Breast ImagingFree Access

Genetic Testing and Screening Recommendations for Patients with Hereditary Breast Cancer

Published Online:https://doi.org/10.1148/rg.2020190181

Abstract

Professionals who specialize in breast imaging may be the first to initiate the conversation about genetic counseling with patients who have a diagnosis of premenopausal breast cancer or a strong family history of breast and ovarian cancer. Commercial genetic testing panels have gained popularity and have become more affordable in recent years. Therefore, it is imperative for radiologists to be able to provide counseling and to identify those patients who should be referred for genetic testing. The authors review the process of genetic counseling and the associated screening recommendations for patients at high and moderate risk. Ultimately, genetic test results enable appropriate patient-specific screening, which allows improvement of overall survival by early detection and timely treatment. The authors discuss pretest counseling, which involves the use of various breast cancer risk assessment tools such as the Gail and Tyrer–Cuzick models. The most common high- and moderate-risk gene mutations associated with breast cancer are also reviewed. In addition to BRCA1 and BRCA2, several high-risk genes, including TP53, PTEN, CDH1, and STK11, are discussed. Moderate-risk genes include ATM, CHEK2, and PALB2. The imaging appearances of breast cancer typically associated with each gene mutation, as well as the other associated cancers, are described.

©RSNA, 2020

See discussion on this article by Butler (pp 937-940).

SA-CME LEARNING OBJECTIVES

After completing this journal-based SA-CME activity, participants will be able to:

  • ■ Discuss the process of genetic counseling before and after genetic testing.

  • ■ Recognize high- and moderate-risk genes associated with breast cancer.

  • ■ Describe the screening recommendations for the most common genetic mutations.

Introduction

Excluding nonmelonama skin cancers, breast cancer is the most common malignancy in women, followed by colorectal, lung, cervical, endometrial, and ovarian cancers. It is estimated that approximately one in eight to one in 12 women will develop breast cancer in their lifetime (1). While there are numerous risk factors for breast cancer, the presence of a strong family history is one of the most significant. Professionals who specialize in breast imaging may be the first to initiate a conversation about genetic counseling with patients who have a strong family history of breast and ovarian cancer or a diagnosis of premenopausal breast cancer. Therefore, it is imperative for radiologists to understand the components of genetic counseling, identify which patients should be referred for genetic testing, and ensure that appropriate patient-specific screening is performed on the basis of the genetic test results. These efforts may improve overall survival by early detection and timely treatment. Genetic counseling is a multifaceted process, which can help identify patients and their family members who carry a mutation associated with an increased risk of breast cancer. The goal of this process is to allow early detection with enhanced screening. Examples of enhanced screening include initiating screening examinations at an earlier age and performing annual breast MRI in addition to annual mammography.

Teaching Point While commercial genetic testing panels have gained popularity and become more affordable in recent years, there are official guidelines established by the National Comprehensive Cancer Network (NCCN) for patients who should be referred for genetic counseling. Patients with a history of breast cancer diagnosed at 50 years of age or younger, a diagnosis of triple-negative breast cancer at 60 years of age or younger, a history of ovarian cancer, and multiple close family members with related cancer types (eg, breast, ovarian, colon, endometrial, prostate, and pancreatic) are a few of the criteria identified by the NCCN for genetic counseling referral (2).
Table 1 provides a more complete list of the NCCN criteria.

Table 1: NCCN Guidelines for Genetic Counseling Referral

Table 1:

In this article, we review the various components of genetic counseling, including pretest counseling in which risk assessment models are implemented, the process of genetic testing, and the various outcomes, as well as the various gene mutations that are associated with an increased risk of breast cancer. While BRCA1 and BRCA2 gene mutations are the gene mutations most commonly associated with an increased risk of breast cancer, there are many other gene mutations that radiologists should be aware of, including their associations with other types of cancers, to help direct patient screening examinations.

Pretest Genetic Counseling

Because radiologists may be the first health care providers to initiate discussions with patients about the possible value of genetic testing, it is important for radiologists to know when to refer patients to board-certified genetic counselors who can provide a complete genetic risk assessment based on a patient’s personal and family history using a pedigree chart and risk assessment models. Understanding a patient’s genetic pedigree pattern of inheritance and predisposition can help identify patients and their family members who carry a gene mutation associated with an increased risk of breast cancer. There are several risk models available that can help determine the probability of developing cancer over a given time period or the risk of having an inherited mutation in a known high-risk gene.

Each model considers multiple personal and genetic variables. Several models included personal variables such as age, body mass index, estrogen exposure, and a history of breast disease. The genetic variables consider a patient’s family history, specifically whether there is a history of breast, bilateral breast, male breast, or ovarian cancer in any first- or second-degree relatives and the age of onset in family members with these cancers. Table 2 demonstrates additional personal and familial risk factors that several of the risk models incorporate. Many of these models have already been integrated within multiple breast dictation software programs (46). Radiologists should be familiar with the most commonly used prediction models and understand the limitations of each.

Table 2: Risk Factors to Evaluate for Breast Cancer

Table 2:

Commonly Used Risk Assessment Models

Gail and Claus Models

The Gail model was designed in 1989 by the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project and was among the first statistical models used for individual risk assessment of breast cancer (7,8). This model was based on the Breast Cancer Detection Demonstration Project, a study that screened over 250 000 Caucasian women for breast cancer (9). There have been numerous revisions of the Gail model to include the African-American population and additional risk factors (9,10).

The Gail model consists of eight questions that are primarily based on personal risk factors, such as age of menarche, age at first live birth, and number of previous breast biopsies, with limited consideration of genetic variables such as family history (11). The Gail model does not take into account family history beyond first-degree family members (8,9). The model is suitable to use for patients who have never been diagnosed with either in situ or invasive cancers (8). The lack of extensive family history makes the Gail model less likely to help determine if breast MRI should be performed for supplemental breast cancer screening (3).

The Claus model, developed by the Centers for Disease Control and Prevention, incorporates an extensive family history, including but not limited to the history of first- and second-degree relatives and the age of breast cancer onset in these family members (1214). The modified or extended Claus model has also factored in a family history of ovarian cancer and risk for bilateral disease (1). The Claus model has been shown to benefit women who are at risk for premenopausal breast cancer.

Tyrer–Cuzick Model

The Tyrer–Cuzick model is considered one of the most comprehensive models and is presently one of the most popular risk assessment models. The model accounts for various personal factors, such as surrogate measures of endogenous estrogen exposure and prior nonmalignant breast biopsy results (2). The model also includes data from several degrees of relatives and the personal risk factors of each family member, and it provides a separate BRCA1 and BRCA2 risk model estimate from the 5-year and lifetime breast cancer risk estimates (2). The latest edition of the model (version 8) now includes mammographic breast density as a risk factor (15). One of the few drawbacks to using this model is that it can be time consuming to perform owing to its degree of comprehensiveness.

BRCA Mutation Probability Models

There are a few models that predict a patient’s risk of carrying a BRCA1 or BRCA2 mutation, such as the BRCAPRO model and the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA).

The BRCAPRO model approximates the probability of a patient being a carrier of a BRCA1 or BRCA2 mutation and demonstrates a testing sensitivity of 85% in the European and Ashkenazi Jewish populations (16). However, it has not been proven to account for the risk of BRCA1 and BRCA2 mutations in any other ethnic groups.

The BOADICEA model is the first polygenic breast cancer risk model that includes familial risks beyond those in second-degree relatives (7). The model includes several low-penetrance genes that may account for the familial clustering of breast cancer outside the BRCA1 and BRCA2 mutation families. When compared with other models, it is not as statistically significant as the BRCAPRO model for discriminating between mutation carriers and noncarriers (17).

Other Considerations

Selecting a Model

There is no single model that applies to patients of all ages and ethnicities. For example, a recent meta-analysis assessing the performance of the Gail model showed that it was more accurate for assessing the risk in American and European women and may overestimate the risk in Asian women (18). While the Gail model now incorporates information from the Hispanic population, researchers are currently conducting additional studies to add more information to improve the model. Regarding age, a recent study assessing the Tyrer–Cuzick model showed that there was a slight overestimation of the risk in women in their 40s and relative underestimation of risk in women in their 70s (19).

Table 3 provides a comparison of several risk assessment models. There are several key components that geneticists can use to help determine which risk model is appropriate for a specific patient. These include considering the patient’s ethnicity, whether there is a presence of a strong family history of disease, and the length of the patient encounter.

Teaching Point The NCCN and the American Cancer Society recommend using the Gail model in patients whose family history is not significant for breast or ovarian cancer and for establishing those patients who have a greater than 10% lifetime risk of developing breast cancer (21). The Tyrer–Cuzick model is the most consistently accurate model for breast cancer risk prediction, as the more information that is collected on the individual risks of the patient, the better the estimation of lifetime risks. However, it is extensive and can be time consuming.

Table 3: Risk Assessment Model Selection Based on Incorporation of Patient Risk Factors

Table 3:

Financial Costs

Insurance coverage for genetic testing is variable. In the United States, test costs vary from less than $100 to more than $2 000 (22). Medicare covers BRCA1 and BRCA2 mutation testing only for patients with a personal history of breast cancer who meet specific criteria, including breast cancer diagnosis before 45 years of age or those with a close relative with a known BRCA1 or BRCA2 mutation (23). Other insurance companies such as UnitedHealthcare have policies that cover BRCA1 and BRCA2 mutation testing, as well as multigene sequencing panels, if patients meet specific criteria (24). Many U.S. insurance companies require documentation from a board-certified genetic counselor and a three-generation pedigree before approving testing coverage.

In March 2018, the U.S. Food and Drug Administration approved the first direct-to-consumer BRCA test by 23andMe, which tests for only three out of all known BRCA mutations and costs $199 (25,26). However, owing to the limited variants it tests, this test has limited patient value.

Privacy and Discrimination Concerns

Some patients may be reluctant to pursue genetic testing owing to the fear that the test results may affect their coverage from insurance companies and employers. The 2008 U.S. Genetic Information Nondiscrimination Act (GINA) prevents health insurers from using genetic information to make policy decisions and employers from using genetic information in employment decisions (27). GINA also clarifies that genetic information is considered health information protected by the Health Insurance Portability and Accountability Act (HIPAA). However, GINA does not address the use of this information for other types of insurance (such as life or long-term care insurance), and therefore no protections are in place regarding the use of genetic information in making eligibility decisions by these insurers.

Genetic Testing and Posttest Counseling

Over the past 20 years, there has been an emphasis on testing for BRCA1 and BRCA2 mutations, which are specifically related to hereditary breast and ovarian cancer syndrome. In patients with a hereditary predisposition to breast cancer, a specific gene mutation is only identified in approximately less than 30% of cases (28). Although there are tests that are specific for BRCA1 and BRCA2 mutations, there are several multigene sequencing panels that include other high-risk genes for developing breast cancer, such TP53, PTEN, CDH1, and STK11. These genes are associated with Li–Fraumeni syndrome, Cowden syndrome, hereditary diffuse gastric cancer, and Peutz–Jeghers syndrome, respectively. Moderate-risk genes that are often included in these panels include ATM, PALB2, CHEK2, and the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) associated with Lynch syndrome (2931). Each of these genes and their relation to breast cancer risk are discussed further in this article, and Table 4 provides a summary of each gene.

Table 4: High- and Moderate-Risk Gene Mutations Associated with Breast Cancer

Table 4:

Teaching Point There are four possible outcomes of genetic testing: positive, true negative, uninformative negative, or variant of unknown significance. A positive result occurs when test results are positive for a gene mutation that is known to be causative of an increased risk for cancer. A true negative result occurs when a patient from a family with a known mutation receives test results that are negative for that mutation, conclusively proving that they have not inherited the familial syndrome. An uninformative negative result occurs when a patient’s genetic testing results are negative in a family where a mutation has yet to be identified (28).

Because of the broad panel of genes that are encompassed in multigene testing, it is not uncommon to encounter a clinical situation in which testing yields a result known as a genetic variant of uncertain significance. This means that the identified genetic variant is rare and the required data are not available to clearly define a risk. Therefore, its influence on medical management remains unclear (46).

High-Risk Genes

BRCA1 and BRCA2

Although most breast cancers manifest sporadically, approximately 6% of breast cancer cases are caused by BRCA1 and BRCA2 mutations (47). BRCA1 and BRCA2 are located on chromosomes 17 and 13, respectively, and are responsible for encoding proteins involved in DNA repair, which are key to maintaining genetic stability (32). Approximately 3500 variations of BRCA gene mutations have been identified, some of which are associated with variable cancer risks, including up to a 50%–85% lifetime risk of developing breast cancer (28,32,48).

The average age of breast cancer onset is 40 years in patients who are BRCA-mutation carriers in comparison with that of 61 years in the general population (32,49). Approximately 55%–65% of women with BRCA1 mutation and 45% of women with BRCA2 mutation will develop breast cancer by age 70 years (3234). The sensitivity of mammography for the detection of breast cancer in patients with a BRCA mutation is approximately 30%, which is significantly lower in comparison with that of 83% in the general population, given that patients with a BRCA mutation are younger at diagnosis and tend to have denser breast tissue, which can often preclude visualization of cancers (32,5052).

In comparison with cancers that manifest sporadically in the general population, cancers in patients with BRCA1 mutation tend to be of a higher grade, are negative for hormone receptors, and are larger in size, with an overall poorer prognosis (53). A majority of the cancers associated with BRCA mutations are invasive ductal carcinomas (IDCs), with invasive lobular carcinomas (ILCs) accounting for 2%–8%, with associated classic imaging appearances such as an ill-defined mass with abnormal shadowing or a developing asymmetry, respectively (32). Figures 1 and 2a2b demonstrate imaging findings of IDC in two patients with BRCA1 mutation. The pedigree depicted in Figure 2c demonstrates the patient’s family history of breast, ovarian, colon, and prostate cancers.

BRCA1 mutation in a 34-year-old African American woman who presented                         with a palpable right breast mass. (a, b) Mediolateral oblique (MLO)                         diagnostic mammogram (a) and US image (b) show a spiculated mass at the                         12-o’clock position. AOI = area of interest, RT = right.                         (c) Targeted transverse (TRV) (left) and longitudinal (right) US images show                         an adjacent satellite lesion that was not well depicted on the mammogram.                         The results of a biopsy confirmed IDC. Dist. = distance.

