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Breast Cancer and the genetics of BRCA

If there is this gene in the family, absolutely do not tell your children.  If you want them tested, then do it secretly and do not tell them until they are 20 yr old.  That is when they would be start to be screened.  A teenager does not need to think about removing their breasts.

BRCA genetics in Breast and Ovarian Cancer

A woman’s lifetime risk of developing breast and/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2. Such a woman has an increased risk of developing breast and/or ovarian cancer at an early age and often has multiple, close family members who have been diagnosed with these diseases. Harmful BRCA1 mutations may also increase a woman’s risk of developing cervical, uterine, pancreatic, and colon cancer. Harmful BRCA2 mutations may additionally increase the risk of pancreatic cancer, stomach cancer, gallbladder and bile duct cancer, and melanoma. These mutations are thought to be responsible for an estimated 5 to 7% of all breast and ovarian cancers.

Men with harmful BRCA1 mutations also have an increased risk of breast cancer and, possibly, of pancreatic cancer, testicular cancer, and early-onset prostate cancer. However, male breast cancer, pancreatic cancer, and prostate cancer appear to be more strongly associated with BRCA2 gene mutations.

The likelihood that a breast and/or ovarian cancer is associated with a harmful mutation in BRCA1 or BRCA2 is highest in families with a history of multiple cases of breast cancer, cases of both breast and ovarian cancer, one or more family members with two primary cancers, or an Ashkenazi (Eastern European) Jewish background.  However, not every woman in such families carries a harmful BRCA1 or BRCA2 mutation, and not every cancer in such families is linked to a harmful mutation in one of these genes. Furthermore, not every woman who has a harmful BRCA1 or BRCA2 mutation will develop breast and/or ovarian cancer.

According to estimates of lifetime risk, about 12 percent of women in the general population will develop breast cancer sometime during their lives compared with about 60 percent of women who have inherited a harmful mutation in BRCA1 or BRCA2.

Lifetime risk estimates for ovarian cancer among women in the general population indicate that 1.4 percent  will be diagnosed with ovarian cancer compared with 15 to 40 percent of women who have a harmful BRCA1 or BRCA2 mutation.

It is important to note, however, that most research related to BRCA1 and BRCA2 has been done on large families with many individuals affected by cancer. Estimates of breast and ovarian cancer risk associated with BRCA1 and BRCA2 mutations have been calculated from studies of these families. No data are available from long-term studies of the general population comparing cancer risk in women who have harmful BRCA1 or BRCA2 mutations with women who do not have such mutations. Therefore, the percentages given above are estimates that may change as more data become available.

Mutations in several other genes, including TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM, MLH1, and MSH2, have been associated with hereditary breast and/or ovarian tumors. However, the majority of hereditary breast cancers can be accounted for by inherited mutations in BRCA1 and BRCA2.

Who should be tested for BRCA genes?
Currently, there are no standard criteria for recommending or referring someone for BRCA1 or BRCA2 mutation testing. In a family with a history of breast and/or ovarian cancer, it may be most informative to first test a family member who has breast or ovarian cancer. If that person is found to have a harmful BRCA1 or BRCA2 mutation, then other family members can be tested to see if they also have the mutation.

Regardless, women who have a relative with a harmful BRCA1 or BRCA2 mutation and women who appear to be at increased risk of breast and/or ovarian cancer because of their family history should consider genetic counseling to learn more about their potential risks and about BRCA1 and BRCA2 genetic tests.

The likelihood of a harmful mutation in BRCA1 or BRCA2 is increased with certain familial patterns of cancer. These patterns include the following:

  • For women who are not of Ashkenazi Jewish descent:
    • two first-degree relatives (mother, daughter, or sister) diagnosed with breast cancer, one of whom was diagnosed at age 50 or younger;
    • three or more first-degree or second-degree (grandmother or aunt) relatives diagnosed with breast cancer regardless of their age at diagnosis;
    • a combination of first- and second-degree relatives diagnosed with breast cancer and ovarian cancer (one cancer type per person);
    • a first-degree relative with cancer diagnosed in both breasts (bilateral breast cancer);
    • a combination of two or more first- or second-degree relatives diagnosed with ovarian cancer regardless of age at diagnosis;
    • a first- or second-degree relative diagnosed with both breast and ovarian cancer regardless of age at diagnosis; and
    • breast cancer diagnosed in a male relative.
  • For women of Ashkenazi Jewish descent:
    • any first-degree relative diagnosed with breast or ovarian cancer; and
    • two second-degree relatives on the same side of the family diagnosed with breast or ovarian cancer.

