The last 5 years have brought significant innovation and advancement in the genetics of breast cancer. This clinical opinion aims to summarize and update current approaches to the care of women at risk for a hereditary predisposition to breast cancer. Implications of the BRCA mutation and several other hereditary syndromes will be discussed. Risk assessment and criteria for referral to cancer genetic professionals as well as high-risk screening and prophylactic options will be reviewed. Finally, the newly available genetic cancer panels and implications of mutations in some of these lesser known genes will be discussed. As the field of cancer genetics continues to evolve, the education of medical students, residents, and faculty will be paramount to identify appropriate candidates for genetic counseling and testing in conjunction with cancer genetic professionals.
The genetics of breast cancer recently became a hot topic in the popular press. In May 2013, actress Angelina Jolie publicly shared her decision to pursue bilateral prophylactic mastectomies after learning that she was a BRCA1 mutation carrier. She published an opinion editorial article in the New York Times discussing her decision and stated that she hoped other women could benefit from her experience. The story lasted several weeks, appearing in newspapers, television, and popular magazines with a large amount of publicity surrounding the genetics of breast cancer.
In what has been termed the Angelina effect, there was a dramatic increase in the number of women seeking referrals for genetic testing. Interestingly, a survey of US adults demonstrated that although 75% of respondents were aware of Angelina Jolie’s bilateral mastectomies, fewer than 10% were able to interpret her risk of developing breast cancer compared with a woman without a BRCA gene mutation.
With this in mind, we plan to review the topic of breast cancer genetics in a manner relevant to the obstetrician and gynecologist. We will review basic epidemiology, mechanisms for screening for genetic mutations, management of patients who have been determined to be at increased risk of developing breast cancer, and issues related to next-generation cancer panel testing.
Epidemiology
In 2014, the American Cancer Society estimated that approximately 235,030 new cases of breast cancer would be diagnosed. Approximately 10% of these cases are likely to be hereditary. Hereditary cancers follow an autosomal dominant pattern of transmission and tend to have an earlier age of onset. Familial cancers, on the other hand, do not follow a specific pattern of inheritance, yet there are more cases of a particular cancer type within a family than would be statistically expected. Among the inherited cases, most are ascribed to defects in the BRCA1 and BRCA2 genes. Interestingly, over the past several years, our knowledge of specific genetic defects that may contribute to familial breast cancer has significantly increased because of genome-wide-association studies. We now recognize several additional mutations associated with an increased risk of breast cancer.
Risk assessment
As obstetricians and gynecologists, we play a vital role in patient risk assessment for a hereditary cancer syndrome. There are several risk assessment models and 2 probability models that are commonly used. Individual risk assessment models include the Gail model, the Claus model, and the Tyrer-Cuzick model. The probability models include breast cancer risk prediction model (BRCAPRO) and the Myriad prevalence data. BRCAPRO incorporates 6 predictive models for inherited or familial breast cancer.
The Gail model calculates a woman’s 5 year and lifetime risk of developing breast cancer. Factors used in the model include age at menarche, age at first live birth, number of first-degree relatives with breast cancer (mother, sister, daughter), number of previous benign breast biopsies, and number of breast biopsies with atypical hyperplasia. This model is often used to assess whether a woman may be a candidate for chemoprevention with tamoxifen. Those women with a 5 year risk of 1.67 or greater are considered high risk and are candidates for tamoxifen, which has been shown to reduce the risk of invasive and non-invasive cancer by approximately 50%. The Gail model is not helpful in patients with a history of breast pathology such as invasive or in situ carcinoma. Other limitations include the following: it underestimates breast cancer risk in African American women; it calculates risk only for women who are 35 years of age or older; and it does not account for age at presentation, bilateral disease, history of ovarian cancer, or extended family history.
The Claus model calculates a woman’s risk of developing breast cancer over 10 year intervals. It differs from the Gail model in that it includes first- and second-degree relatives with breast cancer in either the maternal or paternal lineage, and it accounts for the age when these relatives were diagnosed with breast cancer.
The Tyrer-Cuzick model incorporates both genetic and nongenetic factors. A 3-generation pedigree is used to estimate the likelihood of an individual carrying a BRCA mutation. Some of the factors included are a family history of both breast and ovarian cancer, age at menarche, history of atypical hyperplasia, Ashkenazi inheritance, menopausal status, history of hormone replacement, and personal history of ovarian cancer. This model has been found to be the most accurate of the risk assessment tools. A woman with a lifetime risk greater than 20% by this model is considered high risk and is eligible for magnetic resonance imaging (MRI) screening in addition to annual mammography.
Risk assessment
As obstetricians and gynecologists, we play a vital role in patient risk assessment for a hereditary cancer syndrome. There are several risk assessment models and 2 probability models that are commonly used. Individual risk assessment models include the Gail model, the Claus model, and the Tyrer-Cuzick model. The probability models include breast cancer risk prediction model (BRCAPRO) and the Myriad prevalence data. BRCAPRO incorporates 6 predictive models for inherited or familial breast cancer.
