Endometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity. Here, we report whole exome sequencing of 112 EnOC cases following rigorous pathological assessment. We detect a high frequency of mutation in CTNNB1 (43%), PIK3CA (43%), ARID1A (36%), PTEN (29%), KRAS (26%), TP53 (26%) and SOX8 (19%), a recurrently-mutated gene previously unreported in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy is constructed, identifying clinically distinct EnOC subtypes: cases with TP53 mutation demonstrate greater genomic complexity, are commonly FIGO stage III/IV at diagnosis (48%), are frequently incompletely debulked (44%) and demonstrate inferior survival; conversely, cases with CTNNB1 mutation, which is mutually exclusive with TP53 mutation, demonstrate low genomic complexity and excellent clinical outcome, and are predominantly stage I/II at diagnosis (89%) and completely resected (87%). Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.

Ovarian carcinoma (OC) is an umbrella term for multiple distinct diseases (histotypes), each with their own developmental origins, clinical behaviour and molecular profile. Accordingly, OC management is progressing away from a one-size-fits all approach, toward more molecularly-driven, histotype-specific management strategies. Our knowledge of driver events in high grade serous OC, the most common histotype, has led to major advances in treatments, including PARP inhibitor use. However, these agents are not suitable for all patients, most notably for many of those with rare OC histotypes. Identification of additional targeted therapeutic strategies will require a detailed understanding of the molecular landscape in each OC histotype. Until recently, tumour profiling studies in rare histotypes were sparse; however, significant advances have been made over the last decade. In particular, reports of genomic characterisation in endometrioid, clear cell, mucinous and low grade serous OC have significantly expanded our understanding of mutational events in these tumour types. Nonetheless, substantial knowledge gaps remain. This review summarises our current understanding of each histotype, highlighting recent advances in these unique diseases and outlining immediate research priorities for accelerating progress toward improving patient outcomes.

Genetic and molecular changes in ovarian cancer

The estrogen receptor (ER) has functionality in selected ovarian cancer subtypes and represents a potential target for therapy. The majority (>80%) of high grade serous, low grade serous and endometrioid carcinomas and many granulosa cell tumors express ER-alpha (ERα), and these tumor types have demonstrated responses to endocrine therapy (tamoxifen and aromatase inhibitors) in multiple clinical studies. Biomarkers of responses to these drugs are actively being sought to help identify responsive cancers. Evidence for both pro-proliferative and pro-migratory roles for ERα has been obtained in model systems. ER-beta (ERβ) is generally considered to have a tumor suppressor role in ovarian cancer cells, being associated with the repression of cell growth and invasion. The differential expression of the specific ERβ isoforms may determine functionality within ovarian cancer cells. The more recently identified G protein-coupled receptor (GPER1; GPR30) has been shown to mediate both tumor-suppressive and tumor-promoting action in ovarian cancer cells, suggesting a more complex role. This review will summarize recent findings in this field.

Background: Ovarian carcinosarcoma (OCS) is an uncommon, biphasic and highly aggressive ovarian cancer type, which has received relatively little research attention. Methods: We curated the largest pathologically confirmed OCS cohort to date, performing detailed histopathological characterisation, analysis of features associated with survival and comparison against high-grade serous ovarian carcinoma (HGSOC). Results: Eighty-two OCS patients were identified; overall survival was poor (median 12.7 months). In all, 79% demonstrated epithelial components of high-grade serous (HGS) type, while 21% were endometrioid. Heterologous elements were common (chondrosarcoma in 32%, rhabdomyosarcoma in 21%, liposarcoma in 2%); chondrosarcoma was more frequent in OCS with endometrioid carcinomatous components. Earlier stage, complete resection and platinum-containing adjuvant chemotherapy were associated with prolonged survival; however, risk of relapse and mortality was high across all patient groups. Histological subclassification did not identify subgroups with distinct survival. Compared to HGSOC, OCS patients were older (P < 0.0001), more likely to be FIGO stage I (P = 0.025), demonstrated lower chemotherapy response rate (P = 0.001) and had significantly poorer survival (P < 0.0001). Conclusion: OCS represents a distinct, highly lethal form of ovarian cancer for which new treatment strategies are urgently needed. Histological subclassification does not identify patient subgroups with distinct survival. Aggressive adjuvant chemotherapy should be considered for all cases, including those with early-stage disease.

Objective: Investigate the clinical landscape of ovarian carcinoma (OC) over time.Design: Register‐based prospectively collected data.Setting: South East Scotland.Sample: A total of 2805 OC patients diagnosed in 1981–2015.Methods: Survival times were visualised using the Kaplan–Meier method; median survival, 5‐year survival probabilities and associated restricted mean survival time analyses were used to quantify survival differences.Main outcome measures: Disease‐specific survival.Results: A significant increase in disease‐specific survival (DSS) from 1981–1985 to 2011–2015 was observed (median 1.73 versus 4.23 years, P < 0.0001). Corresponding increase in progression‐free survival (PFS) was not statistically significant (median 1.22 versus 1.58 years, P = 0.2568). An increase in the proportion of cases with low residual disease volume (RD) (<2 cm RD) following debulking was observed (54.0% versus 87.7%, P < 0.0001). The proportion of high grade serous (HGS) cases increased (P < 0.0001), whereas endometrioid and mucinous cases decreased (P = 0.0005 and P = 0.0002). Increases in stage IV HGS OC incidence (P = 0.0009) and stage IV HGS OC DSS (P = 0.0122) were observed. Increasing median age at diagnosis correlated with increasing Eastern Cooperative Oncology Group Performance Status (ECOG PS) over time (r = 0.86).Conclusions: OC DSS has improved over the last 35 years. PFS has not significantly increased, highlighting that improvement in outcome has been limited to extending post‐relapse survival. Distribution of stage at diagnosis, histological subtype and RD following debulking has changed over time, reflecting evolution in tumour classification, staging and optimal debulking definitions (from low RD to minimal or zero RD). Histology, stage, RD and ECOG PS remain reliable outcome predictors. Increasing median age at diagnosis and ECOG PS indicates demographic shifts in the clinical population.Tweetable Significant improvement in ovarian carcinoma survival has been seen over time. Most of this improvement is due to an extension of survival following disease relapse.