Up to 10 percent of breast cancer cases are caused by mutations in BRCA tumor suppressor genes, including breast cancer susceptibility gene-1 (BRCA1) and breast cancer susceptibility gene-2 (BRCA2). Proteins made by these genes are used to repair damaged DNA, thereby preserving chromosome integrity during cell division. Defects in this process cause mutation carriers to have relatively high lifetime risks of developing breast, ovarian and some other cancers.
It is estimated that the cumulative risks to age 70 in female BRCA1 mutation carriers are 57% to 65% for breast cancer and approximately 40% for ovarian cancer. Among BRCA2 carriers, the corresponding risk estimates are 45% to 49% and 18%. BRCA1 mutations are associated primarily with ductal breast cancer, whereas BRCA2 mutations are associated with both ductal and lobular breast cancer.
BRCA mutation carriers are more at risk for heart failure and appear to be more vulnerable to heart-related side effects of chemotherapy agents such Adriamycin (doxorubicin).
One study foud that BRCA1 carriers in Poland had far lower rates of breast cancer than BRCA1 carriers in North America, indicating that the increased risks associated with BRCA mutations might be modified by lifestyle factors. Medium intensity physical activity has been found to be associated with a modest reduction in breast cancer risk for BRCA1 and BRCA2 carriers. In addition, there are some foods that have been found to protect against breast cancer in BRCA1 and/or BRCA2 carriers. Please see our article on breast cancer diet for BRCA mutation carriers. Note that BRCA defects account for only approximately 25% of breast cancers with a hereditary component, which means that many women with familial breast cancer are not BRCA mutation carriers.
Hormone receptor status of tumors among BRCA mutation carriers
BRCA1 is the most frequently mutated of the two genes. The majority of BRCA1 breast cancers are hormone receptor negative (ER-/PR-). However, one large study found evidence that the proportion of ER- and triple negative breast tumors decreased with age at diagnosis among BRCA1 mutation carriers but increased with age at diagnosis among BRCA2 carriers. The BRCA1 protein interacts with and regulates the activity of estrogen receptor alpha (ERα) and androgen receptor in a unique way. For example, BRCA1 alters the response of breast cancer cells to anti-estrogen therapy by directly modulating ERα expression. Therefore, hormonal factors contribute to breast cancer risk in BRCA1 mutation carriers. However, the risk-modifying effects of hormonal factors in BRCA1 carriers is not identical to that in non-carriers. Treatment strategies may also be different.
BRCA2 mutations normally result in ER+/PR+ breast cancer. However, as noted above, the proportion of ER- and triple negative breast tumors appears to increase with age among BRCA2 carriers. Those with BRCA mutations typically do not develop HER2 overexpressing breast cancer. Male breast cancer is often associated with BRCA2 mutations, although the risk of developing breast cancer is also higher in men with BRCA1 mutations. Ashkenazi Jewish women have relatively high rates of BRCA mutations compared to the general U.S. population.
Timing of BRCA mutation-related breast cancer
Women with BRCA1 mutations tend to develop breast cancer at a younger age than those with BRCA2 mutations.
Women with either type of BRCA mutation tend to be diagnosed with breast cancer at a younger age than relatives of the previous generation who had breast or ovarian cancer. Compared to the age of diagnosis in the first BRCA mutation carrier generation, the expected age of cancer onset is estimated to be 7.9 years younger in the next generation, according to one study.
A 2015 study reported that, for BRCA2 mutation carriers, the breast cancer risk was 4.5% annually for women with a first-degree relative who had been diagnosed with breast cancer under the age of 30 but only 0.7% for women with a relative diagnosed when over the age of 60. In other words, breast cancer risk appears to be substantially higher for BRCA2 carriers with a first-degree relative who had been diagnosed with breast cancer very young. However, the same study reported that the age of breast cancer diagnosis in first-degree relatives did not appear to influence the annual breast cancer risk for BRCA1 mutation carriers.
Timing also varies according to parent with BRCA mutation
Women with BRCA mutations inherited from their fathers tend to develop breast cancer at a younger age than women who inherit BRCA mutations from their mothers. For breast cancer patients who inherited BRCA1 mutations from their mothers, the average age of breast cancer diagnosis was 45.73 compared to 38.04 for women who inherited BRCA1 mutations from their fathers in one study. For breast cancer patients who inherited BRCA2 mutations from their mothers, the average age was 50.65 compared to 41.68 for women who inherited BRCA2 mutations from their fathers. The same study found no significant age differences for ovarian cancer based on paternal and maternal inheritance of BRCA mutations.
BRCA mutation carriers have increased risk of second breast cancer
BRCA1 and BRCA2 mutation carriers who develop breast cancer are far more likely than the general population of breast cancer patients to develop a new primary breast cancer in the same breast as the original tumor and also to develop breast cancer in the other breast (the contralateral breast). Furthermore, they may develop such tumors within a relatively short period of time. This suggests than lumpectomy does not make sense for BRCA1/2 mutation carriers and that removal of both breasts may reduce risk for some of those who develop breast cancer. However, the few studies that have addressed this issue have found that while bilateral mastectomy reduces risk of local recurrence, it does not necessarily improve long-term survival.