Figure 1a. BRCA1 mutation in a 34-year-old African American woman who presented with a palpable right breast mass. (a, b) Mediolateral oblique (MLO) diagnostic mammogram (a) and US image (b) show a spiculated mass at the 12-o’clock position. AOI = area of interest, RT = right. (c) Targeted transverse (TRV) (left) and longitudinal (right) US images show an adjacent satellite lesion that was not well depicted on the mammogram. The results of a biopsy confirmed IDC. Dist. = distance.

BRCA1 mutation in a 34-year-old African American woman who presented                         with a palpable right breast mass. (a, b) Mediolateral oblique (MLO)                         diagnostic mammogram (a) and US image (b) show a spiculated mass at the                         12-o’clock position. AOI = area of interest, RT = right.                         (c) Targeted transverse (TRV) (left) and longitudinal (right) US images show                         an adjacent satellite lesion that was not well depicted on the mammogram.                         The results of a biopsy confirmed IDC. Dist. = distance.

Figure 1b. BRCA1 mutation in a 34-year-old African American woman who presented with a palpable right breast mass. (a, b) Mediolateral oblique (MLO) diagnostic mammogram (a) and US image (b) show a spiculated mass at the 12-o’clock position. AOI = area of interest, RT = right. (c) Targeted transverse (TRV) (left) and longitudinal (right) US images show an adjacent satellite lesion that was not well depicted on the mammogram. The results of a biopsy confirmed IDC. Dist. = distance.

BRCA1 mutation in a 34-year-old African American woman who presented                         with a palpable right breast mass. (a, b) Mediolateral oblique (MLO)                         diagnostic mammogram (a) and US image (b) show a spiculated mass at the                         12-o’clock position. AOI = area of interest, RT = right.                         (c) Targeted transverse (TRV) (left) and longitudinal (right) US images show                         an adjacent satellite lesion that was not well depicted on the mammogram.                         The results of a biopsy confirmed IDC. Dist. = distance.

Figure 1c. BRCA1 mutation in a 34-year-old African American woman who presented with a palpable right breast mass. (a, b) Mediolateral oblique (MLO) diagnostic mammogram (a) and US image (b) show a spiculated mass at the 12-o’clock position. AOI = area of interest, RT = right. (c) Targeted transverse (TRV) (left) and longitudinal (right) US images show an adjacent satellite lesion that was not well depicted on the mammogram. The results of a biopsy confirmed IDC. Dist. = distance.

IDC in a 51-year-old African American woman. (a) Photograph shows                         asymmetric edema and erythema in the right breast, which rapidly progressed                         for 1 month. (b) Targeted US image shows a 5-cm hypoechoic mass with                         microlobulated margins. The results of a biopsy confirmed poorly                         differentiated IDC. (c) Pedigree chart shows the patient’s family                         history. The patient (arrow) was referred for genetic counseling, which                         confirmed a BRCA1 mutation. The pedigree chart shows a family history of                         breast cancer in a sibling, the patient’s mother, and the                         patient’s maternal grandmother. Note also the presence of ovarian,                         colon, and prostate cancers. Circle = woman, Dx = diagnosis,                         square = man. Keys are the same for Figures 3c, 5d, 7c, 8a, 9b, and                         15d.

Figure 2a. IDC in a 51-year-old African American woman. (a) Photograph shows asymmetric edema and erythema in the right breast, which rapidly progressed for 1 month. (b) Targeted US image shows a 5-cm hypoechoic mass with microlobulated margins. The results of a biopsy confirmed poorly differentiated IDC. (c) Pedigree chart shows the patient’s family history. The patient (arrow) was referred for genetic counseling, which confirmed a BRCA1 mutation. The pedigree chart shows a family history of breast cancer in a sibling, the patient’s mother, and the patient’s maternal grandmother. Note also the presence of ovarian, colon, and prostate cancers. Circle = woman, Dx = diagnosis, square = man. Keys are the same for Figures 3c, 5d, 7c, 8a, 9b, and 15d.

IDC in a 51-year-old African American woman. (a) Photograph shows                         asymmetric edema and erythema in the right breast, which rapidly progressed                         for 1 month. (b) Targeted US image shows a 5-cm hypoechoic mass with                         microlobulated margins. The results of a biopsy confirmed poorly                         differentiated IDC. (c) Pedigree chart shows the patient’s family                         history. The patient (arrow) was referred for genetic counseling, which                         confirmed a BRCA1 mutation. The pedigree chart shows a family history of                         breast cancer in a sibling, the patient’s mother, and the                         patient’s maternal grandmother. Note also the presence of ovarian,                         colon, and prostate cancers. Circle = woman, Dx = diagnosis,                         square = man. Keys are the same for Figures 3c, 5d, 7c, 8a, 9b, and                         15d.

Figure 2b. IDC in a 51-year-old African American woman. (a) Photograph shows asymmetric edema and erythema in the right breast, which rapidly progressed for 1 month. (b) Targeted US image shows a 5-cm hypoechoic mass with microlobulated margins. The results of a biopsy confirmed poorly differentiated IDC. (c) Pedigree chart shows the patient’s family history. The patient (arrow) was referred for genetic counseling, which confirmed a BRCA1 mutation. The pedigree chart shows a family history of breast cancer in a sibling, the patient’s mother, and the patient’s maternal grandmother. Note also the presence of ovarian, colon, and prostate cancers. Circle = woman, Dx = diagnosis, square = man. Keys are the same for Figures 3c, 5d, 7c, 8a, 9b, and 15d.

IDC in a 51-year-old African American woman. (a) Photograph shows                         asymmetric edema and erythema in the right breast, which rapidly progressed                         for 1 month. (b) Targeted US image shows a 5-cm hypoechoic mass with                         microlobulated margins. The results of a biopsy confirmed poorly                         differentiated IDC. (c) Pedigree chart shows the patient’s family                         history. The patient (arrow) was referred for genetic counseling, which                         confirmed a BRCA1 mutation. The pedigree chart shows a family history of                         breast cancer in a sibling, the patient’s mother, and the                         patient’s maternal grandmother. Note also the presence of ovarian,                         colon, and prostate cancers. Circle = woman, Dx = diagnosis,                         square = man. Keys are the same for Figures 3c, 5d, 7c, 8a, 9b, and                         15d.

Figure 2c. IDC in a 51-year-old African American woman. (a) Photograph shows asymmetric edema and erythema in the right breast, which rapidly progressed for 1 month. (b) Targeted US image shows a 5-cm hypoechoic mass with microlobulated margins. The results of a biopsy confirmed poorly differentiated IDC. (c) Pedigree chart shows the patient’s family history. The patient (arrow) was referred for genetic counseling, which confirmed a BRCA1 mutation. The pedigree chart shows a family history of breast cancer in a sibling, the patient’s mother, and the patient’s maternal grandmother. Note also the presence of ovarian, colon, and prostate cancers. Circle = woman, Dx = diagnosis, square = man. Keys are the same for Figures 3c, 5d, 7c, 8a, 9b, and 15d.

There is a subset of BRCA1-associated breast cancers that mimics benign imaging characteristics similar to those of fibroadenoma or a cystlike mass, with smooth margins and an ovoid appearance (5456). Medullary cancers are included within this subtype, often manifesting as benign-appearing nearly circumscribed masses with or without calcifications, and are not common in cancers that manifest sporadically in the general population or BRCA2 mutation carriers. However, these account for 19% of cancers in BRCA1-associated cancers (32,56,57). In these benign-appearing cases, assigning a Breast Imaging Reporting and Data System (BI-RADS) category 3 is not recommended, and further evaluation with biopsy is warranted (32,54).

Cancers in patients who are BRCA2 mutation carriers are similar in appearance and pathology to cancers that manifest sporadically in the general population (53). Ductal carcinoma in situ (DCIS) is common in BRCA2 mutation carriers (Fig 3a3c), which is in contrast to BRCA1 mutation carriers (53). In addition, BRCA2-associated cancers tend to be estrogen receptor (ER) positive, similar to cancers that manifest sporadically (32,49). Mammographically visible calcifications are primarily demonstrated in BRCA2-associated cancers and generally not with other types of hereditary cancers attributed to other gene mutations (54).

High-grade DCIS in a 46-year-old woman. (a) Craniocaudal (CC)                         mammogram shows two new groups of coarse heterogeneous calcifications                         (circles) in the left breast. A stereotactic biopsy of both groups was                         performed, and the results confirmed high-grade DCIS. (b) Axial contrast                         material–enhanced T1-weighted subtraction image shows segmental                         clumped nonmass enhancement in the upper outer quadrant of the left breast.                         R S = right side. (c) Pedigree chart shows the patient (arrow), who was                         referred for genetic counseling, which confirmed a BRCA2 mutation. The                         pedigree shows a family history of breast cancer in the patient’s                         mother and multiple second-degree relatives, diagnosed as early as ages                         30–40 years. A history of ovarian cancer was additionally noted in a                         maternal aunt. GI = gastrointestinal.

Figure 3a. High-grade DCIS in a 46-year-old woman. (a) Craniocaudal (CC) mammogram shows two new groups of coarse heterogeneous calcifications (circles) in the left breast. A stereotactic biopsy of both groups was performed, and the results confirmed high-grade DCIS. (b) Axial contrast material–enhanced T1-weighted subtraction image shows segmental clumped nonmass enhancement in the upper outer quadrant of the left breast. R S = right side. (c) Pedigree chart shows the patient (arrow), who was referred for genetic counseling, which confirmed a BRCA2 mutation. The pedigree shows a family history of breast cancer in the patient’s mother and multiple second-degree relatives, diagnosed as early as ages 30–40 years. A history of ovarian cancer was additionally noted in a maternal aunt. GI = gastrointestinal.

High-grade DCIS in a 46-year-old woman. (a) Craniocaudal (CC)                         mammogram shows two new groups of coarse heterogeneous calcifications                         (circles) in the left breast. A stereotactic biopsy of both groups was                         performed, and the results confirmed high-grade DCIS. (b) Axial contrast                         material–enhanced T1-weighted subtraction image shows segmental                         clumped nonmass enhancement in the upper outer quadrant of the left breast.                         R S = right side. (c) Pedigree chart shows the patient (arrow), who was                         referred for genetic counseling, which confirmed a BRCA2 mutation. The                         pedigree shows a family history of breast cancer in the patient’s                         mother and multiple second-degree relatives, diagnosed as early as ages                         30–40 years. A history of ovarian cancer was additionally noted in a                         maternal aunt. GI = gastrointestinal.

Figure 3b. High-grade DCIS in a 46-year-old woman. (a) Craniocaudal (CC) mammogram shows two new groups of coarse heterogeneous calcifications (circles) in the left breast. A stereotactic biopsy of both groups was performed, and the results confirmed high-grade DCIS. (b) Axial contrast material–enhanced T1-weighted subtraction image shows segmental clumped nonmass enhancement in the upper outer quadrant of the left breast. R S = right side. (c) Pedigree chart shows the patient (arrow), who was referred for genetic counseling, which confirmed a BRCA2 mutation. The pedigree shows a family history of breast cancer in the patient’s mother and multiple second-degree relatives, diagnosed as early as ages 30–40 years. A history of ovarian cancer was additionally noted in a maternal aunt. GI = gastrointestinal.

High-grade DCIS in a 46-year-old woman. (a) Craniocaudal (CC)                         mammogram shows two new groups of coarse heterogeneous calcifications                         (circles) in the left breast. A stereotactic biopsy of both groups was                         performed, and the results confirmed high-grade DCIS. (b) Axial contrast                         material–enhanced T1-weighted subtraction image shows segmental                         clumped nonmass enhancement in the upper outer quadrant of the left breast.                         R S = right side. (c) Pedigree chart shows the patient (arrow), who was                         referred for genetic counseling, which confirmed a BRCA2 mutation. The                         pedigree shows a family history of breast cancer in the patient’s                         mother and multiple second-degree relatives, diagnosed as early as ages                         30–40 years. A history of ovarian cancer was additionally noted in a                         maternal aunt. GI = gastrointestinal.

Figure 3c. High-grade DCIS in a 46-year-old woman. (a) Craniocaudal (CC) mammogram shows two new groups of coarse heterogeneous calcifications (circles) in the left breast. A stereotactic biopsy of both groups was performed, and the results confirmed high-grade DCIS. (b) Axial contrast material–enhanced T1-weighted subtraction image shows segmental clumped nonmass enhancement in the upper outer quadrant of the left breast. R S = right side. (c) Pedigree chart shows the patient (arrow), who was referred for genetic counseling, which confirmed a BRCA2 mutation. The pedigree shows a family history of breast cancer in the patient’s mother and multiple second-degree relatives, diagnosed as early as ages 30–40 years. A history of ovarian cancer was additionally noted in a maternal aunt. GI = gastrointestinal.

In cases of male breast cancer, a BRCA2 mutation is associated with a greater lifetime risk of 6.8%, in comparison with a 1.2% risk for BRCA1 mutations (5860). The imaging feature of BRCA-related male breast cancer is often an irregular mass (Fig 4). However, a small subset of cases has been associated with a benign appearance. The average age of diagnosis in male BRCA mutation carriers is 60 years, in comparison with 67 years for the diagnosis of cancers that manifest sporadically in the general population (32).

Palpable left breast mass, which had manifested in the past couple of                         weeks, in a 55-year-old man with a history of a BRCA2 mutation. (a, b) Left                         MLO (LMLO) mammogram (a) and US image (b) of the left (LT) breast show a                         2.5-cm oval partially circumscribed hypervascular mass in the upper outer                         quadrant. PALP BY PT = palpable by patient. (c) Magnified MLO mammogram                         of the right breast shows fine-linear branching calcifications (circle) in                         the upper outer quadrant of the right breast, which are better depicted on                         the specimen radiograph (d), owing to the posterior location. The results of                         a biopsy confirmed IDC, with micropapillary features in the left breast and                         DCIS in the right breast.

Figure 4a. Palpable left breast mass, which had manifested in the past couple of weeks, in a 55-year-old man with a history of a BRCA2 mutation. (a, b) Left MLO (LMLO) mammogram (a) and US image (b) of the left (LT) breast show a 2.5-cm oval partially circumscribed hypervascular mass in the upper outer quadrant. PALP BY PT = palpable by patient. (c) Magnified MLO mammogram of the right breast shows fine-linear branching calcifications (circle) in the upper outer quadrant of the right breast, which are better depicted on the specimen radiograph (d), owing to the posterior location. The results of a biopsy confirmed IDC, with micropapillary features in the left breast and DCIS in the right breast.

