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Breast Cancer Screening

    Basics

Breast screening

Close surveillance or screening for cancer uses tests to try to catch cancer in its early stages, when it is most treatable. Surveillance doesn’t prevent cancer. However, early detection improves a person’s chance of surviving their cancer. Studies of breast cancer screening tools for high-risk women, some including women with BRCA mutations, found certain screening more likely to detect cancer. Whether close surveillance will lower the death rate from breast cancer in high-risk women is unknown. Nevertheless, based on these studies, recommendations for breast cancer screening in the high-risk population differ from recommendations for the general population.

In women with BRCA mutations or other hereditary risk factors, breast cancer tends to occur at a younger age, and the lifetime risk for cancer is higher than the general population. Therefore, screening tests that might not be appropriate for women of average risk may be recommended for those in the high-risk category. As surveillance for breast cancer in high-risk women is further researched, screening recommendations will likely change. For the above reasons, it is important to consult with health care experts who are familiar with the standards of care and risk management in high-risk women. Further, it is important to understand that sweeping recommendations regarding cancer surveillance may not apply to women with increased risk for cancer.

The National Comprehensive Cancer Network (NCCN) is a consortium of cancer centers with experts in management of hereditary cancer.In general, NCCN guidelines dictate the standard of care for cancer surveillance in high-risk patients. These risk management guidelines are updated annually based on the latest research. Current NCCN guidelines for surveillance of high risk women include:

  • Breast self-exam training and regular monthly BSE starting at age 18
  • Clinical breast exam, semiannually, starting at age 25
  • Annual mammogram and/or MRI starting at age 25 or individualized based on earliest age of onset in family

Screening terminology

Scientists use the following criteria when considering the utility of a screening test:

  • Sensitivity (true positives):
    the probability of a positive test among those who have the disease. If two women in a group of 100 have cancer, for example, a highly sensitive test would find positive results in both women.
  • Specificity (true negatives):
    the probability of a negative test among those who do not have the disease . If only two women in the group of 100 have cancer, but 10 falsely test positive, the test is not very specific.

The ideal test is both sensitive and specific. If someone tests positive, they likely have the disease. If they test negative they likely don’t. It is difficult to develop a test that is highly sensitive and highly specific. Usually one quality is compromised at the expense of another.

Breast exams

Breast exams refer to the routine examination of breast tissue to look for lumps or other changes that might indicate cancer. There are two categories of breast exams: Breast Self Exam (BSE) and Clinical Breast Exam (CBE). BSE refers to self-examination of the breasts on a regular (usually monthly) basis, using a systematic method to examine all the breast tissue. Studies have looked at whether Breast Self Exam lowers the risk of death by breast cancer. One large randomized study involving 266,000 women found no reduction in breast cancer death in a 10-year period in women who were taught to perform monthly breast exams. The same research discovered women who practiced regular SBE had more biopsies and procedures for benign lumps than women who did not. Based on this data, some expert panels, including NCCN, do not recommend BSE as a standard recommendation for breast cancer screening for women in the general population. There has been no similar study on BSE in high-risk women. Current NCCN recommendations for women with hereditary breast cancer risk include BSE training and monthly BSE in women beginning at age 18.

CBE refers to examination of a patient’s breasts by a health care professional to detect lumps or other abnormalities. In one study CBE was combined with other screening tools to detect breast cancer in BRCA carriers. Used alone, CBE was found to be an ineffective method of finding cancers. However, when combined with mammography, CBE improved the chances of finding cancer. The NCCN recommends a twice-yearly clinical breast exam for high-risk women beginning at age 25.

Mammograms

Mammograms are x-rays that provide an image of the internal breast structure. Screening mammograms refer to x-rays of the breasts of healthy women in order to find abnormalities. Mammograms are considered the standard screening tool for finding breast cancer in the general population of women after age 40. However, mammography is not perfect, nor is it highly sensitive— the technology misses some breast cancers (false negatives), especially in younger women whose denser breasts. Many changes (false positives) detected by mammograms require a biopsy and turn out to be non cancerous.

Most studies of mammograms in high-risk women or BRCA carriers involved comparison with other imaging techniques such as Magnetic Resonance Imaging (MRI). An article addressing MRI and mammograms in BRCA carriers pointed out that while mammograms had a low sensitivity of 36% (meaning the technology failed to identify many cancers), they had a specificity of 99.8% (meaning there were few false positives and most of the abnormalities identified by mammograms as cancer turned out to be cancer). In another study comparing MRI and mammograms in high-risk women (including but not exclusive to BRCA positive women), MRI generally found more cancers than mammograms, but missed some cancers found by mammography. Although imperfect and not as sensitive as MRI, mammograms are readily available. For these reason, annual mammograms beginning at age 25 are still recommended for high-risk women.