These family history patterns apply to about 2 percent of adult women in the general population. Women who have none of these family history patterns have a low probability of having a harmful BRCA1 or BRCA2 mutation.

Treatment Options
Several options are available for managing cancer risk in individuals who have a harmful BRCA1 or BRCA2 mutation. However, high-quality data on the effectiveness of these options are limited.

  • Surveillance—Surveillance means cancer screening, or a way of detecting the disease early. Screening does not, however, change the risk of developing cancer. The goal is to find cancer early, when it may be most treatable.  However, because BRCA carriers are prone to developing fast-growing tumors, even with this surveillance, about 25% to 30% of carriers are diagnosed when the tumor is already more than 2 cm in diameter, she noted.  The MRI is expensive in itself, but useful because it can detect very small tumors that might not be picked up otherwise.  It also detects many other abnormalities that are not cancer, and this implies not just extra cost but also considerable anxiety for the women concerned.  Dr. Kamm and colleagues outlined the results for 196 women with BRCA gene mutations who had been screened between 1999 and 2005. The women were screened for a median period of 2 years, and in total underwent 1149 breast examinations (of which 2% were abnormal), 494 mammograms (9% abnormal), and 436 MRI scans (14% abnormal). When any abnormality was found, the women underwent further investigation, which led to another 32 breast examinations, 17 mammograms, 64 MRI scans, 114 ultrasound examinations, and 48 biopsies.  During the 6-year period, 13 cancers were found, 11 of which were invasive.
  • Prophylactic Surgery—This type of surgery involves removing as much of the "at-risk" tissue as possible in order to reduce the chance of developing cancer. Bilateral prophylactic mastectomy (removal of healthy breasts) and prophylactic salpingo-oophorectomy (removal of healthy fallopian tubes and ovaries) do not, however, offer a guarantee against developing cancer. Not all at-risk tissue can be removed by these procedures. Currently, about half the women who carry the BRCA gene mutation opt for this measure.  Women who carry the BRCA gene mutation have an estimated 85% lifetime risk of developing breast cancer, but a prophylactic mastectomy reduces this risk to less than 1%.
  • Risk Avoidance—Certain behaviors have been associated with breast and ovarian cancer risk in the general population. Research results on the benefits of modifying individual behaviors to reduce the risk of developing cancer among BRCA1 or BRCA2 mutation carriers are limited.
  • Chemoprevention—This approach involves the use of natural or synthetic substances to reduce the risk of developing cancer or to reduce the chance that cancer will come back. For example, the drug tamoxifen has been shown in numerous clinical studies to reduce the risk of developing breast cancer by about 50 percent in women who are at increased risk of this disease.  Another drug, raloxifene, was shown in a large clinical trial sponsored by the National Cancer Institute (NCI) to reduce the risk of developing invasive breast cancer in postmenopausal women at increased risk of this disease by about the same amount as tamoxifen.

Opinions about prophylactic surgery.
Researchers conducted a study that surveyed 312 women who received genetic counseling and were screened for BRCA mutations at the M. D. Anderson Cancer Center between 1997 and 2005. Of those surveyed, 70% (217 women) had breast cancer and 28% (86 women) tested positive for a BRCA mutation.

The survey included questions regarding the fear of developing the disease as well as feelings regarding screening techniques (mammogram and breast self-exam) and prophylactic strategies (tamoxifen [Nolvadex®] and prophylactic mastectomy). The researchers compared the responses of women who were BRCA positive and those who were BRCA negative.

Among BRCA positive women, 70% felt that prophylactic mastectomy was the most effective way to reduce their risk of breast cancer compared with 40% of BRCA negative women. Furthermore, 64.7% of BRCA-positive women felt that prophylactic mastectomy was the only way to reduce their worry regarding the disease compared with 34.4% of BRCA-negative women.

There were no significant differences between the two groups regarding feelings about mammograms, breast self-exams, or tamoxifen; however, feelings about prophylactic surgery appeared to be drastically different and appeared to be driven primarily by worry among BRCA-positive women. Of the women who felt that prophylactic mastectomy was the best way to reduce their risk, 81% underwent the surgery (compared with 19.1% of those who disagreed); and of the women who felt that the surgery was the only way to reduce their worry, 84.2% proceeded with surgery (compared with 15.8% of those who disagreed).

