jiun Kae Jack} 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 Geppert, {Carol I.} 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 Julia Wang 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 Lucie Lafontaine and Pauline Maby and Amine Majdi and Assia Hijazi and {El Sissy}, Carine and Amos Kirilovsky and Anne Berger and Christine Lagorce and Christopher Paustian and Carmen Ballesteros-Merino and Jeroen Dijkstra and {van de Water}, Carlijn and Vliet, {Shannon van Lent van} and Nikki Knijn and Mușin{\u a}, {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 Prabhu Patel 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 Fox, {Bernard A.} and Franck Pag{\`e}s and J{\'e}r{\^o}me Galon",

note = "Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = jan,

doi = "10.3390/cancers15020418",

language = "English (US)",

volume = "15",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "2",

}

TY - JOUR

T1 - Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer

AU - Mlecnik, Bernhard

AU - Lugli, Alessandro

AU - Bindea, Gabriela

AU - Marliot, Florence

AU - Bifulco, Carlo

AU - Lee, Jiun Kae Jack

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 I.

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

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 - Lafontaine, Lucie

AU - Maby, Pauline

AU - Majdi, Amine

AU - Hijazi, Assia

AU - El Sissy, Carine

AU - Kirilovsky, Amos

AU - Berger, Anne

AU - Lagorce, Christine

AU - Paustian, Christopher

AU - Ballesteros-Merino, Carmen

AU - Dijkstra, Jeroen

AU - van de Water, Carlijn

AU - Vliet, Shannon van Lent van

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 - Patel, Prabhu

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 - Fox, Bernard A.

AU - Pagès, Franck

AU - Galon, Jérôme

PY - 2023/1

Y1 - 2023/1

N2 - Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p < 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.

AB - Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p < 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.

KW - colon cancer

KW - early-stage

KW - Immunoscore

KW - predictive biomarkers

KW - prognosis

KW - tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85146799379&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85146799379&partnerID=8YFLogxK

U2 - 10.3390/cancers15020418

DO - 10.3390/cancers15020418

M3 - Article

C2 - 36672367

AN - SCOPUS:85146799379

SN - 2072-6694

VL - 15

JO - Cancers

JF - Cancers

IS - 2

M1 - 418

ER -

Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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