Facts and figures
Risk groups, BRCA, Treatment options
Introduction
When there are several cases of ovarian, breast and/or colon cancer in a family, this is known as familial clustering. In these cases, it is believed that the disease could be caused by an alteration in the genetic makeup.
The genome is the blueprint that contains all the information about how a person’s body should look and work. Genes are located on DNA strands inside the nucleus of every single cell in a person’s body. These DNA strands are organized into individual chromosomes. And sometimes the genetic blueprint is flawed and allows individual genes to be altered, i.e. mutated.
Gene mutations
Cancer is the general term used to describe malignant tumors that form from altered cells. These cell alterations have their root in the alterations (mutations) of individual genes. In general we differentiate between two types of such gene mutations. In the case of acquired mutations, genetic alterations in individual cells develop over the course of a person’s life, which can lead to cell proliferation, which leads to malignant tumors, a.k.a. cancer. These sorts of genetic alterations can be caused by stresses from our environment such as chemical substances or ionizing (radioactive) rays. However, the causes are often unclear. Most cases of ovarian cancer are caused by acquired mutations.
“When just one parent carries the mutated gene, there is a 50% chance that parents will pass on the mutation to their children”
In roughly 20% of cases, ovarian cancer is triggered by a germline mutation. Unlike acquired changes, which are only present in the diseased tissue, germline mutations are present in every single cell of a person’s body. When just one parent carries the mutated gene, there is a 50% chance that parents with a gene alteration in the germline will pass on these altered (mutated) genes to their children. If both mother and father carry the mutated gene, there is a 100% chance that the gene will be passed on to their children.
Today, in certain cases, people can find out whether they carry a mutation that could lead to cancer. The first step is genetic counseling, during which all the relevant information about a person’s family history is collected. This helps determine whether it makes sense to do genetic testing.
There are several syndromes that can lead to familial clustering of cancer diseases, including Lynch syndrome and Cowden syndrome. The most common type of hereditary cancer is HBOC, a.k.a. Hereditary Breast and Ovarian Cancer syndrome. There are various gene mutations that cause HBOC and increase a person’s risk of ovarian or breast cancer.
Two of them are especially important. Considered high-risk mutations, they go by the abbreviations BRCA1 and BRCA2 (BReast Cancer Antigen 1 and 2) and are located as building blocks on chromosome 17 and chromosome 13, respectively. If the BRCA1 and BRCA2 repair genes do not work properly due to a mutation, it may aid the development of cancer.
Source: wikipedia.org/wiki/BRCA_mutation (CC BY-SA 4.0)
Women whose close relatives have or have had breast, ovarian, colon, pancreatic or lung cancer can get tested to find out whether they have mutated forms of BRCA genes. If they do, they have a higher likelihood of developing ovarian and breast cancer over the course of their lifetime. BRCA mutations are more common in some population groups. For example, they affect 3% of the Ashkenazi Jewish population.
HBOC syndrome caused by BRCA1 and BRCA2 mutations
Risk and age
When it comes to risk assessment and genetic testing, age is key. The following graph shows the close relationship between a women’s age and her risk of disease. The older the woman, the higher the risk. For women who carry the gene mutation, the risk of developing breast cancer suddenly jumps up sharply in their mid-20s. With ovarian cancer, the curve begins around age 40 and is somewhat flatter.
There is a correlation between the type of mutation (BRCA1 or 2), a woman’s age and her risk. There is about the same risk of developing breast cancer with BRCA1 and 2. However, the risk of developing ovarian cancer is lower with BRCA2 than with BRCA1.
It may be useful to get genetic counseling and testing if:
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You have two or more first-degree relatives with breast or ovarian cancer, especially before age 50. Close relatives are mothers, sisters and daughters.
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You develop the disease at a very young age (before age 50)
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You have a close relative with more than one tumor, e.g. bilateral breast cancer or breast and ovarian cancer
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You have male family members with breast cancer
A familial clustering of tumors and the relationship of the affected family members can be made clear when mapped out in a family tree. If you think there may be a cluster in your family, you can download and fill out these forms for yourself.
However, a cluster of tumors does not necessarily mean that abnormal genes are present. And not all women who have a mutation end up developing cancer.
If you think that you have a conspicuous family history, talk to your primary care physician, gynecologist or oncologist. They can refer you and your family members for genetic counseling. Or contact a specialized center directly.