Factors that increase cancer in all women.
The following factors have been associated with increased or decreased risk of developing breast and/or ovarian cancer in the general population. It is not yet known exactly how these factors influence risk in people with BRCA1 or BRCA2 mutations. In addition, a significant portion of hereditary breast cancers are not associated with BRCA1 or BRCA2 mutations.

  • Age—The risks of breast and ovarian cancer increase with age. Most breast and ovarian cancers occur in women over the age of 50. Women with harmful BRCA1 or BRCA2 mutations often develop breast or ovarian cancer before age 50.
  • Family History—Women who have a first-degree relative (mother, sister, or daughter) or other close relative with breast and/or ovarian cancer may be at increased risk of developing these cancers. In addition, women with relatives who have had colon cancer may be at increased risk of developing ovarian cancer.
  • Medical History—Women who have already had breast cancer are at increased risk of developing breast cancer again, or of developing ovarian cancer.
  • Hormonal Influences—Estrogen is a hormone that is naturally produced by the body and stimulates the normal growth of breast tissue. It is thought that excess estrogen may contribute to breast cancer risk because of its natural role in stimulating breast cell growth.
  • Birth Control Pills (Oral Contraceptives)—Most studies have shown a slight increase or no change in risk of breast cancer among women taking birth control pills. In contrast, numerous studies have shown that taking birth control pills decreases a woman’s risk of developing ovarian cancer. This protective benefit appears to increase with the duration of oral contraceptive use and persists up to 25 years after discontinuing use. It also appears that the use of birth control pills lowers the risk of ovarian cancer in women who carry harmful BRCA1 or BRCA2 mutations.
  • Hormone Replacement Therapy—Doctors may prescribe hormone replacement therapy (HRT) to reduce the discomfort of certain symptoms of menopause, such as hot flashes. However, the results of the Women’s Health Initiative (WHI), a large clinical study conducted by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH), showed that HRT with the hormones estrogen and progestin is associated with harmful side effects, including an increased risk of breast cancer and increased risks of heart attack, blood clots, and stroke. The WHI also showed that HRT with estrogen alone was associated with increased risks of blood clots and stroke, but the effect on breast cancer risk was uncertain.  Because of these potential harmful side effects, the FDA has recommended that HRT be used only at the lowest doses for the shortest period of time needed to achieve treatment goals. No data have been reported to date regarding the effects of HRT on breast cancer risk among women carrying harmful BRCA1 or BRCA2 mutations, and only limited data are available regarding HRT use and ovarian cancer risk among such women. In one study, HRT use did not appear to affect ovarian cancer risk among women with BRCA1 or BRCA2 mutations.

Other factors increasing breast cancer:

  • Obesity—Substantial evidence indicates that obesity is associated with an increased risk of breast cancer, especially among postmenopausal women who have not used HRT. Evidence also suggests that obesity is associated with increased mortality (death) from ovarian cancer.
  • Physical Activity—Numerous studies have examined the relationship between physical activity and breast cancer risk, and most of these studies have shown that physical activity, especially strenuous physical activity, is associated with reduced risk. This decrease in risk appears to be more pronounced in premenopausal women and women with lower-than-normal body weight.
  • Alcohol—There is substantial evidence that alcohol consumption is associated with increased breast cancer risk. However, it is uncertain whether reducing alcohol consumption would decrease breast cancer risk.
  • Dietary Fat—Although early studies suggested a possible association between a high-fat diet and increased breast cancer risk, more recent studies have been inconclusive. In the WHI, a low-fat diet did not help reduce breast cancer risk.

Cancer in Men
Carcinoma of the male breast has many similarities to breast cancer in women, but the diseases have different genetic and pathologic features. Both BRCA1 and BRCA2 mutations can cause breast cancer in women, but only BRCA2 mutations confer a significant risk to men. Although older articles have reported that men with breast cancer have poorer survival rates than women, most recent series show that men and women have equivalent prognoses when matched for age and stage of disease. Prophylactic mastectomy of the contralateral breast may be indicated in a man with breast cancer. However, there is no published clinical data or evidence-based guidelines on prophylactic mastectomy for men with a BRCA2 mutation or a family history of breast cancer. It has been estimated that approximately 6 percent of men who are positive for BRCA2 will develop breast cancer by the age of 70. This is about equal to the risk of breast cancer in average-risk women without BRCA mutations. This difference in risk of breast cancer between BRCA-positive women and men may be due to the fact that men have much less breast tissue and serum estrogen than women.