BREAST CANCER SCREENING

Breast cancer screening is the medical screening of asymptomatic, apparently healthy women for breast cancer in an attempt to achieve an earlier diagnosis. The assumption is that early detection will improve outcomes. A number of screening tests have been employed, including clinical and self breast exams, mammography, genetic screening, ultrasound, and magnetic resonance imaging.

A clinical or self breast exam involves feeling the breast for lumps or other abnormalities. Medical evidence, however, does not support its use in women with a typical risk for breast cancer.

The use of mammography in universal screening for breast cancer is controversial as it may not reduce all-cause mortality and for causing harms through unnecessary treatments and medical procedures. Many national organizations recommend it for most older women. If screening mammography (as opposed to diagnostic mammography, which is used in a woman with symptoms that suggest breast cancer) is chosen for women at normal risk for breast cancer, it should only be done every two years in women between the ages of 50 and 74. Several tools are available to help target breast cancer screening to older women with longer life expectancies. Similar imaging studies can be performed with magnetic resonance imaging.

Earlier, more aggressive, and more frequent screening is recommended for women at particularly high risk of developing breast cancer, such as those with a confirmed BRCA mutation, those who have previously had breast cancer, and those with a strong family history of breast and ovarian cancer.

Abnormal findings on screening are further investigated by surgically removing a piece of the suspicious lumps (biopsy) to examine them under the microscope. Ultrasound may be used to guide the biopsy needle during the procedure. Magnetic resonance imaging is used to guide treatment, but is not an established screening method for healthy women.

Breast examination (either clinical breast exams (CBE) by a health care provider or by self exams) were once widely recommended. They however are not supported by evidence and may, like mammography and other screening methods that produce false positive results, contribute to harm. The use of screening in women without symptoms and at low risk is thus controversial.

A 2003 Cochrane review found screening by breast self-examination or by clinical exam is not associated with lower death rates among women who report performing breast self-examination and does, like other breast cancer screening methods,

increase harms, in terms of increased numbers of benign lesions identified and an increased number of biopsies performed. They conclude "screening by breast self-examination or physical examination cannot be recommended."

Mammography

Mammography is a common screening method, since it is relatively fast and widely available in developed countries. Mammography is a type of radiography used on the breasts. It is typically used for two purposes: to aid in the diagnosis of a woman who is experiencing symptoms (called diagnostic mammography), and for medical screening of apparently healthy women (called screening mammography).

Mammography is not very useful in finding breast tumors in dense breast tissue characteristic of women under 40 years. In women over 50 without dense breasts, breast cancers detected by screening mammography are usually smaller and less aggressive than those detected by patients or doctors as a breast lump. This is because the most aggressive breast cancers are found in dense breast tissue, which mammograms perform poorly on.

The presumption was that by detecting the cancer in an earlier stage, women will be more likely to be cured by treatment. This assertion however has been challenged by recent reviews which have found the significance of these net benefits to be lacking for women at average risk of dying from breast cancer.

Effectiveness

On balance, screening mammography in older women noticeably increases medical treatment and saves a small number of lives. Usually, it has no effect on the outcome of the cancer. Screening targeted towards women with above-average risk produces more benefit than screening of women at normal or low risk for breast cancer.

Firstly, some argue that its effect on the reduction of breast cancer mortality is overestimated. According to a clinical study conducted in Norway in 2010, screening mammography helped reduce the rate of death of breast cancer by about 2.4 deaths per 100,000 person-years among women between the ages of 50 and 69 years in the screening group compared with the non-screening group, which is accounted for only about a third of the total reduction. The Cochrane Collaboration review found a 15% reduction in mortality, but the absolute reduction in breast cancer mortality was 0.05%. Furthermore,a study published on the Preventive Medicine indicated that the magnitude of such effect might be overestimated in actual communities compared with the result predicted in randomized controlled trials due to factors such as increased self-selection rate among women concerned and increased effectiveness of adjuvant therapies. Secondly, due to the harm from false positive screening and increased mortality from treatment complications, they could not conclude whether screening did more harm than good. The Nordic Cochrane Collection (2012) reviews updated research to state that advances in diagnosis and treatment might make

mammography screening less effective today. They concluded that screening is “no longer effective ” and “it therefore no longer seems reasonable to attend”for breast cancer screening at any age, and warn of misleading information on the internet.