Places to go for consultation include private and public hospitals, specialist doctors trained in genetic counseling, as well as the SAKK database (SAKK = Swiss Working Group for Clinical Cancer Research)
Genetic counseling
Genetic testing
According to Switzerland’s Federal Law on Human Genetic Testing (GUMG), genetic testing can only be performed after an in-depth consultation by a specialist doctor. At the consultation, the doctor will determine whether genetic testing makes sense in your case, explain how the genetic test works, whether your health insurance provider will cover the cost of testing (you must submit a request for an assumption of costs (a.k.a. Kostengutsprache)), and what the results of the mutation analysis may mean for you and your family.
Blood Sample
ca. 4-week wait period
Meeting to discuss results
Lab analysis
As described above, the BRCA1 and BRCA2 genes (i.e. their proteins) play a major role in repairing damages to DNA. However, other genes and factors influence DNA repair, allowing the tumor to exhibit genomic instability even though the BRCA1 and BRCA2 genes are not affected by a mutation. The new HRD tests (HRD = homologous recombination repair deficiency) measure the genomic instability of diseased women directly in their tumor tissue (either on the surgical specimen or on a biopsy). Information about the BRCA1/2 and HRD status help determine which type of therapy to pursue. In particular, to determine whether it makes sense to perform therapy with PARP inhibitors.
Assumption of costs
Genetic testing also raises many other questions: Do I even want to know if I have these mutations in the first place? What does it mean for my life, my children or my family? When you are at a genetic counseling appointment, do not hesitate to ask all the questions on your mind. The consultants are experienced and can help you find order in the chaos of your thoughts.
When the Swiss guidelines for genetic counseling and testing of the SAKK are met, the costs for genetic counseling and possible genetic testing (minus your deductible and 10% retention) must be covered by your health insurance provider. Usually the assumption of costs is obtained before the test.
Determining the age at which family members should undergo genetic counseling and testing is a balancing act: between causing unnecessary anxiety and acknowledging a person’s right to know. A consultation can help understand one’s own family situation better and then make specific decisions.
Talk to your genetic counselor to find out what the test results mean for you and what your next steps might be. It is not mandatory to inform your family if you are a BRCA mutation carrier, but it can be useful since other relatives may want to get tested for it.
Source: SAKK guidelines for genetic counseling in the case of hereditary breast and ovarian cancer
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The cancer risk is determined by the person’s own health and family history.
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Early detection and prevention measures are determined based on the person’s own health and family history.
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Family members: there is no medical reason for testing.
An alteration with unknown significance has been detected
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A family member with the disease has a BRCA1 or 2 mutation, but not you. The risk of developing cancer is 1.5–2.5%.
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Early detection and prevention measures are performed during regular check-ups.
No mutation has been detected
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The risk of developing cancer is higher. With a BRCA1 mutation, it is up to 46% higher; with a BRCA2 mutation, up to 23%.
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Talk to your doctor about the mutation, early detection and prevention options as well as your fears.
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Family members can get specific testing.
A mutation has been detected
Possible test results and what they mean
Prophylactic surgery:
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Prophylactic surgery involving the bilateral removal of the ovaries and fallopian tubes, and possibly also the uterus from age 40 on, can be discussed. This reduces the risk of developing ovarian cancer to one percent. The timing of this surgery is decided on an individual basis. The patient should no longer have the desire to conceive, because removing the ovaries immediately induces menopause in the patient, which usually occurs in women between 45 and 55 years of age (on average at age 50). When removing the ovaries, it is usually possible to avoid an abdominal incision, as the procedure can be performed via laparoscopy, which is minimally invasive.
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This operation also reduces the risk of breast cancer by 50–60% because the hormone estrogen is no longer produced.
Medication:
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Both hormonal contraceptives and IUDs can reduce the risk of ovarian cancer (when used for more than five years).
Talk with the doctor who is treating you about these options in order to find the best solution. In terms of your personal and family situation, consulting the experts cannot be replaced. It is the only way you can be sure to make responsible decisions.
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Gynecological check-ups – Pap smear: Many women believe that a negative Pap smear means there are no gynecological cancers. The sample is taken on outer part of the cervix and only provides information about that particular part.
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Gynecological check-ups – vaginal ultrasound: It is not part of routine screening, but can make sense in certain cases. There are no scientific data showing that regular ultrasound exams of healthy women lead to prolonged survival if they develop ovarian cancer.
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CA 125 test. CA 125 is a tumor marker that can be measured in the blood. CA 125 is found in over 80% of ovarian tumor cells. There is no benefit to testing healthy women regularly for CA 125: a normal CA 125 level does not mean an absence of ovarian cancer; an elevated CA 125 level does not mean the presence thereof. The significance of an elevated marker depends on the stage of cancer at the time of diagnosis. In the early stages, it is only elevated for around half of women with the disease. Regular testing is above all useful for monitoring the progress of ovarian cancer treatment – not for early detection of the disease.