Palpable left breast mass, which had manifested in the past couple of                         weeks, in a 55-year-old man with a history of a BRCA2 mutation. (a, b) Left                         MLO (LMLO) mammogram (a) and US image (b) of the left (LT) breast show a                         2.5-cm oval partially circumscribed hypervascular mass in the upper outer                         quadrant. PALP BY PT = palpable by patient. (c) Magnified MLO mammogram                         of the right breast shows fine-linear branching calcifications (circle) in                         the upper outer quadrant of the right breast, which are better depicted on                         the specimen radiograph (d), owing to the posterior location. The results of                         a biopsy confirmed IDC, with micropapillary features in the left breast and                         DCIS in the right breast.

Figure 4b. Palpable left breast mass, which had manifested in the past couple of weeks, in a 55-year-old man with a history of a BRCA2 mutation. (a, b) Left MLO (LMLO) mammogram (a) and US image (b) of the left (LT) breast show a 2.5-cm oval partially circumscribed hypervascular mass in the upper outer quadrant. PALP BY PT = palpable by patient. (c) Magnified MLO mammogram of the right breast shows fine-linear branching calcifications (circle) in the upper outer quadrant of the right breast, which are better depicted on the specimen radiograph (d), owing to the posterior location. The results of a biopsy confirmed IDC, with micropapillary features in the left breast and DCIS in the right breast.

Palpable left breast mass, which had manifested in the past couple of                         weeks, in a 55-year-old man with a history of a BRCA2 mutation. (a, b) Left                         MLO (LMLO) mammogram (a) and US image (b) of the left (LT) breast show a                         2.5-cm oval partially circumscribed hypervascular mass in the upper outer                         quadrant. PALP BY PT = palpable by patient. (c) Magnified MLO mammogram                         of the right breast shows fine-linear branching calcifications (circle) in                         the upper outer quadrant of the right breast, which are better depicted on                         the specimen radiograph (d), owing to the posterior location. The results of                         a biopsy confirmed IDC, with micropapillary features in the left breast and                         DCIS in the right breast.

Figure 4c. Palpable left breast mass, which had manifested in the past couple of weeks, in a 55-year-old man with a history of a BRCA2 mutation. (a, b) Left MLO (LMLO) mammogram (a) and US image (b) of the left (LT) breast show a 2.5-cm oval partially circumscribed hypervascular mass in the upper outer quadrant. PALP BY PT = palpable by patient. (c) Magnified MLO mammogram of the right breast shows fine-linear branching calcifications (circle) in the upper outer quadrant of the right breast, which are better depicted on the specimen radiograph (d), owing to the posterior location. The results of a biopsy confirmed IDC, with micropapillary features in the left breast and DCIS in the right breast.

Palpable left breast mass, which had manifested in the past couple of                         weeks, in a 55-year-old man with a history of a BRCA2 mutation. (a, b) Left                         MLO (LMLO) mammogram (a) and US image (b) of the left (LT) breast show a                         2.5-cm oval partially circumscribed hypervascular mass in the upper outer                         quadrant. PALP BY PT = palpable by patient. (c) Magnified MLO mammogram                         of the right breast shows fine-linear branching calcifications (circle) in                         the upper outer quadrant of the right breast, which are better depicted on                         the specimen radiograph (d), owing to the posterior location. The results of                         a biopsy confirmed IDC, with micropapillary features in the left breast and                         DCIS in the right breast.

Figure 4d. Palpable left breast mass, which had manifested in the past couple of weeks, in a 55-year-old man with a history of a BRCA2 mutation. (a, b) Left MLO (LMLO) mammogram (a) and US image (b) of the left (LT) breast show a 2.5-cm oval partially circumscribed hypervascular mass in the upper outer quadrant. PALP BY PT = palpable by patient. (c) Magnified MLO mammogram of the right breast shows fine-linear branching calcifications (circle) in the upper outer quadrant of the right breast, which are better depicted on the specimen radiograph (d), owing to the posterior location. The results of a biopsy confirmed IDC, with micropapillary features in the left breast and DCIS in the right breast.

Additional cancers associated with BRCA mutations include ovarian, peritoneum, fallopian tube, pancreas, prostate, and colon (32). Ovarian cancer is more common in BRCA1 mutation carriers than in BRCA2 mutation carriers, with lifetime risks of 40% and 11%–17%, respectively (32). Prostate cancer occurs more in BRCA2 mutation carriers and is more aggressive, with a higher probability of metastasis and increased mortality (32). BRCA1 mutation carriers younger than 50 years have a fivefold relative risk of developing colon cancer (32). More information about the common pathologic and imaging findings of these cancers in BRCA mutation carriers is provided in detail in a 2017 RadioGraphics article by Lee et al (32).

Screening, Risk Management, and Treatment Implications.—Owing to the significantly elevated risk in BRCA mutation carriers, the NCCN recommends performing annual breast MRI or mammography (if MRI is not available) starting at age 25–29 years (32). Annual mammography combined with breast MRI is recommended from age 30 to 75 years (32). There is an increased risk of developing interval cancers owing to the aggressive nature of BRCA-associated cancers. Therefore, alternating MRI and mammographic screening at 6-month intervals has been proposed to make earlier detection possible, which subsequently maximizes treatment options (32).

There are limited studies to support screening mammography in men. The NCCN recommends that men at higher risk for breast cancer undergo a clinical breast examination every 6 to 12 months, starting at age 35 years (35, 60). However, screening for prostate cancer is recommended starting at 45 years of age for BRCA2 mutation carriers and should be considered for BRCA1 mutation carriers (2, 32).

The NCCN currently recommends beginning screening colonoscopies at age 40 every 3–5 years in BRCA1 mutation carriers until the age of 50 (32).

Risk-reducing salpingo-oophorectomy (RRSO) after the completion of childbearing is currently recommended by the NCCN. Of note, there is an additional 50% risk reduction for breast cancer for BRCA mutation carriers if the RRSO procedure is performed before the onset of menopause (32). For patients who choose not to undergo a salpingo-oophorectomy, noninvasive screening options such as periodic pelvic US and serial serum CA-125 level monitoring beginning at age 30–35 years is an alternative (32). Additional treatment with oral contraceptives is associated with a risk reduction of ovarian cancer by 40%–50%, without increasing the risk of breast cancer in patients who are already considered high risk (32,61,62).

The treatment of BRCA-related breast cancer has historically been similar to the treatment of breast cancers that manifest sporadically. However, many recent studies have assessed the response of BRCA-related breast cancer to specific treatments such as platinum-based therapies (eg, cisplatin and carboplatin) and poly (adenosine diphosphate–ribose) polymerase inhibitors (PARPi) in comparison with that of standard chemotherapy. Favorable treatment responses to these specific therapies have been seen in patients with advanced or metastatic breast cancer (63).

In January 2018, olaparib became the first PARPi to be approved for the treatment of germline BRCA-mutated and HER2-negative breast cancer, owing to the favorable progression-free survival of patients compared with patients administered standard chemotherapy in the OlympiAD (Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations) clinical trial (64,65).

TP53

Germline mutations in the TP53 gene are associated with Li–Fraumeni syndrome, which has a familial cancer predisposition. TP53 is a tumor suppressor gene located on chromosome 17p13.1, which serves as a checkpoint for either activating genes to repair DNA damage or to initiate apoptosis (66). The syndrome was initially described in 1969 by Li and Fraumeni (57), who studied four families of children with soft-tissue sarcomas (66). Li–Fraumeni syndrome is suspected in a patient with a sarcoma diagnosed before 45 years of age and with a first- or second-degree relative with any cancer before 45 years of age (66,68).

The most common cancers associated with Li–Fraumeni syndrome are soft-tissue sarcomas, leukemia, and breast, adrenocortical, and brain cancers (36,66). Lung, prostate, and colorectal cancers are associated with older patients who are TP53 mutation carriers (66). The risk of breast cancer is 85% by age 60 years, with a mean age at diagnosis of 34 years (66).

Several studies have demonstrated that most TP53 germline mutation–associated cancers are IDC and DCIS and are likely HER2 and/or ER and/or progesterone receptor–positive (66,69,70). Figure 5a5c shows imaging findings of DCIS in a 26-year-old patient with a TP53 mutation. The pedigree from another older patient with a TP53 mutation in Figure 5d shows a prominent family history of breast cancer and multiple other various cancers, including central nervous system and lung cancers in additional family members.

TP53 mutation–associated cancer. (a, b) MLO diagnostic                         mammogram (a) and US image (b) in a 26-year-old African American woman with                         a TP53 mutation show a palpable (PALB) mass in the right (RT) breast. The                         results of a biopsy confirmed high-grade malignant phyllodes tumor. (c)                         Magnified MLO mammogram in the same patient shows left breast calcifications                         (circle) that were additionally identified, and the biopsy results confirmed                         high-grade DCIS. (d) Pedigree chart in another patient with a TP53 mutation                         shows a history of breast cancer in two siblings and other cancers,                         including central nervous system (CNS) and lung cancers, in other family                         members.

Figure 5a. TP53 mutation–associated cancer. (a, b) MLO diagnostic mammogram (a) and US image (b) in a 26-year-old African American woman with a TP53 mutation show a palpable (PALB) mass in the right (RT) breast. The results of a biopsy confirmed high-grade malignant phyllodes tumor. (c) Magnified MLO mammogram in the same patient shows left breast calcifications (circle) that were additionally identified, and the biopsy results confirmed high-grade DCIS. (d) Pedigree chart in another patient with a TP53 mutation shows a history of breast cancer in two siblings and other cancers, including central nervous system (CNS) and lung cancers, in other family members.

TP53 mutation–associated cancer. (a, b) MLO diagnostic                         mammogram (a) and US image (b) in a 26-year-old African American woman with                         a TP53 mutation show a palpable (PALB) mass in the right (RT) breast. The                         results of a biopsy confirmed high-grade malignant phyllodes tumor. (c)                         Magnified MLO mammogram in the same patient shows left breast calcifications                         (circle) that were additionally identified, and the biopsy results confirmed                         high-grade DCIS. (d) Pedigree chart in another patient with a TP53 mutation                         shows a history of breast cancer in two siblings and other cancers,                         including central nervous system (CNS) and lung cancers, in other family                         members.

Figure 5b. TP53 mutation–associated cancer. (a, b) MLO diagnostic mammogram (a) and US image (b) in a 26-year-old African American woman with a TP53 mutation show a palpable (PALB) mass in the right (RT) breast. The results of a biopsy confirmed high-grade malignant phyllodes tumor. (c) Magnified MLO mammogram in the same patient shows left breast calcifications (circle) that were additionally identified, and the biopsy results confirmed high-grade DCIS. (d) Pedigree chart in another patient with a TP53 mutation shows a history of breast cancer in two siblings and other cancers, including central nervous system (CNS) and lung cancers, in other family members.

TP53 mutation–associated cancer. (a, b) MLO diagnostic                         mammogram (a) and US image (b) in a 26-year-old African American woman with                         a TP53 mutation show a palpable (PALB) mass in the right (RT) breast. The                         results of a biopsy confirmed high-grade malignant phyllodes tumor. (c)                         Magnified MLO mammogram in the same patient shows left breast calcifications                         (circle) that were additionally identified, and the biopsy results confirmed                         high-grade DCIS. (d) Pedigree chart in another patient with a TP53 mutation                         shows a history of breast cancer in two siblings and other cancers,                         including central nervous system (CNS) and lung cancers, in other family                         members.

Figure 5c. TP53 mutation–associated cancer. (a, b) MLO diagnostic mammogram (a) and US image (b) in a 26-year-old African American woman with a TP53 mutation show a palpable (PALB) mass in the right (RT) breast. The results of a biopsy confirmed high-grade malignant phyllodes tumor. (c) Magnified MLO mammogram in the same patient shows left breast calcifications (circle) that were additionally identified, and the biopsy results confirmed high-grade DCIS. (d) Pedigree chart in another patient with a TP53 mutation shows a history of breast cancer in two siblings and other cancers, including central nervous system (CNS) and lung cancers, in other family members.

TP53 mutation–associated cancer. (a, b) MLO diagnostic                         mammogram (a) and US image (b) in a 26-year-old African American woman with                         a TP53 mutation show a palpable (PALB) mass in the right (RT) breast. The                         results of a biopsy confirmed high-grade malignant phyllodes tumor. (c)                         Magnified MLO mammogram in the same patient shows left breast calcifications                         (circle) that were additionally identified, and the biopsy results confirmed                         high-grade DCIS. (d) Pedigree chart in another patient with a TP53 mutation                         shows a history of breast cancer in two siblings and other cancers,                         including central nervous system (CNS) and lung cancers, in other family                         members.

Figure 5d. TP53 mutation–associated cancer. (a, b) MLO diagnostic mammogram (a) and US image (b) in a 26-year-old African American woman with a TP53 mutation show a palpable (PALB) mass in the right (RT) breast. The results of a biopsy confirmed high-grade malignant phyllodes tumor. (c) Magnified MLO mammogram in the same patient shows left breast calcifications (circle) that were additionally identified, and the biopsy results confirmed high-grade DCIS. (d) Pedigree chart in another patient with a TP53 mutation shows a history of breast cancer in two siblings and other cancers, including central nervous system (CNS) and lung cancers, in other family members.

Screening, Risk Management, and Treatment Implications.—The NCCN recommends initiating screening annual breast MRI at age 20–29 years and annual MRI combined with mammography at age 30–75 years (2,66). Given the high risk of contralateral breast cancer in TP53 mutation carriers, a risk-reducing bilateral mastectomy is also recommended (2,66).

The NCCN recommends performing additional screening colonoscopy and endoscopy every 2–5 years at age 25 or 5 years before the earliest known colon cancer in the family, as well as annual dermatologic examination and annual whole body MRI, including the brain (category 2B) (2).

For treatment, mastectomy is recommended over lumpectomy to avoid adjuvant radiation therapy owing to concerns of radiation-induced malignancy (66). Heymann et al (71) studied outcomes in eight patients with TP53-associated breast cancer. Out of the six patients who received radiation therapy, three were diagnosed with radiation-induced cancers such as histiocytoma fibrosarcoma, angiosarcoma of the chest wall, and papillary thyroid cancer, which developed within the radiation field (66,71).

