Controversies in the management of serous borderline tumors and low-grade serous ovarian cancer.

Low-grade serous ovarian cancer has been recognized as a distinct oncologic entity for the last 20 years. Over the last 10 years, treatment strategies tailored to the biological and clinical characteristics of the disease have been tested and implemented. However, several key controversies remain.

The potent human CAR activator CITCO is a non-genotoxic hepatic tumour-promoting agent in humanised constitutive androstane receptor mice but not in wild-type animals.

A large number of drugs and compounds produced by the chemical and agrochemical industry, often referred to as 'non-genotoxic carcinogens' (NGC), score as tumour promotors in rodent models. It is unclear whether these compounds act similarly in humans. The most extensively investigated compounds have been the anti-convulsive drugs, phenobarbital (PB), and phenytoin.

Somatic BRCA1/2 mutations are associated with a similar survival advantage to their germline counterparts in tubo-ovarian high grade serous carcinoma.

Background: Half of high grade serous tubo-ovarian carcinomas (HGSOC) demonstrate homologous recombination repair (HRR) deficiency, most commonly through germline or somatic pathogenic variants in BRCA1/2 (gBRCA1/2 or sBRCA1/2). gBRCA1/2 is associated with favourable survival, greater response rate to platinum-based chemotherapy, and marked sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. sBRCA1/2 has been assumed to confer a similar clinical phenotype; however, few studies have specifically investigated sBRCA1/2 versus gBRCA1/2 to demonstrate their equivalence.

Pembrolizumab in Patients With Advanced Clear Cell Gynecological Cancer: A Phase 2 Nonrandomized Clinical Trial.

Importance: Advanced clear cell gynecological cancers (CCGCs) have a poor prognosis, with response rates to second-line chemotherapy less than 8%. Preliminary clinical activity with programmed cell death 1 protein (PD-1) inhibitors reported in CCGC merits further investigation.

Objective: To assess the clinical benefit of pembrolizumab in patients with previously treated advanced CCGC.

Whole exome sequencing reveals diverse genomic relatedness between paired concurrent endometrial and ovarian carcinomas.

Introduction: Concurrent non-serous endometrial and ovarian tumours are often managed clinically as two separate primary tumours, but almost all exhibit evidence of a genomic relationship.

Methodology: This study investigates the extent of relatedness using whole exome sequencing, which was performed on paired non-serous endometrial and ovarian carcinomas from 27 patients with concurrent tumours in a cohort with detailed clinicopathological annotation. Four whole exome sequencing-derived parameters (mutation, mutational burden, mutational signatures and mutant allele tumour heterogeneity scores) were used to develop a novel unsupervised model for the assessment of genomic similarity to infer genomic relatedness of paired tumours.

The survival benefit associated with complete macroscopic resection in epithelial ovarian cancer is histotype specific.

Background: Complete macroscopic resection is a key factor associated with prolonged survival in ovarian cancer. However, most evidence derives from high-grade serous ovarian carcinoma, and the benefit of complete macroscopic resection in other histotypes is poorly characterized. We sought to determine which histotypes derive the greatest benefit from complete macroscopic resection to better inform future decisions on radical cytoreductive efforts.

Ovarian carcinosarcoma is highly aggressive compared to other ovarian cancer histotypes.

Background: Ovarian carcinosarcoma (OCS) is an unusual ovarian cancer type characterized by distinct carcinomatous and sarcomatous components. OCS has been excluded from many of the pan-histotype studies of ovarian carcinoma, limiting our understanding of its behavior.

Methods: We performed a multi-cohort cross-sectional study of characteristics and outcomes in ovarian cancer patients from Scotland (n=2082) and the Surveillance, Epidemiology and End Results Program (SEER, n=44946) diagnosed with OCS or one of the other major histotypes: high grade serous (HGSOC), endometrioid (EnOC), clear cell (CCOC), mucinous (MOC) or low grade serous ovarian carcinoma (LGSOC).

RFWD3 modulates response to platinum chemotherapy and promotes cancer associated phenotypes in high grade serous ovarian cancer.

Background: DNA damage repair is frequently dysregulated in high grade serous ovarian cancer (HGSOC), which can lead to changes in chemosensitivity and other phenotypic differences in tumours. RFWD3, a key component of multiple DNA repair and maintenance pathways, was investigated to characterise its impact in HGSOC.

Methods: RFWD3 expression and association with clinical features was assessed using analysis in the TCGA HGSOC dataset, and in a further cohort of HGSOC tumours stained for RFWD3 using immunohistochemistry.

