Homologous recombination deficiency and Cyclin E1 amplification are correlated with immune cell infiltration and survival in high-grade serous ovarian cancer.

Abstract How the tumor’s genetic make up (i.e. molecular profiles) is associated with changes in the tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC) is incompletely understood, while these factors influence survival. To investigate this we analyzed the TME and molecular profiles (homologous recombination deficiency (HRD) and Cyclin E1 (CCNE1) amplification) of HGSOC and assessed their associations with each other and overall survival (OS). Patients with advanced-stage HGSOC treated in three Dutch hospitals between 2008-2015 were included. Patient, treatment, and outcome data were collected from medical records. BRCA1/2 mutation, BRCA1 promotor methylation analyses, and copy number variations were used to define five molecular profiles. Immunecell densites were assessed with immunohistochemical staining for T- (CD8 and CD103), B- cells (CD20) and macrophages (CD68). This resulted in the assessability of 348 patients who were categorized as; BRCA mutation or promotor methylation (BRCAm) (30%), non-BRCA mutated HRD (19%), CCNE1-amplification (13%), non-BRCAmut HRD and CCNE1-amplification (double classifier) (20%), and no specific molecular profile (NSMP) (18%). BRCAm tumors showed the highest immune cell densities and CCNE1-amplification the lowest. BRCAm showed the most favorable OS (52.5months), compared to non-BRCAmut HRD (41.0months), CCNE1-amplification (28.0months), double classifier (27.8months), and NSMP (35.4months). CCNE1-amplification and double classifier remained to have a significantly worse OS in multivariable analysis. Higher immune cell densities showed a favorable OS compared to lower densities, also within the molecular profiles. CD8+, CD20+, and CD103+ cells remained associated with OS in multivariable analysis. These results depict that both molecular profiles and TME are associated with OS. Immune composition for lymphocytes and macrophages differ per molecular profile, with higher immune cell densities showing a favorable OS, even within the profiles. HGSOC does not reflect one entity but comprises different variants based on molecular profiles and TME, which ideally is translated into tailored treatment approaches.