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

Goode EL, Block MS, Kalli KR, Vierkant RA, Chen W, Fogarty ZC, Gentry-Maharaj A, Toloczko A, Hein A, Bouligny AL, Jensen A, Osorio A, Hartkopf AD, Ryan A, Chudecka-Glaz A, Magliocco AM, Hartmann A, Jung AY, Gao B, Hernandez BY, Fridley BL, Mccauley BM, Kennedy CJ, Wang C, Karpinskyj C, De Sousa CB, Tiezzi DG, Wachter D, Herpel E, Taran FA, Modugno F, Nelson G, Lubinski J, Menkiszak J, Alsop J, Lester J, Garcia-Donas J, Nation J, Hung J, Palacios J, Rothstein JH, Kelley JL, De Andrade JM, Robles-Diaz L, Intermaggio MP, Widschwendter M, Beckmann M, Rübner M, Jimenez-Linan M, Singh N, Oszurek O, Harnett PR, Rambau PF, Sinn P, Wagner P, Ghatage P, Sharma R, Edwards RP, Ness RB, Orsulic S, Brucker SY, Johnatty SE, Longacre TA, Eilber U, Mcguire V, Sieh W, Natanzon Y, Li Z, Whittemore AS, Defazio A, Staebler A, Karlan BY, Gilks B, Bowtell DD, Hogdall E, Candido Dos Reis FJ, Steed H, Campbell IG, Gronwald J, Benitez J, Koziak JM, Chang-Claude J, Moysich KB, Kelemen LE, Cook LS, Goodman MT, Jose Garcia M, Fasching P, Kommoss S, Deen S, Kjaer SK, Menon U, Brenton JD, Pharoah PDP, Chenevix-Trench G, Huntsman DG, Winham SJ, Kobel M, Ramus SJ (2017)


Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 3

Journal Issue: 12

DOI: 10.1001/jamaoncol.2017.3290

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.

Authors with CRIS profile

Involved external institutions

Mayo Clinic US United States (USA) (US) University of Calgary CA Canada (CA) University College London (UCL) GB United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) PL Poland (PL) Danish Cancer Society Research Center DK Denmark (DK) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) ES Spain (ES) University of São Paulo / Universidade de São Paulo (USP) BR Brazil (BR) University of Sydney (USYD) AU Australia (AU) Universidad de Alcalá (UAH) ES Spain (ES) Icahn School of Medicine at Mount Sinai US United States (USA) (US) University of Pittsburgh US United States (USA) (US) Hospital Universitario 12 de Octubre ES Spain (ES) University of New South Wales (UNSW) AU Australia (AU) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) Stanford University US United States (USA) (US) Universitätsklinikum Tübingen DE Germany (DE) H. Lee Moffitt Cancer Center & Research Institute US United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) University of Hawaii (U.H.) US United States (USA) (US) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) University of Cambridge GB United Kingdom (GB) Cedars-Sinai Medical Center US United States (USA) (US) HM Hospitales ES Spain (ES) Addenbrooke's Hospital GB United Kingdom (GB) Barts Health NHS Trust GB United Kingdom (GB) Universitätsklinikum Heidelberg DE Germany (DE) University of Texas Health Science Center at Houston (UTHealth) US United States (USA) (US) Roswell Park Cancer Institute US United States (USA) (US) Medical University of South Carolina (MUSC) US United States (USA) (US) University of New Mexico (UNM) / Universidad de Nuevo México US United States (USA) (US) University of Nottingham GB United Kingdom (GB) University of British Columbia CA Canada (CA) Peter MacCallum Cancer Centre AU Australia (AU) Royal Alexandra Hospital (RAH) CA Canada (CA) Alberta Health Services (AHS) CA Canada (CA)

How to cite

APA:

Goode, E.L., Block, M.S., Kalli, K.R., Vierkant, R.A., Chen, W., Fogarty, Z.C.,... Ramus, S.J. (2017). Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer. JAMA Oncology, 3(12). https://dx.doi.org/10.1001/jamaoncol.2017.3290

MLA:

Goode, Ellen L., et al. "Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer." JAMA Oncology 3.12 (2017).

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