High throughput screening identifies dasatinib as synergistic with trametinib in low grade serous ovarian carcinoma.

Background: Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies.

Methods: We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches.

Current Applications and Challenges of Next-Generation Sequencing in Plasma Circulating Tumour DNA of Ovarian Cancer.

Circulating tumour DNA (ctDNA) facilitates longitudinal study of the tumour genome, which, unlike tumour tissue biopsies, globally reflects intratumor and intermetastatis heterogeneity. Despite its costs, next-generation sequencing (NGS) has revolutionised the study of ctDNA, ensuring a more comprehensive and multimodal approach, increasing data collection, and introducing new variables that can be correlated with clinical outcomes. Current NGS strategies can comprise a tumour-informed set of genes or the entire genome and detect a tumour fraction as low as 10.

Compartment-specific multiomic profiling identifies SRC and GNAS as candidate drivers of epithelial-to-mesenchymal transition in ovarian carcinosarcoma.

Background: Ovarian carcinosarcoma (OCS) is an exceptionally aggressive and understudied ovarian cancer type harbouring distinct carcinomatous and sarcomatous compartments. Here, we seek to identify shared and compartment-specific events that may represent potential therapeutic targets and candidate drivers of sarcomatous compartment formation through epithelial-to-mesenchymal transition (EMT).

Methods: We performed multiomic profiling (exome sequencing, RNA-sequencing, microRNA profiling) of paired carcinomatous and sarcomatous components in 12 OCS cases.

Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome.

Objectives: Low-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy.

Methods: Genomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation.

Distinct histopathological features are associated with molecular subtypes and outcome in low grade serous ovarian carcinoma.

Low grade serous ovarian carcinoma (LGSOC) demonstrates unique clinical and molecular features compared to other ovarian cancer types. The relationship between common histological features of LGSOC and molecular events, such as hormone receptor expression patterns and MAPK gene mutation status, remains poorly understood. Recent data suggest some of these molecular features may be biomarkers of response to recently introduced biologically-targeted therapies, namely endocrine therapy and MEK inhibitors.

Molecular characteristics and clinical behaviour of epithelial ovarian cancers.

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.

Multisite gynecologic endometrioid adenocarcinomas: Can mutation profiling be used to distinguish synchronous primary cancers from metastases?

It is well recognized that some patients with endometrioid gynecological cancers have tumors arising in multiple sites (ovary, endometrium, and endometriosis) at the time of diagnosis. Molecular analysis has helped discern whether these multisite cancers represent synchronous primary tumors or alternatively metastatic disease. We present a complex case of a patient with endometrioid carcinomas arising in multiple sites.

Impact of BRCA Mutation Status on Tumor Dissemination Pattern, Surgical Outcome and Patient Survival in Primary and Recurrent High-Grade Serous Ovarian Cancer: A Multicenter Retrospective Study by the Ovarian Cancer Therapy-Innovative Models Prolong Survival (OCTIPS) Consortium.

Background: This study seeks to evaluate the impact of breast cancer (BRCA) gene status on tumor dissemination pattern, surgical outcome and survival in a multicenter cohort of paired primary ovarian cancer (pOC) and recurrent ovarian cancer (rOC).

Patients And Methods: Medical records and follow-up data from 190 patients were gathered retrospectively. All patients had surgery at pOC and at least one further rOC surgery at four European high-volume centers.

Ovarian carcinosarcoma is a distinct form of ovarian cancer with poorer survival compared to tubo-ovarian high-grade serous carcinoma.

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.

Multiomic Characterization of High-Grade Serous Ovarian Carcinoma Enables High-Resolution Patient Stratification.

Purpose: High-grade serous ovarian carcinoma (HGSOC) is the most common ovarian cancer type; most patients experience disease recurrence that accumulates chemoresistance, leading to treatment failure. Genomic and transcriptomic features have been associated with differential outcome and treatment response. However, the relationship between events at the gene sequence, copy number, and gene-expression levels remains poorly defined.

Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial.

Background: Low-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma.

Methods: This international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK.

Clinicopathological Determinants of Recurrence Risk and Survival in Mucinous Ovarian Carcinoma.

Mucinous ovarian carcinoma (MOC) is a unique form of ovarian cancer. MOC typically presents at early stage but demonstrates intrinsic chemoresistance; treatment of advanced-stage and relapsed disease is therefore challenging. We harness a large retrospective MOC cohort to identify factors associated with recurrence risk and survival.