A 2011 Cochrane review estimated that mammography in women between 50 and 75 years old results in a relative risk reduction of death from breast cancer of 15% or an absolute risk reduction of 0.05% (however when analysis just the least biased trials there was no change in either overall mortality or breast cancer related mortality). Those who have mammograms however end up with increased surgeries, chemotherapy, radiotherapy and other potentially procedures resulting from the over-detection of harmless lumps. Many women will experience important psychological distress for many months because of false positive findings. Half of suspicious findings will not become dangerous or will disappear over time. Consequently, the value of routine mammography in women at low or average risk is controversial.[9]

With unnecessary treatment of ten women for every one woman whose life was prolonged, the authors concluded that routine mammography may do more harm than good.[9] The Nordic Cochrane Collection (2012) reviews updated research to state that advances in diagnosis and treatment make mammography screening less effective today. They state screening is “no longer effective.” They conclude that “it therefore no longer seems reasonable to attend” for breast cancer screening at any age, and warn of misleading information on the internet.[10] The review also concluded that "half or more" of cancers detected with mammography would have disappeared spontaneously without treatment. They found that most of the earliest cell changes found by mammography screening (carcinoma in situ) should be left alone because they would not have progressed into invasive cancer.[10]

If 1,000 women in their 50s are screened every year for ten years, the following outcomes are considered typical in the developed world:

One woman's life will be extended due to earlier detection of breast cancer. 2–10 women will be overdiagnosed and needlessly treated for a cancer that

would have stopped growing on its own or otherwise caused no harm during the woman's lifetime.

5–15 women will be treated for breast cancer, with the same outcome as if they had been detected after symptoms appeared.

250–500 will be incorrectly told they might have breast cancer (false positive). 125–250 will undergo breast biopsy.

The outcomes are worse for women in their 20s, 30s, and 40s, as they are far less likely to have a life-threatening breast cancer, and more likely to have dense breasts that make interpreting the mammogram more difficult. Among women in their 60s, who have a somewhat higher rate of breast cancer, the proportion of positive outcomes to harms are better:[12]

For women in their 40s: 2,000 women would need to be screened every year for 10 years to prevent one death from breast cancer. 1,000 of these women would experience false results and 250 healthy women would undergo unnecessary biopsies.

For women in their 50s: 1,339 women would need to be screened for every year for 10 years to prevent one death from breast cancer. Half of these women would experience false positives and one quarter would undergo unnecessary biopsies.

For women in their 60s: 377 women would need to be screened for every year for 10 years to prevent one death from breast cancer. Half of these women would experience false positives and one quarter would undergo unnecessary biopsies.

Mammography is not generally considered as an effective screening technique for women at average or low risk of developing cancer who are less than 50 years old. For normal-risk women 40 to 49 years of age, the risks of mammography outweigh the benefits,[13] and the US Preventive Services Task Force says that the evidence in favor of routine screening of women under the age of 50 is "weak".[14] Part of the difficulty in interpreting mammograms in younger women stems from breast density. Radiographically, a dense breast has a preponderance of glandular tissue, and younger age or estrogen hormone replacement therapy contribute to mammographic breast density. After menopause, the breast glandular tissue gradually is replaced by fatty tissue, making mammographic interpretation much more accurate.

Recommendations

Recommendations to attend to mammography screening vary across countries and organizations, with the most common difference being the age at which screening should begin, and how frequently or if it should be performed, among women at typical risk for developing breast cancer. For example, in England, all women were invited for screening once every three years beginning at age 50, though this is transitioning to a start at age 47 by 2016.

Some other organizations recommend mammograms begin as early as age 40 in normal-risk women, and take place more frequently, up to once each year. Women at higher risk may benefit from earlier or more frequent screening. Women with one or more first-degree relatives (mother, sister, daughter) with premenopausal breast cancer often begin screening at an earlier age, perhaps at an age 10 years younger than the age when the relative was diagnosed with breast cancer.

As of 2009 the United States Preventive Services Task Force recommends that women over the age of 50 receive mammography once every two years.

The Cochrane Collaboration (2011) states that the best quality evidence neither demonstrates a reduction in either cancer specific, nor a reduction in all cause

mortality from screening mammography. When less rigorous trials are added to the analysis there is a reduction in breast cancer specific mortality of 0.05% (a relative decrease of 15%). Screening results in a 30% increase in rates of over-diagnosis and over-treatment, resulting in the view that it is not clear whether mammography screening does more good or harm. On their Web site, Cochrane currently concludes that, due to recent improvements in breast cancer treatment, and the risks of false positives from breast cancer screening leading to unnecessary treatment, "it therefore no longer seems reasonable to attend for breast cancer screening" at any age.

Medical ultrasonography is a diagnostic aid to mammography. Adding ultrasonography testing for women with dense breast tissue increases the detection of breast cancer, but also increases false positives.

Magnetic resonance imaging (MRI) has been shown to detect cancers not visible on mammograms. The chief strength of breast MRI is its very high negative predictive value. A negative MRI can rule out the presence of cancer to a high degree of certainty, making it an excellent tool for screening in patients at high genetic risk or radiographically dense breasts, and for pre-treatment staging where the extent of disease is difficult to determine on mammography and ultrasound. MRI can diagnose benign proliferative change, fibroadenomas, and other common benign findings at a glance, often eliminating the need for costly and unnecessary biopsies or surgical procedures. The spatial and temporal resolution of breast MRI has increased markedly in recent years, making it possible to detect or rule out the presence of small in situ cancers, including ductal carcinoma in situ.

