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The role of genetic testing and risk stratification in breast cancer prevention and screening

September 29, 2022 - read ≈ 20 min



DeAnna M. Weaver, APRN, C.N.P, FNP-BC, M.S.N.

Certified Nurse Practitioner | Department of Clinical Genomics | Center for Individualized Medicine | Mayo Clinic | 5881 East Mayo Boulevard | Phoenix, AZ 85054


Lida Mina, MD

Breast Medical Oncologist, Senior Associate Consultant | Women’s Cancer Program, Chair of the Breast and the Gynecology Disease Working Group Mayo Clinic Cancer Center | 5881 East Mayo Boulevard | Phoenix, AZ 85054

Banu Arun, MD

Professor, Department of Breast Medical Oncology. The University of Texas MD Anderson Cancer Center, Houston, Texas



Our understanding of breast cancer has notably evolved from the early ancient times when this malignancy was described as the “black bile containing crab like tumors” by Hippocrates 460 BCE. The advent of modern medicine revolutionized our approach to breast cancer diagnosis and treatment, and further progress was achieved over the past few decades. Our therapies have exponentially improved to match the complexities of this multifaceted malignancy.

Unfortunately, despite our best efforts in the field, breast cancer remains the number one cause of cancer affecting women in the United States and the number two most diagnosed female cancer worldwide, claiming 14% of all cancer deaths. Incidence rates are still increasing at alarming rates begging the question to elucidate the risk factors modulating this disease. Historically, many risk factors have been identified, including age, endogenous estrogen, hormone replacement therapy, lifestyle behaviors, family history and genetic predisposition among other risk factors.

As the risk of breast cancer in a woman increases, the importance of breast cancer prevention and screening increases too.  In this brief chapter, we will review risk stratification models, indications for genetic testing, the different genetic mutations that increase the risk for breast cancer, as well as their implications on screening recommendations. We will also highlight the importance of prevention in women at elevated risk of breast cancer.

Risk factors and Risk stratification:

According to Global Cancer Statistics of 2020, breast cancer remains the leading cause of death in women[1]. Accurately assessing a woman’s risk for breast cancer is an important component when deciding what screening method would be best for early detection and disease prevention. Risk factors such as age, ethnicity, and family history play an essential role in calculating a woman’s risk for breast cancer.

Despite the high incidence of breast cancer worldwide, modalities that exist to predict high-risk women are underused[2]. The use of validated risk models aids in quantifying a woman’s risk for breast cancer and, in turn, provides more accurate ways to screen women. When choosing the most accurate model for an individual, it is important to consider factors such as reproductive history, breast history, genetic testing, and family history beyond first-degree relatives. Breast cancer risk models such as BCRAT, IBIS, BRCAPRO, and BCSC can be used to estimate a woman’s lifetime risk of breast cancer and stratify those at moderate to high risk.[2,3] A comparison of each model is described in Table 1.

Table 1: Comparison of breast cancer risk models

Data inputBCRAT 2,3IBIS (V8) 2,3BRCAPRO 2,3BCSC 2,3
Individual history    
Reproductive history  
Breast history    
Prior biopsy 
Genetic testing    
BRCA1 or BRCA2  
Other high-risk genes    
SNP’s or polygenic risk scores   
Family history    
Cancer first-degree relatives
Cancer second-degree relatives  
Age of onset  
Genetic testing  
Accuracy of risk modelO/E: 0.98O/E: 0.84O/E: 0.94O/E: 0.97
 PPV: 0.029PPV: 0.026PPV: 0.026PPV: 0.029
 NPV: 0.987NPV: 0.987NPV: 0.987NPV: 0.988
O/E = ratio of observed to expected cases; PPV = positive predictive value; NPV = negative predictive value

Breast screening with mammograms remains the gold standard in reducing breast cancer-associated mortality by 40% in women of average risk between the age of 40-75 years [4]. When stratifying those who are at high risk for breast cancer, it is important to understand the population’s risk.  According to recent data from SEER Cancer Statistics Review, the population risk of breast cancer in the United States is 12.9 percent [5]. The National Comprehensive Cancer Network recommends those who are at a 20 percent or higher lifetime risk for breast cancer should consider adding breast magnetic resonance imaging (MRI) in addition to annual mammograms as part of their breast cancer screening routine[6]. A breast MRI is more sensitive to detecting a breast mass and can identify cancer at an earlier stage in those who are at high risk.

