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Reviewed by Dr. C.H. Weaver M.D. 8/2022

All women are at risk for breast cancer, particularly with advancing age. There are specific factors, however, that significantly increase the risk. As more women become aware of these factors, those at high risk can explore their options for reducing their risk. The most common risk factors are inherited genetic mutations that greatly increase the odds of developing breast cancer. For some women, inherited genetic mutations can increase lifetime risks of developing breast cancer to greater than 85%. For women who have seen multiple family members die after struggling with breast cancer, the most common risk-reducing option is bilateral prophylactic mastectomy – the preventive removal of both breasts.

“The decision to undergo prophylactic mastectomy is a difficult one and may not be right for all high-risk women,” says Dr. Constance M. Chen, plastic surgeon and breast reconstruction specialist. “Those who are faced with this decision must weigh various medical and personal factors, one of which is the options available to them for breast reconstruction. We now have the ability to offer women a range of reconstruction solutions that enable each woman to choose the one that is right for her.”

Assessing Risk - BRCA

National Cancer Institute statistics indicate that about 12% of women in the general population will develop breast cancer at some point in their lives. One of the most important factors that increase’s a woman’s risk is an inherited mutation in the BRCA1 or BRCA2 gene that prevents the gene from performing its proper function, which is to produce proteins that help suppress tumors. 

All inherited traits are passed from parents to their children through genes. Each person has two copies of every gene: one gene from each parent.

The name “BRCA” is an abbreviation for “BReast CAncer gene.” BRCA1 and BRCA2 are two different genes that have been found to impact a person’s chances of developing breast cancer.

Every human has both the BRCA1 and BRCA2 genes. BRCA genes do not cause breast cancer, they normally play a role in preventing breast cancer by helping repair DNA damage that can lead to cancer and its growth. Because of this, the BRCA genes are known as tumor suppressor genes.

When a BRCA gene is broken (mutated), it no longer is effective at repairing broken DNA.  People with a BRCA1 or BRCA2 mutation have a much higher lifetime risk for breast cancer, and much of the risk occurs at a younger age.  The lifetime risk of ovarian cancer is estimated to be 39-46% among women with a BRCA1 mutation and 12-20% among women with a BRCA2 mutation. Lifetime risk of breast cancer among BRCA1 or BRCA2 carriers is 65-74%.1

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Other gene mutations that increase breast cancer risk for women include PALB2, CHEK2, ATM, PTEN, TP53, CDH1, and STK11. There are also women with a very strong family history of breast cancer who may have yet unidentified non-BRCA genetic mutations that can seek genetic counseling to help determine their breast cancer risk. 

Genetic Testing for BRCA

An estimated 1 in 300 to 1 in 800 people in the United States have a BRCA1 or BRCA2 gene mutation. The personal and family history of breast and ovarian cancer can help identify women who are at increased risk of carrying a BRCA mutation and benefit from additional genetic risk assessment.  The genetic test itself simply involves taking a small sample of blood or saliva, which is sent to a lab for analysis. Guidelines developed by the leading oncology organizations recommend that women with any of the following should consider genetic testing for BRCA.

  • Women with a personal history of both breast cancer and ovarian cancer
  • Women with ovarian cancer and a close relative—defined as mother, sister, daughter, grandmother, granddaughter, aunt—with ovarian cancer, premenopausal breast cancer, or both
  • Women of Ashkenazi Jewish decent with breast cancer who were diagnosed at age 40 or younger or who have ovarian cancer
  • Women with breast cancer at 50 or younger and who have a close relative with ovarian cancer or male breast cancer at any age
  • Women with a close relative with a known BRCA mutation

Treatment Options for Individuals with BRCA 

If a woman undergoes genetic testing and tests positive for a BRCA1 or BRCA2 mutation, she has several options for managing her risk of breast and ovarian cancer:

Surveillance Women may choose to undergo regular cancer screening in order to detect cancer at an early stage. Screening may need to begin at an early age and screening tests for breast and ovarian cancer include a clinical breast exam, mammography, breast magnetic resonance imaging (MRI), CA 125 testing, and transvaginal ultrasonography. 

