Cold Spring Harbor Perspectives in Medicine

Early Detection of Ovarian Cancer

The risk of death from ovarian cancer is highly associated with the clinical stage at diagnosis. Efforts to implement screening for ovarian cancer have been largely unsuccessful, due to the low prevalence of the disease in the general population and the heterogeneity of the various cancer types that fall under the ovarian cancer designation. A practical test for early detection will require both high sensitivity and high specificity to balance reducing the number of cancer deaths with minimizing surgical interventions for false positive screens. The technology must be cost-effective to deliver at scale, widely accessible, and relatively noninvasive. Most importantly, a successful early detection test must be effective not only at diagnosing ovarian cancer but also in reducing ovarian cancer deaths. Stepwise or multimodal approaches among the various areas under investigation will likely be required to make early detection a reality.

The Emerging Role of the Single-Cell and Spatial Tumor Microenvironment in High-Grade Serous Ovarian Cancer

The development of single-cell and spatial technologies has enabled a more detailed understanding of the tumor microenvironment and its role in therapy response and clinical outcome of high-grade serous ovarian cancer (HGSC). Interestingly, emerging evidence suggests that HGSCs with different genetic drivers harbor distinct tumor-immune microenvironments. Further, spatial cell-cell interactions have been shown to shape the CD8

Rare Epithelial Ovarian Cancers: Low Grade Serous and Mucinous Carcinomas

The ovarian epithelial cancer histotypes can be divided into common and rare types. Common types include high-grade serous ovarian carcinomas and the endometriosis-associated cancers, endometrioid and clear-cell carcinomas. The less common histotypes are mucinous and low-grade serous, each comprising less than 10% of all epithelial carcinomas. Although histologically and epidemiologically distinct from each other, these histotypes share some genetic and natural history features that distinguish them from the more common types. In this review, we will consider the similarities and differences of these rare histological types, and the clinical challenges they pose.

Embryological Insights into the Origin of Epithelial Cancers of the Female Reproductive Tract

The embryology of the female reproductive organs is reviewed focusing on aspects relevant to the histogenesis of reproductive neoplasms. The evidence reviewed suggests that (1) there is no embryological link between the ovarian surface epithelium and the coelomic epithelium; (2) the ovarian surface epithelium is not composed of pluripotent cells that readily differentiate into various components of the reproductive tract before or after birth; (3) there is no embryological link between the ovarian surface epithelium and the Müllerian ducts, from which internal female reproductive organs other than the ovaries, including the endocervix, endometrium, and fallopian tubes, are derived; and (4) there is an embryological link between the Müllerian ducts and the renal collecting system, perhaps accounting for clear cell differentiation in some gynecological malignancies. Implications for our understanding of the origin of the tumors historically classified as ovarian epithelial neoplasms are discussed.

Harnessing Antitumor Immunity in Ovarian Cancer

Despite progress in other tumor types, immunotherapy is not yet part of the standard of care treatment for high-grade serous ovarian cancer patients. Although tumor infiltration by T cells is frequently observed in patients with ovarian cancer, clinical responses to immunotherapy remain low. Mechanisms for immune resistance in ovarian cancer have been explored and may provide insight into future approaches to improve response to immunotherapy agents. In this review, we discuss what is known about the immune landscape in ovarian cancer, review the available data for immunotherapy-based strategies in these patients, and provide possible future directions.

Ovarian Clear Cell Carcinoma: An Endometriosis-Associated Cancer with Therapeutic Challenges

Ovarian Cancer Therapy

Significant advances in basic and translational research have improved our understanding of the molecular alterations and biological vulnerabilities of the different histologic subsets of epithelial ovarian cancer (EOC). This has led to clinical trials that have incorporated novel agents based on molecular aspects into the treatment paradigm for both newly diagnosed and recurrent disease. The past decade has witnessed several regulatory approvals in the United States and Europe for the treatment of EOC, including the antiangiogenic agent, bevacizumab, poly(ADP-ribose) polymerase inhibitors in various therapeutic settings, and the antibody-drug conjugate (ADC), mirvetuximab soravtansine. Immune checkpoint inhibitors do not demonstrate substantial activity as single agents in ovarian cancer, except for the rare entity of microsatellite instability (MSI) high ovarian cancer. Current research is focused on new treatment paradigms such as ADCs, genetically specific therapies, and other novel immunotherapies such as bispecific antibodies, radioligand therapies, cellular therapies, and vaccines. In addition, combination efforts are focused on incorporating conventional chemotherapy, targeted therapies, immune-oncology drugs, and/or novel agents to improve outcomes for patients with newly diagnosed as well as recurrent EOC. This review will focus on the management of high-grade serous ovarian cancer, the most common type of EOC, accounting for ∼75% of cases. Recent advances in the management of rarer histologic subtypes with distinct molecular and clinical characteristics, including clear cell, mucinous, endometrioid, and low-grade serous, will be briefly discussed. Non-EOCs, including germ cell and sex cord stromal tumors and their treatment, have been reviewed elsewhere [see Ray-Coquard et al. (2019)

Models of High-Grade Serous Ovarian Carcinoma

High-grade serous ovarian carcinoma (HGSC) remains an incompletely understood, highly lethal disease. Historically, a lack of fidelitous in vitro and in vivo models representing HGSC biology and therapy response has been a major barrier to progress. As we discuss below, multiple (if not most) early studies used-and some investigators continue to use-human "ovarian cancer cell lines" that lack key genomic/genetic features of HGSC, rendering their conclusions questionable. The frequently deployed ID8 syngeneic mouse model is similarly suspect, as it derives from ovarian surface epithelium (OSE) and is

Prevention of Epithelial Ovarian Cancer

Given the challenges with achieving effective and durable treatment for epithelial ovarian cancer, primary prevention is highly desirable. Fortunately, decades of research have provided evidence for several strategies that can be deployed to optimize risk reduction. These include surgery, chemoprevention, and lifestyle factor modifications. These broad categories vary in terms of the magnitude of risk reduction possible, the possible short-term and long-term side effects, the degree of difficulty, and acceptability. Thus, the concept of a risk-based model to personalize preventive interventions is advocated to guide discussion between care providers and women at risk. For women with inherited major gene mutations that greatly increase risk of ovarian cancer, surgical approaches have favorable risk to benefit ratios. Chemoprevention and lifestyle factor modifications portend a lower degree of risk reduction but confer lower risk of undesirable side effects. Since complete prevention is not currently possible, better methods for early detection remain a high priority.

Germline Genetic Testing for Hereditary Breast and Ovarian Cancer: Current Concepts in Risk Evaluation

Our understanding of hereditary breast and ovarian cancer has significantly improved over the past two decades. In addition to