PTEN

Cowden syndrome is a rare disease characterized by numerous mucocutaneous hamartomas of the skin, brain, breast, thyroid, and gastrointestinal tract (72,73). Cowden syndrome is inherited in an autosomal dominant manner and is associated with a mutation in the PTEN gene, located on chromosome 10q23 (72). The PTEN gene encodes for a tumor suppressor, which is a dual-specificity phosphatase (37,74).

Owing to the variable penetrance of the syndrome, the NCCN has established a subset of major and minor criteria that confirm the diagnosis. The major criteria include the presence of hamartomas, Lhermitte–Duclos disease (dysplastic cerebellar gangliocytoma), breast cancer, follicular or papillary thyroid cancer, endometrial cancer, and macrocephaly (72). There are several minor criteria including other subcutaneous lesions (eg, lipomas and fibromas), mental retardation, fibrocystic breast disease, and genitourinary tumors (72). Figure 6 shows imaging findings of a fibrolipomatous hamartoma of the left posterior tibial nerve.

Left leg swelling in a 12-year-old boy with a history of Cowden                         syndrome. (a) Axial T1-weighted and (b) sagittal contrast-enhanced                         T1-weighted MR images show a diffusely abnormal appearance of much of the                         left calf musculature, with multifocal areas of hyperenhancement and a                         thickened tibial nerve. The findings were concerning for a fibrolipomatous                         hamartoma of the left posterior tibial nerve, with an associated vascular                         malformation of the posterior calf musculature.

Figure 6a. Left leg swelling in a 12-year-old boy with a history of Cowden syndrome. (a) Axial T1-weighted and (b) sagittal contrast-enhanced T1-weighted MR images show a diffusely abnormal appearance of much of the left calf musculature, with multifocal areas of hyperenhancement and a thickened tibial nerve. The findings were concerning for a fibrolipomatous hamartoma of the left posterior tibial nerve, with an associated vascular malformation of the posterior calf musculature.

Left leg swelling in a 12-year-old boy with a history of Cowden                         syndrome. (a) Axial T1-weighted and (b) sagittal contrast-enhanced                         T1-weighted MR images show a diffusely abnormal appearance of much of the                         left calf musculature, with multifocal areas of hyperenhancement and a                         thickened tibial nerve. The findings were concerning for a fibrolipomatous                         hamartoma of the left posterior tibial nerve, with an associated vascular                         malformation of the posterior calf musculature.

Figure 6b. Left leg swelling in a 12-year-old boy with a history of Cowden syndrome. (a) Axial T1-weighted and (b) sagittal contrast-enhanced T1-weighted MR images show a diffusely abnormal appearance of much of the left calf musculature, with multifocal areas of hyperenhancement and a thickened tibial nerve. The findings were concerning for a fibrolipomatous hamartoma of the left posterior tibial nerve, with an associated vascular malformation of the posterior calf musculature.

Breast cancer is the most common cancer in patients with Cowden syndrome, with an elevated lifetime risk of breast cancer ranging from 67% to 87% beginning at age 30 years (3740). Approximately 25% of these patients have bilateral breast cancer (72,75). The majority of breast cancers are typically IDC or DCIS (72,73). High-risk lesions such as atypical ductal hyperplasia and lobular carcinoma in situ and benign lesions such as fibroadenoma, proliferative fibrocystic changes, and nipple malformations are also associated with Cowden syndrome (72,73). Thyroid, renal, and endometrial cancers are associated with an elevated risk of 35%, 33%, and 17%–28%, respectively (37,38,40).

Screening, Risk Management, and Treatment Implications.—The NCCN recommends performing annual screening with breast MRI and mammography between ages 30 and 35 years or 5–10 years before the age of onset in the youngest breast cancer case in the family, whichever is earlier (2,72). The NCCN also recommends performing thyroid US screening beginning at the age of diagnosis, consideration of blind endometrial suction biopsy starting at age 30–35 years, and screening colonoscopy beginning at age 35 years or 5–10 years before the earliest known colon cancer case in the family, whichever is earliest (2,72).

CDH1

Hereditary diffuse gastric cancer is an autosomal dominant disease that is associated with a CDH1 mutation located on chromosome 16q22.1, resulting in the loss of the E-cadherin protein (76,77). E-cadherin plays a role in cellular adhesion and maintains the architecture of the epithelium. A mutation results in numerous tumor cells invading neighboring structures (76,77). Hereditary diffuse gastric cancer manifests as linitis plastica, a poorly differentiated and infiltrative adenocarcinoma of the gastric wall, without evidence of a discrete gastric mass (41).

The average age of diagnosis is 38 years, and the risk of gastric cancer by 80 years is 70% for men and 56% for women (41). Hereditary diffuse gastric cancer is established in (a) a patient with a diagnosis of diffuse gastric cancer before age 40, regardless of family history; (b) a diffuse gastric cancer diagnosis at any age and a family history of one confirmed case of diffuse gastric cancer; or (c) a personal and/or family history of diffuse gastric cancer and lobular breast cancer, with at least one individual diagnosed before age 50 years (Fig 7) (41). Molecular genetic testing for CDH1 mutation ultimately confirms the diagnosis for inconclusive cases.

CDH1 mutation in two patients. (a) Axial MR image in a 42-year-old                         woman who presented with nipple inversion for several months shows an                         irregular mass in the left breast, with associated nipple retraction and                         skin thickening. The results of a biopsy confirmed ILC. (b) Axial CT image                         of the abdomen and pelvis in the same patient obtained for disease staging                         shows diffuse gastric thickening with lymphadenopathy, findings suspicious                         for malignancy. Genetic testing was recommended, as this finding was                         suggestive of a CDH1 mutation. (c) Pedigree chart shows a family history of                         gastric cancer in the patient’s brother, father, and paternal                         grandfather. (d) Axial CT image of the abdomen and pelvis in an 81-year-old                         woman with a CDH1 mutation and a history of right breast DCIS who presented                         with weight loss and abdominal pain shows severe gastric wall thickening,                         extensive peritoneal carcinomatosis, and a thickened endometrium. The                         patient underwent diagnostic laparoscopy and was diagnosed with stage IIIC                         high-grade serous carcinoma with primary peritoneal origin or stage IVB                         uterine serous carcinoma, as it could not be definitively diagnosed at the                         time of surgical staging. The patient’s family history was notable                         for a case of breast or gynecologic primary cancer in a paternal cousin,                         non-Hodgkin lymphoma in her daughter, esophageal cancer in a maternal                         grandfather, brain cancer in a maternal first cousin, and gastric cancer in                         a paternal first cousin (pedigree chart not available).

Figure 7a. CDH1 mutation in two patients. (a) Axial MR image in a 42-year-old woman who presented with nipple inversion for several months shows an irregular mass in the left breast, with associated nipple retraction and skin thickening. The results of a biopsy confirmed ILC. (b) Axial CT image of the abdomen and pelvis in the same patient obtained for disease staging shows diffuse gastric thickening with lymphadenopathy, findings suspicious for malignancy. Genetic testing was recommended, as this finding was suggestive of a CDH1 mutation. (c) Pedigree chart shows a family history of gastric cancer in the patient’s brother, father, and paternal grandfather. (d) Axial CT image of the abdomen and pelvis in an 81-year-old woman with a CDH1 mutation and a history of right breast DCIS who presented with weight loss and abdominal pain shows severe gastric wall thickening, extensive peritoneal carcinomatosis, and a thickened endometrium. The patient underwent diagnostic laparoscopy and was diagnosed with stage IIIC high-grade serous carcinoma with primary peritoneal origin or stage IVB uterine serous carcinoma, as it could not be definitively diagnosed at the time of surgical staging. The patient’s family history was notable for a case of breast or gynecologic primary cancer in a paternal cousin, non-Hodgkin lymphoma in her daughter, esophageal cancer in a maternal grandfather, brain cancer in a maternal first cousin, and gastric cancer in a paternal first cousin (pedigree chart not available).

CDH1 mutation in two patients. (a) Axial MR image in a 42-year-old                         woman who presented with nipple inversion for several months shows an                         irregular mass in the left breast, with associated nipple retraction and                         skin thickening. The results of a biopsy confirmed ILC. (b) Axial CT image                         of the abdomen and pelvis in the same patient obtained for disease staging                         shows diffuse gastric thickening with lymphadenopathy, findings suspicious                         for malignancy. Genetic testing was recommended, as this finding was                         suggestive of a CDH1 mutation. (c) Pedigree chart shows a family history of                         gastric cancer in the patient’s brother, father, and paternal                         grandfather. (d) Axial CT image of the abdomen and pelvis in an 81-year-old                         woman with a CDH1 mutation and a history of right breast DCIS who presented                         with weight loss and abdominal pain shows severe gastric wall thickening,                         extensive peritoneal carcinomatosis, and a thickened endometrium. The                         patient underwent diagnostic laparoscopy and was diagnosed with stage IIIC                         high-grade serous carcinoma with primary peritoneal origin or stage IVB                         uterine serous carcinoma, as it could not be definitively diagnosed at the                         time of surgical staging. The patient’s family history was notable                         for a case of breast or gynecologic primary cancer in a paternal cousin,                         non-Hodgkin lymphoma in her daughter, esophageal cancer in a maternal                         grandfather, brain cancer in a maternal first cousin, and gastric cancer in                         a paternal first cousin (pedigree chart not available).

Figure 7b. CDH1 mutation in two patients. (a) Axial MR image in a 42-year-old woman who presented with nipple inversion for several months shows an irregular mass in the left breast, with associated nipple retraction and skin thickening. The results of a biopsy confirmed ILC. (b) Axial CT image of the abdomen and pelvis in the same patient obtained for disease staging shows diffuse gastric thickening with lymphadenopathy, findings suspicious for malignancy. Genetic testing was recommended, as this finding was suggestive of a CDH1 mutation. (c) Pedigree chart shows a family history of gastric cancer in the patient’s brother, father, and paternal grandfather. (d) Axial CT image of the abdomen and pelvis in an 81-year-old woman with a CDH1 mutation and a history of right breast DCIS who presented with weight loss and abdominal pain shows severe gastric wall thickening, extensive peritoneal carcinomatosis, and a thickened endometrium. The patient underwent diagnostic laparoscopy and was diagnosed with stage IIIC high-grade serous carcinoma with primary peritoneal origin or stage IVB uterine serous carcinoma, as it could not be definitively diagnosed at the time of surgical staging. The patient’s family history was notable for a case of breast or gynecologic primary cancer in a paternal cousin, non-Hodgkin lymphoma in her daughter, esophageal cancer in a maternal grandfather, brain cancer in a maternal first cousin, and gastric cancer in a paternal first cousin (pedigree chart not available).

CDH1 mutation in two patients. (a) Axial MR image in a 42-year-old                         woman who presented with nipple inversion for several months shows an                         irregular mass in the left breast, with associated nipple retraction and                         skin thickening. The results of a biopsy confirmed ILC. (b) Axial CT image                         of the abdomen and pelvis in the same patient obtained for disease staging                         shows diffuse gastric thickening with lymphadenopathy, findings suspicious                         for malignancy. Genetic testing was recommended, as this finding was                         suggestive of a CDH1 mutation. (c) Pedigree chart shows a family history of                         gastric cancer in the patient’s brother, father, and paternal                         grandfather. (d) Axial CT image of the abdomen and pelvis in an 81-year-old                         woman with a CDH1 mutation and a history of right breast DCIS who presented                         with weight loss and abdominal pain shows severe gastric wall thickening,                         extensive peritoneal carcinomatosis, and a thickened endometrium. The                         patient underwent diagnostic laparoscopy and was diagnosed with stage IIIC                         high-grade serous carcinoma with primary peritoneal origin or stage IVB                         uterine serous carcinoma, as it could not be definitively diagnosed at the                         time of surgical staging. The patient’s family history was notable                         for a case of breast or gynecologic primary cancer in a paternal cousin,                         non-Hodgkin lymphoma in her daughter, esophageal cancer in a maternal                         grandfather, brain cancer in a maternal first cousin, and gastric cancer in                         a paternal first cousin (pedigree chart not available).

Figure 7c. CDH1 mutation in two patients. (a) Axial MR image in a 42-year-old woman who presented with nipple inversion for several months shows an irregular mass in the left breast, with associated nipple retraction and skin thickening. The results of a biopsy confirmed ILC. (b) Axial CT image of the abdomen and pelvis in the same patient obtained for disease staging shows diffuse gastric thickening with lymphadenopathy, findings suspicious for malignancy. Genetic testing was recommended, as this finding was suggestive of a CDH1 mutation. (c) Pedigree chart shows a family history of gastric cancer in the patient’s brother, father, and paternal grandfather. (d) Axial CT image of the abdomen and pelvis in an 81-year-old woman with a CDH1 mutation and a history of right breast DCIS who presented with weight loss and abdominal pain shows severe gastric wall thickening, extensive peritoneal carcinomatosis, and a thickened endometrium. The patient underwent diagnostic laparoscopy and was diagnosed with stage IIIC high-grade serous carcinoma with primary peritoneal origin or stage IVB uterine serous carcinoma, as it could not be definitively diagnosed at the time of surgical staging. The patient’s family history was notable for a case of breast or gynecologic primary cancer in a paternal cousin, non-Hodgkin lymphoma in her daughter, esophageal cancer in a maternal grandfather, brain cancer in a maternal first cousin, and gastric cancer in a paternal first cousin (pedigree chart not available).

CDH1 mutation in two patients. (a) Axial MR image in a 42-year-old                         woman who presented with nipple inversion for several months shows an                         irregular mass in the left breast, with associated nipple retraction and                         skin thickening. The results of a biopsy confirmed ILC. (b) Axial CT image                         of the abdomen and pelvis in the same patient obtained for disease staging                         shows diffuse gastric thickening with lymphadenopathy, findings suspicious                         for malignancy. Genetic testing was recommended, as this finding was                         suggestive of a CDH1 mutation. (c) Pedigree chart shows a family history of                         gastric cancer in the patient’s brother, father, and paternal                         grandfather. (d) Axial CT image of the abdomen and pelvis in an 81-year-old                         woman with a CDH1 mutation and a history of right breast DCIS who presented                         with weight loss and abdominal pain shows severe gastric wall thickening,                         extensive peritoneal carcinomatosis, and a thickened endometrium. The                         patient underwent diagnostic laparoscopy and was diagnosed with stage IIIC                         high-grade serous carcinoma with primary peritoneal origin or stage IVB                         uterine serous carcinoma, as it could not be definitively diagnosed at the                         time of surgical staging. The patient’s family history was notable                         for a case of breast or gynecologic primary cancer in a paternal cousin,                         non-Hodgkin lymphoma in her daughter, esophageal cancer in a maternal                         grandfather, brain cancer in a maternal first cousin, and gastric cancer in                         a paternal first cousin (pedigree chart not available).