However, breast MRI has long been regarded to have disadvantages. For example, although it is 27–36% more sensitive, it has been claimed to be less specific than mammography. As a result, MRI studies may have more false positives (up to 30%), which may have undesirable financial and psychological costs. It is also a relatively expensive procedure, and one which requires the intravenous injection of gadolinium, which has been implicated in a rare reaction called nephrogenic systemic fibrosis. Although NSF is extremely uncommon, patients with a history of renal disease may not be able to undergo breast MRI. Further, an MRI may not be used for screening patients with a pacemaker or breast reconstruction patients with a tissue expander due to the presence of metal.

Proposed indications for using MRI for screening include:

Strong family history of breast cancer Patients with BRCA-1 or BRCA-2 oncogene mutations Evaluation of women with breast implants History of previous lumpectomy or breast biopsy surgeries Axillary metastasis with an unknown primary tumor Very dense or scarred breast tissue

BRCA testing

Genetic testing does not detect cancers, but may reveal a propensity to develop cancer. Women who are known to have a higher risk of developing breast cancer usually undertake more aggressive screening programs.

A BRCA mutation is a mutation in either of the genes BRCA1 and BRCA2. Harmful mutations in these tumor suppressor genes produce a hereditary breast-ovarian cancer syndrome in affected families. Mutations in BRCA1 and BRCA2 are uncommon, and breast cancer is relatively common, so these mutations consequently account for only five to ten percent of all breast cancer cases in women.

Hundreds of different types of mutations in these genes have been identified. High-risk mutations, which disable an important error-free DNA repair process (homology directed repair), significantly increase the person's risk of developing breast cancer, ovarian cancer and certain other cancers. Why BRCA1 and BRCA2 mutations lead preferentially to cancers of the breast and ovary is not known, but lack of BRCA1 function seems to lead to non-functional x-chromosome inactivation. Not all mutations are high-risk; some appear to be harmless variations. The cancer risk associated with any given mutation varies significantly and depends on the exact type and location of the mutation and possibly other individual factors.

Women with harmful mutations in either BRCA1 or BRCA2 have risk of breast cancer that is about five times the normal risk, and a risk of ovarian cancer that is about ten to thirty times normal.

BRCA1 mutations typically confer a higher risk of breast and ovarian cancer in women than BRCA2 mutations. Having a high-risk mutation does not guarantee that the woman will develop any type of cancer, or guarantee that any cancer that appears was actually caused by the mutation, rather than some other factor, like alcohol consumption.

Mutations can be inherited from either parent and may be passed on to both sons and daughters. Each child of a genetic carrier, regardless of sex, has a 50% chance of inheriting the mutated gene from the parent who carries the mutation. As a result, half of the people with BRCA gene mutations are male. The risk of BRCA-related breast cancers for men with the mutation is higher than for other men, but still low. However, BRCA mutations can increase the risk of other cancers, such as colon cancer, pancreatic cancer, and prostate cancer.

Both BRCA genes are tumor suppressor genes that produce proteins that are used by the cell in an enzymatic pathway that makes very precise, perfectly matched repairs to DNA molecules that have double-stranded breaks.[8]:39–50[9] The pathway requires proteins produced by several other genes, including CHK2, FANCD2 and ATM.[10]

Harmful mutations in any of these genes disable the gene or the protein that it produces.

The cancer risk caused by BRCA1 and BRCA2 mutations are inherited in a dominant fashion even though usually only one mutated allele is directly inherited. This is because people with the mutation are likely to acquire a second mutation, leading to dominant expression of the cancer. A mutated BRCA gene can be inherited from either parent. Because they are inherited from the parents, they are classified as hereditary or germline mutations rather than acquired or somatic mutations. Cancer caused by a mutated gene inherited from an individual's parents is a hereditary cancer rather than a sporadic cancer.

Because humans have a diploid genome, each cell has two copies of the gene (one from each biological parent). Typically only one copy contains a disabling, inherited mutation, so the affected person is heterozygous for the mutation. If the functional copy is harmed, however, then the cell is forced to use alternate DNA repair mechanisms, which are more error-prone. The loss of the functional copy is called loss of heterozygosity (LOH).[12] Any resulting errors in DNA repair may result in cell death or a cancerous transformation of the cell.[8]:39–50

There are many variations in BRCA genes, and not all changes confer the same risks. [8]:39–50 Some variants are harmless; others are known to be very harmful. Some single nucleotide polymorphisms may confer only a small risk, or may only confer risk in the presence of other mutations or under certain circumstances. In other cases, whether the variant is harmful is unknown. Variants are classified as follows:[8]:39–50:109

Deleterious mutation: The change is proven to cause significant risks. Often, these are frameshift mutations that prevent the cell from producing more than the first part of the necessary protein.

Suspected deleterious: While nothing is proven, the variation is currently believed to be harmful.

Variant of unknown significance (VUS): Whether the change has any effect is unknown. This is a common test result, and most variations began in this category. As more evidence is acquired, these are re-classified.

Variant, favor polymorphism: While nothing is proven, the variation is currently believed to be harmless.

Benign polymorphism: The change is classified as harmless. These may be reported as "no mutation".

