Abstract
Epithelial ovarian cancer (OC) comprises molecularly distinct disease types, with high-grade serous ovarian cancer (HGSOC) accounting for ~75% of OC diagnoses; ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC) at ~10% each; mucinous ovarian carcinoma (MOC) and low-grade serous ovarian carcinoma (LGSOC) at ⩽5% each; and ovarian carcinosarcoma (OCS), the rarest type of OC at 1%-4% of OC diagnoses. LGSOC has the best prognosis, followed by EnOC, MOC and OCCC, with HGSOC then OCS being the most aggressive. For all types of OC, diagnosis at the advanced-stage results in dramatically reduced survival. Initial treatment consists of debulking surgery and platinum-based chemotherapy, usually in combination with a taxane; however, response rates vary depending on the OC type. Treatments specific to the OC type may improve treatment outcomes. For HGSOC, poly(ADP-ribose) polymerase inhibitor (PARPi) therapy has improved survival for women with DNA homologous recombination repair (HRR) defects; however, acquired resistance remains an issue and more effective treatments are needed. Next-generation sequencing of distinct types of OC has revealed the complexity of genetic variants and larger-scale genomic and epigenomic alterations harboured, including proven and putative biomarkers of drug response. A predominance of distinct gene classes is altered in specific OC types: HRR genes (e.g. BRCA1 and BRCA2) in HGSOC; ARID1A and PIK3CA in OCCC; PIK3CA and KRAS in EnOC; CDKN2A and KRAS in MOC and MAPK pathway genes (e.g. BRAF and KRAS) in LGSOC. Generating evidence for effective drug combination therapies targeting relevant aberrations in each OC type is urgently needed. The effects of long-term drug treatment on OC genomes, acquired drug-resistance and OC relapse require clarification, especially in women with HGSOC with acquired resistance to PARPi. This article provides an overview of the main types of OC and their genomic profiles. It highlights recent encouraging clinical trials, with an emphasis on the future of genomically-targeted combination therapies, for both first-line and subsequent treatment of OC. We focus on PARPi combinations for HGSOC, MAPK pathway inhibitors for LGSOC, cell cycle checkpoint inhibitors for OC with CCNE1 amplification, the potential of immune checkpoint inhibitors in OCCC and encouraging, as yet preliminary, responses for antibody-drug conjugate-based therapy. Thus, OC type-specific genomic susceptibilities provide direction for personalised therapy in OC.