Ovarian Cancer

Ovaries are female reproductive organs. Women have 2 ovaries, which are located in the pelvic region, on each side of the uterus. Each ovary is approximately the size of an almond. The ovaries play a crucial role in the reproductive system. They produce and release eggs, which travel through the fallopian tubes and attach to the uterus after fertilization by a sperm. The ovaries are also responsible for producing the female sex hormones, estrogenA steroid sex hormone. Estrogen's structure is closely related to cholesterol. Produced by the ovaries, estrogen has effects on the reproductive, cardiovascular and skeletal systems. Estrogen is also a growth factor for some types of cells, including breast cells. Inhibitors of estrogen function such as tamoxifen and arimidex are used to block the growth effects of estrogen. See also, estrogen receptor., and progesterone3. Below is a picture of the ovaries.

The 3 main tissue types found in the ovaries are:

• Epithelial layer - this tissue type makes up the outer surface of the ovaries
• Germ layer - this tissue type is made of cells that produce eggs (ova)
• Stromal layer - this tissue type is made of cells that connect the parts of the ovary together and secrete female hormones

Also shown in the picture are:

• Uterus - the uterus is an organ located in the female pelvis. The uterus is where an unborn baby (fetus) develops inside the mother.4
• Fallopian tubes - fallopian tubes refer to the two slender tubes that allow the egg to go from the ovary to the uterus5
• Cervix - the cervix is the bottom part of the uterus that forms a passage between the uterus and vagina.6
• Myometrium - myometrium is the layer of muscleon the outside of the uterus.7
• Endometrium - endometrium is the layer of tissue that lines the uterus.8

During a woman's lifetime, she has around a 1.4% chance of developing invasive ovarian cancer and around a 1.0% chance of dying from invasive ovarian cancer. The following is a list of some of the risk factors for developing ovarian cancer. Note that having a risk factor does not necessarily mean the individual will develop ovarian cancer. Furthermore, it is difficult to pinpoint exactly how big of a role a certain risk factor may have in the development of ovarian cancer10.

The following is a list of some risk factors for ovarian cancer. These risk factors are expanded upon, below.

• Family history
• Genetic predisposition
• Age
• Race
• Reproductive history
• HormoneA chemical produced by cells that alters the activity of other cells. The chemicals may be lipids, such as testosterone and estrogen or proteins like insulin. Hormones may act at locations far from their site of origin. Estrogen, for example, is produced primarily by cells in the ovaries but acts on cells in the breast and elsewhere. Replacement Therapy (HRT)
• Age of first menstrual period and menopause
• Regularity and duration of menstrual cycle
• Sexual Identity
• Infertility
• Women with endometriosis
• Residence in North America
• Body-mass-index  (BMI)
• Talcum powder use

Prevention and factors that reduce the risk for ovarian cancer include the following:

Age of first menstruation: Late-onset of menstruation (the first menstrual period is also called menarche) is associated with a lower risk of ovarian cancer 15.

Age of menopause: Early age at entering menopause is correlated with a decreased ovarian cancer risk 15.

Breastfeeding: Women who breastfed are at a decreased ovarian cancer risk 15.

Diet: No food or supplement has conclusively been shown to reduce the risk of ovarian cancer but research is ongoing.  Preliminary results indicate that specific dietary items may reduce the risk of ovarian cancer. These items include:

• Vitamins A, C, D, E
• A diet that includes the recommended amount of fruits and vegetables
• Tea, especially green and black tea 15.

CancerQuest's disclaimer

Hysterectomy: Women who undergo a hysterectomy (removing their ovaries) are at a decreased risk for developing ovarian cancer. However, they can still develop a rare form of cancer known as primary peritoneal carcinomaCancer of epithelial cells, the cells that cover the outside and inside of body surfaces. This is the most common form of cancer. 10.

Intrauterine device (IUD): IUD use is correlated with a decrease in ovarian cancer risk 15.