Deleterious mutations have high, but not complete, genetic penetrance, which means that people with the mutation have a high risk of developing disease as a result, but that some people will not develop cancer despite carrying a harmful mutation.

Getting tested

Indications

Genetic counseling is commonly recommended to people whose personal or family health history suggests a greater than average likelihood of a mutation. Genetic counselors are allied health professionals who are trained to explain genetics to people; some of them are also licensed as registered nurses or social workers. A medical geneticist is a physician who specializes in genetics. The purpose of genetic counseling is to educate the person about the likelihood of a positive result, the risks and benefits of being tested, the limitations of the tests, the practical meaning of the results, and the risk-reducing actions that could be taken if the results are positive. They are also trained to support people through any emotional reactions and to be a neutral person who helps the client make his or her own decision in an informed consent model, without pushing the client to do what the counselor might do. Because the knowledge of a mutation can produce substantial anxiety, some people choose not to be tested or to postpone testing until a later date.

Relative indications for testing for a mutation in BRCA1 or BRCA2 include a family history among 1st, 2nd, or 3rd degree relatives in either lineage (=cell line, homosigotic genomes) with any of the following:

Breast cancer diagnosed at age 50 or younger Ovarian cancer Multiple primary breast cancers either in the same breast or opposite breast in

an individual Both breast and ovarian cancer Male breast cancer Triple-negative (estrogen receptor negative, progesterone receptor negative,

and HER2/neu negative) breast cancer Pancreatic cancer with breast or ovarian cancer in the same individual or on the

same side of the family Ashkenazi Jewish ancestry Two or more relatives with breast cancer, one under age 50 Three or more relatives with breast cancer at any age A previously identified BRCA1 or BRCA2 mutation in the family

Testing young children is considered medically unethical because the test results would not change the way the child's health is cared for.

1. What are BRCA1 and BRCA2?

BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of the cell’s genetic material. When either of these genes is mutated, or altered, such that its protein product is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

Specific inherited mutations in BRCA1 and BRCA2 increase the risk of female breast and ovarian cancers, and they have been associated with increased risks of several additional types of cancer. Together, BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers (1) and about 5 to 10 percent of all breast cancers (2). In addition, mutations in BRCA1 and BRCA2 account for around 15 percent of ovarian cancers overall (3). Breast cancers associated with BRCA1 and BRCA2 mutations tend to develop at younger ages than sporadic breast cancers.

A harmful BRCA1 or BRCA2 mutation can be inherited from a person’s mother or father. Each child of a parent who carries a mutation in one of these genes has a 50 percent chance of inheriting the mutation. The effects of mutations in BRCA1 and BRCA2 are seen even when a person’s second copy of the gene is normal.

2. How much does having a BRCA1 or BRCA2 gene mutation increase a woman’s risk of breast and ovarian cancer?

A woman’s lifetime risk of developing breast and/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2.

Breast cancer: About 12 percent of women in the general population will develop breast cancer sometime during their lives (4). By contrast, according to the most recent estimates, 55 to 65 percent of women who inherit a harmful BRCA1 mutation and around 45 percent of women who inherit a harmful BRCA2 mutation will develop breast cancer by age 70 years (5, 6).

Ovarian cancer: About 1.4 percent of women in the general population will develop ovarian cancer sometime during their lives (4). By contrast, according to the most recent estimates, 39 percent of women who inherit a harmful BRCA1 mutation (5, 6) and 11 to 17 percent of women who inherit a harmful BRCA2 mutation will develop ovarian cancer by age 70 years (5, 6).

It is important to note that these estimated percentages of lifetime risk are different from those available previously; the estimates have changed as more

information has become available, and they may change again with additional research. No long-term general population studies have directly compared cancer risk in women who have and do not have a harmful BRCA1 or BRCA2 mutation.

It is also important to note that other characteristics of a particular woman can make her risk higher or lower than the average risks. These characteristics include her family history of breast, ovarian, and, possibly, other cancers; the specific mutation(s) she has inherited; and other risk factors, such as her reproductive history. However, none of these other factors is as strong as the effect of carrying a harmful BRCA1 or BRCA2 mutation.   

3. What other cancers have been linked to mutations in BRCA1 and BRCA2?

Harmful mutations in BRCA1 and BRCA2 increase the risk of several cancers in addition to breast and ovarian cancer. BRCA1 mutations may increase a woman’s risk of developing fallopian tube cancer and peritoneal cancer (7, 8). Men with BRCA2 mutations, and to a lesser extent BRCA1 mutations, are also at increased risk of breast cancer (9). Men with harmful BRCA1 or BRCA2 mutations have a higher risk of prostate cancer (10). Men and women with BRCA1 or BRCA2 mutations may be at increased risk of pancreatic cancer (11).

4. Do inherited mutations in other genes increase the risk of breast and/or ovarian tumors?

Yes. Mutations in a number of other genes have been associated with increased risks of breast and/or ovarian cancers (2, 12). These other genes include several that are associated with inherited disorders, such as Lynch syndrome and Li-Fraumeni syndrome, that increase the risk of many cancer types.

