Dr. Dharmen Patel was most recently Fellow at Westchester Medical Center and Dr. Lawrence Shapiro is Professor of Pediatrics at New York Medical College and Director, Regional Medical Genetics Center, Westchester Medical Center.

Not long ago, breast cancer was shrouded in mystery. Though doctors knew it affected the human body and had a number of fairly effective treatments, they knew little about its cause. The same could be said for the factors that affect risk. Now, however, thanks to recent advances in genetics, this is all changing, and quickly.

Today medical scientists can pinpoint mutations in individual genes which increase breast cancer risk. While these mutations do not account for all cases of breast cancer — there are other factors remaining to be explored — the presence of the mutations offers a more accurate picture of a person's risk for breast cancer. Some of these mutations are passed down through families and ethnic groups. For many women, this has important implications for monitoring, prevention and even treatment of breast and other cancers, such as ovarian cancer.

For example, let us look at the case of one real woman.

The Case of "Sarah"
A 44-year-old woman, whom we will call Sarah, is asking her doctor for advice about whether or not to seek genetic counseling. With good reason — she has an extensive family history of breast and ovarian cancer. Her mother had been diagnosed with ovarian cancer at age 67. Her maternal grandmother reportedly had breast cancer in her 40's. Her maternal aunt had breast cancer in her 30's. Recently, this aunt had genetic testing and was found to carry a gene mutation known to be associated with breast cancer.

Sarah's family is of Ashkenazi (Eastern or Central European) Jewish ancestry. She is premenopausal and has never taken oral contraceptives. She exercises one half-hour a day, three days a week. She does not smoke or drink. She has three children, a daughter who is 21 years old and two boys, 23 and 17. Her physical examination is normal, as was a mammogram done the year before.

A Question of Risk
What did Sarah's doctor tell her? According to what we know today, there are two categories of risk faced by women like Sarah. One relates to the gene mutation she shares with her aunt; this carries a definite and quantifiable risk for breast cancer. The other type of risk faced by Sarah is 'familial tendency' — Sarah is at greater risk of developing breast cancer simply because of her family history, whether or not her tests turn up a known gene mutation.

The risk from familial tendency can be expressed in this way: first degree relatives of breast cancer patients and fraternal twins have about 1.7 times the usual risk of developing breast cancer, while identical twins have about 4.4 times the usual risk.

As for specific genetic mutations, according to the National Cancer Institute, those most associated with breast cancer risk occur in a pair of genes called BRCA1 and BRCA2. BRCA1 and BRCA2 are genes which are involved in the immune system's tumor suppression function; mutations in these genes lead to increased cancer susceptibility. Once identified, different mutations in these genes are given names that resemble a long string of code; these tell doctors and researchers where they are found and also distinguish them from other types of mutations that may occur in the same gene.

In Sarah's case, doctors were able to identify a gene mutation in her maternal aunt called BRCA2-6174delT. They then looked for and, unfortunately, found the same mutation in Sarah. This mutation, along with a BRCA1 mutation called BRCA1-185delAG, happens to be common among Ashkenazi Jews.

Studies have found that the frequencies for these mutations in the general Jewish population are 1.1 percent for the BRCA1-185delAG mutation and 1.5 percent for the BRCA2-6174delT mutation. The chances of having both of these mutations is about 1 in 50 among Ashkenazi Jews. These two mutations account for 25 percent of early-onset breast cancer and up to 90 percent of families with more than one case of both breast and ovarian cancer among Ashkenazi Jews:

The prevalence of inherited BRCA1 and BRCA2 mutations in the world population is lower, 0.1 to 0.2 percent. These mutations are implicated in about 10 percent of all cases of breast cancer. However, the numbers can change quite a lot, depending on an individual woman's history and circumstances. For instance, in women under 40 who have breast cancer and who also have close relatives with breast cancer, approximately 75 percent carry these mutations.

Carriers of a BRCA1 mutation alone are thought to have a very high — 50 to 85 percent — lifetime risk of breast cancer and a 20 to 40 percent lifetime risk of ovarian cancer. Women with a BRCA2 mutation alone appear to have similar risk of breast cancer and a 10 to 20 percent risk of ovarian cancer. Familial cancer tends to occur at a younger age than non-familial cases. However, the increased risk in women with both of these mutations is lifelong.

Genetic Counseling
Now that we are learning much more about these genetic mutations and their affect on a woman's risk of developing breast (or ovarian) cancer, what can an individual such as Sarah do with this information? An easy answer is to have genetic testing to see if one of these mutations is present. A more difficult issue is how to use the results in making decisions about monitoring, prevention or treatment. Before testing, a patient must be informed about and have a clear understanding of the risks and benefits of genetic testing. Genetic counseling should be offered before testing as well as after the results are received.

Let us look at what doctors would tell a woman in Sarah's circumstances. To start with, while Sarah seems to be perfectly healthy now, her risk for developing breast cancer is, unfortunately, very high. Studies of her specific type of BRCA2 mutation in high-risk families indicate that she may have as much as an 84 percent risk of breast cancer.

In addition, mutations in BRCA2 may also confer as much as a 27 percent risk of ovarian cancer by age 70. And the increased risk does not stop, even after a woman has had an episode of cancer. These mutations also seem to significantly increase a woman's risk of developing a second case of breast cancer (or ovarian cancer) within five years of a first case, as compared to those of a woman without the mutation who has also had breast cancer.

We have been discussing the case of Sarah and other women in her family but, like many other gene mutations, this one is also passed on to men. According to studies, the mutation carries up to a 6 percent risk of male breast cancer and an 8 percent risk of prostate cancer by age 70, as well as increased (albeit low) risks for some other cancers. Men may also pass it on to their sons and daughters, who also may benefit from being screened. This is a particularly important point because in many families, breast cancer information is shared only among the women; many men may be unaware that they or their children are at risk.

As for Sarah, statistically, each of her children has a 50 percent chance of inheriting the mutation.

Prevention and Treatment
There is no question that someone like Sarah should be monitored closely so that if she does develop cancer she can be treated as early as possible. Sarah will need monthly breast self-examinations, a clinical breast examination every six months and frequent breast imaging, including mammography. In some cases, she might even consider the radical step of total bilateral mastectomy (surgical removal of both breasts).

As for her increased risk of ovarian cancer, Sarah's options include removal of the ovaries (oophorectomy) with or without hysterectomy (removal of the uterus). While this may seem extreme, it is a fact that once ovarian cancer is detected it is usually too late to treat it successfully. Oophorectomy reduces, but does not totally eliminate, the risk for ovarian cancer. There remains a small risk of developing ovarian cancer in the fallopian tube and elsewhere. Another factor for premenopausal women who are considering an oopherectomy is that the operation can lead to osteoporosis, cardiovascular disease, hot flashes and sexual dysfunction. Hormone replacement therapy is not an option because it is associated with an increased risk for breast cancer and endometrial cancer.

Recent advances in genetics now enable many women — and men — to gain a much clearer picture of their and their children's risk of developing cancers such as breast and ovarian cancer. Armed with this knowledge, concerned individuals can consult their doctor and work out a program of close monitoring.

We can hope that further genetic discoveries will lead to advances in treatment as well. In the meantime, however, a woman like Sarah, who has an extremely high risk factor based on family history and the presence of certain specific inherited gene mutations, may wish to speak to her doctor about more radical measures. These might include oophorectomy and other types of surgery, which have been shown to dramatically lower a person's risk of developing cancer.