Figure 7d. CDH1 mutation in two patients. (a) Axial MR image in a 42-year-old woman who presented with nipple inversion for several months shows an irregular mass in the left breast, with associated nipple retraction and skin thickening. The results of a biopsy confirmed ILC. (b) Axial CT image of the abdomen and pelvis in the same patient obtained for disease staging shows diffuse gastric thickening with lymphadenopathy, findings suspicious for malignancy. Genetic testing was recommended, as this finding was suggestive of a CDH1 mutation. (c) Pedigree chart shows a family history of gastric cancer in the patient’s brother, father, and paternal grandfather. (d) Axial CT image of the abdomen and pelvis in an 81-year-old woman with a CDH1 mutation and a history of right breast DCIS who presented with weight loss and abdominal pain shows severe gastric wall thickening, extensive peritoneal carcinomatosis, and a thickened endometrium. The patient underwent diagnostic laparoscopy and was diagnosed with stage IIIC high-grade serous carcinoma with primary peritoneal origin or stage IVB uterine serous carcinoma, as it could not be definitively diagnosed at the time of surgical staging. The patient’s family history was notable for a case of breast or gynecologic primary cancer in a paternal cousin, non-Hodgkin lymphoma in her daughter, esophageal cancer in a maternal grandfather, brain cancer in a maternal first cousin, and gastric cancer in a paternal first cousin (pedigree chart not available).

ILC is highly associated with hereditary diffuse gastric cancer (41,77). Women with a CDH1 mutation have an increased lifetime risk of 42%–60% for lobular breast cancer (36,41,42). The average age of diagnosis is 53 years (41,78). ILC is not as common as IDC and accounts for 10% of all breast cancers in the general population (77,79). Several studies have suggested that ILC may have a strong hereditary component, owing to the high frequency of bilateral disease (77).

ILC, like hereditary diffuse gastric carcinoma, is also associated with the loss of E-cadherin and shares a similar pathologic appearance, with scattered tumor cells and characteristic signet cells in the background of stromal tissue (77). The first case of histologically defined lobular breast carcinoma with hereditary diffuse gastric cancer was described by Keller et al (80) in 1998 (77). Of note, there have been several reported cases of lobular breast carcinoma in patients with germline mutations in CDH1 without gastric cancer (36,41,77).

Screening, Risk Management, and Treatment Implications.—The NCCN recommends early screening with annual mammography and MRI starting at age 30 years (2). The treatment of patients with CDH1-related breast cancer is similar to the treatment of sporadic manifestations of ILC (41). Most ILCs tend to be ER positive (77). With reference to the increased risk of gastric cancer, a prophylactic total gastrectomy is recommended at age 18–40 years. The overall 5-year survival rate when diagnosed early is greater than 90% (41).

STK11

Peutz–Jeghers syndrome is characterized by mucocutaneous perioral pigmentation and gastrointestinal hamartomatous polyps. The disease is associated with an inherited autosomal dominant germline mutation in the STK11 gene located on chromosome 19p13.3 (35,43,78,81). The pedigree chart in Figure 8a shows the autosomal dominant pattern in a patient with Peutz–Jeghers syndrome. Peutz–Jeghers syndrome was initially described in 1896 by John Hutchinson, who reported a novel case of female twins with perioral pigmentation, one of whom died secondary to intestinal obstruction at age 20 and the other of breast cancer at age 52 (8284). Additional observations in similar patients were made by Jeghers, McKusick, and Katz, with the syndrome officially named in 1954 (82,85).

Peutz–Jeghers syndrome. (a) Pedigree chart of a 46-year-old                         woman (arrow) with Peutz–Jeghers syndrome shows a prominent family                         history of Peutz–Jeghers syndrome and a history of breast cancer in                         her maternal grandmother. Sm bowel resec = small bowel resection. (b,                         c) US images in a 16-year-old adolescent boy with a history of                         Peutz–Jeghers syndrome and small bowel polyps show tiny bilateral                         testicular cysts and left testicular microlithiasis. Inf = inferior,                         Mid = middle, Sag = sagittal.

Figure 8a. Peutz–Jeghers syndrome. (a) Pedigree chart of a 46-year-old woman (arrow) with Peutz–Jeghers syndrome shows a prominent family history of Peutz–Jeghers syndrome and a history of breast cancer in her maternal grandmother. Sm bowel resec = small bowel resection. (b, c) US images in a 16-year-old adolescent boy with a history of Peutz–Jeghers syndrome and small bowel polyps show tiny bilateral testicular cysts and left testicular microlithiasis. Inf = inferior, Mid = middle, Sag = sagittal.

Peutz–Jeghers syndrome. (a) Pedigree chart of a 46-year-old                         woman (arrow) with Peutz–Jeghers syndrome shows a prominent family                         history of Peutz–Jeghers syndrome and a history of breast cancer in                         her maternal grandmother. Sm bowel resec = small bowel resection. (b,                         c) US images in a 16-year-old adolescent boy with a history of                         Peutz–Jeghers syndrome and small bowel polyps show tiny bilateral                         testicular cysts and left testicular microlithiasis. Inf = inferior,                         Mid = middle, Sag = sagittal.

Figure 8b. Peutz–Jeghers syndrome. (a) Pedigree chart of a 46-year-old woman (arrow) with Peutz–Jeghers syndrome shows a prominent family history of Peutz–Jeghers syndrome and a history of breast cancer in her maternal grandmother. Sm bowel resec = small bowel resection. (b, c) US images in a 16-year-old adolescent boy with a history of Peutz–Jeghers syndrome and small bowel polyps show tiny bilateral testicular cysts and left testicular microlithiasis. Inf = inferior, Mid = middle, Sag = sagittal.

Peutz–Jeghers syndrome. (a) Pedigree chart of a 46-year-old                         woman (arrow) with Peutz–Jeghers syndrome shows a prominent family                         history of Peutz–Jeghers syndrome and a history of breast cancer in                         her maternal grandmother. Sm bowel resec = small bowel resection. (b,                         c) US images in a 16-year-old adolescent boy with a history of                         Peutz–Jeghers syndrome and small bowel polyps show tiny bilateral                         testicular cysts and left testicular microlithiasis. Inf = inferior,                         Mid = middle, Sag = sagittal.

Figure 8c. Peutz–Jeghers syndrome. (a) Pedigree chart of a 46-year-old woman (arrow) with Peutz–Jeghers syndrome shows a prominent family history of Peutz–Jeghers syndrome and a history of breast cancer in her maternal grandmother. Sm bowel resec = small bowel resection. (b, c) US images in a 16-year-old adolescent boy with a history of Peutz–Jeghers syndrome and small bowel polyps show tiny bilateral testicular cysts and left testicular microlithiasis. Inf = inferior, Mid = middle, Sag = sagittal.

The mucocutaneous pigmented lesions are typically flat and can be visualized in the perioral, buccal mucosa, and perianal regions. The mucocutaneous lesions are distinctive from freckles in that they cross the vermilion border of the lip (82). The hamartomatous polyps are scattered throughout the gastrointestinal tract, most commonly in the jejunum (82,86,87). The polyps have a characteristic appearance on histopathologic images, which consists of a branched smooth muscle core covered by normal epithelium (82,88).

The diagnostic criteria for Peutz–Jeghers syndrome recommended by the World Health Organization is initially based on whether a patient has a positive family history of Peutz–Jeghers syndrome. In patients with a positive family history, a diagnosis of Peutz–Jeghers syndrome should be suspected with any number of histologically confirmed Peutz–Jeghers syndrome polyps and characteristic mucocutaneous pigmentation. In patients without a family history, criteria include three or more histologically confirmed Peutz–Jeghers syndrome polyps or any number of histologically confirmed polyps and characteristic mucocutaneous pigmentation (82,89).

There is an associated elevated risk of various cancers including gastrointestinal, pancreatic, breast, uterine, ovarian, and cervical (35). The lifetime risk of breast cancer in patients with Peutz–Jeghers syndrome is estimated to be 44%–50% by age 70 years (35,43,44). The mean age of diagnosis is 37 years, with IDC as the most common subtype (35,90). Additionally, men have an increased risk for Sertoli cell tumors, which are hormonally active, and can present with gynecomastia (82,91,92). Figure 8b and 8c show testicular cysts and microlithiasis in a young patient with Peutz–Jeghers syndrome.

Screening, Risk Management, and Treatment Implications.—According to the NCCN guidelines, screening with annual breast MRI at age 25 years and annual mammography combined with MRI screening starting at age 30 years are recommended (35,93,94). Currently, there is no evidence to support the benefit of performing risk-reducing mastectomy for STK11 carriers. However, this option may be considered on the basis of family history (2).

Moderate-Risk Genes

There are several gene mutations associated with a moderate risk of breast cancer. The more prominent mutations include ATM, PALB2, and CHEK2. Moderate-risk genes are often included in multigene sequencing panels. A combination of personal and family history is used to guide management for low- to moderate-risk genes (95).

Teaching Point Identifying low- and moderate-risk genes may be beneficial to the patient, with a potentially greater effect on family members (95). Close family members of patients who carry mutations in genes associated with low or moderate risk are generally encouraged to undergo genetic testing. A positive result is likely to change patient management owing to associated enhanced screening guidelines (95).
A negative result may lead to determining patient management on the basis of personal and family history alone.

ATM

Patients with a single ATM mutation are at an increased risk for breast, pancreatic, and prostate cancer (ovarian to a lesser degree). The overall lifetime risk of breast cancer is approximately 20%, which is considered moderate relative to the risk of genes associated with high-risk syndromes (36).

Figure 9a demonstrates imaging findings of DCIS in a patient with a single ATM mutation. The patient’s pedigree chart (Fig 9b) shows breast cancer in her mother, in addition to cervical and colon cancer in several second-degree relatives. Of note, biallelic ATM genetic mutations can also be inherited in an autosomal recessive pattern and are then causative of ataxia telangiectasia, a disease characterized by cerebellar degeneration, immune deficiency, and increased sensitivity to ionization radiation, which increases the risk of cancer (96104). While ataxia telangiectasia is rare, an estimated 1%–2% of the population is considered heterozygous for a pathogenic ATM variant (96104).

ATM mutation in a 45-year-old African American woman who presented                         with abnormal results at screening mammography. (a) CC diagnostic mammogram                         shows grouped calcifications (circle) in the subareolar region of the right                         breast, for which a stereotactic biopsy was performed. The results confirmed                         high-grade DCIS. She was referred for genetic counseling, and an ATM                         mutation was identified. (b) Pedigree chart shows the patient’s                         (arrow) family history of breast cancer in the patient’s mother, in                         addition to cervical and colon cancer in several second-degree                         relatives.

Figure 9a. ATM mutation in a 45-year-old African American woman who presented with abnormal results at screening mammography. (a) CC diagnostic mammogram shows grouped calcifications (circle) in the subareolar region of the right breast, for which a stereotactic biopsy was performed. The results confirmed high-grade DCIS. She was referred for genetic counseling, and an ATM mutation was identified. (b) Pedigree chart shows the patient’s (arrow) family history of breast cancer in the patient’s mother, in addition to cervical and colon cancer in several second-degree relatives.

ATM mutation in a 45-year-old African American woman who presented                         with abnormal results at screening mammography. (a) CC diagnostic mammogram                         shows grouped calcifications (circle) in the subareolar region of the right                         breast, for which a stereotactic biopsy was performed. The results confirmed                         high-grade DCIS. She was referred for genetic counseling, and an ATM                         mutation was identified. (b) Pedigree chart shows the patient’s                         (arrow) family history of breast cancer in the patient’s mother, in                         addition to cervical and colon cancer in several second-degree                         relatives.

Figure 9b. ATM mutation in a 45-year-old African American woman who presented with abnormal results at screening mammography. (a) CC diagnostic mammogram shows grouped calcifications (circle) in the subareolar region of the right breast, for which a stereotactic biopsy was performed. The results confirmed high-grade DCIS. She was referred for genetic counseling, and an ATM mutation was identified. (b) Pedigree chart shows the patient’s (arrow) family history of breast cancer in the patient’s mother, in addition to cervical and colon cancer in several second-degree relatives.

Over 300 ATM variants have been identified, the majority of which have an unknown clinical significance owing to the challenges of adequately assessing each variant (96,105). The V2424G missense variant has been particularly associated with a high risk of breast cancer, up to 52% at the age of 70 years (96,106).

Screening, Risk Management, and Treatment Implications.—The NCCN recommends that patients undergo annual mammography starting at age 40 years and that annual breast MRI at age 40 years should be considered (2,96).

Several studies have shown an increased risk of severe radionecrosis from radiation therapy owing to increased sensitivity to ionizing radiation in patients with ATM mutations (96,107). However, in patients with a single mutation, there is mixed evidence, with studies suggesting increased toxicity versus improved clinical benefit (96). According to the NCCN, there is insufficient evidence for performing risk-reducing mastectomy or to recommend against radiation therapy, and management should be based on family history (2).

CHEK2

The CHEK2 mutation is a common germline mutation, which is associated with a 20%–25% lifetime risk of breast cancer (28,36). The breast cancers in carriers are typically ER positive (36). Figure 10 shows imaging findings of breast cancer in a patient with a CHEK2 mutation. Additional associated cancers include colorectal, stomach, prostate, kidney, and thyroid cancers, as well as sarcomas (36).

CHEK2 mutation in a 47-year-old woman who presented with skin changes                         in her right breast. (a) CC diagnostic mammogram shows marked skin                         thickening, with increased density in the central portion of the right                         breast, extending into the upper outer quadrant. (b) Targeted US image shows                         three separate masses in the right breast, one of which measures up to 3.5                         cm. The results of a biopsy confirmed IDC and DCIS. Given her prominent                         family history of breast cancer, the patient was referred for genetic                         counseling, and a CHEK2 mutation was identified. fn = from the                         nipple.

