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)

Pizarro, David; Romero, Ignacio; Pérez-Mies, Belén; Redondo, Andrés; Caniego-Casas, Tamara; Carretero-Barrio, Irene; Cristóbal, Eva; Gutiérrez-Pecharromán, Ana; Santaballa, Ana; D’Angelo, Emanuela; Hardisson, David; Vieites, Begoña; Matías-Guiu, Xavier; Estévez, Purificación; Guerra, Eva; Prat, Jaime; Poveda, Andrés; López-Guerrero, José Antonio; Palacios, José

doi:10.3390/ijms241311183

Open AccessArticle

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)

by

David Pizarro

^1,†,

Ignacio Romero

^2,3,†,

Belén Pérez-Mies

^1,4,5,

Andrés Redondo

^3,6,7,8

,

Tamara Caniego-Casas

^1,4,

Irene Carretero-Barrio

^1,4,5

,

Eva Cristóbal

⁴,

Ana Gutiérrez-Pecharromán

⁹,

Ana Santaballa

^3,10,

Emanuela D’Angelo

¹¹

,

David Hardisson

^4,7,8,12

,

Begoña Vieites

¹³,

Xavier Matías-Guiu

^4,14,15,

Purificación Estévez

^3,16,17,

Eva Guerra

^3,18,

Jaime Prat

¹⁹,

Andrés Poveda

^3,20,

José Antonio López-Guerrero

^2,3,*

and

José Palacios

^1,3,4,5,*

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

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^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2023, 24(13), 11183; https://doi.org/10.3390/ijms241311183

Submission received: 9 May 2023 / Revised: 25 June 2023 / Accepted: 28 June 2023 / Published: 6 July 2023

(This article belongs to the Special Issue Molecular Immunology of Solid Tumors, 2nd Edition)

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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.

Keywords: high-grade serous ovarian carcinoma; early stage; PD-L1; BRCA; TMB

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MDPI and ACS Style

Pizarro, D.; Romero, I.; Pérez-Mies, B.; Redondo, A.; Caniego-Casas, T.; Carretero-Barrio, I.; Cristóbal, E.; Gutiérrez-Pecharromán, A.; Santaballa, A.; D’Angelo, E.; et al. 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). Int. J. Mol. Sci. 2023, 24, 11183. https://doi.org/10.3390/ijms241311183

AMA Style

Pizarro D, Romero I, Pérez-Mies B, Redondo A, Caniego-Casas T, Carretero-Barrio I, Cristóbal E, Gutiérrez-Pecharromán A, Santaballa A, D’Angelo E, et al. 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). International Journal of Molecular Sciences. 2023; 24(13):11183. https://doi.org/10.3390/ijms241311183

Chicago/Turabian Style

Pizarro, David, Ignacio Romero, Belén Pérez-Mies, Andrés Redondo, Tamara Caniego-Casas, Irene Carretero-Barrio, Eva Cristóbal, Ana Gutiérrez-Pecharromán, Ana Santaballa, Emanuela D’Angelo, and et al. 2023. "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)" International Journal of Molecular Sciences 24, no. 13: 11183. https://doi.org/10.3390/ijms241311183

APA Style

Pizarro, D., Romero, I., Pérez-Mies, B., Redondo, A., Caniego-Casas, T., Carretero-Barrio, I., Cristóbal, E., Gutiérrez-Pecharromán, A., Santaballa, A., D’Angelo, E., Hardisson, D., Vieites, B., Matías-Guiu, X., Estévez, P., Guerra, E., Prat, J., Poveda, A., López-Guerrero, J. A., & Palacios, J. (2023). 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). International Journal of Molecular Sciences, 24(13), 11183. https://doi.org/10.3390/ijms241311183

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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)

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