Homologous Recombination Deficiency and Cyclin E1 Amplification Are Correlated with Immune Cell Infiltration and Survival in High-Grade Serous Ovarian Cancer

Simple Summary Ovarian cancer is the deadliest gynecological cancer in developed countries of which high-grade serous ovarian carcinoma (HGSOC) is the most common subtype. How the tumor's genetic characteristics are associated with the tissue surrounding the tumor; the tumor microenvironment (TME), is incompletely understood. Our study assessed the TME and genetic profiles of HGSOC and their associations with survival. 347 patients with HGSOC were categorized in the following profiles: BRCA mutation (BRCAm) (30%), non-BRCA mutated homologous recombination deficiency(HRD) (19%), CCNE1-amplification (13%), non-BRCAmut HRD and CCNE1-amplification (double classifier) (20%), and no specific molecular profile (NSMP) (18%). BRCAm profile showed the best survival and CCNE1 and double classifier the worst. Higher immune cell densities showed a favorable survival, also within the molecular profiles. Furthermore, immune cell densities differed per molecular profile with BRCAm profile tumors showing the highest and CCNE1 lowest densities. Our study showed that HGSOC is not one group but is grouped by different molecular profiles and TME. Background: How molecular profiles are associated with tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC) is incompletely understood. Therefore, we analyzed the TME and molecular profiles of HGSOC and assessed their associations with overall survival (OS). Methods: Patients with advanced-stage HGSOC treated in three Dutch hospitals between 2008-2015 were included. Patient data were collected from medical records. BRCA1/2 mutation, BRCA1 promotor methylation analyses, and copy number variations were used to define molecular profiles. Immune cells were assessed with immunohistochemical staining. Results: 348 patients were categorized as BRCA mutation (BRCAm) (BRCAm or promotor methylation) (30%), non-BRCA mutated HRD (19%), Cyclin E1 (CCNE1)-amplification (13%), non-BRCAmut HRD and CCNE1-amplification (double classifier) (20%), and no specific molecular profile (NSMP) (18%). BRCAm showed highest immune cell densities and CCNE1-amplification lowest. BRCAm showed the most favorable OS (52.5 months), compared to non-BRCAmut HRD (41.0 months), CCNE1-amplification (28.0 months), double classifier (27.8 months), and NSMP (35.4 months). Higher immune cell densities showed a favorable OS compared to lower, also within the profiles. CD8+, CD20+, and CD103+ cells remained associated with OS in multivariable analysis. Conclusions: Molecular profiles and TME are associated with OS. TME differs per profile, with higher immune cell densities showing a favorable OS, even within the profiles. HGSOC does not reflect one entity but comprises different entities based on molecular profiles and TME.

Automated summary

Ovarian cancer is a deadly gynecological cancer, and high-grade serous ovarian carcinoma (HGSOC) is the most common subtype. This study investigated the associations between the tumor microenvironment (TME), genetic profiles, and overall survival (OS) in HGSOC. The results showed that HGSOC can be categorized into different entities based on molecular profiles and TME. Higher immune cell densities in the TME were associated with better survival, regardless of the molecular profiles.