However, in nearly half of families with multiple cases of breast cancer and in up to 90 percent of families with both breast and ovarian cancer, their disease is caused by harmful mutations in BRCA1 or BRCA2.

5. Are mutations in BRCA1 and BRCA2 more common in certain racial/ethnic populations than others?

Yes. People of Ashkenazi Jewish descent have a higher prevalence of harmful BRCA1 and BRCA2 mutations than people in the general population. Other ethnic and geographic populations around the world, such as the Norwegian, Dutch, and Icelandic peoples, also have higher prevalences of specific harmful BRCA1 and BRCA2 mutations.

In addition, limited data indicate that the prevalence of specific harmful BRCA1 and BRCA2 mutations may vary among individual racial and ethnic

groups in the United States, including African Americans, Hispanics, Asian Americans, and non-Hispanic whites (13, 14).

6. Are genetic tests available to detect BRCA1 and BRCA2 mutations?

Yes. Several different tests are available, including tests that look for a known mutation in one of the genes (i.e., a mutation that has already been identified in another family member) and tests that check for all possible mutations in both genes. DNA (from a blood or saliva sample) is needed for mutation testing. The sample is sent to a laboratory for analysis. It usually takes about a month to get the test results.

7. Who should consider genetic testing for BRCA1 and BRCA2 mutations?

Because harmful BRCA1 and BRCA2 gene mutations are relatively rare in the general population, most experts agree that mutation testing of individuals who do not have cancer should be performed only when the person’s family history suggests the possible presence of a harmful mutation in BRCA1 or BRCA2.

In December 2013, the United States Preventive Services Task Force recommended that women who have family members with breast, ovarian, fallopian tube, or peritoneal cancer be evaluated to see if they have a family history that is associated with an increased risk of a harmful mutation in one of these genes (15).

Several screening tools are now available that doctors can use to help them with this evaluation (15). These tools assess family history factors that are associated with an increased likelihood of having a harmful mutation in BRCA1 or BRCA2, including:

Breast cancer diagnosed before age 50 years Cancer in both breasts Both breast and ovarian cancers Multiple breast cancers Two or more primary types of BRCA1- or BRCA2-related cancers

in a single family member Cases of male breast cancer Ashkenazi Jewish ethnicity

When an individual has a family history that is suggestive of the presence of a BRCA1 or BRCA2 mutation, it may be most informative to first test a family member who has cancer if that person is still alive and willing to be tested. If that person is found to have a harmful BRCA1 or BRCA2 mutation, then other family members may want to consider genetic counseling to learn more about their potential risks and whether genetic testing for mutations in BRCA1 and BRCA2 might be appropriate for them.

If it is not possible to confirm the presence of a harmful BRCA1 or BRCA2 mutation in a family member who has cancer, it is appropriate for men and women with a family medical history that suggests the presence of such a mutation to have genetic counseling for possible testing.

Some individuals—for example, those who were adopted at birth—may not know their family history. In cases where a woman with an unknown family history has an early-onset breast cancer or ovarian cancer or a man with an unknown family history is diagnosed with breast cancer, it may be reasonable for that individual to consider genetic testing for a BRCA1 or BRCA2 mutation. Individuals with an unknown family history who do not have an early-onset cancer or male breast cancer are at very low risk of having a harmful BRCA1 or BRCA2 mutation and are unlikely to benefit from routine genetic testing.

Professional societies do not recommend that children, even those with a family history suggestive of a harmful BRCA1 or BRCA2 mutation, undergo genetic testing for BRCA1 or BRCA2. This is because no risk-reduction strategies exist for children, and children's risks of developing a cancer type associated with a BRCA1 or BRCA2 mutation are extremely low. After children with a family history suggestive of a harmful BRCA1 or BRCA2 mutation become adults, however, they may want to obtain genetic counseling about whether or not to undergoing genetic testing.

8. Should people considering genetic testing for BRCA1 and BRCA2 mutations talk with a genetic counselor?

Genetic counseling is generally recommended before and after any genetic test for an inherited cancer syndrome. This counseling should be performed by a health care professional who is experienced in cancer genetics. Genetic counseling usually covers many aspects of the testing process, including:

A hereditary cancer risk assessment based on an individual’s personal and family medical history

Discussion of: The appropriateness of genetic testing The medical implications of a positive or a negative test result The possibility that a test result might not be informative (see

Question 12) The psychological risks and benefits of genetic test results The risk of passing a mutation to children

Explanation of the specific test(s) that might be used and the technical accuracy of the test(s)

9. How much does BRCA1 and BRCA2 mutation testing cost?

The cost for BRCA1 and BRCA2 mutation testing usually ranges from several hundred to several thousand dollars. Insurance policies vary with regard to whether or not the cost is covered. People considering BRCA1 and BRCA2 mutation testing may want to find out about their insurance coverage for genetic tests before having the test.

Some of the genetic testing companies that offer testing for BRCA1 and BRCA2 mutations may offer testing at no charge to patients who lack insurance and meet specific financial and medical criteria.

