The Prognostic Significance of Tumor-Infiltrating Lymphocytes, PD-L1, BRCA Mutation Status and Tumor Mutational Burden in Early-Stage High-Grade Serous Ovarian Carcinoma—A Study by the Spanish Group for Ovarian Cancer Research (GEICO)

Author:

Pizarro David1,Romero Ignacio23,Pérez-Mies Belén145,Redondo Andrés3678ORCID,Caniego-Casas Tamara14,Carretero-Barrio Irene145ORCID,Cristóbal Eva4,Gutiérrez-Pecharromán Ana9,Santaballa Ana310,D’Angelo Emanuela11ORCID,Hardisson David47812ORCID,Vieites Begoña13,Matías-Guiu Xavier41415,Estévez Purificación31617,Guerra Eva318,Prat Jaime19,Poveda Andrés320,López-Guerrero José Antonio23ORCID,Palacios José1345ORCID

Affiliation:

1. Pathology Department, University Hospital Ramón y Cajal, IRYCIS, 28034 Madrid, Spain

2. Instituto Valenciano de Oncología, 46009 Valencia, Spain

3. Spanish Group for Investigation on Ovarian Cancer (GEICO), 28003 Madrid, Spain

4. Biomedical Research Network in Oncology (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain

5. Faculty of Medicine, University of Alcalá, 28801 Alcalá de Henares, Spain

6. Oncology Department, University Hospital La Paz, IdiPAZ, 28046 Madrid, Spain

7. Instituto de Investigación Sanitaria del Hospital Universitario La Paz, 28029 Madrid, Spain

8. Faculty of Medicine, Autonomous University of Madrid, 28029 Madrid, Spain

9. Pathology Department, University Hospital Getafe, 28905 Getafe, Spain

10. Oncology Department, University Hospital La Fe, 46026 Valencia, Spain

11. Department of Medical, Oral, and Biotechnological Sciences, University “G.D’Annunzio” of Chieti-Pescara, 66013 Chieti, Italy

12. Pathology Department, University Hospital La Paz, 28046 Madrid, Spain

13. Pathology Department, University Hospital Virgen del Rocío, 41013 Sevilla, Spain

14. Pathology and Medical Oncology Departments, Hospital Universitari Arnau de Vilanova, IRBLLEIDA, University of Lleida, 25003 Lleida, Spain

15. Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, University of Barcelona, 08007 Barcelona, Spain

16. Oncology Department, University Hospital Virgen del Rocío, 41013 Sevilla, Spain

17. Seville Biomedical Research Institute (IBIS), 41013 Sevilla, Spain

18. Oncology Department, University Hospital Ramón y Cajal, IRYCIS, 28034 Madrid, Spain

19. Pathology Department, Emeritus Faculty, Autonomous University of Barcelona, 08193 Barcelona, Spain

20. Initia Oncología, Hospital Quironsalud Valencia, 46010 Valencia, Spain

Abstract

Early stages are under-represented in studies on the molecular and immune features of high-grade serous ovarian carcinoma (HGSOC), and specific studies focused on early-stage HGSOC are required for a better prognostic stratification and to personalize chemotherapy. The aim of this study was to determine the prognostic significance of CD8+ and CD4+ tumor-infiltrating lymphocytes (TILs), tumoral cell PD-L1 expression, BRCA mutational status and tumor mutation burden (TMB) in early-stage HGSOC. A retrospective study was performed on stage I and II HGSOC from the Molecular Reclassification of Early Stages of Ovarian Cancer (RECLAMO) cohort from the Spanish Group of Ovarian Cancer Research (GEICO). Centralized histological typing was performed based on morphological and immunohistochemical features. Intraepithelial (i) and stromal (s) CD8+ and CD4+ T cells and PD-L1 were evaluated on tissue microarrays by immunohistochemistry. BRCA1 and BRCA2 mutation status and TMB were analyzed in tumor DNA using next-generation sequencing. The study included 124 tumors. High iCD8+ (>20 TILs/core), low/intermediate CD4+ (<20 TILs/core) and high CD8+/CD4+ ratio (>35/core) were associated with favorable outcomes. Tumor cell PD-L1 expression (TPS ≥ 1) was present in only 8% of tumors. In total, 11 (16%) and 6 (9%) out of 69 HGSOC tested carried pathogenic or likely pathogenic BRCA1 or BRCA2 mutations, respectively. Median TMB of 40 tumors analyzed was 5.04 mutations/Mb and only 6 tumors had 10 or more mutations/Mb. BRCA status and TMB were not associated with TILs or prognosis. When compared with studies on advanced HGSOC, our results suggested that prognostic variables differed according to stage and that more studies focused on early stages of HGSOC are needed to better stratify these tumors.

Funder

Instituto de Salud Carlos III

CIBERONC

European Development Regional Fund ‘A way to achieve Europe’

Spanish Group of Research in Ovarian Cancer

Spanish Association Against Cancer Scientific Foundation

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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