Abstract

Non-epithelial ovarian tumors are heterogeneous and account for approximately 10% of ovarian malignancies. The most common subtypes of non-epithelial ovarian tumors arise from germ cells or sex cord and stromal cells of the gonads. These tumors are usually detected at an early stage, and management includes surgical staging and debulking. When indicated for advanced disease, most respond to chemotherapy; however, options for patients with refractory disease are limited, and regimens can be associated with significant toxicities, including permanent organ dysfunction, secondary malignancies, and death. Targeted therapies that potentially decrease chemotherapy-related adverse effects and improve outcomes for patients with chemotherapy-refractory disease are needed. Here, we review the molecular landscape of non-epithelial ovarian tumors for the purpose of informing rational clinical trial design. Recent genomic discoveries have uncovered recurring somatic alterations and germline mutations in subtypes of non-epithelial ovarian tumors. Though there is a paucity of efficacy data on targeted therapies, such as kinase inhibitors, antibody–drug conjugates, immunotherapy, and hormonal therapy, exceptional responses to some compounds have been reported. The rarity and complexity of non-epithelial ovarian tumors warrant collaboration and efficient clinical trial design, including high-quality molecular characterization, to guide future efforts.

Highlights

  • Non-epithelial ovarian tumors are an uncommon group of malignancies that arise from germ cells, sex cord cells, and/or stromal cells of the ovary

  • There is controversy regarding the need for adjuvant chemotherapy for early-stage, non-dysgerminoma malignant ovarian germ cell tumors (MOGCT), including stage IA grade 2–3 immature teratoma, stage IA or IB yolk sac tumors, and other less common histologies [14,55]

  • A 17% partial response rate accompanied by decreases in tumor markers met the pre-specified criteria for further investigation with combination regimens based on the prior retrospective data suggesting higher response rates in granulosa cell tumors treated with dual bevacizumab therapy and chemotherapy [131]

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Summary

Introduction

Non-epithelial ovarian tumors are an uncommon group of malignancies that arise from germ cells, sex cord cells, and/or stromal cells of the ovary. The term non-epithelial is used to distinguish these tumors from their epithelial counterparts, which usually arise from the external lining of the ovaries or the fallopian tube epithelium (Figure 1). This histological distinction is based on the World. Organization’s classification [1,2]and andhas hasimportant important genomic, epigenetic, Organization’s classificationofofovarian ovarian tumors tumors [1,2]. Genomic, epigenetic, and clinical implications [3,4]. Clinical implications [3,4]

Epithelial andand non-epithelial
GeneralNon-epithelial
Dysgerminoma
Yolk Sac Tumors
Immature Teratoma
Mixed Germ Cell Ovarian Tumors and Others
Granulosa Cell Tumors
Sertoli–Leydig
Sertoli–Leydig Cell Tumors
Application of Targeted Therapies in Clinical Trials
Tyrosine Kinase and Other Small Molecule Inhibitors
Angiogenesis Inhibition
Immunotherapy
Results
Endocrine Therapy
Other Agents
Drugs Evaluated in Testicular Tumor
Conclusions and Future Directions
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