10.What does a positive BRCA1 or BRCA2 genetic test result mean?

BRCA1 and BRCA2 gene mutation testing can give several possible results: a positive result, a negative result, or an ambiguous or uncertain result.

A positive test result indicates that a person has inherited a known harmful mutation in BRCA1 or BRCA2 and, therefore, has an increased risk of developing certain cancers. However, a positive test result cannot tell whether an individual will actually develop cancer or when. Many women who inherit a harmful BRCA1 or BRCA2 mutation will never develop breast or ovarian cancer.

A positive genetic test result may also have important health and social implications for family members (see Question 15), including future generations. Unlike most other medical tests, genetic tests can reveal information not only about the person being tested but also about that person’s relatives:

Both men and women who inherit harmful BRCA1 or BRCA2 mutations, whether or not they develop cancer themselves, may pass the mutations on to their sons and daughters. Each child has a 50 percent chance of inheriting a parent’s mutation.

If a person learns that he or she has inherited a harmful BRCA1 or BRCA2 mutation, this will mean that each of his or her siblings has a 50 percent chance of having inherited the mutation as well.

11.What does a negative BRCA1 or BRCA2 test result mean?

A negative test result can be more difficult to understand than a positive result because what the result means depends in part on an individual’s family history of cancer.

If a close (first- or second-degree) relative of the tested person is known to carry a harmful BRCA1 or BRCA2 mutation, a negative test result is clear: it means that person does not carry the harmful mutation and cannot pass it on to their children. Such a test result is called a “true negative.” A person with such a test result has the same risk of cancer as someone in the general population.

If the tested person has a family history that suggests the possibility of having a harmful mutation in BRCA1 or BRCA2 but no such mutation has been identified in the family, a negative result is less clear. The likelihood that genetic testing will miss a known harmful BRCA1 or BRCA2 mutation is very low, but it could happen. Moreover, scientists continue to discover new BRCA1 and BRCA2 mutations and have not yet identified all potentially harmful ones. Therefore, it is possible that a person in this scenario with a negative test result actually has an as-yet unknown harmful BRCA1 or BRCA2 mutation that has not been identified.

It is also possible for people to have a mutation in a gene other than BRCA1 or BRCA2 that increases their cancer risk but is not detectable by the test used. People considering genetic testing for BRCA1 and BRCA2 mutations may want to discuss these potential uncertainties with a genetic counselor before undergoing testing (see Question 8).

12.What does an ambiguous BRCA1 or BRCA2 test result mean?

Sometimes, a genetic test finds a change in BRCA1 or BRCA2 that has not been previously associated with cancer. This type of test result may be described as “ambiguous” (often referred to as “a genetic variant of uncertain significance”) because it isn’t known whether the gene change affects a person’s risk of developing cancer. One study found that 10 percent of women who underwent BRCA1 and BRCA2 mutation testing had this type of ambiguous result (16).

As more research is conducted and more people are tested for BRCA1 and BRCA2 mutations, scientists will learn more about these changes and cancer risk. Genetic counseling can help a person understand what an ambiguous change in BRCA1 or BRCA2 may mean in terms of cancer risk.

13.How can a person who has a positive test result manage their risk of cancer?

Several options are available for managing cancer risk in individuals who have a known harmful BRCA1 or BRCA2 mutation. These include enhanced screening, prophylactic (risk-reducing) surgery, and chemoprevention.

Enhanced Screening. Some women who test positive for BRCA1 and BRCA2 mutations may choose to start screening at younger ages than the general population or have more frequent screening. For example, some experts recommend that women who carry a harmful BRCA1 or BRCA2 mutation undergo clinical breast examinations beginning at age 25 to 35 years (17). And some expert groups recommend that women who carry such a mutation have a mammogram every year, beginning at age 25 to 35 years.

Enhanced screening may increase the chance of detecting breast cancer at an early stage, when it may have a better chance of being treated successfully. However, women who carry mutations in BRCA1 and BRCA2 may be more likely to develop radiation-associated breast cancer than women in the general population because those genes are involved in the repair of DNA breaks, which can be caused by exposure to radiation. Women who have a positive test result should ask their health care provider about the risks of diagnostic tests that involve radiation (mammograms or x-rays).

Recent studies have shown that MRI may be more sensitive than mammography for women at high risk of breast cancer (18, 19). However, mammography can identify some breast cancers that are not identified by MRI (20), and MRI may be less specific (i.e., lead to more false-positive results) than mammography. Several organizations, such as the American Cancer Society and the National Comprehensive Cancer Network, now recommend annual screening with mammography and MRI for women who have a high risk of breast cancer.

No effective methods of ovarian cancer screening currently exist. Some groups recommend transvaginal ultrasound examinations, blood tests for the antigen CA-125, and clinical examinations for ovarian cancer screening in women with harmful BRCA1 or BRCA2 mutations, but none of these methods appears to detect ovarian tumors at an early enough stage to reduce the risk of dying from ovarian cancer (21).

