Breast/Ovarian Cancer: BRCA1 & BRCA2

Breast cancer is the most common type of cancer among American women, affecting about 1 in 8 during their lifetime. Ovarian cancer affects about 1 in 70 women. In 2004, about 217,000 individuals in the United States (215,990 women and 1,450 men -- estimate based on Surveillance Epidemiology and End Results (SEER ) -- were diagnosed with breast cancer. SEER is a program of the National Cancer Institute that is a source of information on cancer incidence and survival in the United States. As an individual ages, the chance of developing cancer increases. Breast cancer is uncommon in men, with male breast cancer accounting for less than 1 percent of all cases of breast cancer.

It has been estimated that about 5 to 10 percent of all female breast and ovarian cancer cases are hereditary. The proportion of male breast cancer that is hereditary is thought to be similar. Hereditary cancers occur as the result of inheriting an alteration in a gene that increases the likelihood of developing breast or ovarian cancer. In most families with this inherited alteration in a gene, several individuals will be affected with cancer.

Inherited information is contained in every cell in our body on structures called chromosomes. We have 46 chromosomes that come in 23 pairs; one member of each pair comes from our fathers, and the other from our mothers. Each chromosome is made up of thousands of genes. Genes, like chromosomes, come in pairs. They are packages of genetic information (DNA) that act as instructions for making the substances that help our bodies function properly. An alteration in genetic information can interfere with proper body functions by causing the gene to no longer work. These gene alterations are called mutations.

BRCA1 and BRCA2 are genes involved in cell growth, division, and repair of damage to DNA that occurs during one's lifetime. An altered (mutated) BRCA1 or BRCA2 gene increases the likelihood that cancer will develop. Individuals with mutations in either of these genes may be diagnosed with cancer at an earlier age and may develop breast cancer in both breasts (bilateral cancer), or more than one type of cancer, e.g., breast and ovarian cancers in one individual.

The most common types of cancers associated with BRCA1 and BRCA2 alterations are female breast and ovarian cancers. Having a BRCA2 mutation increases a man's chance of developing breast cancer. Men with BRCA1 mutations may also have an increased risk to develop breast cancer. Men with BRCA1 and BRCA2 mutations are at increased risk of developing prostate cancer.

It is important to remember that the majority of all breast cancers are not hereditary. Of those that are hereditary, about a third is due to mutations in the BRCA1 gene. About a third of the remaining hereditary breast cancers are due to mutations in the BRCA2 gene. There are additional, as yet unidentified, breast cancer genes that account for the remaining hereditary breast cancer clusters. Other genes may account for the smaller fraction of families with both breast and ovarian cancers.

Both of the BRCA genes, BRCA1 and BRCA2, are inherited in an autosomal dominant fashion. Autosomal means that both men and women can inherit and pass along a BRCA mutation. Dominant means that it only takes one altered breast cancer gene to cause the increased likelihood for developing cancer. All individuals, whether they have cancer or not, have two copies of both BRCA genes (one copy from each parent). If an individual has a parent with a BRCA1 or a BRCA2 mutation, he or she may either inherit that parent's altered (nonworking) BRCA gene or the working BRCA gene. Therefore, that individual has a 50 percent chance of inheriting an altered BRCA gene and an increased likelihood of developing certain cancers. Likewise, the individual has a 50 percent chance of not inheriting an altered BRCA gene and would then be at the same risk level for developing cancer as a person in the general population.

Studies have shown that there are specific mutations of the BRCA1 and BRCA2 genes that are common in persons of Eastern European Jewish (Ashkenazi) descent. These mutations are called 185delAG and 6174delT.

About 2 out of 100 individuals of Ashkenazi familial background have one of these mutations in their BRCA genes. Women of Ashkenazi descent who have these mutations have an increased chance of developing breast and ovarian cancers. The same is true for other mutations of the BRCA genes. Our research indicates that about a quarter of women of Jewish descent, who are diagnosed with breast cancer before the age of 41, have one of these mutations.