Surveillance among BRCA carrier breast cancer survivors
High-risk breast cancer survivors should be followed by an oncologist or other cancer specialist, not a general practitioner or internist. One study found that survivors followed by specialists were more often seen at recommended intervals, were more likely to have clinical examinations of the breast and lymph nodes, and to have annual mammograms.
Women with known BRCA mutations and/or whose mothers or aunts from either side of the family have a BRCA mutation are advised to start breast cancer screening (including with breast MRIs) beginning at age 25. This guideline makes sense in that it is likely to provide cancer-free baseline images to which subsequent imaging results can be compared. Of course, high-risk women with symptoms of breast cancer should be screened as soon as any symptoms are detected (although very rare, even teenagers can develop breast cancer).
Prophylactic mastectomy and oophorectomy
The choice of breast cancer prevention among BRCA1 and BRCA2 carriers involves multiple factors, including ones that have to do with family planning or are otherwise very personal. Cancer specialists often are reluctant to recommend a specific course of action, leaving the decisions up to the women themselves. However, given the lack of definitive information regarding the risks and outcomes of various possible strategies, the decision making process can be difficult.
One 2010 analysis attempted to model possible strategies and outcomes. Two broad possible types of strategies were evaluated for 25 year old BRCA1 or BRCA2 mutation carriers: (1) annual mammography plus magnetic resonance imaging (MRI) from ages 25 to 69 years (i.e., heightened surveillance); and (2) prophylactic mastectomy at various ages and/or prophylactic oophorectomy at age 40 or 50 years. The probability of survival to age 70 for heightened surveillance with no surgical intervention was estimated to be 53% for BRCA1 and 71% for BRCA2 mutation carriers. The most effective single intervention for BRCA1 mutation carriers was found to be prophylactic oophorectomy at age 40, which resulted in a 15% absolute survival gain, according to the model. For BRCA2 mutation carriers, the most effective single intervention was prophylactic mastectomy, resulting in a 7% survival gain if performed at age 40 years. However, combining prophylactic mastectomy and prophylactic oophorectomy at age 40 improved survival more than any single intervention, resulting in a 24% survival gain for BRCA1 mutation carriers and 11% for BRCA2 mutation carriers. Having a prophylactic mastectomy at age 25 instead of age 40 appears to result in minimal incremental benefit (1% to 2%); using mammography plus MRI screening during the period from age 25 to 40 instead appears to offer comparable survival.
Having said this, high risk women who wish to start families or harvest eggs for future use should attempt to do so, if possible, several years before a diagnosis of breast cancer becomes increasingly more likely. This would also set the stage for prophylactic mastectomy and/or oophorectomy for those who choose to reduce their risk of breast cancer in this way. Those whose mothers develop breast cancer in their thirties appear to be at risk of being diagnosed with breast cancer as much as 12 years earlier, based on available evidence. For example, if a mother was 37 at diagnosis, her daughter's risk might increase sharply starting at age 25. Those whose mothers were in their forties at diagnosis appear to be at heightened risk of being diagnosed starting 10 years earlier. Those whose mothers were in their fifties at diagnosis appear to be at heightened risk of being diagnosed starting eight years earlier.
Breast cancer survival compared to non-carriers
Studies have been inconsistent as to whether BRCA1 mutation carrier have inferior short-term and long-term survival rates compared to non-carriers when tumor characteristics and other prognostic factors are taken into account. The most recent evidence suggests that breast cancer patients who are BRCA1 carriers have a 20% higher likelihood of death from breast cancer than non-carrier patients. A BRCA2 mutation does not appear to affect short-term or long-term survival rates.
BRCA1 mutation carriers may have reduced fertility
While both BRCA1 and BRCA2 mutation carriers have been shown to be less likely to miscarry than non-carriers, women with BRCA1 gene mutations are more likely to be infertile as a result of an early loss of egg reserves. Such women should take this possible early reduction in egg supply into account when planning their families. One 2015 study reported that treatment for infertility does not appear to increase the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation.
Breastfeeding reduces risk of breast cancer for BRCA1 mutation carriers
Women with BRCA1 mutations who breastfeed for at least one year are less likely to have breast cancer than those who never breastfeed, according to one study. No such association has been found for BRCA2 mutation carriers.
Oral contraceptive use at young age increases risk
Use of oral contraceptives (birth control pills) reduces the risk of ovarian cancer among BRCA mutation carriers. However, oral contraceptive use at a very young age increases the risk of breast cancer. Longer duration of use, especially before first full-term pregnancy, is associated with greater risk of breast cancer among both BRCA1 and BRCA2 mutation carriers.
Non-carrier relatives of BRCA mutation carriers
Several studies have reported that relatives of BRCA mutation carriers who do not themselves have a harmful BRCA mutation do not appear to have increased risk of breast cancer compared to the general population. However, recent evidence suggests that such non-carriers do have an elevated risk of breast cancer. In addition, they tend to develop the disease at a younger-than-expected age if they do develop breast cancer. This suggests that such non-carriers might benefit from breast cancer screening starting no later than age 40.
Below are links to recent studies on this topic. For a more complete list of studies, please click on BRCA1 and BRCA2.