Chemoprevention Hormonal therapy with tamoxifen has been shown to reduce the risk of breast cancer among women with a BRCA2 mutation. Tamoxifen may provide less of a breast cancer benefit among women with a BRCA1 mutation.

Bilateral Prophylactic Mastectomy Surgical removal of both breasts before cancer develops greatly reduces the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. Prophylactic removal of the ovaries and fallopian tubes reduces the risk of ovarian, fallopian tube, and peritoneal cancer. For women who are premenopausal, removal of the ovaries also reduces the risk of breast cancer.

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What is Autologous Reconstruction?

Breast reconstruction following prophylactic mastectomy can be done during or shortly after the mastectomy or it can be done months or even years later. A new breast can be formed with artificial implants or with the woman’s own tissue, in a procedure known as autologous reconstruction.

The primary advantage of implants is that the reconstructive surgery is easier and faster. Implants are not a permanent solution, however, as they are foreign bodies that can cause various cosmetic and medical problems. Although implants in the United States have a ten-year warranty, many have to be removed or replaced well before that. For women who opt for implants, Dr. Chen will often place implants above the pectoral muscle using cohesive gel implants, which are a new type of implant that is softer than a saline implant and hold their shape better than a traditional silicone gel implant.

Autologous reconstruction provides the longest-lasting results and the highest levels of patient satisfaction. Since they are made of the patient’s own tissue, the restored breasts are soft, warm, and look and feel more natural than implants. The most advanced type of reconstruction, called “perforator flap” breast reconstruction, uses microsurgical techniques to preserve the underlying muscle at the donor site while carefully transferring fat and skin along with a blood supply to create a new breast. Perforator flap surgery most often uses tissue from the abdomen but the thigh also serves as a donor site, usually when the abdomen is not serviceable.

Treatment of Early Stage Hereditary Breast Cancer

Experts reviewed 58 key studies and formed the evidentiary basis regarding recommendations for the local management of hereditary breast cancer. Patients with BRCA1/2 mutations and newly diagnosed breast cancer may be considered for breast-conserving therapy (BCT) for the affected breast however due to the significant risk of developing breast cancer in the other breast individuals should consider a bilateral mastectomy in consultation with their treating physician.1

  • For women with mutations in BRCA1/2 or moderate risk genes a nipple-sparing mastectomy is a reasonable approach. When indicated radiation therapy should not be withheld.
  • For patients with germline TP53 mutations, mastectomy is advised; radiation therapy is contraindicated except in those with significant risk of locoregional recurrence.
  • In the adjuvant/neoadjuvant setting, data do not support the routine addition of platinum to anthracycline- and taxane-based chemotherapy.
  • Although poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and talazoparib) are preferable to nonplatinum single-agent chemotherapy for treatment of advanced BC in BRCA1/2 carriers. Data are insufficient to recommend PARP inhibitor use in the early setting or in moderate-penetrance carriers.

Frequently Asked Questions About Hereditary Breast Cancer

What is the risk of developing a second breast cancer in women with BRCA1 or BRCA2?

Young women with BRCA1 or BRCA2 mutations who have been diagnosed with breast cancer have an increased risk of developing a second breast cancer following conservative therapy. This is referred to as a contralateral breast cancer. Compared with women without a BRCA1 or BRCA2 mutation the risk of a subsequent contralateral breast cancer was found to be 4.5 times higher among women with a BRCA1 mutation and 3.4 times higher among women with a BRCA2 mutation.