In addition to the 185delAG mutation of BRCA1 and the 6174delT mutation of BRCA2, there is another BRCA1 mutation called 5382insC that is also more common in those of Ashkenazi Jewish descent. One in 40 Ashkenazi Jewish individuals has one of the three most common mutations of BRCA1 or BRCA2. Some families of Jewish origin with breast and/or ovarian cancers have been found to have mutations other than the three recurring ones, although mutations elsewhere are not as common. Certain BRCA mutations also appear more frequently in individuals from some Scandinavian countries and other geographically isolated areas, such as Iceland.

It is possible to test for BRCA mutations. By taking a blood sample from someone who has had breast or ovarian cancer, a laboratory team can detect alterations in these genes. Once an alteration has been found in a BRCA gene in someone with cancer, we can look for that same alteration in family members who have or have not had cancer. Presently, testing is not routinely available on material such as stored tumors from deceased family members. Testing can also be performed on individuals without cancer even if there is no affected relative who wishes to be tested or is able to be tested. If a mutation is found, screening guidelines, described herein, would be recommended. However, the absence of a BRCA mutation in the unaffected person may be difficult to interpret. This is because the cancers in the family may have been due to different genes or other factors.

Negative results (meaning a BRCA1 or BRCA2 mutation is not found) can mean several things. First, it might mean that there is a BRCA1 or BRCA2 gene mutation that cannot be detected by the testing method utilized. No one testing method is capable of finding all BRCA mutations.

It could also mean that a different gene is responsible for the cancers in the family. Families who do not have a mutation in one of the genes may wish to pursue testing for other breast cancer genes in the future should other genetic tests become available. It is also possible that the cancers in the family are not hereditary. Since breast cancer is a common disease, by chance alone, more than one woman in a given family may have breast cancer.

Finally, some individuals may participate in studies that only test for certain mutations (i.e., 185delAG) in the BRCA genes. If the particular mutation being tested for is not found in these individuals, there still may be a mutation in the BRCA genes for which he/she was not tested.

Important Information for Individuals
Who Had BRCA Testing Prior to August 12, 2002

While sequence analysis is the most powerful genetic testing method currently known to detect BRCA mutations, it has been shown that some genetic changes, called "rearrangements," will not be detected using this approach. In August of 2002, the largest commercial laboratory that provides BRCA testing for patients began to offer a clinical test for specific BRCA1 rearrangements and also began to incorporate "rearrangement" testing into their routine sequence analysis.

For families with multiple cases of breast and ovarian cancers, but in whom no BRCA1 or BRCA2 mutation was found on analysis performed before August 12, 2002, additional "rearrangement" analysis may be performed. The test has an additional cost and requires a new blood sample to be taken and sent to the laboratory. This test should be considered by those with a significant family history of breast and/or ovarian cancer who have tested negative by full sequence BRCA analysis. To schedule a time to provide a blood sample for this testing, please call 212-434-5149 and indicate that you would like "rearrangement" panel testing.

Women who inherit a BRCA1 mutation are at increased risk of developing breast and ovarian cancers. Research is taking place to determine the exact risks for developing these cancers. These risks may vary from family to family and from one individual to another. Women who have an altered BRCA1 gene have between a 50 to 85 percent risk of developing breast cancer by age 70. Their risk for ovarian cancer ranges from 40 to 60 percent by age 85.

A woman who has already had breast cancer and is found to have an altered BRCA1 gene has an increased risk for breast cancer in her other breast, as well as for ovarian cancer. Recent studies suggest that up to 25 to 30 percent of women with a BRCA mutation may develop a contralateral or opposite breast cancer within ten years after an initial breast cancer diagnosis.