Genetic susceptibility to breast cancer is also an important consideration when assessing the overall risk for breast cancer and how a woman should be screened. It is estimated that 5-10 percent of breast cancer is related to one or more gene mutations [7]. Genetic testing can help determine if a person has such a mutation and is therefore at an increased risk for developing breast cancer. Personal and family history should be considered when deciding whether genetic testing is appropriate for a patient. Pre-test genetic counseling can assist patients and providers in determining if genetic testing is warranted. Indications for genetic testing and counseling are reviewed in Table 2.

Table 2: Genetic testing indications

Personal history of breast cancer (current or prior) 8Family history of breast cancer only (no personal history) 8
Age of onset < 45 yearsUnaffected individual with a first or second-degree relative who meets the criteria to the left
Age of onset 45-50 AND:
• Unknown/limited family history
• Multiple primary breast cancers
• Family history of breast, ovarian, pancreatic, or prostate cancer at any age
First-degree relative with a history of pancreatic or prostate cancer who are unable to undergo genetic testing
Age of onset > 51 years AND:
• Family history of breast cancer age of onset < 50 or any male breast cancer
• Family history of ovarian, pancreatic, or prostate cancer (metastatic, high or very high-grade group)
• Multiple primary breast cancer > 3
• Two or more relatives with breast or prostate cancer at any age
Unaffected individual with > 5% probability of being a BRCA 1 or 2 carriers through use of probability model (IBIS, BRCAPro, CanRisk)
At any age:
• Triple-negative breast cancer
• Lobular breast cancer with a personal or family history of diffuse gastric cancer
• To aid systemic treatment decisions for metastatic breast cancer or adjuvant treatment
• Male breast cancer
• Close relative with male breast cancer
Ashkenazi Jewish ancestry 

Hereditary breast cancer:

Once a patient is identified as a potential candidate for genetic testing, next-generation sequencing technology can be used to establish a molecular diagnosis for hereditary breast cancer. A blood sample or a collection of saliva can be used to assess the DNA for altered genes passed down through generations. Alterations in certain genes cause an increased probability of developing breast cancer. It is estimated that approximately 30 percent of hereditary breast and ovarian cancer are caused by specific gene variants, mostly in BRCA 1 or BRCA 2 [9].

However, there are many other breast cancer genes that equally cause an increased likelihood to develop hereditary breast cancer. By using genetic testing to identify women at risk of developing hereditary breast cancer, steps can be taken to reduce developing cancer. It is essential that post-test counseling is provided once a diagnosis is made so that patients fully understand personal as well as risk to family members. For this section management of several autosomal dominant hereditary breast cancer conditions will be reviewed.

Hereditary Breast and Ovarian Cancer Syndrome:

Pathogenic variants in BRCA 1 and BRCA 2 indicate that the patient has Hereditary Breast and Ovarian Cancer (HBOC) syndrome. The absolute lifetime risk of primary breast cancer in female BRCA1 and BRCA2 carriers is greater than 60 percent and an approximate 16-40 percent risk to develop a second primary when there is prior breast cancer history [10,11]. Breast cancer risk management includes the options of increased screening, prophylactic surgery, and chemoprevention. 

For those who elect to screen, recommendations include clinical breast examination every 6-12 months beginning at age 25, annual breast MRI (preferred), or mammogram with or without ultrasound if MRI is unavailable for individuals between the ages of 25-29 or individualized based on the earliest age of onset in the family. Breast ultrasound is a more sensitive cancer screening modality in 25–29-year-old women and for women with dense breasts compared to mammogram and should be used in high-risk women when MRI is not available. Annual mammograms and breast MRIs are recommended for individuals between the ages of 30-75. Management should be considered on an individual basis for individuals over the age of 75.  Prophylactic mastectomy should be considered.  However, chemoprevention medication for breast cancer risk reduction also exists [10,11].

