Abnormal Breast Cancer Genes

Abnormal Breast Cancer Genes Are as Common in Women with DCIS as in Women with Invasive Breast Cancer

E. Claus et al., Journal of the American Medical Association, February 23, 2005

Is this for me?: You might want to read this article if you have DCIS (ductal carcinoma in situ) and a family history of breast cancer, or if you were diagnosed with DCIS before age 50. Women in either situation may be more likely to have an abnormal breast cancer gene—BRCA1 or BRCA2.

Background and importance of the study: In their normal form, BRCA1 and BRCA2 genes prevent breast cancer by producing a protein that stops cells from growing out of control. But if one or both of these genes are abnormal, they can't stop breast cells from multiplying much more than normal. If some of these cells invade the surrounding normal, healthy breast tissue, the result is invasive breast cancer.

Abnormal BRCA1 and BRCA2 genes account for about 5-10% of all breast cancers. The average woman (without an inherited breast cancer gene abnormality) in the United States has about a 12% risk of developing breast cancer over a 90-year life span. In contrast, women who have an abnormal BRCA1 or BRCA2 gene have up to an 85% risk of developing breast cancer by age 70. Women with BRCA1 or BRCA2 abnormalities are also at increased risk of developing ovarian cancer. The lifetime risk is about 55% for women with BRCA1 mutations and about 25% for women with BRCA2 mutations. By comparison, about 1.8% of women without an inherited BRCA abnormality get ovarian cancer.

It's important to remember that not every person with an abnormal BRCA gene develops breast cancer. The risk may also be affected by the particular type of mutation in the BRCA 1 or BRCA2 gene, other kinds of abnormal genes or proteins, and lifestyle factors such as being significantly overweight, drinking a lot of alcohol, and smoking.

Ductal carcinoma in situ (DCIS) is uncontrolled growth of the cells that line the inside of the milk ducts within the breast. This cancer is not invasive and does not spread to other parts of the body.

Although DCIS is non-invasive, it is associated with an increased risk for developing an invasive breast cancer in the future. About 25% of women whose DCIS is treated only by surgery will develop an invasive cancer. Most of those cancers occur within 5 to 10 years. But a new cancer may turn up as long as 25 years after the DCIS is diagnosed.

In the study reviewed here, Yale University researchers wanted to see how many women who had been diagnosed with DCIS had abnormal BRCA1 and BRCA2 genes. This is one of the first studies to look at this issue.

Study design: The first part of the study looked at 1068 Connecticut women, age 20 to 79, who had been diagnosed with non-invasive breast cancer from 1994 to 1998. Most of these women had DCIS. The women were interviewed by telephone about factors that, in other studies, have been related to breast cancer risk:

• their family history of cancer,
• their history of pregnancies,
• when they had started and stopped menstruating,
• their use of hormones,
• their medical and breast cancer screening history, and
• their age, race, and other demographic information.

The researchers conducted the same interviews with 999 women who didn't have breast cancer to compare these characteristics.

In the second part of the study (reviewed here), the researchers got back in touch with the women with non-invasive cancer. They asked the women if they would be interviewed again and if they would have genetic testing for abnormal BRCA1 or BRCA2 genes. Genetic testing consisted of taking a sample of blood or a cheek swab and testing it for abnormal BRCA1 or BRCA2 genes. As part of the testing, the women were offered two genetic counseling sessions at the Yale Cancer Center, one before testing and one to provide the results of the test.

Of the 422 women who agreed to participate in the second part, 369 had been diagnosed with DCIS. This is the group the researchers analyzed.

The researchers had followed the women for at least five years when this study was published.

Results: Of the 369 women with DCIS who had genetic testing, 11 women had abnormal BRCA1 or BRCA2 genes:

• 3 women (0.8%) had an abnormal BRCA1 gene, and
• 9 women (2.4%) had an abnormal BRCA2 gene.

(One woman had both an abnormal BRCA1 and BRCA2 gene.)

One of the women with an abnormal BRCA2 gene identified herself as being of Ashkenazi Jewish heritage. Women of this heritage are at high risk for having abnormal breast cancer genes. Information on this women's family history was limited because many of her relatives were killed during the Holocaust. A second woman was adopted and did not know her ethnic heritage or family cancer history.

Women with abnormal BRCA genes were more likely than the other women:

• to be diagnosed with cancer earlier—average age 49 compared to 54;
• to have a mother, sister, or daughter with breast cancer;
• to have had a mother, sister, or daughter diagnosed with breast cancer at an early age (younger than 50), and
• to have a personal history of ovarian cancer.

Type of DCIS:

Of the 11 women with abnormal genes, 6 had comedo necrosis DCIS, a type of DCIS that has debris from dead cancer cells in it. This usually means that the cancer is growing quickly. As a result, some cells die because there's not enough blood to feed all of them. Comedo necrosis DCIS is associated with a higher risk of invasive cancer.

Risk of recurrence and new cancers:

After following the 11 women for at least 5 years, the researchers found that:

• two women had DCIS come back in the same breast,
• two women developed breast cancer in the other breast, and
• two women developed ovarian cancer.

The researchers did not specify if the breast cancers that came back were invasive or non-invasive.

Initial treatment for DCIS:

• None of the 11 women knew their BRCA status when they were first diagnosed with DCIS. Their treatments had varied from lumpectomy to mastectomy, both with and without additional treatment.

Comparison of women with and without a BRCA gene abnormality:

There were no differences between the women with and without abnormal BRCA genes in terms of their:

• age when they had their first live birth,
• number of sisters or daughters,
• age at first menstrual period,
• history of benign breast biopsy,
• use of birth control pills,
• use of hormone therapy,
• race, or
• mammogram history.