Number of children: Having multiple children (multiparity) is correlated with a decreased risk for ovarian cancer 15.

Oral contraceptive use: Long-term use of oral contraceptivesA device used to prevent pregnancy. Oral contraceptives used by women contain different mixtures of hormones such as estradiol and progesterone. has been shown to reduce the risk of developing ovarian cancer. Research shows that the use of oral contraceptives reduces the risk of developing ovarian cancer in general. However, this risk reduction is maximized after 5 years of use 13. Protective benefits persist after discontinuation of OCP for at least ten, and possibly 20 years and are not dose dependent 15.

Physical activity and exercise: Healthy amounts of physical activity and exercise are associated with a lower incidence of ovarian cancer 15.

Regular health exams for women: The doctor will conduct a pelvic exam to check the size and shape of female organs. Early stage ovarian tumors may be hard to find due to its small size and location deep within the body 10.

Tubal ligationA surgical procedure in which the fallopian tubes are sealed. The procedure prevents the delivery of an egg to the uterus and prevents pregnancy.: Women who undergo tubal ligation are at a decreased risk for developing ovarian cancer 15.

Daily low dose aspirin: Preliminary research indicates that taking aspirin can help lower ovarian cancer risk and increase survival of ovarian cancer patients. Learn about ovarian cancer and aspirin on our Prevention page.

Symptoms

Early stages of ovarian cancer typically do not produce symptoms. Ovarian cancer that has spread (metastasized) to other parts of the body will more likely produce symptoms. The symptoms listed below may or may not be due to ovarian cancer; they may be caused by other things.10

• Abdominal swelling or bloating - this may be due to a build-up of fluid (ascites) or the presence of a tumor
• Increased pressure or pain - typically in the lower half of the body, such as the pelvis, back, abdomen or legs16
• Indigestion
• Nausea
• Constipation or diarrhea
• A feeling of fullness or inability to eat normally
• Fatigue
• Frequent urination
• Menstrual changes - this may appear as bleeding after menopause or heavy bleeding during menstruation.
• Dyspnea (shortness of breath)
• Difficulty eating16

Detection And Diagnosis

If an individual suspects she may have ovarian cancer, she should consult a doctor who specializes in treating women with ovarian cancer. This type of doctor is known as a gynecologic oncologist. During a visit with a gynecologic oncologist, the doctor will ask the patient about her health history and may choose to conduct further tests to find out more information. The following are some examples of tests that the oncologist may perform 10. For more general information on cancer detection and diagnosis, visit CancerQuest's page: Cancer Detection and DIagnosis.

• Physical exams

During physical exams, doctors will feel (palpate) for growths and indications of fluid buildup (ascites) in the abdomen. Fluid may be sampled and examined for the presence of ovarian cancer cells. A pelvic exam is an example of a physical exam that can be used to identify lumps or changes in the shape and size of the ovaries and nearby organs.

• Ultrasound

An ultrasound may be used to detect ovarian cancer. A transvaginal ultrasound is a specific type of ultrasound where an instrument (transducer) is inserted into the vagina in order to obtain a more accurate and clearer view of the ovaries.

For more information, visit CancerQuest's page on ultrasounds.

• BiopsyA medical procedure in which a sample of tissue is removed for examination. Biopsies can range from a small sample drawn into a needle to samples taken during more invasive surgery.

If the doctor is concerned about any lumps or changes in size/shape of an existing lump, a biopsy may be performed to detect cancer cells. In this procedure, tissue or fluid is removed from the pelvis or abdomen. There are two primary ways to perform a biopsy for ovarian cancer:

1. Laparotomy - The surgeon cuts into the abdomen and examines the abdominal organs. The patient is usually given general anesthesia.
2. Laparoscopy - The surgeon inserts a thin tube through a small cut in the abdomen. This procedure can be used to remove small benign cysts or ovarian cancer in its early stages. Furthermore, it can be used to see if the cancer has spread into other areas.

For more information, visit CancerQuest's page on biopsies.