Figure 10a. CHEK2 mutation in a 47-year-old woman who presented with skin changes in her right breast. (a) CC diagnostic mammogram shows marked skin thickening, with increased density in the central portion of the right breast, extending into the upper outer quadrant. (b) Targeted US image shows three separate masses in the right breast, one of which measures up to 3.5 cm. The results of a biopsy confirmed IDC and DCIS. Given her prominent family history of breast cancer, the patient was referred for genetic counseling, and a CHEK2 mutation was identified. fn = from the nipple.

CHEK2 mutation in a 47-year-old woman who presented with skin changes                         in her right breast. (a) CC diagnostic mammogram shows marked skin                         thickening, with increased density in the central portion of the right                         breast, extending into the upper outer quadrant. (b) Targeted US image shows                         three separate masses in the right breast, one of which measures up to 3.5                         cm. The results of a biopsy confirmed IDC and DCIS. Given her prominent                         family history of breast cancer, the patient was referred for genetic                         counseling, and a CHEK2 mutation was identified. fn = from the                         nipple.

Figure 10b. CHEK2 mutation in a 47-year-old woman who presented with skin changes in her right breast. (a) CC diagnostic mammogram shows marked skin thickening, with increased density in the central portion of the right breast, extending into the upper outer quadrant. (b) Targeted US image shows three separate masses in the right breast, one of which measures up to 3.5 cm. The results of a biopsy confirmed IDC and DCIS. Given her prominent family history of breast cancer, the patient was referred for genetic counseling, and a CHEK2 mutation was identified. fn = from the nipple.

Screening, Risk Management, and Treatment Implications.—The NCCN recommends screening with annual mammography starting at age 40 and to consider performing annual breast MRI at age 40 as well. There is insufficient evidence for performing risk-reducing mastectomy, and management should be based on family history (2).

PALB2

The PALB2 gene is involved in nuclear stability and is associated with BRCA2 (28). Carriers of a single PALB2 mutation have an increased risk of breast cancer. The risk is approximately 33% by age 70 years in patients without a family history of breast cancer and 58% by age 70 years in those patients with a family history (36). Figures 11 and 12 show imaging findings of breast cancer in two patients with PALB2 mutation. Pancreatic cancer is an additional common cancer in carriers of a single PALB2 mutation (36). Figure 13 shows a solid pseudopapillary epithelial neoplasm of the pancreas in a patient with a PALB2 mutation. Similar to ATM, biallelic PALB2 mutations are causative of a different genetic condition, in this case Fanconi anemia.

PALB2 mutation in a 40-year-old woman with a strong family history of                         breast cancer, with her mother having been diagnosed with breast cancer                         twice (diagnosed at ages 31 and 50 years) and a paternal grandmother                         diagnosed with breast cancer in her 40s. The patient presented with a                         palpable mass in her right breast. Targeted US image shows an irregular                         hypoechoic nonparallel mass. The results of a biopsy confirmed IDC. The                         patient was referred for genetic counseling, and both the patient and her                         mother were diagnosed with PALB2 mutation. A Rad = antiradial, fn                         = from the nipple.

Figure 11. PALB2 mutation in a 40-year-old woman with a strong family history of breast cancer, with her mother having been diagnosed with breast cancer twice (diagnosed at ages 31 and 50 years) and a paternal grandmother diagnosed with breast cancer in her 40s. The patient presented with a palpable mass in her right breast. Targeted US image shows an irregular hypoechoic nonparallel mass. The results of a biopsy confirmed IDC. The patient was referred for genetic counseling, and both the patient and her mother were diagnosed with PALB2 mutation. A Rad = antiradial, fn = from the nipple.

PALB2 mutation in a 56-year-old woman. (a, b) Lateromedial (a) and                         magnified (b) screening mammograms show segmental calcifications (oval) in                         the central and upper outer quadrant of the left breast. (c) Axial MR image                         shows a large region of segmental nonmass enhancement measuring                         approximately 8 cm, predominantly within the lower outer quadrant of the                         left breast, with some extension into the lower inner quadrant and upper                         outer quadrant. The results of a biopsy confirmed intermediate-grade DCIS.                         The patient was referred for genetic counseling, and a PALB2 mutation was                         identified. Her family history confirmed a sister diagnosed with bilateral                         stage IV breast cancer, two paternal half-sisters with a history of breast                         cancer (diagnosed at ages 56 and 58 years), and a paternal aunt with a                         history of breast cancer (age of onset unknown).

Figure 12a. PALB2 mutation in a 56-year-old woman. (a, b) Lateromedial (a) and magnified (b) screening mammograms show segmental calcifications (oval) in the central and upper outer quadrant of the left breast. (c) Axial MR image shows a large region of segmental nonmass enhancement measuring approximately 8 cm, predominantly within the lower outer quadrant of the left breast, with some extension into the lower inner quadrant and upper outer quadrant. The results of a biopsy confirmed intermediate-grade DCIS. The patient was referred for genetic counseling, and a PALB2 mutation was identified. Her family history confirmed a sister diagnosed with bilateral stage IV breast cancer, two paternal half-sisters with a history of breast cancer (diagnosed at ages 56 and 58 years), and a paternal aunt with a history of breast cancer (age of onset unknown).

PALB2 mutation in a 56-year-old woman. (a, b) Lateromedial (a) and                         magnified (b) screening mammograms show segmental calcifications (oval) in                         the central and upper outer quadrant of the left breast. (c) Axial MR image                         shows a large region of segmental nonmass enhancement measuring                         approximately 8 cm, predominantly within the lower outer quadrant of the                         left breast, with some extension into the lower inner quadrant and upper                         outer quadrant. The results of a biopsy confirmed intermediate-grade DCIS.                         The patient was referred for genetic counseling, and a PALB2 mutation was                         identified. Her family history confirmed a sister diagnosed with bilateral                         stage IV breast cancer, two paternal half-sisters with a history of breast                         cancer (diagnosed at ages 56 and 58 years), and a paternal aunt with a                         history of breast cancer (age of onset unknown).

Figure 12b. PALB2 mutation in a 56-year-old woman. (a, b) Lateromedial (a) and magnified (b) screening mammograms show segmental calcifications (oval) in the central and upper outer quadrant of the left breast. (c) Axial MR image shows a large region of segmental nonmass enhancement measuring approximately 8 cm, predominantly within the lower outer quadrant of the left breast, with some extension into the lower inner quadrant and upper outer quadrant. The results of a biopsy confirmed intermediate-grade DCIS. The patient was referred for genetic counseling, and a PALB2 mutation was identified. Her family history confirmed a sister diagnosed with bilateral stage IV breast cancer, two paternal half-sisters with a history of breast cancer (diagnosed at ages 56 and 58 years), and a paternal aunt with a history of breast cancer (age of onset unknown).

PALB2 mutation in a 56-year-old woman. (a, b) Lateromedial (a) and                         magnified (b) screening mammograms show segmental calcifications (oval) in                         the central and upper outer quadrant of the left breast. (c) Axial MR image                         shows a large region of segmental nonmass enhancement measuring                         approximately 8 cm, predominantly within the lower outer quadrant of the                         left breast, with some extension into the lower inner quadrant and upper                         outer quadrant. The results of a biopsy confirmed intermediate-grade DCIS.                         The patient was referred for genetic counseling, and a PALB2 mutation was                         identified. Her family history confirmed a sister diagnosed with bilateral                         stage IV breast cancer, two paternal half-sisters with a history of breast                         cancer (diagnosed at ages 56 and 58 years), and a paternal aunt with a                         history of breast cancer (age of onset unknown).

Figure 12c. PALB2 mutation in a 56-year-old woman. (a, b) Lateromedial (a) and magnified (b) screening mammograms show segmental calcifications (oval) in the central and upper outer quadrant of the left breast. (c) Axial MR image shows a large region of segmental nonmass enhancement measuring approximately 8 cm, predominantly within the lower outer quadrant of the left breast, with some extension into the lower inner quadrant and upper outer quadrant. The results of a biopsy confirmed intermediate-grade DCIS. The patient was referred for genetic counseling, and a PALB2 mutation was identified. Her family history confirmed a sister diagnosed with bilateral stage IV breast cancer, two paternal half-sisters with a history of breast cancer (diagnosed at ages 56 and 58 years), and a paternal aunt with a history of breast cancer (age of onset unknown).

Axial contrast-enhanced T1-weighted MR image shows a heterogeneously                         enhancing necrotic mass, measuring up to 5.3 cm, within the tail of the                         pancreas, a finding compatible with solid pseudopapillary epithelial                         neoplasm of the pancreas in a patient with a known PALB2                         mutation.

Figure 13. Axial contrast-enhanced T1-weighted MR image shows a heterogeneously enhancing necrotic mass, measuring up to 5.3 cm, within the tail of the pancreas, a finding compatible with solid pseudopapillary epithelial neoplasm of the pancreas in a patient with a known PALB2 mutation.

Screening, Risk Management, and Treatment Implications.—The NCCN recommends performing annual mammography starting at age 30 years and to consider performing annual breast MRI at age 30 years. There is insufficient evidence for the benefit of performing risk-reducing mastectomy, and management should be determined on the basis of family history (2).

Lynch Syndrome

Lynch syndrome, or hereditary nonpolyposis colorectal cancer, is an autosomal dominantly inherited disorder caused by germline mutations in the DNA mismatch repair genes, which include MLH1, MSH2, MSH6, and PMS2 (108). Lynch syndrome is characterized by an increased predisposition to a spectrum of cancers, including colorectal, gastric, endometrial, ovarian, renal, and hepatobiliary (108). The specific cancer risks associated with Lynch syndrome are dependent on which gene is mutated (109). For example, MLH1 and MSH2 mutations have been associated with an increased predisposition to colon cancer relative to the other gene mutations associated with Lynch syndrome (109).

Breast cancer is not traditionally associated with Lynch syndrome, as the risk is relatively low in comparison with the other cancers previously mentioned. The current studies are overall conflicting. According to the most recent NCCN guidelines from July 2019, there are a 12%–25% risk and an average age of diagnosis of 53 years associated with an MLH1 mutation and a 10% risk and average age of diagnosis of 52 years associated with an MLH2 mutation (94,110112). Figures 14 and 15a15c show imaging findings of IDC in two patients with Lynch syndrome. The second patient’s pedigree (Fig 15d) was atypical for Lynch syndrome and shows a family history of lung cancer in her father and maternal grandmother.

IDC in a 59-year-old woman with a history of Lynch syndrome. (a) CC                         mammogram shows a spiculated mass at the 6-o’clock position in the                         right breast. (b) Targeted US image shows an irregular hypoechoic mass,                         measuring up to 2.6 cm. PALP BY PT = palpable by patient, RT =                         right. (c) Axial MR image shows a solitary heterogeneously enhancing mass in                         the lower inner quadrant of the right breast. The results of a biopsy                         confirmed triple-negative IDC.

Figure 14a. IDC in a 59-year-old woman with a history of Lynch syndrome. (a) CC mammogram shows a spiculated mass at the 6-o’clock position in the right breast. (b) Targeted US image shows an irregular hypoechoic mass, measuring up to 2.6 cm. PALP BY PT = palpable by patient, RT = right. (c) Axial MR image shows a solitary heterogeneously enhancing mass in the lower inner quadrant of the right breast. The results of a biopsy confirmed triple-negative IDC.

IDC in a 59-year-old woman with a history of Lynch syndrome. (a) CC                         mammogram shows a spiculated mass at the 6-o’clock position in the                         right breast. (b) Targeted US image shows an irregular hypoechoic mass,                         measuring up to 2.6 cm. PALP BY PT = palpable by patient, RT =                         right. (c) Axial MR image shows a solitary heterogeneously enhancing mass in                         the lower inner quadrant of the right breast. The results of a biopsy                         confirmed triple-negative IDC.

Figure 14b. IDC in a 59-year-old woman with a history of Lynch syndrome. (a) CC mammogram shows a spiculated mass at the 6-o’clock position in the right breast. (b) Targeted US image shows an irregular hypoechoic mass, measuring up to 2.6 cm. PALP BY PT = palpable by patient, RT = right. (c) Axial MR image shows a solitary heterogeneously enhancing mass in the lower inner quadrant of the right breast. The results of a biopsy confirmed triple-negative IDC.

IDC in a 59-year-old woman with a history of Lynch syndrome. (a) CC                         mammogram shows a spiculated mass at the 6-o’clock position in the                         right breast. (b) Targeted US image shows an irregular hypoechoic mass,                         measuring up to 2.6 cm. PALP BY PT = palpable by patient, RT =                         right. (c) Axial MR image shows a solitary heterogeneously enhancing mass in                         the lower inner quadrant of the right breast. The results of a biopsy                         confirmed triple-negative IDC.

Figure 14c. IDC in a 59-year-old woman with a history of Lynch syndrome. (a) CC mammogram shows a spiculated mass at the 6-o’clock position in the right breast. (b) Targeted US image shows an irregular hypoechoic mass, measuring up to 2.6 cm. PALP BY PT = palpable by patient, RT = right. (c) Axial MR image shows a solitary heterogeneously enhancing mass in the lower inner quadrant of the right breast. The results of a biopsy confirmed triple-negative IDC.

Lynch syndrome in a 30-year-old African American woman who presented                         with right breast pain and swelling. (a) Targeted US image shows a complex                         cystic and solid mass at the 10-o’clock position, which measures up                         to 4.0 cm. CNFN = centimeters from the nipple. (b, c) MLO mammogram (b)                         and axial MR image (c) show a mass in the upper outer quadrant of the right                         breast. Bloody fluid was aspirated, and the results of a pathologic                         examination confirmed poorly differentiated triple-negative IDC with                         extensive necrosis. The patient was referred for genetic counseling, and a                         mutation suggestive of Lynch syndrome was confirmed. (d) The                         patient’s pedigree chart is atypical for Lynch syndrome and shows a                         family history of lung cancer in the patient’s father and maternal                         grandmother. Arrow = patient.