The Gail model calculates a woman’s 5 year and lifetime risk of developing breast cancer. Factors used in the model include age at menarche, age at first live birth, number of first-degree relatives with breast cancer (mother, sister, daughter), number of previous benign breast biopsies, and number of breast biopsies with atypical hyperplasia. This model is often used to assess whether a woman may be a candidate for chemoprevention with tamoxifen. Those women with a 5 year risk of 1.67 or greater are considered high risk and are candidates for tamoxifen, which has been shown to reduce the risk of invasive and non-invasive cancer by approximately 50%. The Gail model is not helpful in patients with a history of breast pathology such as invasive or in situ carcinoma. Other limitations include the following: it underestimates breast cancer risk in African American women; it calculates risk only for women who are 35 years of age or older; and it does not account for age at presentation, bilateral disease, history of ovarian cancer, or extended family history.
The Claus model calculates a woman’s risk of developing breast cancer over 10 year intervals. It differs from the Gail model in that it includes first- and second-degree relatives with breast cancer in either the maternal or paternal lineage, and it accounts for the age when these relatives were diagnosed with breast cancer.
The Tyrer-Cuzick model incorporates both genetic and nongenetic factors. A 3-generation pedigree is used to estimate the likelihood of an individual carrying a BRCA mutation. Some of the factors included are a family history of both breast and ovarian cancer, age at menarche, history of atypical hyperplasia, Ashkenazi inheritance, menopausal status, history of hormone replacement, and personal history of ovarian cancer. This model has been found to be the most accurate of the risk assessment tools. A woman with a lifetime risk greater than 20% by this model is considered high risk and is eligible for magnetic resonance imaging (MRI) screening in addition to annual mammography.
High-risk screening recommendations
Once a woman has undergone a risk assessment, screening recommendations can be made. The American Cancer Society recommends MRI in addition to mammography for women with a high (≥20%) lifetime risk of breast cancer according to risk assessment tools that are based mainly on a family history (Tyrer-Cuzick or Claus models).
Women at a moderately increased risk (15-20%) should discuss benefits and limitations of MRI screening with their physicians because there is not enough evidence in support for or against MRI. This would include women with a history of invasive or in situ breast cancer or atypical ductal or lobular hyperplasia and women with very dense breasts on mammogram. At this time, the use of screening MRI in women with dense breasts is an area of ongoing research. The decision to screen with MRI in a woman with dense breast should be considered in the context of family history. Finally, MRI is not recommended for women whose lifetime risk of breast cancer is less than 15%.
There are other women we would consider high risk and for whom MRI screening would be recommended. These would include women with a BRCA mutation or who decline or do not undergo testing but who have a first-degree relative with the mutation. Also, a patient who has undergone mantle radiation between the ages of 10 and 30 years for Hodgkin’s lymphoma or anyone with Li-Fraumeni, Cowden’s, or one of the other high-risk syndromes is eligible for MRI screening.
Recommendations for genetic counseling and testing
BRCA1 and BRCA2 are tumor suppressor genes that were discovered in the mid-1990s. A woman who carries a BRCA1 mutation has a 57% lifetime risk of developing breast cancer, whereas a woman with a BRCA2 mutation has a 49% risk. Once a woman is diagnosed with breast cancer, if she is a carrier of a BRCA1 or BRCA2 mutation, she has an increased risk of developing a second breast cancer in the contralateral breast. This often becomes important in decision making surrounding breast cancer management. Interestingly, the risk is related to a woman’s age. Women who are younger have been found to carry a higher risk of contralateral malignancy than women who are diagnosed with their first breast cancer at an older age.
Since the early 1990s, our knowledge of the BRCA mutations has grown immensely, and as a result, the National Comprehensive Cancer Network annually updates and publishes thorough guidelines with respect to counseling and testing. Current guidelines recommend the following women undergo genetic counseling and/or testing: breast cancer at age 50 years or younger, bilateral breast cancer, triple-negative (estrogen receptor negative, progesterone receptor negative, Her2Neu negative) breast cancer, breast cancer at any age with close relatives with breast/ovarian/pancreatic cancer, breast cancer with Ashkenazi Jewish ancestry, male breast cancer, women with breast cancer who have a known mutation for a breast cancer susceptibility gene within the family, and women with a history of ovarian cancer.
The Society of Gynecologic Oncology also has guidelines for genetic assessment, and these are subdivided based on a 20-25% risk and a 5-10% risk of an inherited predisposition to breast and ovarian cancer ( Table ).
Patients with a >20–25% risk of having a genetic predisposition to breast and ovarian cancer and genetic assessment recommended:
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Patients with >5-10% chance of having a genetic predisposition to breast and ovarian cancer and genetic assessment may be helpful:
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