• Blood tests

Some ovarian cancers produce proteins that can be detected in the blood. The proteins, which are indicators of cancer, are called ‘biomarkers’. There are several ovarian cancer biomarkers that are currently being researched.

• Examples of other tests that have been approved by the FDA to assist in the detection of ovarian cancer:
  • ROMA - Risk of Ovarian Malignancy Algorithm (ROMA) uses serum levels of Human Epididymis proteinOne of the four basic types of biomolecule. Proteins are polymers made up of strings of amino acids. Proteins serve many functions in organisms including transport of molecules, structure, cell adhesion and as signaling molecules such as hormones. Many transcription factors, including p53 and Rb are proteins. 4 (HE4) and CA125, which are often overexpressed in ovarian cancer, to assess the risk of malignancy in patients with a confirmed pelvic mass. (9)
  • OVA-1 - OVA-1 combines results from five tests (CA-125A glycoprotein secreted by some ovarian cancers into the bloodstream. The protein can be detected in the blood and is used to monitor the progression of those cancers. CA-125 levels may also rise in response to inflammation even if cancer is not present. II, prealbumin, apolipoprotein A-1, β2-microglobulin, and transferrin) to assess the likelihood of malignancy in women with an ovarian mass. (8)

For more information on the CA-125 test, visit CancerQuest's page on CA-125 test.

• CT scans

For information, visit CancerQuest's page on CT scans.

• MRIAlso: nuclear magnetic resonance imaging (NMR). Magnetic Resonance Imaging is a non-invasive imaging procedure that utilizes strong magnets and radio waves to visualize tissues. Subtle differences in the ways that the tissues and organs absorb and reflect the waves enable the detection of many different disorders.

For information, visit CancerQuest's page on MRI scans.

• PET scans

For information, visit CancerQuest's page on PET scans.

If cancer is found, additional tests may be conducted to determine the location of the cancer and the extent of the cancer's development.

Note: Ovarian cysts may develop on the external surface or within the ovaries; most cysts do NOT indicate the presence of cancer. Cysts typically decrease in size with time; if a cyst continues to grow it should be examined by a physician and possibly biopsied to rule out cancer. Patients should always alert their doctors to any abnormalities they detect and mention changes that occur over time. (7). 

Staging allows doctors to figure out the degree to which the cancer has spread (metastasized) so that they will be able to assign a proper course of treatment. Staging is most often done during surgery, where a surgical oncologist takes tissue samples from targeted regions, such as the pelvis and abdomen, for analysis10.

There are 2 staging systems used for ovarian cancer. These systems categorize ovarian cancer based on the extent of the tumor.

1. TNM staging - For information on TNM staging, visit CancerQuest's page on TNM staging.
2. FIGO staging - For information on FIGO staging, visit National Cancer Institute's page on the FIGO staging system.

The following is a general summary of the stages of ovarian cancer.17

• Stage I – Cancer cells are found on the outer surface of one or both ovaries.
• Stage II – Cancer cells are found in one or both ovaries and have spread (metastasized) to the bladder, colon, rectum, or uterus.
• Stage III – Cancer cell are found in one or both ovaries and has spread (metastasized) to the abdominal lining or the lymph nodesA grape-like cluster of lymphatic tissue. Lymph nodes (or lymph glands) filter the lymph fluid that flows through the lymphatic system. Lymph nodes collect fluid from discrete regions of the body and are often examined for the presence of metastasizing cancer cells..
• Stage IV – This is the most advanced stage of ovarian cancer. Cancer cells are found in one or both ovaries and has spread (metastasized) to the lung, liver, or other distant organs.

BRCA1 and BRCA2 genes

Genetic changes that may lead to cancer include mutations of key regulatory genes, changes in protein products, and changes in the amount of products produced by genes (gene expressionThe act of transcription and, if needed, translation of a gene. Regulation of gene expression is tightly regulated. Genes must only be expressed in the correct cells, at the right time and in the correct amount. Abnormal gene expression is always found in cancer cells.). As these changes accumulate, cells become increasingly abnormal, resulting in cancer progression. Details on genetic changes that are associated with cancer can be found in the Mutation section.

