Exploring pathways and proteins implicated in ovarian cancer cell growth,
survival and motility as promising therapeutic targets.
INCIDENCE & MORTALITY
Compared to other cancers, ovarian cancer is relatively rare. It is the 20th most often diagnosed cancer globally, representing ~1.6% of all new cancer cases overall.1
- Approximately 88% of new cases are diagnosed in women ≥45 years of age.19
- Median age at diagnosis is 63 years.19
Worldwide, approximately 207,000 women died from ovarian cancer during 2020, representing 2.1% of all cancer deaths.1
While the rate at which women are diagnosed with ovarian cancer has been slowly falling an average of 2.3% per year over the past 10 years, the 5-year survival rate has only increased by ~4%.2 Ovarian cancer remains the fifth leading cause of cancer death in women in the United States and the eighth leading cause of cancer death in women globally.1,3
Overall, ovarian cancer is rare, but 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.14 The quintessential example is 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.18
All types of ovarian cancer are characterized by early peritoneal spread of metastases.4 The vast majority of ovarian cancers are high-grade serous carcinomas (HGSCs).5 These are aggressive tumors and account for approximately 70% of deaths due to ovarian cancer.5,6
Ovarian cancers generally develop from one of 3 cell types: epithelial cells, sex-cord stromal cells, or germ cells.7
- Stromal and germ cell tumors are relatively uncommon, comprising fewer than 10% of cases.4
- The most common of these, that rising from epithelial cells, is also the most lethal form.7
The etiology of ovarian cancer is not completely understood. Genetic, morphologic and molecular data divide ovarian cancers into 2 groups.5,8
- 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 — high-grade serous (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.6
- Cancer-related signaling pathways that were dysregulated included the RB1 (67%), PI3K/RAS (45%), Notch signaling pathway (23%), and homologous recombination (HR) pathways (49%).6
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.
Signs or symptoms of ovarian cancer often only appear after the cancer has advanced and metastasized.4
When signs or symptoms do emerge, they often go unrecognized.4 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.10,11
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.17
Theories for therapy resistance that provide research opportunities11:
- Genetic and epigenetic mutations that lead to expelling or inactivation of cytotoxic drugs12,16
- Impaired apoptosis enhanced repair mechanisms12
- A microenvironment leading to inhibition of the immune system13
- Presence of cancer stem cells13
PARP expression has been detected in up to 60% of epithelial ovarian tumor specimens.17
PARP inhibitors have been found to sensitize cancer cells with defects in homologous recombination (HR) DNA repair caused by molecular aberrations (e.g. BRCA1/2 mutations) to DNA damaging agents while sparing normal cells; this concept is called "synthetic lethality".12
Relevant Biomarker Pathways
Learn how PARP inhibitors may sensitize cells to the effects of DNA-damaging chemotherapy. MORE>
- Global Burden of Disease Cancer Collaboration; Sung H; Ferlay J, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: Cancer J. Clin. 2021;71(3):209-249.
- Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2017. Bethesda, MD: National Cancer Institute. https://seer.cancer.gov/statfacts/html/ovary.html. Updated April 2020. Accessed November 2020.
- Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.
- PDQ ® Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 06/05/2019. https://www.cancer.gov/types/ovarian/hp/ovarian-epithelial-treatment-pdq. Accessed July 2019.
- Kurman RJ. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma. Ann Oncol. 2013;24(suppl 10):x16-x21.
- Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615.
- Dubeau L, Drapkin R. Coming into focus: the nonovarian origins of ovarian cancer. Ann Oncol. 2013;24(suppl 8):viii28-viii35.
- Szajnik M, Czystowska-Kuźmicz M, Elishaev E, Whiteside TL. Biological markers of prognosis, response to therapy and outcome in ovarian carcinoma. Expert Rev Mol Diagn. 2016;16(8):811-826.
- Nelson HD, Fu R, Goddard K, et al. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: systematic review to update the U.S. Preventive Services Task Force recommendation. Evidence Synthesis No. 101. AHRQ Publication No. 12-05164-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2013.
- Prat J; for the FIGO Committee on Gynecologic Oncology. FIGO's staging classification for cancer of the ovary, fallopian tube, and peritoneum: abridged republication. J Gynecol Oncol. 2015;26(2):87-89.
- Ottevanger PB. Ovarian cancer stem cells more questions than answers. Semin Cancer Biol. 2017;44:67-71.
- Lim JSJ, Tan DSP. Understanding resistance mechanisms and expanding the therapeutic utility of PARP inhibitors. Cancers (Basel). 2017;9(8):1-4.
- Varas-Godoy M, Rice G, Illanes SE. The crosstalk between ovarian cancer stem cell niche and the tumor microenvironment. Stem Cells Int. 2017;2017:5263974.
- Bolton KL, et al. Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the ovarian cancer association consortium (OCAC). Journal of Internal Medicine. 2012;271:366–378.
- Genetics of Breast and Gynecologic Cancers (PDQ®)–Health Professional Version. Bethesda, MD: National Cancer Institute. https://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq. Updated 06/25/2019. https://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq#link/_1544. Accessed July 2019.
- Farmer H, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–921.
- Wysham WZ, Mhawech-Fauceglia P, Li H, et al. BRCAness profile of sporadic ovarian cancer predicts disease recurrence. PLoS One. 2012;7(1):e30042.
- Neff RT, et al. BRCA mutation in ovarian cancer: testing, implications and treatment considerations. Ther Adv Med Oncol. 2017 Aug; 9(8): 519–531.
- NCI. Cancer Stat Facts: Ovarian Cancer. https://seer.cancer.gov/statfacts/html/ovary.html. Accessed September 2021.