09e0615323b55de3794018b04a6c7459 319576.pdf b5aafb01f7637e99bb3a9d4d40c4785584a899b8 319576.pdf dbd57060e9f6df43954ec51f176a84c928b2ecbfcc6ae0715efd9ace821eefcb 319576.pdf Title: 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) Subject: 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 Author: David Pizarro, Ignacio Romero, Belén Pérez-Mies, Andrés Redondo, Tamara Caniego-Casas, Irene Carretero-Barrio, Eva Cristóbal, Ana Gutiérrez-Pecharromán, Ana Santaballa, Emanuela D’Angelo, David Hardisson, Begoña Vieites, Xavier Matías-Guiu, Purificación Estévez, Eva Guerra, Jaime Prat, Andrés Poveda, José Antonio López-Guerrero and José Palacios Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Jul 6 16:03:16 2023 CEST ModDate: Thu Jul 6 16:10:41 2023 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 5179866 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- JYPLJJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 OPZDHV+VnURWPalladioL Type 1 Custom yes yes no 15 0 TPNMQL+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 LQMKQH+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 DEAJTF+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 46 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 49 0 PDTLUH+CMSY10 Type 1 Builtin yes yes no 71 0 OVNEXW+EURM10 Type 1 Builtin yes yes no 81 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-11-26 04:32:12 CET RepresentationInformation: 319576.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-11-25 09:01:22 CET Size: 5179866 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 320 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Clinicopathological and Immunohistochemical Features Destination: subsection.2.1 Item: Title: BRCA1 and BRCA2 Mutational Status Destination: subsection.2.2 Item: Title: Tumor Mutational Burden (TMB) Destination: subsection.2.3 Item: Title: Survival Analysis Destination: subsection.2.4 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Pathology and Immunohistochemistry Destination: subsection.4.1 Item: Title: BRCA1 and BRCA2 Mutation Analysis Destination: subsection.4.2 Item: Title: TMB Destination: subsection.4.3 Item: Title: Statistical Analysis Destination: subsection.4.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.A. Info: Title: 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: David Pizarro, Ignacio Romero, Belén Pérez-Mies, Andrés Redondo, Tamara Caniego-Casas, Irene Carretero-Barrio, Eva Cristóbal, Ana Gutiérrez-Pecharromán, Ana Santaballa, Emanuela D’Angelo, David Hardisson, Begoña Vieites, Xavier Matías-Guiu, Purificación Estévez, Eva Guerra, Jaime Prat, Andrés Poveda, José Antonio López-Guerrero and José Palacios Subject: 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. 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