The genes that are most frequently associated with ovarian cancer are the BRCA1 and BRCA2 genes. BRCA1 and BRCA2 mutations are also implicated in breast cancer (male and female), prostate cancer, and pancreatic cancer. Note that having a BRCA mutation does not mean an individual will definitely develop cancer. Rather, studies show that a BRCA mutation increases the risk of developing certain types of cancer.

• General information on BRCA1 and BRCA2 genes

The BRCA1 and BRCA2 genes are important tumor suppressorA gene that functions in the control of cell division. Tumor suppressors normally work to limit cell division and may be contrasted with oncogenes. genes that are involved in the repair of damaged DNAAbbreviation for deoxyribonucleic acid. Composed of very long strings of nucleotides, which are abbreviated as A, C, G and T. DNA is the storage form of our genetic material. All of the instructions for the production of proteins are encoded in our DNA. . More information on cancer genes can be found in the Cancer Genes section.

BRCA mutations are responsible for 90% of hereditary ovarian cancer cases as well as 84% of hereditary breast cancer cases 18. However, the high percentages do not mean that BRCA mutations are common; the general population's risk of developing ovarian cancer is 1%-2%.

BRCA1 and BRCA2 mutations are germline mutations, which means the mutations are found in the DNA of eggs and sperms and can therefore, be passed down from parent to child. If an individual has a germline mutation in BRCA1, her risk of developing ovarian cancer increases from the general population's risk of (1%-2%) to 24%-40%. If an individual has a germline mutation in BRCA2, her risk of developing ovarian cancer increases from the general population's risk (1%-2%) to 11%-18%. Individuals who have 2 mutated copies of BRCA1 or 2 mutated copies of BRCA2 (homozygous for a BRCA1 or BRCA2 mutation) are at a higher risk of developing ovarian cancer than individuals who have 1 mutated copy of BRCA1 or 1 mutated copy of BRCA2 (heterozygousThe state of having two different forms (alleles) of any particular gene. Humans have two full sets of genes, one obtained from each parent. Although the each set has the same genes, they may not be exactly the same forms for each gene. Variations in the genes give us a wide range of different characteristics. Examples would be genes involved in the production of pigments. Variations in expression of these genes give us black, brown, blonde or red hair and all the colors in between. When the versions of a gene received from both parents are the same, the genes are said to be homozygous. When they are different then the genes are heterozygous. Homo- and hetero- refer to same and different, respectively and -zygous refers to the formation of a zygote or embryo. for a BRCA1 or BRCA2 mutation). Studies suggest that approximately 10% of women who have epithelial ovarian cancer have a germline mutation in either BRCA1 or BRCA2.19, 20

The penetrance (cancer risk) of germline mutations in BRCA1 and BRCA2 is still an ongoing area of research. This is because of the significant variability that exists between ovarian cancer cases; some individuals with a cancer-related germline mutation may never develop cancer or they may develop cancer at a later age compared with other individuals with that same cancer-related germline mutation.

• Genetic Testing for BRCA: Overview

Individuals may choose to be tested for BRCA mutations. By doing so, they will be informed of their risks for developing breast cancer, ovarian cancer, etc., and will be educated on preventive measures that may help them decrease their risks. Prior to any genetic testing, a patient must provide their informed consent in order for the test to be conducted. Genetic counselors, who are trained healthcare providers, will be present to help patients through the genetic testing process. The following are some of the main things genetic counselors do:

• Consult with patients to determine if a genetic test is necessary.
• Analyze and interpret the data from a genetic test to assess a patient's risk.
• Assist patients with the emotional and psychological toll that may be associated with genetic testing.
• Genetic Testing for BRCA: Stages

The BRCA testing process is typically separated into two stages.