A recent publication explored the theoretical benefits and risks of mammography in young, high-risk women younger than 30. The study affirms the benefits of mammograms for BRCA carriers over age 30, but raises questions about relative risks versus benefits for younger women. One of the researchers, reported that results of this exercise raise questions about the practice of recommending mammograms from age 25, but do not provide enough evidence to change protocols.

Magnetic Resonance Imaging

Breast MRI is an imaging method using magnetic fields rather than x-rays to produce a detailed picture of the breasts.

One study compared mammography and MRI in women with risk factors for hereditary cancer. The majority of women in this research did not have BRCA mutations .Mammography missed two-thirds (66%) of the breast cancers identified by MRI, but found 61% of cancers missed by MRI. Cancers found in women receiving MRI were more likely to be earlier stage and less likely to involve lymph nodes than cancers detected by mammography.

Another study compared MRI, mammograms and ultrasound in 236 women aged 25 to 65 years with BRCA1 or BRCA2 mutations. Even though MRI was generally more sensitive than mammograms, mammography still found cancers MRI failed to detect. However, MRI may be particularly good at finding cancers in premenopausal, high-risk women, a group with typically dense breasts that don’t image well by mammogram. In a study of high-risk women age 35-49, adding MRI to mammography increased the sensitivity from 40% to 94% for finding cancer in high-risk women. This study found that MRI was particularly sensitive in finding breast cancer in women with BRCA 1 mutations.

MRI has some drawbacks. It is less specific than some other screening tests for breast cancer. Although MRI is sensitive and may pick up an abnormality missed by other techniques, there is a greater chance for the abnormality to be benign. Unfortunately, a biopsy is required to determine if a change is cancerous. Women who undergo breast MRI are more likely to have biopsies for changes that are not cancerous. Although this lower specificity may not be acceptable for screening of women of average risk, many experts believe the benefit of MRI outweighs the risk for women with hereditary risk for breast cancer.

Because MRI is still a relatively expensive test, not all insurance companies will pay for it, even in women with a demonstrated BRCA mutation. Further, not all facilities have MRIs specifically made for imaging the breast or radiologists capable of interpreting breast MRI results. And some facilities are not set up for MRI-guided biopsy. That means even if the facility has a breast MRI, it may not have the capability to biopsy an MRI-detected abnormality not seen by mammography or ultrasound. For these reasons, MRI is not yet universally considered standard of care for BRCA carriers, although NCCN and the American Cancer Society have both included MRI in their recommendations for screening of high-risk women.

Additional studies to further determine the benefits of MRI in high-risk women are ongoing.

Ultrasound

Breast ultrasound (also called sonogram) is an imaging method using sound waves to look at the internal structure of breasts. Ultrasound is particularly sensitive at distinguishing fluid-filled cysts from solid masses. Therefore, in women of average risk, ultrasound is not used as a screening tool for breast cancer, but is used as a diagnostic tool to get a better view of abnormalities found through examination or mammogram. Studies have looked at ultrasound as a screening tool for breast cancer in high-risk women. One study compared mammograms, MRI and ultrasound for screening in women with BRCA mutations. In this study, ultrasound found only 33% of the cancers found in the study compared with 77% found by MRI. Research to further determine the benefits of ultrasound in high-risk women are ongoing. Currently there are no NCCN recommendations for breast screening using ultrasound.

Breast screening in men

Men with BRCA mutations have a lifetime risk of up to 7% for breast cancer; higher than men in the general population but much lower than high-risk women. Male breast cancer is uncommon, even in men with BRCA mutations. Therefore, there is very little research on breast cancer detection in high-risk men. Current NCCN recommendations for breast cancer surveillance in male BRCA carriers include:

  • Breast self-exam training and regular monthly practice
  • Annual clinical breast exam
  • Consider baseline mammogram,
  • annual mammogram if gynecomastia (breast enlargement) or breast density on baseline study

Breast chemoprevention overview

Chemoprevention is the use of medication to lower the risk or prevent cancer in healthy people. Some chemoprevention medications reduce breast cancer risk. However, just how well these drugs perform in high-risk women depends on each woman’s individual level of risk. Many past studies of these medications focused on women in the general population or women whose risk for breast cancer was based on the Gail Model not on a BRCA mutation, therefore the research may not apply to everyone with hereditary cancer risk. When choosing the best risk management option for yourself, you need a clear sense of your risk (a health care team with expertise in managing high-risk patients can help you identify this) and an understanding of the potential benefits and side effects of chemopreventive medications

Tamoxifen & raloxifene

Tamoxifen and raloxifene are both examples Selective Estrogen Receptor Modulators (SERMs); drugs that block the effects of estrogen on breast tissue. Tamoxifen, is FDA approved for decreasing breast cancer risk in high-risk women. A large study found women who took tamoxifen for 5 years lowered their breast cancer risk by one half. This study identified women at high-risk for breast cancer according to the Gail Model, which does not always accurately measure risk in women with BRCA mutations. Smaller studies looking at tamoxifen for breast cancer prevention in women with BRCA mutations have been inconclusive. In a study of 19 women with BRCA mutations, women with BRCA 2 mutations who took tamoxifen had a lower breast cancer risk. However, the results were based on only 11 women and were not statistically significant.  In the same study, women with BRCA 1 mutations who took tamoxifen did not have any decrease in breast cancer risk.  Again the sample size was small (8 women) and the results were not statistically significant.