The benefits of screening for breast and other cancers in men who carry harmful mutations in BRCA1 or BRCA2 is also not known, but some expert groups recommend that men who are known to carry a harmful mutation undergo regular mammography as well as testing for prostate cancer.

Prophylactic (Risk-reducing) Surgery. Prophylactic surgery involves removing as much of the "at-risk" tissue as possible. Women may choose to have both breasts removed (bilateral prophylactic mastectomy) to reduce their risk of breast cancer. Surgery to remove a woman's ovaries and fallopian tubes (bilateral prophylactic salpingo-oophorectomy) can help reduce her risk of ovarian cancer. Removing the ovaries also reduces the risk of breast cancer in premenopausal women by eliminating a source of hormones that can fuel the growth of some types of breast cancer.

No evidence is available regarding the effectiveness of bilateral prophylactic mastectomy in reducing breast cancer risk in men with a harmful BRCA1 or BRCA2 mutation or a family history of breast cancer. Therefore, bilateral prophylactic mastectomy for men at high risk of breast cancer is considered an experimental procedure, and insurance companies will not normally cover it.

Prophylactic surgery does not completely guarantee that cancer will not develop because not all at-risk tissue can be removed by these procedures. Some women have developed breast cancer, ovarian cancer, or primary peritoneal carcinomatosis (a type of cancer similar to ovarian cancer) even after prophylactic surgery. Nevertheless, the mortality reduction associated with this surgery is substantial: one study showed that women who underwent bilateral prophylactic salpingo-oophorectomy had a nearly 80 percent reduction in risk of dying from ovarian cancer and a more than 50 percent reduction in risk of dying from breast cancer (22).

Some evidence suggests that the amount of protection that removing the ovaries and fallopian tubes provides against the development of breast and ovarian cancer may differ between carriers of BRCA1 and BRCA2 mutations (23).

Chemoprevention. Chemoprevention is the use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the recurrence of, cancer. Although two chemopreventive drugs (tamoxifen and raloxifene) have been approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at increased risk, the role of these drugs in women with harmful BRCA1 or BRCA2 mutations is not yet clear.

Data from three studies suggest that tamoxifen may be able to help lower the risk of breast cancer in BRCA1 and BRCA2 mutation carriers (24), including the risk of cancer in the opposite breast among women previously diagnosed with breast cancer (25, 26). Studies have not examined the effectiveness of raloxifene in BRCA1 and BRCA2 mutation carriers specifically.

Oral contraceptives (birth control pills) may lower the risk of ovarian cancer in women with harmful BRCA1 or BRCA2 mutations (27).

14.What are some of the benefits of genetic testing for breast and ovarian cancer risk?

There can be benefits to genetic testing, regardless of whether a person receives a positive or a negative result.

The potential benefits of a negative result include a sense of relief and the possibility that special checkups, tests, or preventive surgeries may not be needed.

A positive test result can bring relief from uncertainty and allow people to make informed decisions about their future, including taking steps to reduce their cancer risk. In addition, people who have a positive test result may be

able to participate in medical research that could, in the long run, help reduce deaths from breast and ovarian cancer (see Question 17).

15.What are some of the risks of genetic testing for breast and ovarian cancer risk?

The direct medical risks, or harms, of genetic testing are minimal, but knowledge of test results may have harmful effects on a person’s emotions, social relationships, finances, and medical choices.

People who receive a positive test result may feel anxious, depressed, or angry. They may have difficulty making choices about whether to have preventive surgery or about which surgery to have.

People who receive a negative test result may experience “survivor guilt,” caused by the knowledge that they likely do not have an increased risk of developing a disease that affects one or more loved ones.

Because genetic testing can reveal information about more than one family member, the emotions caused by test results can create tension within families. Test results can also affect personal choices, such as decisions about marriage and childbearing.

Violations of privacy and of the confidentiality of genetic test results are additional potential risks. However, the federal Health Insurance Portability and Accountability Act and various state laws protect the privacy of a person’s genetic information. Moreover, the federal Genetic Information Nondiscrimination Act, along with many state laws, prohibits discrimination based on genetic information in relation to health insurance and employment, although it does not cover life insurance, disability insurance, or long-term care insurance.

Finally, there is a small chance that test results may not be accurate, leading people to make decisions based on incorrect information. Although inaccurate results are unlikely, people with these concerns should bring them up during genetic counseling.

16.What are the implications of having a BRCA1 or BRCA2 mutation for breast and ovarian cancer prognosis and treatment?

A number of studies have investigated possible differences between breast and ovarian cancers that are associated with harmful BRCA1 or BRCA2 mutations and cancers that are not associated with these mutations.

There is some evidence that, over the long term, women who carry these mutations are more likely to develop a second cancer in both the same

(ipsilateral) breast and the opposite (contralateral) breast than women who do not carry these mutations. Thus, some women with a harmful BRCA1 or BRCA2 mutation who develop breast cancer in one breast opt for a bilateral mastectomy, even if they would otherwise be candidates for breast-conserving surgery. In fact, because of the increased risk of a second breast cancer among BRCA1 and BRCA2 mutation carriers, some doctors recommend that women with early-onset breast cancer and those whose family history is consistent with a mutation in one of these genes have genetic testing at diagnosis.