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For women without any symptoms, neither MRIs (magnetic resonance imaging) nor CT scans are suitable for detecting early-stage ovarian cancer. Furthermore, performing MRIs and CT scans is costly and, in the case of CT scans, involves radioactive irradiation.
Prevention:
There is no single reliable method for early detection. Since the symptoms of the disease are non-specific, ovarian cancer is diagnosed in the late stages in many women. That’s how ovarian cancer earned a reputation as the “silent killer”. This is what is medically possible:
Early detection and prevention
Ovarian cancer treatment approaches
Approaches to ovarian cancer treatment are very similar, if not identical, in most centers for gynecologic oncology. Naturally, it is possible that there are small deviations in the assessment and therapy process from center to center, but the concept is always the same.
Once ovarian cancer is suspected, there are a number of assessments to perform. These include routine gynecological check-ups as well as transvaginal and transabdominal ultrasound exams. A clinical internal exam of the patient determines her global health in order to judge whether she is healthy and robust enough to undergo complex treatments such as extensive surgery and chemotherapy. A CT scan of the abdomen and chest cavity, a colonoscopy as well as blood tests (for general blood levels indicating the function of the internal organs and tumor markers) support the suspected diagnosis of ovarian cancer and provide a first assessment of the state of the tumor.
The tumor board review – specialists consult together
Then the patient’s findings are discussed for the first time at a tumor board review. The tumor board review is a meeting in which all specialists for gynecologic cancer diseases (gynecologists, abdominal surgeons, radiologists, pathologists, internal oncologists, radiation oncologists, etc.) take part. During this meeting, the specialists determine whether the patient will undergo primary surgery and, if necessary, be treated with chemotherapy, or be treated with chemotherapy first and get surgery later.
Primary surgery is chosen in most cases
Primary surgery is chosen in most cases. This type of surgery entails a midline incision of the abdomen to perform a complete assessment of the person’s organs, removal of the uterus and ovaries, removal of the greater omentum and, depending on the situation, removal of parts of the intestines, removal of the diaphragm or lymph nodes; and, rarely, removal of the spleen or parts of the liver. The idea is to remove all identifiable diseased tissue, ensuring that none of it is left behind. It is possible to do in most but not all cases.
The pathologist studies the tissue that has been removed to make the definitive, detailed diagnosis. Once this information is available, the tumor board specialists convene and determine whether the patient should also undergo chemotherapy (usually with platinum and taxane). Depending on the situation, they may recommend other therapies as well (bevazicumab, PARP inhibitors, etc.). The possibility of participating in scientific studies may also be considered. After each tumor board presentation, the recommendation is discussed with the patient and, if necessary, her relatives before the next steps are taken.
When treatment begins with chemotherapy
When treatment begins with chemotherapy, after three months the tumor board discusses and evaluates how the treatment has progressed, and usually surgery is performed afterwards.
The path that is taken depends on a variety of factors and needs to be discussed on a case-by-case basis. From an oncological perspective we know today that both paths have the same likelihood of ensuring survival, so individual factors (age, comorbidities, the probability that a full tumor removal is possible, etc.) are of utmost importance.
Once the primary treatment (surgery plus chemotherapy) is finished, then the patient is monitored for five years. That means gynecological checks every three months for the first two years and then every six months for another three years. After five years the patient can switch to annual check-ups.
If the cancer comes back, it makes sense to perform a clinical, serological (e.g. CA 125 test) and radiological (e.g. CT scan) assessment of the situation. With this information, your treatment team can recommend the possible next steps. Often, the recommendation is to perform another surgery followed by another round of systemic therapy.
The SOLO and PRIMA clinical studies have shown that BRCA1 mutations, BRCA2 mutations or genomic instability (HRD positive) are characteristics relevant to deciding whether maintenance chemotherapy with PARP inhibitors is recommended. In the SOLO study the BRCA mutation was used as a stratification criterion while in the PRIMA study it was the HRD deficiency regardless of BRCA status.
PARP inhibitors are a targeted cancer therapy in which the cancer cells destroy themselves. They can only be given as maintenance therapy after the therapy for ovarian cancer relapse. Currently, there are three PARP inhibitors approved for treatment of recurrent ovarian cancer: olaparib (Lynparza), niraparib (Zejula) and rucaparib (Rubraca).