Conclusions: In this study of women with DCIS, the percentage of women with an abnormal BRCA gene is similar to what's been found in studies of women with invasive breast cancer. The same risk factors considered for women with invasive breast cancer may be helpful in predicting BRCA gene abnormalities in women with DCIS:

• a personal or family history of breast cancer,
• a young age (under 50) when diagnosed with breast cancer, and
• a personal or family history of ovarian cancer.

Genetic counseling and genetic testing can provide important information you can use to guide your care. Women with DCIS who have these risk factors may benefit from following the same screening strategies recommended for women at high risk of invasive cancer:

• starting annual mammograms earlier than age 40;
• having additional screening tests if necessary (MRI or ultrasound);
• having tests more often than once a year (for example, a mammogram in January and an MRI scan in July); and
• having more frequent breast exams than previously recommended for you.

Take-home message: This small study suggests that abnormal BRCA1 and BRCA2 genes are as common in women with DCIS as they are in women with invasive breast cancer—about 5% or less. This is the first time that researchers have looked for and established an association between these abnormal breast cancer genes and DCIS.

If you have DCIS, then you may be asking yourself these questions: Do I have an abnormal BRCA gene? If I do, what does it mean? And what should I do about it?

First, if you have DCIS, you may want to talk to your doctor about the risk factors in this study that may signal a greater likelihood of having a BRCA gene abnormality:

• an early age of DCIS diagnosis (under 50),
• having a mother, sister, or daughter with breast cancer,
• having a mother, sister, or daughter diagnosed with breast cancer before age 50, and
• having a personal or family history of ovarian cancer.

Second, you also may be interested in genetic counseling and testing. Anyone wanting to learn the details of her or his genetic makeup should consider both the benefits and drawbacks of knowing such information.

Seeking genetic testing has several advantages:

• If you get genetic testing in a research setting, or if you participate in other clinical studies, you'll be contributing to research that could eventually help to prevent or cure breast or ovarian cancer.
• If your test result is normal, your genetic counselor can estimate your risk of developing invasive breast cancer with greater certainty. Screening for breast cancer (self-exams, mammograms, doctor visits) will still be important for you, as it is for all women.
• If your family has a BRCA gene abnormality and your test result is normal, then you can feel reassured that you are at an average (not high) risk of breast and ovarian cancer.
• If your test result is abnormal, closely monitoring the health of your breasts and ovaries can help find a cancer in its earliest stage, when it is most treatable and curable.

In addition, if your test result is abnormal:

• You may want to consider taking a medication such as tamoxifen, which might reduce your risk of developing breast cancer.
• You may want to consider preventive (prophylactic) surgical removal of your breasts, ovaries, or both before cancer has an opportunity to form.
• If you do develop cancer, knowing you have a genetic abnormality will give you more information on which to base your treatment decisions.
• Knowing that you carry an abnormal breast cancer gene may prompt you and your family members to make lifestyle and family planning changes or decisions to help improve your odds.

There are also drawbacks to genetic testing:

• If your test result is abnormal, you may make the difficult decision to remove the breasts and ovaries to lower cancer risk (called prophylactic surgery). But such surgery does not get rid of every breast- and ovary-related cell. So even though it can lower your risk a lot, it still does not entirely eliminate it. Even after such surgery, a woman with an abnormal breast cancer gene must be monitored regularly. These diseases may show up in nearby or distant tissues and organs.
• Normal test results don't guarantee healthy genes. In some families, many women have had breast cancer, yet they all test normal for the known breast cancer mutations. These families may have an inherited form of breast cancer caused by an abnormality or other gene that simply hasn't been identified yet. A woman from such a family must be followed closely.
• You may decide to be closely monitored (checked for possible breast cancer) if your genetic test is abnormal. But close monitoring does not always succeed in detecting breast cancer early. Some women end up being diagnosed with later-stage disease despite the best surveillance techniques.
• For some women, an abnormal test result can trigger anxiety, depression, or anger. Even though a positive test result doesn't mean that a woman will definitely get breast cancer, many women with an abnormal gene assume they will. If you think that knowing the information may be too hard for you emotionally, consider not having genetic testing until more is known about how to beat the disease.
• If you and a child are tested and you learn that you've passed on an abnormal gene to your children, then you may feel guilty and worried. (Yet such knowledge may also prepare you for helping your children cope with their genetic information.)

Knowing that you have an abnormal breast cancer gene will help you design a surveillance plan that is right for you. You may want to follow the same screening strategies for women at high risk of invasive breast cancer:

• starting annual mammograms earlier than age 40,
• having additional screening if necessary (MRI or ultrasound),
• having screening tests more often that once a year (for example, a mammogram in January and MRI scan in July), and
• having more frequent breast exams than previously recommended for you.

You should follow these screening strategies because women who have an abnormal BRCA1 or BRCA2 gene have up to an 85% risk of developing invasive breast cancer by age 70.

Women with BRCA1 and BRCA2 abnormalities are also at increased risk of developing ovarian cancer. The lifetime risk is about 55% for women with BRCA1 mutations and about 25% for women with BRCA2 mutations. So you may also want to talk to your doctor about ovarian cancer.

It's important to remember that not every person with a BRCA1 or BRCA2 abnormality develops cancer. But if you have been diagnosed with DCIS and have a personal or family history that suggests you may be at high risk for breast cancer, you may want to consider genetic testing and counseling. Your results will help a counselor estimate your risk more accurately. You also may want to talk to your doctor about screening strategies for women at high risk. Together you can develop a screening plan that is right for you. And check in with breastcancer.org frequently for the latest information on inherited breast cancer risk, diagnosis, testing, and treatment.