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Prognostic markers of inflammation in endometrioid and clear cell ovarian cancer
  1. Alejandro Gallego1,
  2. Marta Mendiola2,3,
  3. Barbara Hernando4,
  4. Alberto Berjon2,5,
  5. Alice Cadiz4,
  6. Blas Chaves-Urbano4,
  7. Victoria Heredia-Soto6,
  8. Emanuela Spagnolo7,
  9. Alicia Hernández Gutiérrez7,8,
  10. David Hardisson2,3,5,8,
  11. Geoff Macintyre4,
  12. Andres Redondo1,9 and
  13. Maria Jose Garcia4
  1. 1Department of Medical Oncology, La Paz University Hospital, Madrid, Spain
  2. 2Molecular Pathology and Therapeutic Targets Group, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
  3. 3Center for Biomedical Research in the Cancer Network (Centro de Investigación Biomédica en Red de Cáncer, CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
  4. 4Computational Oncology Group, Structural Biology Department, CNIO, Madrid, Spain
  5. 5Department of Pathology, La Paz University Hospital, Madrid, Spain
  6. 6Translational Oncology Research Laboratory, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
  7. 7Department of Obstetrics & Gynecology, La Paz University Hospital, Madrid, Spain
  8. 8Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
  9. 9Cátedra UAM-ANGEM, Faculty of Medicine, Universidad Autonoma de Madrid, Madrid, Spain
  1. Correspondence to Dr Andres Redondo, Department of Medical Oncology, La Paz University Hospital, 28046 Madrid, Spain; andres.redondos{at}uam.es; Dr Maria Jose Garcia; mjgarcia{at}cnio.es

Abstract

Objectives Cancer-related systemic inflammation has been associated with prognosis in multiple cancer types. Conversely, local inflammation, which is characterized by dense intratumoral immune infiltrates, is a favorable predictor of survival outcome. However, these survival associations are not well established in ovarian cancer, particularly in the less frequent endometrioid and clear cell endometriosis associated histotypes.

Methods This retrospective study included 119 patients (63 endometrioid and 56 clear cell ovarian carcinomas). We performed a comprehensive survival association analysis of both systemic (neutrophil-to-lymphocyte ratio or presence of endometriosis) and local inflammation markers (CD3+ and CD8+ tumor infiltrating lymphocytes) using multivariate Cox proportional hazards models that account for confounding factors.

Results Medium to high levels of intraepithelial CD8+ tumor infiltrating lymphocytes are associated with longer survival in endometrioid ovarian cancer (p=0.04). In addition, we found that intraepithelial CD8+ tumor infiltrating lymphocytes are prognostic in clear cell ovarian cancer (p=0.02), and that intraepithelial CD3+ tumor infiltrating lymphocytes are also associated with improved outcome (p=0.02). Furthermore, intratumoral CD3+ and CD8+ tumor infiltrating lymphocytes showed improved prognosis in the endometrioid subtype (p<0.1). No prognostic value was observed for systemic immune markers.

Conclusions In this study, patients with endometrioid and clear cell ovarian cancer with moderate to high CD8+ and CD3+ intraepithelial tumor infiltrating lymphocytes had longer overall survival. Higher expression of intratumoral CD3+ and CD8+ tumor infiltrating lymphocytes also showed an improved outcome in endometrioid ovarian cancer. In contrast, systemic inflammation, evaluated by neutrophil-to-lymphocyte ratio or presence of endometriosis, did not have a prognostic impact in these histologic subtypes.

  • ovarian cancer

Data availability statement

Data are available in a public, open access repository. All code and data to reproduce the analyses found in this paper can be found in the following repository: https://github.com/macintyrelab/InmflammationMarkers.

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Data availability statement

Data are available in a public, open access repository. All code and data to reproduce the analyses found in this paper can be found in the following repository: https://github.com/macintyrelab/InmflammationMarkers.

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Footnotes

  • Twitter @DHardissonMD

  • Contributors Conceptualization: AG, GM, AR, MJG. Data collection: AG, MM, AB. Data analysis: AG, BG, BC, GM. Writing—original draft preparation: AG, BH, AC, GM, AR, MJG. Writing—review and editing: AG, MM, AB, BH, AC, BC, VH-S, ES, AH, DH, GM, AR, MJG. Supervision: GM, AR, MJG. AG is responsible for the overall content as the guarantor.

  • Funding This research received funding from the 7th Jan Vermorken Research Grant for Research in Gynaecological Cancer awarded by the Spanish Group for Investigation on Ovarian Cancer (GEICO). This study was funded by the Acción Estrategica en Salud (AES) from the Instituto de Salud Carlos III (PI19/01730) and co-funded by the European Regional Development Fund (FEDER). BH, GM and MJG were supported by funding from the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation.

  • Competing interests AG reports honoraria and advisory/consultancy (Pharmamar), travel/accommodation/expenses (Roche, Tesaro-GSK, Pierre-Fabre, Pharmamar, MSD), speakers bureau (Roche, Clovis, Astra Zeneca, MSD) outside the submitted work. MM reports having received honoraria (MSD, AstraZeneca and GSK), research grant/funding to her institution (Eisai and PharmaMar), and travel/accommodation/expenses (AstraZeneca, GSK, PharmaMar, Roche and Pfizer) outside the submitted work. GM is a founder, director and shareholder of Tailor Bio Ltd, a genomics company using copy number signatures for precision medicine. AR reports having received honoraria and providing advisory/consultancy services (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar, Amgen), research grant/funding to his institution (Eisai, PharmaMar, Roche), travel/accommodation/expenses (AstraZeneca, Tesaro: A GSK Company, PharmaMar, Roche), and participating in a speakers bureau (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar) outside the submitted work.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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