Ovarian Cancer

Exploring pathways and proteins implicated in ovarian cancer cell growth, survival and motility as promising therapeutic targets.

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About 251,000 women globally received a new diagnosis of ovarian cancer during 2015.1

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Approximately 60% of diagnoses are made after disease has metastasized.2

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Eighth leading cause of cancer death in women globally.1

Incidence & Mortality

Compared to other cancers, ovarian cancer is relatively rare. It is the 19th most often diagnosed cancer globally, representing 1.4% of all new cancer cases overall.1

  • Approximately 88% of new cases are diagnosed in women ≥45 years of age.2
  • Median age at diagnosis is 63 years.2

Approximately 161,000 women globally died from ovarian cancer during 2015, representing 1.8% of all cancer deaths.1

  • Median age at death is 70 years.2
  • Overall 5-year survival in the US is 46.5%. While 5-year relative survival is 92.5% for the 14.8% of women diagnosed with localized disease, only 28.9% of women will survive ≥5 years when diagnosed with distant metastases (60% of new cases).2

While the rate at which women are diagnosed with ovarian cancer has been slowly falling over the past 20 years, the 5-year survival rate has only increased by 3.5%.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

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.

  • 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 unknown. Genetic, morphologic and molecular data divide ovarian cancers into 2 groups.8

  • Type I — low-grade serous carcinoma, endometrioid, mucinous and clear cell carcinomas
    • Characterized by slow growth and multiple oncogenetic mutations (ie, KRAS, BRAF, PTEN and ARID1A)
  • Type II — high-grade serous and endometrioid carcinomas, carcinosarcomas and undifferentiated carcinomas
    • Characterized by aggressive growth, TP53 mutations, and a high level of chromosomal disruption
      • While approximately 13% of HGSCs result from germline 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%) and homologous recombination (HR) pathways (~50%).6

The risk of developing ovarian cancer may be increased in women with BRCA1/2 mutations.

  • Ovarian cancer penetrance is 41% to 46% for BRCA1 and 17% to 23% for BRCA2 mutations.9

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

FIGO Staging Tumor Extension 5- Year Survival
Stage I Tumor confined to the ovaries or fallopian tubes; has not spread to the abdomen, pelvis or lymph nodes, or to distant sites 85% to 94%
Stage II Tumor involves one or both ovaries or fallopian tubes with pelvic extension or primary peritoneal cancer 73% to 78%
Stage III Tumor involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes 39% to 59%
Stage IV Distant metastasis excluding peritoneal metastases 17%
Recurrent Malignant cells reappear after cancer treatments such as surgery or chemotherapy have been completed for a period of time
FIGO Stage 1
Tumor Extension
Tumor confined to the ovaries or fallopian tubes; has not spread to the abdomen, pelvis or lymph nodes, or to distant sites
5- Year Survival
85% to 94%
FIGO Stage II
Tumor Extension
Tumor involves one or both ovaries or fallopian tubes with pelvic extension or primary peritoneal cancer
5- Year Survival
73% to 78%
FIGO Stage III
Tumor Extension
Tumor involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes
5- Year Survival
39% to 59%
FIGO Stage IV
Tumor Extension
Distant metastasis excluding peritoneal metastases
5- Year Survival
17%
Recurrent
Tumor Extension
Malignant cells reappear after cancer treatments such as surgery or chemotherapy have been completed for a period of time
5- Year Survival

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.

Theories for therapy resistance that provide research opportunities11:

  • Genetic and epigenetic mutations that lead to expelling or inactivation of cytotoxic drugs
  • Impaired apoptosis enhanced repair mechanisms
  • A microenvironment leading to inhibition of the immune system
  • Presence of cancer stem cells

Relevant Biomarker Pathways

  1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3(4):524-548.
  2. Howlader N, Noone AM, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2014. Bethesda, MD: National Cancer Institute. https://seer.cancer.gov/csr/1975_2014. Published November 2016. Updated April 2017. Accessed December 2017.
  3. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.
  4. PDQ ® Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 09/13/2017. https://www.cancer.gov/types/ovarian/hp/ovarian-epithelial-treatment-pdq. Accessed November 23, 2017.
  5. Kurman RJ. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma. Ann Oncol. 2013;24(suppl 10):x16-x21.
  6. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615.
  7. Dubeau L, Drapkin R. Coming into focus: the nonovarian origins of ovarian cancer. Ann Oncol. 2013;24(suppl 8):viii28-viii35.
  8. 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.
  9. 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.
  10. 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.
  11. Ottevanger PB. Ovarian cancer stem cells more questions than answers. Semin Cancer Biol. 2017;44:67-71.
  12. Lim JSJ, Tan DSP. Understanding resistance mechanisms and expanding the therapeutic utility of PARP inhibitors. Cancers (Basel). 2017;9(8):1-4.
  13. 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. https://doi.org/10.1155/2017/5263974. Accessed December 2017.

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