Breast Cancer Susceptibility Genes
Two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified. The lifetime risk for breast cancer for women with BRCA mutations ranges between families from approximately 50 to as high as 85 percent. The lifetime risk for ovarian cancer varies even more significantly between families, but may range between 20 and 60 percent. The higher end of these risk ranges were obtained from studies done on high risk families, and are probably over-estimates for most families with only moderate evidence of hereditary cancer. Ovarian cancer risks appear to be lower with BRCA2 mutations compared to BRCA1 mutations, in most studies. BRCA gene mutations also appear to increase the risk for colon cancer (approximately 6 percent by age 70) and for prostate cancer (approximately 8 percent by age 70). Studies also suggest the BRCA2 gene poses increased risks for male breast cancer (approximately 6 percent lifetime risk) and for pancreatic cancer (approximately 7 percent risk).
An individual with a BRCA mutation may develop one of these cancers, more than one, or none at all, during their lifetime.
Genetic testing can be done to help determine whether a BRCA mutation is present in a family. There have been hundreds of different mutations identified throughout the BRCA genes. Thus, genetic testing involves reading through the entire genetic code of both genes to try and identify if a mutation is present. It is important to remember, however, that there are certain mutations in the BRCA genes that cannot be detected by the laboratory techniques being used. It is also possible that a family’s cancer, if hereditary, is due to a mutation in a different cancer susceptibility gene which has not yet been identified. Thus, a negative (or “normal”) BRCA test result does not rule out the possibility that a hereditary cancer syndrome is present in a family, unless another relative has already been shown to have a BRCA mutation.
In addition, normal variations can also occur within genes which do not affect the way they function. Unfortunately, it can sometimes be difficult to determine whether a change found in one of the BRCA genes is a normal variation, or a mutation that can lead to cancer. Thus it is possible to get an ambiguous result from genetic testing (“genetic variant of uncertain significance”).
We recommend that testing be performed first on someone in the family who has had cancer, since the results obtained from testing an unaffected woman first may be difficult to interpret. If a person with breast or ovarian cancer is found to carry a BRCA mutation, then other relatives can be tested reliably and with high accuracy.
Once a mutation is identified in a family, the benefits of genetic testing include identifying family members who are at high risk for cancer (and who need to be followed carefully) and identifying family members who are not at increased risk for cancer because they did not inherit the mutation. A potential risk of genetic testing is possible emotional stress from being at increased risk for cancer. Another potential risk is the possibility of discrimination by insurance companies. A national law specifies that pre-symptomatic genetic conditions can not be considered a “pre-existing” condition by group health insurers. The ability to obtain life and disability insurance are not protected by any laws. Every person considering testing may want to consider these issues.
Options for Screening and Prevention
Options for people at risk of having a BRCA mutation include careful screening, chemoprevention, and prophylactic surgery.
Individuals with BRCA mutations or at-risk individuals should receive careful breast cancer screening. This should include monthly breast self-examination beginning at age 18, clinical breast examination every 6 to 12 months beginning at age 25, and annual mammography beginning at age 34. These women should also consider ovarian cancer screening. Ovarian cancer screening includes transvaginal ultrasounds with color-Doppler and CA-125 blood tests every 6 to 12 months beginning at age 25 to 30. Unfortunately, the available tests for ovarian cancer have not proven to be very effective (with frequent false positive and false negative results), and some women choose not to undergo this screening. In general, there are little or no data on the effectiveness of any cancer screening for women with BRCA mutations.
In addition to the screening discussed above, individuals with BRCA mutations/at-risk individuals should follow the general American Cancer Society guidelines to screen for other BRCA-related cancers. Colon cancer screening should begin at age 50 and include annual fecal occult blood tests (testing the stool for blood) and sigmoidoscopy or colonoscopy every 5 to 10 years. The men in the family should undergo prostate cancer screening including annual digital rectal examination and PSA blood tests beginning at age 50.
Chemoprevention involves taking a medication that may decrease breast cancer risk. Use of Tamoxifen for 5 years has been shown to decrease the risk of developing breast cancer by nearly 50 percent. Because Tamoxifen has a number of side effects, a large study (called the STAR trial) has been set up to compare Tamoxifen with another medication called Raloxifene. It is hoped that Raloxifene will have the protective effect of Tamoxifen, but with fewer side effects. For ovarian cancer chemoprevention, the use of oral contraceptives for a total of at least 6 years decreases the risk for developing ovarian cancer in women with BRCA mutations. Therefore, the use of oral contraceptives is an alternative for women who opt to do screening rather than prophylactic surgery, and for women too young to do screening. Although some physicians are concerned about the possible role of birth control pills in increasing breast cancer risk, most feel that they do not significantly increase this risk.
Some women at hereditary risk for developing breast and ovarian cancer consider prophylactic surgery(removing tissue to try and reduce the risk of developing cancer). After prophylactic mastectomy (removal of the breasts) it is still possible to develop breast cancer in the remaining breast tissue. A recent study by the Mayo clinic, however, suggests that this surgery reduces the risk for developing breast cancer by nearly 90 percent. Prophylactic oophorectomy (removal of the ovaries) should be considered by women at high risk for developing ovarian cancer, because ovarian cancer screening is so ineffective. One recent study found a 90 percent reduction in the risk to develop ovarian cancer and a 75 percent reduction in the risk to develop breast cancer when oophorectomy was performed before age 40. The reduction in breast cancer risk was 40 percent if oophorectomy was performed from age 40 to 49. Although a woman cannot develop cancer in the ovaries once they are removed, there is still a small risk of developing an “ovarian-like” cancer in the lining of the abdomen, called the peritoneum.
The issues involved in genetic testing are complex. We recommend that you consider these issues by talking with your physician as well as a genetics professional.
Please feel free to contact us at 860-523-6464 if you have any questions regarding this information.