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

Ellen L Goode Matthew S Block Kimberly R Kalli Robert A Vierkant Wenqian Chen Zachary C Fogarty Aleksandra Gentry-Maharaj Aleksandra Tołoczko Alexander Hein Aliecia L Bouligny Allan Jensen Ana Osorio Andreas Hartkopf Andy Ryan Anita Chudecka-Głaz Anthony M Magliocco Arndt Hartmann Audrey Y Jung Bo Gao Brenda Y Hernandez Brooke L Fridley Bryan M McCauley Catherine J Kennedy Chen Wang Chloe Karpinskyj Christiani B de Sousa Daniel G Tiezzi David L Wachter Esther Herpel Florin Andrei Taran Francesmary Modugno Gregg Nelson Jan Lubiński Janusz Menkiszak Jennifer Alsop Jenny Lester Jesús García-Donas Jill Nation Jillian Hung José Palacios Joseph H Rothstein Joseph L Kelley Jurandyr M de Andrade Luis Robles-Díaz Maria P Intermaggio Martin Widschwendter Matthias W Beckmann Matthias Ruebner Mercedes Jimenez-Linan Naveena Singh Oleg Oszurek Paul R Harnett Peter F Rambau Peter Sinn Philipp Wagner Prafull Ghatage Raghwa Sharma Robert P Edwards Roberta B Ness Sandra Orsulic Sara Y Brucker Sharon E Johnatty Teri A Longacre Eilber Ursula Valerie McGuire Weiva Sieh Yanina Natanzon Zheng Li Alice S Whittemore deFazio Anna Annette Staebler Beth Y Karlan Blake Gilks David D Bowtell Estrid Høgdall Francisco J Candido dos Reis Helen Steed Ian G Campbell Jacek Gronwald Javier Benítez Jennifer M Koziak Jenny Chang-Claude Kirsten B Moysich Linda E Kelemen Linda S Cook Marc T Goodman María José García Peter A Fasching Stefan Kommoss Suha Deen Susanne K Kjaer Usha Menon James D Brenton Paul DP Pharoah Georgia Chenevix-Trench David G Huntsman Stacey J Winham Martin Köbel Susan J Ramus

JAMA Oncol 2017 12;3(12):e173290

School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia

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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December 2017
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