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by Dr. C.H. Weaver M.D. 11/2021

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

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. Women 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.  Mutations in these genes can be passed down through either the mother’s or the father’s side of the family. 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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Experts do not agree on the exact statistics for women with genetic mutations because different studies of families with BRCA and other mutations have identified different lifetime risks. 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. 

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. 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

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 an 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.

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

According to a study published in The Lancet, 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. 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

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 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.

Should women with hereditary risk of breast cancer consider removing their ovaries?

Inherited mutations in BRCA1 and BRCA2 also increase the lifetime risk of developing ovarian cancer. Mutations in these genes can be passed down through either the mother’s or the father’s side of the family. Women with a BRCA mutation have a 36-85% lifetime risk of developing breast cancer and a 16-60% lifetime risk of developing ovarian cancer; these statistics are compared with a 13% lifetime risk of breast cancer and a 2% lifetime risk of ovarian cancer in the general population.

In order to reduce the risk of developing ovarian cancer, some women will elect to have an oophorectomy. Doctors evaluated 211 known unaffected BRCA1/2 mutation carriers as well as 3,515 women at a greater than 25% lifetime risk but without mutations.

The results indicated that 40% of the 211 mutation carriers underwent bilateral risk-reducing mastectomy and 45% underwent bilateral risk-reducing sapingo-oophorectomy (BRRSO). The BRRSO was more common among BRCA1 mutation carriers, with 52% of these women choosing the surgery compared with 28% of women with a BRCA2 mutation.

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.