Hereditary Diffuse Gastric Cancer Syndrome:

Pathogenic variants in the CDH1 gene indicate that the patient has hereditary diffuse gastric cancer syndrome. The CDH1 gene is associated with an increased risk for gastric and breast cancer. The absolute risk for breast cancer is 41-60% with a predisposition to lobular disease [12,13].

The CDH1 gene is specifically associated with diffuse gastric cancer. However, penetrance depends on the specific variant that is identified. Gastric cancer is estimated to be present in 83% of women and 67% of men by age 80. The average age at which gastric cancer is diagnosed is 37 years old [14].

Management for breast cancer risk includes annual mammograms with consideration of tomosynthesis and consideration of breast MRI with contrast starting at age 30. Discussion of a risk-reducing mastectomy (RRM) can be considered. However, this should be managed based on family history [12,13]. Management for the risk of gastric cancer should be referred to an expert facility that focuses on this condition.


Women with a pathogenic variant in PALB2 have an estimated lifetime risk of developing breast cancer between 41-60%, with higher risks for those with a greater number of relatives with breast cancer [15,16,17]. One study has suggested that individuals with a pathogenic variant in PALB2 have a 10% risk to develop contralateral breast cancer within five years after initial diagnosis [18].

Management should be modified based on family history and includes annual mammograms with consideration of tomosynthesis and annual breast MRIs beginning at age 30. The option of RRM or chemoprevention medication may be considered [15,16,17].

Cowden Syndrome:

Cowden syndrome is caused by mutations in the PTEN gene and is associated with an increased risk of developing several types of cancer, particularly cancers of the breast, thyroid, and uterus. Other cancers that have been identified in those with the PTEN gene, include colorectal cancer, kidney cancer, melanoma, and brain tumors called Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum, a slow-growing hamartoma). The risk of breast cancer for patients with Cowden syndrome has been estimated between 40 to 60% in historical cohorts but is projected to potentially be above 60% by other estimates. Breast cancer management is similar to those with a BRCA mutation.

Management includes annual mammograms with consideration of tomosynthesis and breast MRI screening with contrast starting at age 35 years or 5-10 years before the earliest known breast cancer in the family (whichever comes first). The option for RRM in women with pathogenic/likely pathogenic variants should be discussed [19-22].

Li Fraumeni syndrome:

Pathogenic mutations in the TP53 gene cause a rare, high-risk hereditary cancer predisposition syndrome known as Li Fraumeni syndrome (LFS).  The tumors most closely associated with LFS are soft tissue sarcoma, osteosarcoma, early-onset breast cancer, brain tumors, and adrenocortical carcinomas.

These cancers account for about 70% of all LFS-related tumors.  In addition, a variety of other cancers have been reported in individuals with this condition.  These include gastrointestinal cancers (colorectal, esophageal, pancreatic, stomach), genitourinary cancers (renal cell carcinoma, endometrial, ovarian, and prostate), leukemias, and lymphomas, among others. LFS-related cancers often occur in childhood or young adulthood. The risk of cancer is estimated to be 50% by age 30 years and 90% by age 60 years. The lifetime risk for cancer for females is thought to approach 100%, given the high risk for pre-menopausal breast cancer.

Breast cancer management includes:

  1. Clinical breast examination every 6-12 months beginning at age 20 or at the earliest age of diagnosis of breast cancer in the family if diagnosed before age 20;
  2. Annual breast MRI or mammogram if MRI is unavailable for individuals between the ages of 20-29 (individualized based on earliest age of onset in the family);
  3. Annual mammogram with consideration of tomosynthesis and breast MRI for individuals between the ages of 30-75. Management should be considered on an individual basis for individuals over the age of 75. Individuals may consider the option of RRM [23,24].