Studies of BRCA carriers who were diagnosed with cancer in one breast and took Tamoxifen demonstrated a reduced risk for breast cancer in the other breast. One such study showed Tamoxifen lowered the risk for a new breast cancer in the other breast by about 40% in women with BRCA 1 mutations and by about 25% in women with BRCA 2 mutations. However, it is uncertain if the same risk-lowering affect applies to BRCA carriers who have not had cancer or to BRCA mutation carriers whose prior breast cancers did not express estrogen or progesterone receptors. 

Tamoxifen may have some side effects and risks. Women who take this medication are at a slightly higher risk for developing uterine cancer. Tamoxifen can also increase the risk of blood clots. Tamoxifen may also have less serious side effects such as hot flashes and vaginal dryness.

Raloxifene is a medication that blocks the effects of estrogen similar to Tamoxifen. Raloxifene may have many similar benefits to Tamoxifen and lowers the risk for breast cancer in certain high-risk women. The STAR Trial (Study of Tamoxifen and Raloxifene), a large research study which compared Tamoxifen and Raloxifene in certain post-menopausal high-risk women concluded that Raloxifene was as effective as Tamoxifen in reducing invasive breast cancer risk. This study included only post-menopausal women who are high-risk based on the risk assessment using the Gail Model , but did not looking specifically at women with BRCA mutations, so the benefits of Raloxifene in BRCA mutation carriers remain uncertain. Raloxifene appears to have fewer side effects than Tamoxifen, including a lower risk for uterine cancer, blood clots and cataracts. One study showed that Raloxifene lowered the risk for uterine cancer by half compared to women who did not take the medication, while Tamoxifen increased the risk for uterine cancer.

Tamoxifen and raloxifene protect bone density and reduce osteoporosis risk in postmenopausal women who are not on hormone replacement.

Aromatase inhibitors

Aromatase inhibitors are medications used to keep post-menopausal women from producing estrogen in their fat cells and adrenal cells. These drugs are used as adjuvant (additional) therapy for preventing breast cancer recurrence in women with cancers that are estrogen or hormone receptor positive. Common aromatase inhibitors include anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin). The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, studied anastrozole as an adjuvant treatment for women with breast cancer. The trial found anastrozole reduced the risk of developing a new cancer in the other breast by 58 percent. This study did not look specifically at women with BRCA mutations, so the benefits of Arimidex to prevent breast cancer in this population remain uncertain.

Unlike SERM medications, aromatase inhibitors do not improve bone density. In fact, they may actually accelerate bone loss in post-menopausal women. However, aromatase inhibitors appear to cause fewer side effects than, and do not appear to have the risk of blood clots or uterine cancer as seen with Tamoxifen.

Clinical trials are studying whether aromatase inhibitors can reduce post-menopausal, high-risk women’s likelihood of developing breast cancer. Some of these studies are looking at women with BRCA mutations. Results from this research will not be available for several years.

Nonsteroidal anti-inflammatories

Nonsteroidal anti-inflammatory drugs (NSAIDs) are medications used for pain relief. This category includes many common over-the-counter painkillers, such as aspirin, ibuprofen (Advil, Motrin) and naproxen sodium (Aleve). Several studies have tried to determine whether aspirin and other NSAIDs reduce breast cancer risk. The Women’s Health Initiative studied the use of NSAIDs by women over the age of 50. Those who used aspirin on a regular basis had a 21% decreased chance of developing breast cancer than women who did not regularly use the medication .Regular use of ibuprofen was associated with a 49% risk reduction in breast cancer risk. This lowered risk also applied to women with a family history of breast cancer (first-degree female relatives only: mother, sister or daughter). However, the study did not specifically focus on women who had BRCA mutations or had evidence of a hereditary breast and ovarian cancer syndrome.This study was “observational” only, meaning although women who regularly took NSAIDs were less likely to develop breast cancer, the study does not prove NSAIDs are responsible for the reduced risk of breast cancer. A clinical trial is needed to show that NSAID use lessens the risk for breast cancer.

Certain NSAIDs increase the risk for death from heart disease. A recent clinical trial studying whether Celebrex could lessen the risk for colon polyps was discontinued when there were more heart disease and heart-disease related deaths in participants who took the medication compared to participants who took a placebo. The risk was still low for death by heart disease: about 3% of people who were on the highest dose, and 2% risk for people on the lower dose. In that particular study, however, the benefits of Celebrex were not believed to outweigh the risks.

Clinical trials are looking at whether nonsteroidal anti-inflammatory agents can decrease breast cancer risk in high-risk women, including some studies looking at women with BRCA mutations. Results from this research will not be available for several years. 


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