Researchers from Yale University evaluated data of treatment and outcomes of 127 women with early-stage breast cancer who were treated at their institution. Of these patients, 15 had mutations within their BRCA1 gene and seven had mutations within their BRCA2 gene. Twelve years following the initial diagnosis of breast cancer, 49% of patients with BRCA1 or BRCA2 mutations had a second cancer in the same breast as the initial cancer compared to only 21% of women without these gene mutations. A second breast cancer occurred in the other breast (contralateral) in 42% of patients with BRCA1 or BRCA2 mutations, compared to only 9% of women without these mutations. The average time to develop a second cancer was six to eight years following initial diagnosis.2  The risk of contralateral breast cancer among women previously diagnosed with unilateral breast cancer was 62 percent lower for BRCA1 mutation carriers and 67 percent lower for BRCA2 mutation carriers who took tamoxifen compared with those who didn’t.10

What is the risk of developing a second breast cancer in women with hereditary breast cancer and no BRCA1 or BRCA2 mutation?

A study of women with hereditary breast cancer that is not due to mutations in BRCA1 or BRCA2 reported that these women have a high risk of subsequently developing breast cancer in the opposite breast (contralateral breast cancer). To assess the frequency of contralateral breast cancer in women with hereditary non-BRCA-related breast cancer, researchers in Sweden conducted a study among 204 breast cancer patients from 120 families. The families had been referred to a genetics clinic for suspected hereditary breast cancer. The study excluded women who were initially diagnosed with bilateral breast cancer, as well as women who tested positive for BRCA1 or BRCA2 gene mutations.

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  • After 20 years, the probability of developing contralateral breast cancer was 27% among women with hereditary breast cancer, compared to 5% among women with breast cancer in the general population.
  • The risk of contralateral breast cancer was highest among women with hereditary breast cancer that was diagnosed before the age of 50. More than 40% of these women were expected to develop contralateral breast cancer during the 20 years after their initial breast cancer diagnosis.
  • Adjuvant hormone therapy reduced the risk of contralateral breast cancer.

Another study included 6,294 patients who had been diagnosed with breast cancer under the age of 50 years. The patients were tested for the most prevalent BRCA1/2 mutations and were followed for 12.5 years. Of these patients, 578 developed contralateral breast cancer.

  • Age of the first breast cancer was a significant predictor of the risk of a second contralateral breast cancer. However, this association only existed for those with BRCA1/2 mutations.
  • Specifically, patients diagnosed with their first breast cancer before the age of 41 years had an approximately 24% increased risk of developing contralateral breast cancer 10 years following the initial diagnosis (25.5% for BRCA1 mutations and 17.2% for BRCA2 mutations).
  • Patients diagnosed with their initial breast cancer between the ages of 41 and 49 years had a 12.6% risk of developing a contralateral breast cancer 10 years following their initial diagnosis (15.6% for BRCA1 mutations, and 7.2% for BRCA2 mutations).4

The researchers conclude that women with hereditary non-BRCA-related breast cancer have a high risk of subsequently developing cancer in the opposite breast. Risk was particularly high for women who were initially diagnosed with breast cancer at a young age. The researchers note that “When genetic counseling is provided for this group of women, it is important to consider and provide information regarding the risk of contralateral breast cancer.3

Does the risk of breast cancer among BRCA1/2 carriers vary across families? 

The answer appears to be yes. Researchers have evaluated breast cancer risk among female first-degree relatives (mothers, sisters, daughters) of breast cancer patients with a BRCA1 or BRCA2 mutation.16 Relatives of women who were diagnosed with breast cancer at a younger age were more likely to develop breast cancer themselves. The estimated risk of breast cancer by the age of 70 was 52% for relatives of women diagnosed before the age of 35 and 36% for relatives of women diagnosed between the ages of 45 and 55. Even after accounting for factors such as age at diagnosis and presence of contralateral breast cancer, risk of breast cancer varied across BRCA1/2 families. The researchers conclude that there is broad variation in risk of breast cancer among carriers of BRCA1 and BRCA2 mutations.

Does oral contraceptive use increase breast cancer risk among women with a BRCA mutation? 