Men with BRCA1 mutations also have an increased risk for developing prostate cancer, although the risk is not as high as for breast and ovarian cancer in women. During their lifetime, individuals who have inherited a BRCA1 mutation may develop one or more cancers or none at all. It is not possible to predict ahead of time what type of cancer, if any, such a person will develop.

Both men and women who inherit a BRCA2 mutation have an increased chance for developing breast cancer. Women who have an altered BRCA2 gene appear to have a similar risk of developing breast cancer compared with women with BRCA1 mutations. The risk for ovarian cancer is also increased. Studies suggest that the ovarian cancer risk is between 16 and 27 percent.

The chance for a male with a BRCA2 mutation to develop breast cancer is quite low but is considerably higher than the chance for male breast cancer in the general population. Men with BRCA2 mutations have a higher risk of prostate cancer compared with men in the general population. Some studies suggest that pancreatic cancer and skin (melanoma) cancer risk may also be elevated in individuals carrying BRCA2 mutations. Further research is ongoing to better define the disease spectrum and these risks.

Genes are written in letters called bases. There may be different spellings of bases in different people. Sometimes a different spelling of bases can cause a disease. We are still learning which spellings are "normal" variants and which are "abnormal" and therefore increase the risk for disease. If you have a "variant" BRCA gene we may not be able to tell you if this is a normal pattern. We may be able to test other family members or do other lab tests to help learn if this variant increases your risk for cancer. However, there are times we cannot tell if a variant will increase your risk. If you have a variant, we will advise you to follow breast and ovarian cancer screening recommendations.

A woman with an altered BRCA gene has several options. The goal of these options is to prevent cancers or to find cancers at the earliest possible stage -- when they are most easily treated. Women with BRCA alterations should be sure to practice regular breast cancer screening. This means having yearly mammograms, having breast examinations by a physician at frequent intervals, and performing monthly breast self-examinations. Mammography screening and physician examination should start by age 25 at the very least, and self-examination even earlier. Mammography does not detect all breast cancers at early stages. Screening using breast ultrasound and MRI should also be employed for those at the highest hereditary risk and their family members.

Recent studies show that in women with BRCA mutations, MRI is of value in identifying breast cancers that are not detected by mammography or ultrasound. Unlike mammograms, MRIs use magnetic fields to detect cancers. Breast ultrasound and/or MRI (performed annually 6 months after annual mammograms) and/or more frequent mammography are being investigated in women at the highest level of hereditary risk.

While some studies raise a concern about risks of mammography in very young women, it remains to be seen if these risks undermine the known benefits of early detection in this group.

For more information about MRI exams, see Clinical Research Updates 2005-2006.

Screening for ovarian cancer is more difficult, and current tests cannot always find early ovarian cancers. We generally recommend an ultrasound screening of the ovaries, a pelvic examination, and a blood test called CA125 twice a year. The age at which to begin ultrasound screening remains unclear; however, we usually recommend beginning ultrasound screening starting around age 35. We now believe that the greatest risk for ovarian cancer in women with BRCA mutations occurs when they are in their mid- to-late 40s; however, studies indicate that women with BRCA mutations remain at increased risk for ovarian cancer in their later years of life as well.

Another option is to take part in chemoprevention trials. These are experimental trials that use drugs in an attempt to prevent or delay the onset of cancer. Examples of drugs used in experimental trials are tamoxifen, raloxifene, or other new agents that may prevent breast cancer. While tamoxifen has been shown to lower breast cancer risk in women with a family history of breast cancer, it is not clear whether (and to what extent) it is effective or will be effective in preventing breast cancers among women with BRCA1 and BRCA2 mutations. Other studies suggest that oral contraceptives may reduce the risk of hereditary ovarian cancer, although studies have thus far shown only a slight, if any, increase in breast cancer risk in BRCA mutation carriers.

