Ellen L Goode1, Matthew S Block2, Kimberly R Kalli2, Robert A Vierkant1, Wenqian Chen3, Zachary C Fogarty1, Aleksandra Gentry-Maharaj4, Aleksandra Tołoczko5, Alexander Hein6, Aliecia L Bouligny1,7, Allan Jensen8, Ana Osorio9,10, Andreas Hartkopf11, Andy Ryan4, Anita Chudecka-Głaz12, Anthony M Magliocco13, Arndt Hartmann14, Audrey Y Jung15, Bo Gao16,17, Brenda Y Hernandez18, Brooke L Fridley19, Bryan M McCauley1, Catherine J Kennedy16,20, Chen Wang1, Chloe Karpinskyj4, Christiani B de Sousa21, Daniel G Tiezzi21, David L Wachter14, Esther Herpel22, Florin Andrei Taran11, Francesmary Modugno23,24,25, Gregg Nelson26, Jan Lubiński5, Janusz Menkiszak12, Jennifer Alsop27, Jenny Lester28, Jesús García-Donas29, Jill Nation26, José Palacios30, Joseph H Rothstein31, Joseph L Kelley23, Jurandyr M de Andrade21, Luis Robles-Díaz32, Maria P Intermaggio33, Martin Widschwendter4, Matthias W Beckmann6, Matthias Ruebner6, Mercedes Jimenez-Linan34, Naveena Singh35, Oleg Oszurek5, Paul R Harnett16,17, Peter F Rambau3,36, Peter Sinn37, Philipp Wagner11, Prafull Ghatage26, Raghwa Sharma38,39, Robert P Edwards23, Roberta B Ness40, Sandra Orsulic28, Sara Y Brucker11, Sharon E Johnatty41, Teri A Longacre42, Eilber Ursula15, Valerie McGuire43, Weiva Sieh31, Yanina Natanzon1, Zheng Li1,44, Alice S Whittemore45, deFazio Anna16,20, Annette Staebler46, Beth Y Karlan28, Blake Gilks47, David D Bowtell48,49,50, Estrid Høgdall8,51, Francisco J Candido dos Reis21, Helen Steed52, Ian G Campbell53,54,55, Jacek Gronwald5, Javier Benítez9,10, Jennifer M Koziak56, Jenny Chang-Claude15,57, Kirsten B Moysich58, Linda E Kelemen59, Linda S Cook60, Marc T Goodman61, María José García9,10, Peter A Fasching6,62, Stefan Kommoss11, Suha Deen63, Susanne K Kjaer8,64, Usha Menon4, James D Brenton65,66,67, Paul DP Pharoah27,68, Georgia Chenevix-Trench41, David G Huntsman69,70, Stacey J Winham1, Martin Köbel3, Susan J Ramus33,50. 1. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA 2. Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA 3. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada 4. Gynaecological Cancer Research Centre, Department of Women’s Cancer, Institute for Women’s Health, University College London, London, UK 5. International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland 6. Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Germany 7. Department of Health Sciences, Spelman College, Atlanta, GA, USA 8. Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark 9. Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain 10. Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain 11. Tübingen University Hospital, Department of Women’s Health, Tübingen, Germany 12. Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland 13. Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA 14. Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University 15. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 16. Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia 17. The Crown Princess Mary Cancer Centre, Westmead Hospital, The University of Sydney, Australia 18. Cancer Center, University of Hawaii, Honolulu, HI, USA 19. Department of Biostatistics and Bioinformatics, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL, USA 20. Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia 21. Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil 22. Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Germany and Institute of Pathology, University of Heidelberg, Heidelberg, Germany 23. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 24. Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA 25. Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA 26. Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada 27. Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK 28. Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA 29. Medical Oncology Service, HM Hospitales – Centro Integral Oncológico HM Clara Campal, Madrid, Spain 30. Pathology Department, Hospital Universitario Ramón y Cajal. IRYCIS. Universidad de Alcalá, Madrid, Spain. CIBERONC 31. Department of Population Health Science and Policy, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA 32. Familial Cancer Unit and Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain 33. School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia 34. Department of Histopathology, Addenbrookes Hospital, Cambridge, UK 35. Department of Pathology, Barts Health National Health Service Trust, London, UK 36. Pathology Department, Catholic University of Health and Allied Sciences-Bugando, Mwanza, Tanzania 37. Department of Pathology, Institute of Pathology, Heidelberg University Hospital, Germany 38. Pathology West ICPMR Westmead, Westmead Hospital, The University of Sydney, Sydney, Australia 39. University of Western Sydney at Westmead Hospital, Westmead, New South Wales, Australia 40. The University of Texas School of Public Health, Houston, TX, USA 41. Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia 42. Department of Pathology, Stanford University, Stanford, CA, USA 43. Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA 44. Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming, China 45. Department of Health Research and Policy, Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA 46. Tübingen University Hospital, Institute of Pathology, Tübingen, Germany 47. Genetic Pathology Evaluation Centre, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia,Canada 48. Cancer Genomics Program, Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia 49. Sir Peter MacCallum Department of Oncology, the University of Melbourne, Parkville, Victoria, Australia 50. The Garvan Institute, Sydney, New South Wales, Australia 51. Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark 52. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Royal Alexandra Hospital, Edmonton, Alberta, Canada 53. Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia 54. Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia 55. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia 56. Alberta Health Services-Cancer Care, Calgary, Alberta, Canada 57. University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 58. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA 59. Department of Public Health Sciences, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC, USA 60. Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, USA 61. Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA 62. David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, CA, USA 63. Department of Histopathology, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK 64. Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark 65. Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK 66. Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, UK 67. Cambridge Experimental Cancer Medicine Centre, Cambridge, UK 68. Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK 69. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada 70. Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Abstract
Importance: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design, Setting, and Participants: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Exposures: Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures: Overall survival time. Results: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form. Conclusions and Relevance: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.