Although use of oral contraceptives has been linked with a decreased risk of ovarian cancer, some studies have suggested that it may also be linked with a small increase in breast cancer risk. An international group of researchers conducted a study among close to 1,600 female BRCA1/2 carriers. Seventy-three percent of the study participants had used oral contraceptives. Compared to women who had never used oral contraceptives, risk of breast cancer was 47% higher in women who had ever used oral contraceptives. Risk of breast cancer increased with longer duration of oral contraceptive use, particularly use prior to the first full-term pregnancy. Compared to women who had never used oral contraceptives, risk of breast cancer was 85% higher among women who had used oral contraceptives for at least nine years before first full-term pregnancy. The link between oral contraceptive use and increased breast cancer risk was observed among both BRCA1 and BRCA2 carriers. These results suggest that oral contraceptive use-particularly long-term use before first full-term pregnancy-may increase the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.11,19

Do chest X-rays increase the risk of developing breast cancer? 

X-rays involve exposure to low doses of ionizing radiation, which may cause damage to DNA. Because the BRCA1 and BRCA2 genes play a role in repairing DNA damage, women with mutations in these genes may be more susceptible to the damaging effects of radiation.12,18

Researchers in Europe and Canada conducted a study among 1,601 women. Three-quarters of the study participants had a BRCA1 mutation and one-quarter had a BRCA2 mutation. Women who had ever had a chest X-ray had a 54% increased risk of breast cancer. The age at which a woman received a chest X-ray, as well as the number of chest X-rays she received, influenced the degree to which her risk of breast cancer was increased: risk was increased to a greater extent if a woman had received a chest X-ray before the age of 20 years, or if she had received more than four chest X-rays either before or after the age of 20. The researchers conclude that exposure to ionizing radiation from chest X-rays may increase the risk of breast cancer among women who carry a BRCA1 or BRCA2 gene mutation. Receipt of a chest X-ray before the age of 20 and receipt of a greater number of chest X-rays were linked with the greatest increase in risk.13,14

Does prophylactic mastectomy reduce the risk of developing breast cancer to zero?

Not completely the risk of developing breast cancer is near zero but cancers can occur.5

Are the majority of women satisfied with their decision to undergo prophylactic mastectomy?

The Mayo Clinic evaluated 639 women who underwent bilateral mastectomy an average of 14 years ago. All of these women had a family history of breast cancer and were classified as moderate to high risk of developing an additional breast cancer within their lifetime. Seventy-four percent of women reported diminished emotional stress about their concern of developing breast cancer. Overall, 70% of women were satisfied with the procedure, 11% were neutral, and 19% were dissatisfied. The majority of women reported either no change or else favorable improvements in emotional stability, level of stress, self-esteem, sexual relationships and feelings of femininity. However, 9-36% reported negative effects for one or more of these variables.6

Researchers concluded that the most positive outcome of prophylactic mastectomy was the decreased emotional stress over the concern of developing breast cancer. This must be weighed against the irreversibility of the decision, potential problems with implants and reconstructive surgery and the occurrence of psychological problems in a minority of women. At the present time women with a family history of breast cancer can be tested to see if they carry one of the major breast cancer genes BCRA-1 or BCRA-2. Women who have the gene are considered to be at high risk for developing breast cancer and may choose between frequent screenings, prophylactic chemotherapy (tamoxifen) and prophylactic mastectomy. This decision can only be reached after careful genetic counseling and discussions with the treating physician.

Does BRCA influence treatment outcomes?

According to an article published in the New England Journal of Medicine, women with breast cancer who have BRCA mutations have similar outcomes compared to patients without these mutations. Researchers from Israel conducted a clinical study to compare outcomes of patients with breast cancer and BRCA1 or BRCA2 mutations to outcomes of breast cancer patients without these mutations in more than 1500 women between 1987 and 1988 and found that mortality from breast cancer was not significantly different among patients with BRCA1 or BRCA2 mutations compared to women without the mutations. Among patients who underwent treatment with chemotherapy, deaths rates from breast cancer were not significantly different between patients with BRCA1 or BRCA2 mutations from those without the mutations. The researchers concluded that breast cancer patients with BRCA1 or BRCA2 mutations have similar outcomes as patients without the mutations in terms of death rates caused by breast cancer.17

Are Women with BRCA and Breast Cancer at Increased Risk of Ovarian Cancer?