Breast cancers in women with a harmful BRCA1 mutation are also more likely to be triple-negative cancers, and these cancers generally have poorer prognosis than other breast cancers. However, one study found that, among women with ovarian cancer, those with a harmful BRCA1 or BRCA2 mutation were more likely to survive for 5 years than those without such a mutation. The outcomes were best among women with a BRCA2 mutation (28).

Because the products of the BRCA1 and BRCA2 genes are involved in DNA repair, some investigators have suggested that cancer cells with a harmful mutation in either of these genes may be more sensitive to anticancer agents that act by damaging DNA, such as cisplatin. In preclinical studies, drugs called PARP inhibitors, which block the repair of DNA damage, have been found to arrest the growth of cancer cells that have BRCA1 or BRCA2 mutations. These drugs have also shown some activity in cancer patients who carry BRCA1 or BRCA2 mutations, and researchers are continuing to develop and test these drugs.

Ashkenazi Jews, also known as Ashkenazic Jews or simply Ashkenazim are a Jewish ethnic division which coalesced in the Holy Roman Empire around the turn of the first millennium. The traditional language of Ashkenazi Jews consisted of various dialects of Yiddish.

They established communities throughout Central and Eastern Europe, which had been their primary region of concentration and residence until recent times, evolving their own distinctive characteristics and diasporic identities. Once emancipated, weaving Jewish creativity into the texture of European life (Hannah Arendt), the Ashkenazi made a 'quite disproportionate and remarkable contribution to humanity' (Eric Hobsbawm), and to European culture in all fields of endeavour: philosophy, scholarship, literature, art, music and science. The genocidal impact of the Holocaust, the mass murder of approximately six million Jews during World War II devastated the Ashkenazi and their Yiddish culture, affecting almost every Jewish family

The genetics of Ashkenazi Jews have been particularly well-studied, resulting in the discovery of many genetic disorders associated with this ethnic group.

Tay-Sachs DiseaseA condition where children develop normally until about four to six months of age. It is at this time that the central nervous system begins to degenerate. Individuals with Tay-Sachs Disease lack an enzyme called hexosaminidase (Hex A). The child loses all motor skills and becomes blind, deaf and unresponsive. Death usually occurs by the age of four. The carrier rate in the Ashkenazi Jewish population is approximately 1 in 25. More rare than the infantile type is Late Onset Tay-Sachs Disease, where the progression of symptoms is slower and milder.

Canavan DiseaseVery similar to Tay-Sachs Disease, with normal development until age two to four months, followed by progressive loss of previously attained skills. Most individuals with Canavan Disease die by the age of five. An estimated 1 in 40 Ashkenazi Jews is a carrier for this disease.

Niemann-Pick Disease – Type A A disease in which a harmful amount of a fatty substance accumulates in different parts of the body. Failure to thrive and a progressive neurodegenerative course lead to death by three years of age. The carrier rate in the Ashkenazi Jewish population is approximately 1 in 90.

Gaucher Disease – Type 1(Pronounced go-shay) is a variable condition, both in age of onset and in progression of symptoms. A painful, enlarged and overactive spleen, with anemia and low white blood cell count are usually the initial features of Gaucher Disease. Bone deterioration is a major cause of discomfort and disability. Approximately 1 in 14 Ashkenazi Jews is a carrier of this condition. Treatment is available.

Familial DysautonomiaA disease that causes the autonomic and sensory nervous systems to malfunction. This affects the regulation of body temperature, blood pressure, stress response, normal swallowing and digestion. An estimated 1 in 30 Ashkenazi Jews is a carrier of FD.

Bloom SyndromeCharacterized by short stature, sun-sensitive facial skin lesions, an increased susceptibility to infections and a higher incidence of leukemia and certain cancers. The carrier rate is about 1 in 100 in the Ashkenazi Jewish population.

Fanconi anemia – Type CA disease associated with short stature, bone marrow failure and a predisposition to leukemia and other cancers. Some children may have

learning difficulties or mental retardation. Approximately 1 in 89 Ashkenazi Jews is a carrier for this condition.

Mucolipidosis IVCaused by the accumulation of certain harmful substances throughout the body. Individuals with ML IV experience a range of levels of motor and mental retardation, with developmental delays often manifesting themselves as early as the first year of life. Other symptoms can be related to the eyes, such as corneal clouding, pseudostrabismus and retinal degeneration.

Cystic FibrosisA multi-system disorder that causes the body to produce a thick mucus. The mucus accumulates primarily in the lungs and the digestive tract, resulting in chronic lung infections and poor growth. CF does not affect intelligence. The carrier rate for CF among all Caucasian individuals is approximately 1 in 25. The CF carrier test has a detection rate of 97% in the Ashkenazi Jewish population.

Genetic disorders common in Ashkenazi Jews