A third option is the surgical removal of an at-risk organ before cancer develops. An example of this approach would be undergoing a risk-reducing mastectomy, a type of surgery to remove the breasts in an attempt to prevent breast cancer. Women can also have their ovaries and fallopian tubes removed, a procedure known as "risk-reducing salpingo-oophorectomy," to decrease the chances of developing ovarian cancer. We do know that in rare cases, even these surgeries have not prevented breast, ovarian, or peritoneal cancers from occurring. For this reason, following the risk-reducing surgical removal of the ovaries, CA125 blood testing may still be considered a screening tool for the small-risk peritoneal cancer. Recent studies indicate that the earlier an oophorectomy is performed, the greater the protection against both breast and ovarian cancers. We have observed cases of early stage ovarian cancer (undetected by ultrasound) in women who have had risk-reducing ovarian surgery, which highlights the limitations of ovarian cancer screening.

Because of the increased prostate cancer risk, prostate cancer screening is recommended for men with BRCA1 or BRCA2 mutations beginning between ages 40 and 50. Such screening consists of an annual digital rectal examination and serum prostate specific antigen (PSA) screening. Because of an increased risk of male breast cancer, men with BRCA mutations should seek medical evaluation for any breast mass or change.

It is possible to assess a person's familial cancer risk without genetic testing. Testing may sometimes but not always improve the estimate of that risk. If a person does not have genetic testing but does have a close relative (or multiple relatives) who had breast cancer at an early age or ovarian cancer at any age, it is important to get screened for both of these cancers. Screening for breast cancer involves yearly mammograms, physician examinations, and monthly self-examination. Ovarian screening consists of a physician exam, transvaginal ultrasound, and CA125 blood testing.

The following risks and benefits should be considered before undergoing genetic testing. There is no physical risk from genetic testing other than that of a routine blood draw. The process of genetic testing may be emotionally difficult regardless of whether a BRCA1 or BRCA2 mutation is found. Once an alteration is found, this result may indirectly provide information about other family members, who may have chosen not to be tested. In addition, healthcare costs for the cancer screening and prevention options may or may not be covered by health insurance.

Another issue of genetic testing is the possibility that the results could be used by an employer or insurance company to discriminate against an individual. Insurers may seek higher health insurance rates, and possibly even cancel or deny policies for individuals with genetic "pre-existing conditions." Several states have outlawed "genetic discrimination" by insurers, but no such law currently exists in New York State. State laws may not apply to some businesses that provide their own health insurance.

At present, however, we are not aware of any instances of genetic discrimination against any individuals who have received breast and ovarian cancer genetic testing as part of research studies at Memorial Sloan-Kettering. Of late, some insurers have begun to cover costs of genetic testing.

The possible advantages of learning BRCA1 and BRCA2 test results include reduced uncertainty about cancer risk; the ability to appropriately increase or decrease cancer screening depending on the results of testing; and the ability to consider other options for cancer risk-reduction.

In New York State, by law, the results of a person's genetic test can be given to no one without that person's written permission.

At Memorial, testing is generally offered as part of a research study. For this reason, test results are stored in a file separate from the regular medical records. In many cases, we have obtained certificates of confidentiality from federal agencies to protect the research information in these files. Should you verbally communicate test information to anyone else, that communication may be recorded in your medical record. Should a person wish to undergo genetic counseling for cancer risk based only on family history, this information will be part of the medical record.

We have successfully recovered costs for genetic counseling for cancer risk from many insurance plans. Because of special concerns about the confidentiality of genetic testing, many individuals have chosen to pay directly for testing. Increasingly, however, some insurers and managed care providers are covering costs of genetic testing for cancer risk. Individuals may want to learn more about the policies of their healthcare provider prior to submitting charges for genetic testing.

The decision to participate in BRCA1 or BRCA2 testing is a complicated one. Individuals and families must not only weigh the risks and benefits of testing, they must also consider their unique situations. Ultimately, individuals must make their own decisions. These are best made after discussion with genetic counselors, physicians, and other healthcare professionals experienced in this area.