Figure 15a. Lynch syndrome in a 30-year-old African American woman who presented with right breast pain and swelling. (a) Targeted US image shows a complex cystic and solid mass at the 10-o’clock position, which measures up to 4.0 cm. CNFN = centimeters from the nipple. (b, c) MLO mammogram (b) and axial MR image (c) show a mass in the upper outer quadrant of the right breast. Bloody fluid was aspirated, and the results of a pathologic examination confirmed poorly differentiated triple-negative IDC with extensive necrosis. The patient was referred for genetic counseling, and a mutation suggestive of Lynch syndrome was confirmed. (d) The patient’s pedigree chart is atypical for Lynch syndrome and shows a family history of lung cancer in the patient’s father and maternal grandmother. Arrow = patient.

Lynch syndrome in a 30-year-old African American woman who presented                         with right breast pain and swelling. (a) Targeted US image shows a complex                         cystic and solid mass at the 10-o’clock position, which measures up                         to 4.0 cm. CNFN = centimeters from the nipple. (b, c) MLO mammogram (b)                         and axial MR image (c) show a mass in the upper outer quadrant of the right                         breast. Bloody fluid was aspirated, and the results of a pathologic                         examination confirmed poorly differentiated triple-negative IDC with                         extensive necrosis. The patient was referred for genetic counseling, and a                         mutation suggestive of Lynch syndrome was confirmed. (d) The                         patient’s pedigree chart is atypical for Lynch syndrome and shows a                         family history of lung cancer in the patient’s father and maternal                         grandmother. Arrow = patient.

Figure 15b. Lynch syndrome in a 30-year-old African American woman who presented with right breast pain and swelling. (a) Targeted US image shows a complex cystic and solid mass at the 10-o’clock position, which measures up to 4.0 cm. CNFN = centimeters from the nipple. (b, c) MLO mammogram (b) and axial MR image (c) show a mass in the upper outer quadrant of the right breast. Bloody fluid was aspirated, and the results of a pathologic examination confirmed poorly differentiated triple-negative IDC with extensive necrosis. The patient was referred for genetic counseling, and a mutation suggestive of Lynch syndrome was confirmed. (d) The patient’s pedigree chart is atypical for Lynch syndrome and shows a family history of lung cancer in the patient’s father and maternal grandmother. Arrow = patient.

Lynch syndrome in a 30-year-old African American woman who presented                         with right breast pain and swelling. (a) Targeted US image shows a complex                         cystic and solid mass at the 10-o’clock position, which measures up                         to 4.0 cm. CNFN = centimeters from the nipple. (b, c) MLO mammogram (b)                         and axial MR image (c) show a mass in the upper outer quadrant of the right                         breast. Bloody fluid was aspirated, and the results of a pathologic                         examination confirmed poorly differentiated triple-negative IDC with                         extensive necrosis. The patient was referred for genetic counseling, and a                         mutation suggestive of Lynch syndrome was confirmed. (d) The                         patient’s pedigree chart is atypical for Lynch syndrome and shows a                         family history of lung cancer in the patient’s father and maternal                         grandmother. Arrow = patient.

Figure 15c. Lynch syndrome in a 30-year-old African American woman who presented with right breast pain and swelling. (a) Targeted US image shows a complex cystic and solid mass at the 10-o’clock position, which measures up to 4.0 cm. CNFN = centimeters from the nipple. (b, c) MLO mammogram (b) and axial MR image (c) show a mass in the upper outer quadrant of the right breast. Bloody fluid was aspirated, and the results of a pathologic examination confirmed poorly differentiated triple-negative IDC with extensive necrosis. The patient was referred for genetic counseling, and a mutation suggestive of Lynch syndrome was confirmed. (d) The patient’s pedigree chart is atypical for Lynch syndrome and shows a family history of lung cancer in the patient’s father and maternal grandmother. Arrow = patient.

Lynch syndrome in a 30-year-old African American woman who presented                         with right breast pain and swelling. (a) Targeted US image shows a complex                         cystic and solid mass at the 10-o’clock position, which measures up                         to 4.0 cm. CNFN = centimeters from the nipple. (b, c) MLO mammogram (b)                         and axial MR image (c) show a mass in the upper outer quadrant of the right                         breast. Bloody fluid was aspirated, and the results of a pathologic                         examination confirmed poorly differentiated triple-negative IDC with                         extensive necrosis. The patient was referred for genetic counseling, and a                         mutation suggestive of Lynch syndrome was confirmed. (d) The                         patient’s pedigree chart is atypical for Lynch syndrome and shows a                         family history of lung cancer in the patient’s father and maternal                         grandmother. Arrow = patient.

Figure 15d. Lynch syndrome in a 30-year-old African American woman who presented with right breast pain and swelling. (a) Targeted US image shows a complex cystic and solid mass at the 10-o’clock position, which measures up to 4.0 cm. CNFN = centimeters from the nipple. (b, c) MLO mammogram (b) and axial MR image (c) show a mass in the upper outer quadrant of the right breast. Bloody fluid was aspirated, and the results of a pathologic examination confirmed poorly differentiated triple-negative IDC with extensive necrosis. The patient was referred for genetic counseling, and a mutation suggestive of Lynch syndrome was confirmed. (d) The patient’s pedigree chart is atypical for Lynch syndrome and shows a family history of lung cancer in the patient’s father and maternal grandmother. Arrow = patient.

Screening, Risk Management, and Treatment Implications.—Currently, there is insufficient evidence to recommend above average risk screening for breast cancer. Colonoscopy is recommended starting at age 20–25 years or 2–5 years before the youngest age of diagnosis of colorectal cancer in the family, repeated every 1–2 years (94).

Additional Imaging Characteristics of Hereditary Breast Cancer

Teaching Point Hereditary breast cancer in general has variable imaging characteristics and can range from an aggressive appearance to a mimic of a benign entity across all imaging modalities, as discussed.
Imaging phenotypes may vary with high- and moderate-risk genes (54).

There is additionally no significant difference in the mammographic fibroglandular tissue densities among women in different risk groups (54). In terms of location, up to two-thirds of hereditary breast cancer resides in the posterior aspect of the breast in the prepectoral region (54). In women with a moderately increased risk, the location tends to be evenly distributed throughout the breast (54).

Conclusion

Radiologists should be able to provide patients with an idea of what to expect when they are referred for genetic counseling, which involves a detailed risk assessment that often requires an extensive family history review. Patients should know that it is possible that testing may give uninformative results or genetic variants of unknown clinical significance. While BRCA1 and BRCA2 are the most common genes associated with an increased risk of breast cancer, there are many additional genes that result in a high and moderate risk. Genetic counseling and testing can improve overall survival by analyzing patient risk factors, identifying mutations, and recommending specific screening guidelines. Many of these gene mutations are associated with particular imaging appearances and pathologic conditions, which are important for radiologists to recognize.

Presented as an education exhibit at the 2018 RSNA Annual Meeting.

For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships.

