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JAMA Oncol. 2017 Dec 1;3(12):e173290. doi: 10.1001/jamaoncol.2017.3290.

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer.

Author information

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.

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