Importance: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors. Objective: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. Design, Setting, and Participants: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Exposures: Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures: Overall survival time. Results: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form. Conclusions and Relevance: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.
Authors: Martin Köbel; Steve E Kalloger; Sandra Lee; Máire A Duggan; Linda E Kelemen; Leah Prentice; Kimberly R Kalli; Brooke L Fridley; Daniel W Visscher; Gary L Keeney; Robert A Vierkant; Julie M Cunningham; Christine Chow; Roberta B Ness; Kirsten Moysich; Robert Edwards; Francesmary Modugno; Clareann Bunker; Eva L Wozniak; Elizabeth Benjamin; Simon A Gayther; Aleksandra Gentry-Maharaj; Usha Menon; C Blake Gilks; David G Huntsman; Susan J Ramus; Ellen L Goode Journal: Cancer Epidemiol Biomarkers Prev Date: 2013-07-23 Impact factor: 4.254
Authors: Gottfried E Konecny; Chen Wang; Habib Hamidi; Boris Winterhoff; Kimberly R Kalli; Judy Dering; Charles Ginther; Hsiao-Wang Chen; Sean Dowdy; William Cliby; Bobbie Gostout; Karl C Podratz; Gary Keeney; He-Jing Wang; Lynn C Hartmann; Dennis J Slamon; Ellen L Goode Journal: J Natl Cancer Inst Date: 2014-09-30 Impact factor: 13.506
Authors: S J L Mesnage; A Auguste; C Genestie; A Dunant; E Pain; F Drusch; S Gouy; P Morice; E Bentivegna; C Lhomme; P Pautier; J Michels; A Le Formal; B Cheaib; J Adam; A F Leary Journal: Ann Oncol Date: 2017-03-01 Impact factor: 32.976
Authors: Naiyer A Rizvi; Matthew D Hellmann; Alexandra Snyder; Pia Kvistborg; Vladimir Makarov; Jonathan J Havel; William Lee; Jianda Yuan; Phillip Wong; Teresa S Ho; Martin L Miller; Natasha Rekhtman; Andre L Moreira; Fawzia Ibrahim; Cameron Bruggeman; Billel Gasmi; Roberta Zappasodi; Yuka Maeda; Chris Sander; Edward B Garon; Taha Merghoub; Jedd D Wolchok; Ton N Schumacher; Timothy A Chan Journal: Science Date: 2015-03-12 Impact factor: 47.728
Authors: Lin Zhang; Jose R Conejo-Garcia; Dionyssios Katsaros; Phyllis A Gimotty; Marco Massobrio; Giorgia Regnani; Antonis Makrigiannakis; Heidi Gray; Katia Schlienger; Michael N Liebman; Stephen C Rubin; George Coukos Journal: N Engl J Med Date: 2003-01-16 Impact factor: 91.245
Authors: Claudia C Preston; Matthew J Maurer; Ann L Oberg; Daniel W Visscher; Kimberly R Kalli; Lynn C Hartmann; Ellen L Goode; Keith L Knutson Journal: PLoS One Date: 2013-11-14 Impact factor: 3.240
Authors: Drew C Deniger; Anna Pasetto; Paul F Robbins; Jared J Gartner; Todd D Prickett; Biman C Paria; Parisa Malekzadeh; Li Jia; Rami Yossef; Michelle M Langhan; John R Wunderlich; David N Danforth; Robert P T Somerville; Steven A Rosenberg Journal: Clin Cancer Res Date: 2018-05-31 Impact factor: 12.531
Authors: Mary L Disis; Matthew H Taylor; Karen Kelly; J Thaddeus Beck; Michael Gordon; Kathleen M Moore; Manish R Patel; Jorge Chaves; Haeseong Park; Alain C Mita; Erika P Hamilton; Christina M Annunziata; Hans Juergen Grote; Anja von Heydebreck; Jaspreet Grewal; Vikram Chand; James L Gulley Journal: JAMA Oncol Date: 2019-03-01 Impact factor: 31.777
Authors: Ashley E Stenzel; Scott I Abrams; Janine M Joseph; Ellen L Goode; Joseph D Tario; Paul K Wallace; Divjot Kaur; Anna-Kay Adamson; Matthew F Buas; Amit A Lugade; Angela Laslavic; Sarah E Taylor; Brian Orr; Robert P Edwards; Esther Elishaev; Kunle Odunsi; Jennifer M Mongiovi; John Lewis Etter; Stacey J Winham; Scott H Kaufmann; Francesmary Modugno; Kirsten B Moysich Journal: Am J Reprod Immunol Date: 2020-09-21 Impact factor: 3.886