References

  • 1. Evans DGR, Howell A. Breast cancer risk-assessment models. Breast Cancer Res 2007;9(5):213. Crossref, MedlineGoogle Scholar
  • 2. NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Breast and Ovarian Version 3.2019. National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Published 2019. Accessed August 29, 2019. Google Scholar
  • 3. Himes DO, Root AE, Gammon A, Luthy KE. Breast Cancer Risk Assessment: Calculating Lifetime Risk Using the Tyrer-Cuzick Model. J Nurse Pract 2016;12(9): 581–592. CrossrefGoogle Scholar
  • 4. Medical Reporting Software. MRS7 Reporting. https://www.mrsys.com/products/mrs7-reporting. Accessed June 3, 2019. Google Scholar
  • 5. PenRad MIS. Automated Mammography Reporting Workflow. https://www.penrad.com/penrad-mis/. Accessed June 3, 2019. Google Scholar
  • 6. MagView. Our Robust Breast Cancer Risk Assessment Tool- MagView. https://www.magview.com/risk-assessment2/. Accessed June 3, 2019. Google Scholar
  • 7. Antoniou AC, Pharoah PPD, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer 2004;91(8):1580–1590. Crossref, MedlineGoogle Scholar
  • 8. Amir E, Evans DG, Shenton A, et al. Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme. J Med Genet 2003;40(11):807–814. Crossref, MedlineGoogle Scholar
  • 9. Bondy ML, Newman LA. Breast cancer risk assessment models: applicability to African-American women. Cancer 2003;97(1 Suppl):230–235. Crossref, MedlineGoogle Scholar
  • 10. Pace LE, Keating NL. A systematic assessment of benefits and risks to guide breast cancer screening decisions. JAMA 2014;311(13):1327–1335. Crossref, MedlineGoogle Scholar
  • 11. Brentnall AR, Harkness EF, Astley SM, et al. Mammographic density adds accuracy to both the Tyrer-Cuzick and Gail breast cancer risk models in a prospective UK screening cohort. Breast Cancer Res 2015;17(1):147. Crossref, MedlineGoogle Scholar
  • 12. Ozanne EM, Drohan B, Bosinoff P, et al. Which risk model to use? Clinical implications of the ACS MRI screening guidelines. Cancer Epidemiol Biomarkers Prev 2013;22(1):146–149. Crossref, MedlineGoogle Scholar
  • 13. Rubinstein WS, O’Neill SM, Peters JA, Rittmeyer LJ, Stadler MP. Mathematical modeling for breast cancer risk assessment: State of the art and role in medicine. Oncology (Williston Park) 2002;16(8):1082–1094; discussion 1094, 1097–1099. MedlineGoogle Scholar
  • 14. Berry DA, Iversen ES Jr, Gudbjartsson DF, et al. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 2002;20(11):2701–2712. Crossref, MedlineGoogle Scholar
  • 15. Cuzick J, Brentnall A. Models of Assessment of Breast Cancer Risk. Diagn Imaging Eur 2016; 54–55. https://www.dieurope.com/pdf/129177.pdf. Published October 2016. Accessed May 1, 2018. Google Scholar
  • 16. Vogel KJ, Atchley DP, Erlichman J, et al. BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model. J Clin Oncol 2007;25(29):4635–4641. Crossref, MedlineGoogle Scholar
  • 17. Amir E, Freedman OC, Seruga B, Evans DG. Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst 2010;102(10):680–691. Crossref, MedlineGoogle Scholar
  • 18. Wang X, Huang Y, Li L, Dai H, Song F, Chen K. Assessment of performance of the Gail model for predicting breast cancer risk: a systematic review and meta-analysis with trial sequential analysis. Breast Cancer Res 2018;20(1):18. Crossref, MedlineGoogle Scholar
  • 19. Brentnall AR, Cuzick J, Buist DSM, Bowles EJA. Long-term Accuracy of Breast Cancer Risk Assessment Combining Classic Risk Factors and Breast Density. JAMA Oncol 2018;4(9):e180174. Crossref, MedlineGoogle Scholar
  • 20. Singletary SE. Rating the Risk Factors for Breast Cancer. Ann Surg 2003; 237(4): 474–482. Crossref, MedlineGoogle Scholar
  • 21. Euhus DM, Smith KC, Robinson L, et al. Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO. J Natl Cancer Inst 2002;94(11):844–851. Crossref, MedlineGoogle Scholar
  • 22. Genetic Testing FAQ. National Human Genome Research Institute. https://www.genome.gov/FAQ/Genetic-Testing. Published 2019. Accessed June 8, 2019. Google Scholar
  • 23. Genetic Testing Coverage and Reimbursement. American Society of Clinical Oncology. https://www.asco.org/practice-policy/cancer-care-initiatives/genetics-toolkit/genetic-testing-coverage-reimbursement. Accessed June 3, 2019. Google Scholar
  • 24. United Healthcare. Genetic testing for hereditary cancer. https://www.uhcprovider.com/content/dam/provider/docs/public/policies/signaturevalue-mmg/genetic-testing-hboc-sv.pdf. Published 2019. Accessed June 3, 2019. Google Scholar
  • 25. U.S. Food and Drug Administration. FDA authorizes, with special controls, direct-to-consumer test that reports three mutations in the BRCA breast cancer genes. https://www.fda.gov/news-events/press-announcements/fda-authorizes-special-controls-direct-consumer-test-reports-three-mutations-brca-breast-cancer. Published 2018. Accessed June 8, 2019. Google Scholar
  • 26. 23andMe. Health + Ancestry Service. https://www.23andme.com/dna-health-ancestry/. Accessed June 8, 2019. Google Scholar
  • 27. National Human Genome Research Institute. Genetic Discrimination. https://www.genome.gov/about-genomics/policy-issues/Genetic-Discrimination. Published 2017. Accessed June 3, 2019. Google Scholar
  • 28. Shiovitz S, Korde LA. Genetics of breast cancer: a topic in evolution. Ann Oncol 2015;26(7):1291–1299. Crossref, MedlineGoogle Scholar
  • 29. Couch FJ, Shimelis H, Hu C, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol 2017;3(9):1190–1196. Crossref, MedlineGoogle Scholar
  • 30. Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014;32(19):2001–2009. Crossref, MedlineGoogle Scholar
  • 31. Maxwell KN, Wubbenhorst B, D’Andrea K, et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med 2015;17(8):630–638. Crossref, MedlineGoogle Scholar
  • 32. Lee MV, Katabathina VS, Bowerson ML, et al. BRCA-associated Cancers: Role of Imaging in Screening, Diagnosis, and Management. RadioGraphics 2017;37(4):1005–1023. LinkGoogle Scholar
  • 33. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007;25(11):1329–1333. Crossref, MedlineGoogle Scholar
  • 34. Antoniou A, Pharoah PDP, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003;72(5):1117–1130. Crossref, MedlineGoogle Scholar
  • 35. Pederson HJ, Padia SA, May M, Grobmyer S. Managing patients at genetic risk of breast cancer. Cleve Clin J Med 2016;83(3):199–206. Crossref, MedlineGoogle Scholar
  • 36. Cobain EF, Milliron KJ, Merajver SD. Updates on breast cancer genetics: Clinical implications of detecting syndromes of inherited increased susceptibility to breast cancer. Semin Oncol 2016;43(5):528–535. Crossref, MedlineGoogle Scholar
  • 37. Heaney RM, Farrell M, Stokes M, Gorey T, Murray D. Cowden Syndrome: Serendipitous Diagnosis in Patients with Significant Breast Disease: Case Series and Literature Review. Breast J 2017;23(1):90–94. Crossref, MedlineGoogle Scholar
  • 38. Nieuwenhuis MH, Kets CM, Murphy-Ryan M, et al. Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome. Fam Cancer 2014;13(1):57–63. Crossref, MedlineGoogle Scholar
  • 39. Bubien V, Bonnet F, Brouste V, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet 2013;50(4):255–263. Crossref, MedlineGoogle Scholar
  • 40. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 2012;18(2):400–407. Crossref, MedlineGoogle Scholar
  • 41. Kaurah P, Huntsman DG. Hereditary Diffuse Gastric Cancer. In: Adam M, Ardinger H, Pagon R, eds. GeneReviews. Seattle, Wash: University of Washington, 2002. Google Scholar
  • 42. Hansford S, Kaurah P, Li-Chang H, et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol 2015;1(1):23–32. Crossref, MedlineGoogle Scholar
  • 43. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 2006;12(10):3209–3215. Crossref, MedlineGoogle Scholar
  • 44. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;119(6):1447–1453. Crossref, MedlineGoogle Scholar
  • 45. Breast Cancer Screening for Women at High Risk. Susan G. Komen. https://ww5.komen.org/BreastCancer/BreastCancerScreeningForWomenAtHigherRisk.html. Accessed April 10, 2019. Google Scholar
  • 46. Young EL, Feng BJ, Stark AW, et al. Multigene testing of moderate-risk genes: be mindful of the missense. J Med Genet 2016;53(6):366–376. Crossref, MedlineGoogle Scholar
  • 47. Kurian AW, Ward KC, Howlader N, Deapen D, Hamilton AS. Genetic Testing and Results in a Population-Based Cohort of Breast Cancer Patients and Ovarian Cancer Patients. J Clin Oncol 2019;37(15):1305–1315. Crossref, MedlineGoogle Scholar
  • 48. Petrucelli N, Daly MB, Feldman GL. Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2. Genet Med 2010;12(5):245–259. Crossref, MedlineGoogle Scholar
  • 49. Mavaddat N, Barrowdale D, Andrulis IL, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 2012;21(1):134–147. Crossref, MedlineGoogle Scholar
  • 50. Kemp Jacobsen K, O’Meara ES, Key D, et al. Comparing sensitivity and specificity of screening mammography in the United States and Denmark. Int J Cancer 2015;137(9):2198–2207. Crossref, MedlineGoogle Scholar
  • 51. Warner E, Plewes DB, Hill KA, et al. Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA 2004;292(11):1317–1325. Crossref, MedlineGoogle Scholar
  • 52. Peer PGM, Verbeek ALM, Straatman H, Hendriks JHCL, Holland R. Age-specific sensitivities of mammographic screening for breast cancer. Breast Cancer Res Treat 1996;38(2):153–160. Crossref, MedlineGoogle Scholar
  • 53. Gilbert FJ, Warren RM, Kwan-Lim G, et al. Cancers in BRCA1 and BRCA2 carriers and in women at high risk for breast cancer: MR imaging and mammographic features. Radiology 2009;252(2):358–368. LinkGoogle Scholar
  • 54. Schrading S, Kuhl CK. Mammographic, US, and MR imaging phenotypes of familial breast cancer. Radiology 2008;246(1):58–70. LinkGoogle Scholar
  • 55. Tilanus-Linthorst M, Verhoog L, Obdeijn IM, et al. A BRCA1/2 mutation, high breast density and prominent pushing margins of a tumor independently contribute to a frequent false-negative mammography. Int J Cancer 2002;102(1):91–95. Crossref, MedlineGoogle Scholar
  • 56. Eisinger F, Noguès C, Birnbaum D, Jacquemier J, Sobol H. BRCA1 and medullary breast cancer. JAMA 1998;280(14):1227–1228. Crossref, MedlineGoogle Scholar
  • 57. Rapin V, Contesso G, Mouriesse H, et al. Medullary breast carcinoma: A reevaluation of 95 cases of breast cancer with inflammatory stroma. Cancer 2018;61(12):2503–2510. CrossrefGoogle Scholar
  • 58. Evans DGR, Susnerwala I, Dawson J, Woodward E, Maher ER, Lalloo F. Risk of breast cancer in male BRCA2 carriers. J Med Genet 2010;47(10):710–711. Crossref, MedlineGoogle Scholar
  • 59. Tai YC, Domchek S, Parmigiani G, Chen S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2007;99(23):1811–1814. Crossref, MedlineGoogle Scholar
  • 60. Paluch-Shimon S, Cardoso F, Sessa C, et al. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol 2016;27(suppl 5):v103–v110. Crossref, MedlineGoogle Scholar
  • 61. Cibula D, Zikan M, Dusek L, Majek O. Oral contraceptives and risk of ovarian and breast cancers in BRCA mutation carriers: a meta-analysis. Expert Rev Anticancer Ther 2011;11(8):1197–1207. Crossref, MedlineGoogle Scholar
  • 62. Iodice S, Barile M, Rotmensz N, et al. Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer 2010;46(12):2275–2284. Crossref, MedlineGoogle Scholar
  • 63. Tung NM, Garber JE. BRCA1/2 testing: therapeutic implications for breast cancer management. Br J Cancer 2018;119(2):141–152. Crossref, MedlineGoogle Scholar
  • 64. U.S. Food and Drug Administration. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-germline-brca-mutated-metastatic-breast-cancer. Content current as of January 12, 2018. Accessed June 8, 2019. Google Scholar
  • 65. Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 2017;377(6):523–533. Crossref, MedlineGoogle Scholar
  • 66. Schon K, Tischkowitz M. Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat 2018;167(2):417–423. Crossref, MedlineGoogle Scholar
  • 67. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms: A familial syndrome? Ann Intern Med 1969;71(4):747–752. Crossref, MedlineGoogle Scholar
  • 68. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988;48(18):5358–5362. MedlineGoogle Scholar
  • 69. Melhem-Bertrandt A, Bojadzieva J, Ready KJ, et al. Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer 2012;118(4):908–913. Crossref, MedlineGoogle Scholar
  • 70. Masciari S, Dillon DA, Rath M, et al. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat 2012;133(3):1125–1130. Crossref, MedlineGoogle Scholar
  • 71. Heymann S, Delaloge S, Rahal A, et al. Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. Radiat Oncol 2010;5(1):104. Crossref, MedlineGoogle Scholar
  • 72. Seo M, Cho N, Ahn HS, Moon HG. Cowden syndrome presenting as breast cancer: imaging and clinical features. Korean J Radiol 2014;15(5):586–590. Crossref, MedlineGoogle Scholar
  • 73. Pilarski R. Cowden syndrome: a critical review of the clinical literature. J Genet Couns 2009;18(1):13–27. Crossref, MedlineGoogle Scholar
  • 74. Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A 1998;95(23):13513–13518. Crossref, MedlineGoogle Scholar
  • 75. Hobert JA, Eng C. PTEN hamartoma tumor syndrome: an overview. Genet Med 2009;11(10):687–694. Crossref, MedlineGoogle Scholar
  • 76. McColl KEL. Cancer of the gastric cardia. Best Pract Res Clin Gastroenterol 2006;20(4):687–696. Crossref, MedlineGoogle Scholar
  • 77. Schrader KA, Masciari S, Boyd N, et al. Hereditary diffuse gastric cancer: association with lobular breast cancer. Fam Cancer 2008;7(1):73–82. Crossref, MedlineGoogle Scholar
  • 78. Pharoah PD, Guilford P, Caldas C; International Gastric Cancer Linkage Consortium. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 2001;121(6):1348–1353. Crossref, MedlineGoogle Scholar
  • 79. Arpino G, Bardou VJ, Clark GM, Elledge RM. Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res 2004;6(3):R149–R156. Crossref, MedlineGoogle Scholar
  • 80. Keller G, Vogelsang H, Becker I, et al. Diffuse type gastric and lobular breast carcinoma in a familial gastric cancer patient with an E-cadherin germline mutation. Am J Pathol 1999;155(2):337–342. Crossref, MedlineGoogle Scholar
  • 81. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families: The Breast Cancer Linkage Consortium. Am J Hum Genet 1998;62(3):676–689. Crossref, MedlineGoogle Scholar
  • 82. Korsse SE, van Leerdam ME, Dekker E. Gastrointestinal diseases and their oro-dental manifestations: Part 4—Peutz-Jeghers syndrome. Br Dent J 2017;222(3):214–217. Crossref, MedlineGoogle Scholar
  • 83. Weber FP. Patches of deep pigmentation of oral mucous membrane not connected with Addison’s disease. Q J Med 1949;12:404–408. Google Scholar
  • 84. Jeghers H, McKusick VA, Katz KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits: a syndrome of diagnostic significance. N Engl J Med 1949;241(26):1031–1036. Crossref, MedlineGoogle Scholar
  • 85. Bruwer A, Bargen JA, Kierland RR. Surface pigmentation and generalized intestinal polyposis: (Peutz-Jeghers syndrome). Proc Staff Meet Mayo Clin 1954;29(6):168–171. MedlineGoogle Scholar
  • 86. Utsunomiya J, Gocho H, Miyanaga T, Hamaguchi E, Kashimure A. Peutz-Jeghers syndrome: its natural course and management. Johns Hopkins Med J 1975;136(2):71–82. MedlineGoogle Scholar
  • 87. van Lier MGF, Mathus-Vliegen EMH, Wagner A, van Leerdam ME, Kuipers EJ. High cumulative risk of intussusception in patients with Peutz-Jeghers syndrome: time to update surveillance guidelines? Am J Gastroenterol 2011;106(5):940–945. Crossref, MedlineGoogle Scholar
  • 88. World Health Organization. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press, 2010. Google Scholar
  • 89. Hamilton SR, Aaltonen LA, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Digestive System. Lyon, France: IARC Press, 2001. Google Scholar
  • 90. Beggs AD, Latchford AR, Vasen HFA, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut 2010;59(7):975–986. Crossref, MedlineGoogle Scholar
  • 91. Young S, Gooneratne S, Straus FH 2nd, Zeller WP, Bulun SE, Rosenthal IM. Feminizing Sertoli cell tumors in boys with Peutz-Jeghers syndrome. Am J Surg Pathol 1995;19(1):50–58. Crossref, MedlineGoogle Scholar
  • 92. Wilson DM, Pitts WC, Hintz RL, Rosenfeld RG. Testicular tumors with Peutz-Jeghers syndrome. Cancer 1986;57(11):2238–2240. Crossref, MedlineGoogle Scholar
  • 93. Fitzgerald RC, Hardwick R, Huntsman D, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet 2010;47(7):436–444. Crossref, MedlineGoogle Scholar
  • 94. NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Colorectal Version 2.2019. National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Published 2019. Accessed August 29, 2019. Google Scholar
  • 95. Desmond A, Kurian AW, Gabree M, et al. Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncol 2015;1 (7):943–951. Crossref, MedlineGoogle Scholar
  • 96. Jerzak KJ, Mancuso T, Eisen A. Ataxia: telangiectasia gene (ATM) mutation heterozygosity in breast cancer—a narrative review. 2018;25(2):176–180. Google Scholar
  • 97. Teive HAG, Moro A, Moscovich M, et al. Ataxia-telangiectasia: A historical review and a proposal for a new designation—ATM syndrome. J Neurol Sci 2015;355(1-2):3–6. Crossref, MedlineGoogle Scholar
  • 98. Thompson D, Duedal S, Kirner J, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 2005;97(11):813–822. Crossref, MedlineGoogle Scholar
  • 99. Furtado S, Das S, Suchowersky O. A review of the inherited ataxias: recent advances in genetic, clinical and neuropathologic aspects. Parkinsonism Relat Disord 1998;4(4):161–169. Crossref, MedlineGoogle Scholar
  • 100. Morrell D, Cromartie E, Swift M. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst 1986;77(1):89–92. MedlineGoogle Scholar
  • 101. Levy A, Lang AE. Ataxia-telangiectasia: A review of movement disorders, clinical features, and genotype correlations. Mov Disord 2018;33(8):1238–1247. Crossref, MedlineGoogle Scholar
  • 102. Silwal-Pandit L, Vollan HKM, Chin SF, et al. TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res 2014;20(13):3569–3580. Crossref, MedlineGoogle Scholar
  • 103. Su Y, Swift M. Mortality rates among carriers of ataxia-telangiectasia mutant alleles. Ann Intern Med 2000;133(10):770–778. Crossref, MedlineGoogle Scholar
  • 104. Dombernowsky SL, Weischer M, Allin KH, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. Risk of cancer by ATM missense mutations in the general population. J Clin Oncol 2008;26(18):3057–3062. Crossref, MedlineGoogle Scholar
  • 105. Ahmed M, Rahman N. ATM and breast cancer susceptibility. Oncogene 2006;25(43):5906–5911. Crossref, MedlineGoogle Scholar
  • 106. Bernstein JL, Teraoka S, Southey MC, et al. Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry. Hum Mutat 2006;27(11):1122–1128. Crossref, MedlineGoogle Scholar
  • 107. Weissberg JB, Huang DD, Swift M. Radiosensitivity of normal tissues in ataxia-telangiectasia heterozygotes. Int J Radiat Oncol Biol Phys 1998;42(5):1133–1136. Crossref, MedlineGoogle Scholar
  • 108. Win AK, Lindor NM, Jenkins MA. Risk of breast cancer in Lynch syndrome: a systematic review. Breast Cancer Res 2013;15(2):R27. Crossref, MedlineGoogle Scholar
  • 109. Roberts ME, Jackson SA, Susswein LR, et al. MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med 2018;20(10):1167–1174. Crossref, MedlineGoogle Scholar
  • 110. Burt R, Neklason DW. Genetic testing for inherited colon cancer. Gastroenterology 2005;128(6):1696–1716. Crossref, MedlineGoogle Scholar
  • 111. Henley SJ, Singh SD, King J, et al. Invasive cancer incidence and survival: United States, 2011. MMWR Morb Mortal Wkly Rep 2015;64(9):237–242. MedlineGoogle Scholar
  • 112. Cheng L, Eng C, Nieman LZ, Kapadia AS, Du XL. Trends in colorectal cancer incidence by anatomic site and disease stage in the United States from 1976 to 2005. Am J Clin Oncol 2011;34(6):573–580. Crossref, MedlineGoogle Scholar

Article History

Received: July 13 2019
Revision requested: Aug 22 2019
Revision received: Sept 19 2019
Accepted: Sept 20 2019
Published online: May 29 2020
Published in print: July 2020