The rate at which women are diagnosed with ovarian cancer has been slowly falling an average of 2.7% each year over 2012-2021 and age-adjusted death rates have been decreasing ~2.4% per year over the 2013-2022 period.² However, ovarian cancer remains the top 20 leading cause of cancer death in women in the United States (18^th) and globally (14^th).^1,3

Women with a family history of ovarian cancer have an increased risk for the disease.² It has been estimated that ~22% of the risk of ovarian cancer is attributable to heritable factors. Germline, or inherited, genetics may play a role over the entire course of ovarian cancer, from its inception to the response of patients to chemotherapy.⁴ Patients who have germline mutations in either BRCA1/2 are at a higher risk of developing ovarian cancer. In a seminal paper analyzing over 8000 unselected cases of breast or ovarian cancer, the average cumulative risk of developing ovarian cancer with a BRCA1/2 mutation was 39% and 11% respectively.⁵

All types of ovarian cancer are characterized by early peritoneal spread of metastases.^4,6 The vast majority of ovarian cancers are high-grade serous carcinomas (HGSCs).⁶ These are aggressive tumors and account for approximately 70% of deaths.^5,6

Ovarian cancers generally develop from one of 3 cell types: epithelial cells, sex-cord stromal cells, or germ cells.⁹

• Stromal and germ cell tumors are relatively uncommon, comprising fewer than 10% of cases.⁶
• The most common of these, that rising from epithelial cells, is also the most lethal form.⁹

The etiology of ovarian cancer is not completely understood. Genetic, morphologic and molecular data divide ovarian cancers into 2 groups.^7,10

• Type I — low-grade serous carcinoma, endometrioid, mucinous and clear cell carcinomas
  • Believed to originate from cortical inclusion cysts (CIC) lesions¹¹
  • Characterized by slow growth and multiple oncogenetic mutations (e.g., KRAS, BRAF, PTEN and ARID1A) and typically presenting as large cystic masses in one ovary
• Type II — HGSCs and endometrioid carcinomas, carcinosarcomas and undifferentiated carcinomas
  • Believed to develop from the secretory cells of the fallopian tube and especially the fimbriae, probably induced by inflammatory stimuli caused by ovulation¹¹
  • Characterized by aggressive growth, TP53 mutations, and a high level of chromosomal disruption and typically presenting at an advanced stage which contributes to their high fatality rate
    • While approximately 22% of HGSCs result from germline and somatic mutations in BRCA1/2, an integrated genomic analysis demonstrated that TP53 was mutated in at least 96% of HGSC samples.⁸
    • Cancer-related signaling pathways that were dysregulated included the RB1 (67%), PI3K/RAS (45%), Notch signaling pathway (23%), and homologous recombination (HR) pathways (49%).⁸

However rare in most populations, the risk of developing ovarian cancer may be increased in women with mutations in tumor suppressor genes, BRCA1 and BRCA2.

• BRCA1/2 mutations occur in <0.5% (~1 in 400) of individuals in the general population^3,12
• Ovarian cancer penetrance to age 70 years is 41% to 46% for BRCA1 and 17% to 23% for BRCA2 mutations.¹³

Signs or symptoms of ovarian cancer often only appear after the cancer has advanced and metastasized.⁶

When signs or symptoms do emerge, they often go unrecognized.^2,6 These include:

• Pain, swelling, or a feeling of pressure in the abdomen or pelvis
• Vaginal bleeding that is heavy or irregular, especially after menopause
• Vaginal discharge that is clear, white, or colored with blood
• A lump in the pelvic area
• Gastrointestinal problems such as gas, bloating, or constipation

Ovarian cancer is classified as stages I to IV using the tumor-node-metastasis (TNM) and International Federation of Gynecology and Obstetrics (FIGO) classifications.^11,14

Major causes of poor survival rates of ovarian cancer patients¹¹:

• Ovarian cancer is usually diagnosed at a late stage, after metastasis into the peritoneal cavity has already occurred.
• Tumor recurrence occurs in most patients; multiple lines of therapy lead to multi-drug resistance, shorter remissions, and eventual death.
• Patients with concomitantly high levels of PARP, FANCD2 and P53 protein expression have been shown to be at increased risk of early ovarian cancer recurrence and platinum resistance.¹⁵

Theories for therapy resistance that provide research opportunities¹¹:

• Genetic and epigenetic mutations that lead to expelling or inactivation of cytotoxic drugs^16,17
• Impaired apoptosis enhanced repair mechanisms¹⁶
• A microenvironment leading to inhibition of the immune system¹⁸
• Presence of cancer stem cells¹⁸