Women with a BRCA mutation have a 16-60% lifetime risk of developing ovarian cancer compared with a 2% lifetime risk of ovarian cancer in the general population. The 10-year risk of ovarian cancer after breast cancer is ~ 13% for BRCA1 carriers and 7% for BRCA2 carriers. The use of chemotherapy or tamoxifen does not significantly impact the risk of developing ovarian cancer. Overall, 25% of the deaths in women diagnosed with stage I breast cancer have been reported to be due to subsequent ovarian cancer.15

Because the ovaries produce estrogen, which is linked to the development of both cancers, some women who are at a high risk for developing either cancer will opt to have an oophorectomy (removal of ovaries) or a salpingo-oophorectomy (removal of the ovaries and the fallopian tubes). This surgery is known as a risk-reducing salpingo-oophorectomy (RRSO).

In evaluating the factors associated with the choice to undergo preventive surgery, the researchers found that age and level of risk impacted the decision:

  • Older women were less likely to undergo mastectomy but more likely to undergo oophorectomy.
  • Women with a higher risk factor were more likely to undergo surgery.
  • Women who underwent biopsy after risk evaluation were twice as likely to undergo BRRM.
  • Women typically opted for surgery within two years after the genetic mutation test; however, some waited up to seven years.

The researchers that concluded careful risk counseling influences a woman’s decision to undergo preventive surgery. They particularly suggest long-term follow-up in women who choose to delay BRRSO.

Impact of BRCA on Fertility

Women with BRCA mutations may be at higher risk for infertility after chemotherapy

Researchers have determined that women who harbor BRCA mutations face increased risk for infertility after undergoing chemotherapy for breast cancer. It is known that women with BRCA mutations have a faster decline of ovarian egg reserve compared with women without the mutations. In addition, women who have BRCA mutations tend to have more DNA damage in their eggs to begin with because BRCA genes are DNA repair genes. As women age, they repair DNA damage less efficiently, and as a result, there is an accumulation of DNA damage. So, women with BRCA mutations are losing more eggs to begin with because the eggs are more sensitive to environmental damage and the body eliminates them.

Chemotherapy is also known to increase a woman’s risk for infertility, and the researchers theorized that chemotherapy which damages DNA would make the egg reserve even less. In a clinical study published in Fertility and Sterility researchers evaluated 177 women who were undergoing chemotherapy for the treatment of breast cancer. The researchers assessed the women during chemotherapy and at 12, 18 and 24 months after therapy, measuring their levels of anti-mullerian hormones which is indicative of a woman’s ovarian reserves. They found that after chemotherapy, women with BRCA mutations had significantly lower rates of anti-müllerian hormone recovery than women without these mutations. They determined that if you compare the ovarian reserve, there was a threefold difference after chemotherapy. For women who did not have mutations or were at low risk for mutations, there was about 6% of the reserve remaining. In the BRCA mutation group, however, it was about 1.5% to 2%.

Women with BRCA mutations should be more aggressively counseled about preserving their fertility before treatment. For woman considering embryo freezing doctors can now test the embryo genetically for the presence or absence of mutations.9

Constance M. Chen, MD, is a board-certified plastic surgeon with special expertise in the use of innovative natural techniques to optimize medical and cosmetic outcomes for women undergoing breast reconstruction. She is Clinical Assistant Professor of Surgery (Plastic Surgery) at Weill Cornel Medical College and Clinical Assistant Professor of Surgery (Plastic Surgery) at Tulane University School of Medicine. She is also Chief of Microsurgery at New York Eye and Ear Infirmary of Mount Sinai. www.constancechenmd.com