1. First stage - blood is drawn from the patient. The DNA from the white blood cells will then be analyzed in a laboratory to identify possible BRCA mutations.
2. Second stage - this stage is similar to the first stage except blood is drawn from the patient's family members.21

Biomarkers

A biomarkerA biological indicator for a disease or process , for example, the level of a specific protein in the blood that goes up when a disease is present. is something that indirectly indicates the presence of a disease (or the potential for a disease). An example of a biomarker is cholesterolA type of lipid, cholesterol is part of a group of molecules called steroids. Cholesterol is essential for the structure and function of our cellular membranes. Testosterone and estrogen are other steroids that are very similar to cholesterol in structure. found in the blood. Measurements of blood cholesterol levels serve as indicators for cardiovascular health.

Ongoing studies are being conducted in the field of ovarian cancer biomarkers. The following are some examples of potential therapeutic biomarkers for ovarian cancer.

• FGF18 - The FGF18 gene encodes for the FGF18 protein, which is a growth factorA substance that stimulates cell division. Growth factors are usually small proteins or steroid hormones. They may be secreted by the same cells on which they act or by cells that reside in a different part of the body than the target cells. Some examples of growth factors include estrogen, a growth factor for breast cells, and VEGF, a growth factor that causes the development of blood vessels. Several different anti-cancer treatments are designed to inhibit the activity of growth factors. involved in a variety of cellular activities. Although the exact mechanism of FGF18's role in ovarian cancer is still unknown, studies have linked FGF18 overexpressionA term describing the abnormal regulation of a gene. When the controls on gene expression (transcription) break down, the gene may be turned off inappropriately, or it may be transcribed at high rates. High transcription levels lead to the production of large amounts of mRNA and large amounts of the protein product. If that protein is important in regulating cell division or some other key process, then too much protein can lead to unregulated cell division. An example is the overexpression of the Her2/neu protein on the surface of some breast and ovarian cancers. The presence of large amounts of this protein increases abnormal cell division. and gene amplificationAlso: gene amplification. An abnormal process in which many copies of the same chromosome region are produced via DNA replication. The result can be a small 'microsatellite' chromosome or a region of DNA within a chromosome with many contiguous copies of a small set of genes. to approximately half of high-grade serous tumor cases. Studies suggest that increased levels of FGF18 protein may promote tumor growth via upregulation of the NF-kB pathway - one of the pathways implicated in ovarian cancer development. The upregulation of the NF-kB pathway leads to increased cytokine and chemokine signaling, which can lead to enhanced tumor growth.22
• HE4 - The HE4 gene encodes for the human epididymis protein, HE4. Studies have found that the HE4 protein is overexpressed in ovarian cancer. When testing for ovarian cancer tumors, HE4 can complement the commonly used ovarian cancer biomarker, cancer antigenAny substance capable of being recognized by the immune system. Recognition of such a substance leads to the generation of an immune response. 125 (CA 125), in order to increase the specificity and sensitivity of the biomarker detection technique.23, 24

The increase in interest in epigenetics has led to the discovery of a new type of biomarker: DNA methylation-based biomarkers. EpigeneticGene expression can be altered by changes to the DNA and chromatin that do not change the DNA sequence, and are termed epigenetic changes. Two types are: Methylation: where some DNA nucleotides are modified by the addition of a methyl (-CH3) group. Methylation of DNA is associated with the inactivation of that particular region of DNA. Abnormal DNA methylation patterns have been seen in cancer cells. Acetylation: histone proteins around which the DNA is wound are modified by the addition of acetyl (-CH3CHO) groups. This loosens the DNA:histone interaction and is associated with increased gene expression. Understanding the addition and removal of acetyl groups to DNA is an active area of cancer treatment research. changes do not change the DNA sequence, but they affect how the genes function. DNA methylation, a type of epigenetic change, makes a region of genes stop working (inactivated). However, there are some hurdles to overcome in the study of epigenetics. Regarding DNA methylation-based biomarkers, studies are still ongoing as researchers try to figure out ways to distinguish between DNA methylations that are associated with cancer from DNA methylations that are simply associated with age. 25The following are some examples of DNA methylation-based biomarkers for epithelial ovarian cancer, the most prevalent form of ovarian cancer.26