Moderate-risk breast cancer genes:

It is estimated that women who have likely pathogenic or pathogenic mutations in moderate-risk breast cancer genes in ATM, CHEK2, RAD51C, and RAD51D have a lifetime risk of 15-40% risk to develop breast cancer.  There is insufficient evidence to recommend RRM in any of these mentioned genes. Management should be based on family history. However, screening mammograms with consideration of tomosynthesis in addition to breast MRI with contrast are recommended starting at age 40 in those who carry certain ATM or CHEK2 variants [25-30].

Limitations of genetic testing and high-risk breast calculations:

Traditionally, single gene testing in those who met the criteria has been the standard. Specific genes tested were based on cancer type. However, today, due to significant cost reduction, next-generation sequencing for analysis of multiple genes has slowly changed this approach. In 2015, multigene panel testing (MGTP) was ordered in approximately two-thirds of cases undergoing genetic testing, whereas BRCA1/2 testing was ordered in only one-third of cases [31]

Limitations exist in both genetic testing and high-risk breast models that have been reviewed in this chapter. Limitations include underrepresentation of minorities, poor understanding of penetrance in genes on the larger panels, and high rates of a variant of uncertain significance (VUS).  The incidence of germline mutations associated with breast cancer risk has primarily been derived from the non-Hispanic white populations [32].

Moreover, despite the importance of genetic counseling, uptake is still unequally divided among patients with testing particularly marginal in minority patients. An example is the African American community, where there is significant underutilization, yet a higher risk of BRCA mutations.

Finally, raising awareness and providing information about the implications of the test remains a challenge. A negative genetic test report does not definitively imply that a patient is not at high risk. Therefore, utilization of high-risk breast cancer risk models may still benefit the patient when making accurate recommendations for screening. It is important that patients understand risk vs benefit as well as limitations to testing. Pre and post-test genetic counseling are strongly recommended for those considering testing.

Prevention remains key:

Once a woman is identified as high risk, the wisdom of focusing on prevention rather than treating consequences remains priceless. As mentioned above, bilateral mastectomies are an option if a woman’s risk is considered high (usually >50%) and that is usually linked to a genetic predisposition. However, in most other women at elevated risk for breast cancer secondary to family history, atypical hyperplasia, and other conditions, chemoprevention with endocrine therapies is the recommended approach. Several medications have been approved, including tamoxifen, raloxifene and aromatase inhibitors. Those medications have been shown to decrease the risk of invasive and noninvasive disease.  However, they were were not shown to affect breast cancer specific or all-cause mortality. Tamoxifen has been shown to decrease invasive breast cancer risk by 40%, aromatase inhibitors can decrease the risk by up to 60%. However, those medications have been associated with several side effects. Tamoxifen is known to cause an increased risk of thromboembolic events, as well as an increased risk of endometrial cancer among other side effects. Aromatase inhibitors have been more associated with increased arthralgias, myalgias as well as loss of bone density. [33-35]

Because of their bad reputations, underutilization of those medications remains a problem. Primary providers find it hard to tackle this issue in their busy clinics and remain shy about prescribing any drugs related to cancer. Patients themselves are reluctant to commit to years of medication especially in view of side effects. It remains challenging to raise awareness and improve access to women to a clinic that is committed to risk stratifying and offering effective chemopreventive measures while monitoring side effects.

Finally, it remains vital to stress the importance of lifestyle changes and adherence to a good nutritional plan as key factors in decreasing the risk of breast cancer. Exercise has been shown to decrease the risk of breast cancer. Adhering to a healthy diet and limiting alcohol intake have also been linked to a better risk profile. [36-38]


Assessing the risk of a woman’s breast cancer remains complicated and requires a personalized approach. It is important to offer each woman a better understanding of her risk and a fair discussion about methods of screening as well as preventive methods. Not every woman will decide to comply with those recommendations. However, it is our duty to help her make the best-informed decision.


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