References

  1. ascopubs.org/doi/full/10.1200/JCO.20.00299%C2%A0
  2. Haffty B, Harrold E, Khan A, et al. Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. The Lancet. 2002;359:1471-1477.
  3. Shahedi K, Emanuelsson M, Wiklund F et al. High Risk of Contralateral Breast Carcinoma in Women with Hereditary/Familial Non-BRCA1/BRCA2 Breast Carcinoma. Cancer. 2006;106:1237-42
  4. van den Broek A, van’t Veer, L, Hooning M, et al. Impact of age at primary breast cancer on contralateral breast cancer risk in BRCA1/2 mutation carriers. Journal of Clinical Oncology. 2016; 23(5): 409-418. Available here. Accessed February 18, 2016.
  5. Geiger A, Yu O, Herrinton L. et al. A Population Based Study of Bilateral Prophylactic Mastectomy Efficacy in Women at Elevated Risk for Breast Cancer in Community Practices. Archives of Internal Medicine. 2005; 165: 516-520.
  6. Geiger A, Yu O, Herrinton L. et al. A Population Based Study of Bilateral Prophylactic Mastectomy Efficacy in Women at Elevated Risk for Breast Cancer in Community Practices. Archives of Internal Medicine. 2005; 165: 516-520.
  7. Evans GR, Lalloo F, Ashcroft L, et al. Uptake of risk-reducing surgery in unaffected women at high risk of breast and ovarian cancer is risk, age, and time dependent. Cancer Epidemiology, Biomarkers & Prevention. 2009; 18:2318-2324.
  8. ACOG Practice Bulletin No. 103: Hereditary Breast and Ovarian Cancer Syndrome. Obstetrics and Gynecology. 2009;113:957-966.
  9. Oktay KH, Bedoschi G, Goldfarb SB, et al. Impact of BRCA mutations on chemotherapy-induced loss of ovarian reserve: a prospective longitudinal study. Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract PD6-06.
  10. Phillips KA, Milne RL, Rookus MA, et al. Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. Journal of Clinical Oncology. Published early online August 5, 2013. doi: 10.1200/JCO.2012.47.8313
  11. Brohet RM, Goldgar DE, Easton DF et al. Oral contraceptives and breast cancer risk in the International BRCA1/2 Carrier Cohort Study: A report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. Journal of Clinical Oncology [early online publication]. July 16, 2007.

  12. Andreu N, Easton DF, Chang-Claude J et al. Effect of Chest X-rays on the Risk of Breast Cancer Among BRCA1/2 Mutation Carriers in the International BRCA1/2 Carrier Cohort Study. Journal of Clinical Oncology. Early Online Publication June 26, 2006.

  13. Begg CB, Haile RW, Borg A et al. Variation of breast cancer risk among BRCA1/2 carriers. Journal of the American Medical Association. 2008;299:194-2Brohet RM, Goldgar DE, Easton DF et al. 

  14. Oral contraceptives and breast cancer risk in the International BRCA1/2 Carrier Cohort Study: A report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. Journal of Clinical Oncology [early online publication]. July 16, 2007.

  15. Metcalfe K, Lynch H, Ghadirian P. et al. The Risk of Ovarian Cancer After Breast Cancer in BRCA1 and BRCA2 Carriers. Gynecologic Oncology. 2005; 96: 222-226.

  16. Begg CB, Haile RW, Borg A et al. Variation of breast cancer risk among BRCA1/2 carriers. Journal of the American Medical Association. 2008;299:194-201.

  17.  Rennert G, Bisland-Naggan S, Barnett-Griness O, et al. Clinical Outcomes of Breast Cancer in Carriers of BRCA1 or BRCA2 Mutations. New EnglandJournal of Medicine. 2007;357:115-123. 

  18. Andreu N, Easton DF, Chang-Claude J et al. Effect of Chest X-rays on the Risk of Breast Cancer Among BRCA1/2 Mutation Carriers in the International BRCA1/2 Carrier Cohort Study. Journal of Clinical Oncology. Early Online Publication June 26, 2006.

  19. Brohet RM, Goldgar DE, Easton DF et al. Oral contraceptives and breast cancer risk in the International BRCA1/2 Carrier Cohort Study: A report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. Journal of Clinical Oncology [early online publication]. July 16, 2007.