• BRCA1 - hypermethylation of this gene's promoterThe portion of a gene that controls when and how much that particular gene will be expressed (transcribed). Promoters are likened to an on/off switch that determines the activity of a gene. Promoters do not control gene activity themselves, they work by binding to proteins called transcription factors. The transcription factors act as flags to wave down the enzymes (RNA polymerases) that make RNA copies of the genes. Changes (mutations) in the promoter portion of a gene can lead to disruptions in the regulation of gene expression. These changes are often seen in cancer. is found in 10-15% of sporadic ovarian cancer cases and is linked to loss of gene expression
• HOXA9 - hypermethylation of this gene's CpG island promoter is found in many cancer types, such as ovarian cancer, bladder cancer, and neuroblastoma.
• MLH1 - methylation of this gene's promoter is partly responsible for the impairment of the mismatch repair pathway, which results in the resistance of epithelial ovarian cancer cells to platinum-based treatments, such as cisplatin.

Treatment

Cancer Quest's focus is on the cancer's biology and the biology of possible treatments. Brief descriptions of some ovarian cancer treatments can be found below. For more detailed references of ovarian cancer treatments and guidelines, visit:

• How cancer treatments work: CancerQuest's section on Cancer Treatments
• Information regarding clinical trials:
  • General clinical trial information from CancerQuest
  • Clinical trials at Winship Cancer Institute of Emory University
  • Clinical trials from the National Cancer Institute.
  • Clinical trials from Georgia Clinical Trials Online.

Treatments for ovarian cancer include surgery, chemotherapyTreatment of cancer patients with anticancer drugs. Commonly called 'chemo'. These drugs work by attacking cell growth or division. Often these agents are used in combination to take advantage of their different modes of attack on cell division., and radiationIn cancer biology: A cancer treatment in which high energy beams are used to kill cancer cells. Radiation can also cause genetic damage that can lead to cancer. As an example, skin cancer is believed to be greatly increased by exposure to ultraviolet (UV) radiation from the sun..27 The paragraphs below describe several treatment options. The treatment that any particular patient receives will be determined by the patient and physician and depend on many factors.

Introduction

• Ovarian cancer is the 5th leading cause of death in women.
• Approximately 50% of women who are diagnosed with ovarian cancer are above the age of 62.

Types of Ovarian Cancer

• There are 3 main types of ovarian tumors: epithelial tumors, germ cell tumors, and stromal tumors.
• Epithelial tumors are the most common type of ovarian tumors and form on the surface of the ovaries.

Risk Factors

• Women who have one or more family members who have or had ovarian cancer, breast cancer, uterine cancer, colon cancer, or rectal cancer are at an increased risk of developing ovarian cancer.
• Women are genetically predisposed to ovarian cancer if they have inherited mutations in the BRCA1 and/or BRCA2 genes.
• Other risk factors include: age, body-mass-index (BMI), hormone replacement therapy (HRT) usage, and more.

Symptoms and Detection

• Early stages of ovarian cancer typically do not produce symptoms.
• Several medical tests can be used to detect or rule out ovarian cancer. Examples include: physical exams, CT scans, PET scans, and ultrasound scans, MRI scans, biopsies, and blood tests.

Staging and Pathology

• Two staging systems are used for ovarian cancer: TNM system and FIGO system.
• The T/N/M system assigns a degree of severity based on the size and location of the cancer.
• The FIGO system is another system used to stage the cancer based on tumor histology and how the cancer has spread.

Treatments

• Treatments depend on the patient's age, patient's health conditions, cancer stage, and type of ovarian cancer.
• Treatments can include local therapy, chemotherapy, and radiation therapy.