Bernhard Mlecnik1,2,3,4, Carlo Bifulco5, Gabriela Bindea1,2,3, Florence Marliot1,2,3,6, Alessandro Lugli7, J Jack Lee8, Inti Zlobec7, Tilman T Rau7, Martin D Berger9, Iris D Nagtegaal10, Elisa Vink-Börger10, Arndt Hartmann11, Carol Geppert11, Julie Kolwelter11, Susanne Merkel12, Robert Grützmann12, Marc Van den Eynde13, Anne Jouret-Mourin14, Alex Kartheuser15, Daniel Léonard15, Christophe Remue15, Julia Y Wang16,17,18, Prashant Bavi18, Michael H A Roehrl17,18,19, Pamela S Ohashi20, Linh T Nguyen20, SeongJun Han20, Heather L MacGregor20, Sara Hafezi-Bakhtiari17, Bradly G Wouters20, Giuseppe V Masucci21, Emilia K Andersson21, Eva Zavadova22, Michal Vocka22, Jan Spacek22, Lubos Petruzelka22, Bohuslav Konopasek22, Pavel Dundr23, Helena Skalova23, Kristyna Nemejcova23, Gerardo Botti24, Fabiana Tatangelo24, Paolo Delrio25, Gennaro Ciliberto26, Michele Maio27, Luigi Laghi28, Fabio Grizzi29, Tessa Fredriksen1,2,3, Bénédicte Buttard1,2,3, Lucie Lafontaine1,2,3, Daniela Bruni1,2,3, Anastasia Lanzi1,2,3, Carine El Sissy1,2,3,6, Nacilla Haicheur6, Amos Kirilovsky1,2,3,6, Anne Berger1,2,3,30, Christine Lagorce1,2,3,31, Christopher Paustian32, Carmen Ballesteros-Merino32, Jeroen Dijkstra10, Carlijn van de Water10, Shannon van Lent-van Vliet10, Nikki Knijn10, Ana-Maria Muşină33, Dragos-Viorel Scripcariu33, Boryana Popivanova34, Mingli Xu34, Tomonobu Fujita34, Shoichi Hazama35, Nobuaki Suzuki36, Hiroaki Nagano36, Kiyotaka Okuno37, Toshihiko Torigoe38, Noriyuki Sato38, Tomohisa Furuhata39, Ichiro Takemasa39, Kyogo Itoh40, Prabhu S Patel41, Hemangini H Vora41, Birva Shah41, Jayendrakumar B Patel41, Kruti N Rajvik41, Shashank J Pandya41, Shilin N Shukla41, Yili Wang42, Guanjun Zhang42, Yutaka Kawakami34, Francesco M Marincola43, Paolo A Ascierto44, Bernard A Fox31,45, Franck Pagès1,2,3,6, Jérôme Galon1,2,3. 1. INSERM, Laboratory of Integrative Cancer Immunology, Paris, France. 2. Equipe Labellisée Ligue Contre le Cancer, Paris, France. 3. Centre de Recherche des Cordeliers, Sorbonne Université, Sorbonne Paris Cité, Université de Paris, Paris, France. 4. Inovarion, Paris, France. 5. Department of Pathology, Providence Portland Medical Center, Portland, OR. 6. Immunomonitoring Platform, Laboratory of Immunology, AP-HP, Assistance Publique-Hopitaux de Paris, Georges Pompidou European Hospital, Paris, France. 7. Institute of Pathology, University of Bern, Bern, Switzerland. 8. Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX. 9. Department of Medical Oncology, University Hospital of Bern, Bern, Switzerland. 10. Department of Pathology, Radboud Institute of Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands. 11. Department of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 12. Department of Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. 13. Institut Roi Albert II, Department of Medical Oncology Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium. 14. Department of Pathology, Cliniques Universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole GAEN), Université Catholique de Louvain, Brussels, Belgium. 15. Institut Roi Albert II, Department of Digestive Surgery, Cliniques Universitaires St-Luc Université Catholique de Louvain, Brussels, Belgium. 16. Curandis Laboratories, Boston, MA. 17. Department of Pathology and Laboratory Medicine, University Health Network, Toronto, Ontario, Canada. 18. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 19. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. 20. Princess Margaret Cancer Centre, UHN, Toronto, Ontario, Canada. 21. Department of Oncology-Pathology, Karolinska Institutet, Karolinska University, Stockholm, Sweden. 22. Department of Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. 23. Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. 24. Department of Pathology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy. 25. Colorectal Surgery Department, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy. 26. IRCCS Istituto Nazionale Tumori "Regina Elena", Rome, Italy. 27. Center for Immuno-Oncology, University Hospital, Siena, Italy. 28. Department of Medicine and Surgery, University of Parma, and Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 29. Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, Italy and Humanitas University, Rozzano, Milan, Italy. 30. Digestive Surgery Department, AP-HP, Assistance Publique-Hopitaux de Paris, Georges Pompidou European Hospital, Paris, France. 31. Department of Pathology, AP-HP, Assistance Publique-Hopitaux de Paris, Georges Pompidou European Hospital, Paris, France. 32. Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR. 33. University of Medicine and Pharmacy "Grigore T. Popa" Iaşi, Department of Surgical Oncology, Regional Institute of Oncology, Iaşi, Romania. 34. Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. 35. Department of Translational Research and Developmental Therapeutics against Cancer, Yamaguchi University School of Medicine, Yamaguchi, Japan. 36. Department of Gastroenterological, Breast, and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan. 37. Department of Surgery, Kindai University, School of Medicine, Osaka-sayama, Japan. 38. Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan. 39. Department of Surgery, Surgical Oncology, and Science, Sapporo Medical University School of Medicine, Sapporo, Japan. 40. Department of Immunology and Immunotherapy, Kurume University School of Medicine, Kurume, Japan. 41. The Gujarat Cancer & Research Institute, Asarwa, Ahmedabad, India. 42. Institute of Cancer Research, Center of Translational Medicine, Health Science Center of Xi'an Jiaotong University, Xian, China. 43. Refuge Biotechnologies, Menlo Park, CA. 44. Melanoma, Cancer Immunotherapy, and Innovative Therapies Unit, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Napoli, Italy. 45. Laboratory of Molecular and Tumor Immunology, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR.
Abstract
PURPOSE: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR). METHODS: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy. RESULTS: Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high v low], 0.48; 95% CI, 0.32 to 0.71; P = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all P < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high v low], 0.41; 95% CI, 0.25 to 0.67; P = .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high v low], 0.36; 95% CI, 0.21 to 0.62; P = .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy v no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; P = .0011) and high-risk (HR [chemotherapy v no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; P = .0015) patients, in contrast to the low-Immunoscore group (P > .12). CONCLUSION: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.
PURPOSE: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR). METHODS: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy. RESULTS:Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high v low], 0.48; 95% CI, 0.32 to 0.71; P = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all P < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high v low], 0.41; 95% CI, 0.25 to 0.67; P = .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSSpatients (HR [high v low], 0.36; 95% CI, 0.21 to 0.62; P = .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy v no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; P = .0011) and high-risk (HR [chemotherapy v no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; P = .0015) patients, in contrast to the low-Immunoscore group (P > .12). CONCLUSION: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.
Authors: Marc Van den Eynde; Bernhard Mlecnik; Gabriela Bindea; Tessa Fredriksen; Sarah E Church; Lucie Lafontaine; Nacilla Haicheur; Florence Marliot; Mihaela Angelova; Angela Vasaturo; Daniela Bruni; Anne Jouret-Mourin; Pamela Baldin; Nicolas Huyghe; Karin Haustermans; Annelies Debucquoy; Eric Van Cutsem; Jean-Francois Gigot; Catherine Hubert; Alex Kartheuser; Christophe Remue; Daniel Léonard; Viia Valge-Archer; Franck Pagès; Jean-Pascal Machiels; Jérôme Galon Journal: Cancer Cell Date: 2018-12-10 Impact factor: 31.743
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Authors: Frank A Sinicrope; Qian Shi; Aurelie Catteau; Graham M Poage; Tyler J Zemla; Bernhard Mlecnik; Al B Benson; Sharlene Gill; Richard M Goldberg; Morton S Kahlenberg; Suresh G Nair; Anthony F Shields; Thomas C Smyrk; Jerome Galon; Steven R Alberts Journal: JCO Precis Oncol Date: 2022-08
Authors: Stanley P Leong; Isaac P Witz; Orit Sagi-Assif; Sivan Izraely; Jonathan Sleeman; Brian Piening; Bernard A Fox; Carlo B Bifulco; Rachel Martini; Lisa Newman; Melissa Davis; Lauren M Sanders; David Haussler; Olena M Vaske; Marlys Witte Journal: Clin Exp Metastasis Date: 2021-05-10 Impact factor: 5.150
Authors: Vegar Johansen Dagenborg; Serena Elizabeth Marshall; Krzysztof Grzyb; Åsmund Avdem Fretland; Marius Lund-Iversen; Gunhild Mari Mælandsmo; Anne Hansen Ree; Bjørn Edwin; Sheraz Yaqub; Kjersti Flatmark Journal: Front Oncol Date: 2021-06-09 Impact factor: 6.244