G e n e t i c s o f B re a s t C a n c e r

Risk Models, Who to Test, and Management

Options

Marguerite M. Rooney, BSa, Krislyn N. Miller, DO

a
,
Jennifer K. Plichta, MD, MSa,b,c,*

KEYWORDS
 Breast cancer risk  Breast cancer genetics  Genetic testing
 Breast cancer prevention  Breast cancer screening

KEY POINTS
 Women age 25 years old should undergo breast cancer risk assessment, particularly
those with a family history of cancer.
 Multiple risk models exist to help evaluate a patient’s risk of developing breast cancer, and
they differ based on the risk factors included and the types of risk calculations provided.
 Not all risk models are appropriate for assessing breast cancer risk for every patient.
 Depending on risk level or known genetic mutation, increased imaging surveillance may
be recommended.
 Depending on risk level or known genetic mutation, bilateral risk-reducing mastectomy
may be considered.

INTRODUCTION

Breast cancer is the most common noncutaneous cancer in women, with more than
285,000 estimated cases to be diagnosed in 2022 in the United States.1 Efforts to
improve breast cancer treatment and increase survival focus not only on treatment
development and early detection but also on the identification of patients at a higher
risk of developing breast cancer. Breast cancer risk factors can include hormonal and
lifestyle factors, family history, and/or known germline mutations in a breast-cancer-
related gene.2 Current research has identified several germline mutations that contribute
to a patient’s risk of developing breast cancer.3,4 In addition to known genetic muta-
tions, patients can also be considered high risk based on family history alone.5

a
Department of Surgery, Duke University Medical Center, Durham, NC 22710, USA; b Duke
Cancer Institute, Duke University Medical Center, Durham, NC 22710, USA; c Department of
Population Health Sciences, Duke University Medical Center, Durham, NC 27710, USA
* Corresponding author. Department of Surgery, Duke University Medical Center, DUMC 3513,
Durham, NC 22710.
E-mail address: jennifer.plichta@duke.edu

Surg Clin N Am 103 (2023) 35–47

https://doi.org/10.1016/j.suc.2022.08.016 surgical.theclinics.com
0039-6109/23/ª 2022 Elsevier Inc. All rights reserved.
36 Rooney et al

In all, approximately 5% to 10% of breast cancers are from identifiable germline ge-
netic causes.6 As such, many breast cancer risk models have been developed to
combine risk factors to estimate an individual’s risk of developing breast cancer,
risk of carrying a BRCA1 or BRCA2 mutation, or the risk of both. These tools can assist
clinicians when selecting which patients to refer for genetic counseling and when pa-
tients may qualify for genetic testing, increased imaging surveillance, and/or consid-
eration of other medical or surgical interventions, thus helping to guide testing,
treatment, and screening recommendations for these patients. Several organizations,
including the National Comprehensive Cancer Network (NCCN), recommend genetic
risk evaluation for selected patients. The American Society for Breast Surgeons
(ASBrS) recommends that all women aged 25 years or more undergo formal risk
assessment for breast cancer with updates based on changes in family or personal
medical history.7 The United States Preventive Services Task Force, meanwhile, rec-
ommends risk assessment only for patients with a personal or family history of breast,
ovarian, tubal, or peritoneal cancers, or for those with ancestry associated with muta-
tions, such as Ashkenazi Jews.8,9
At present, the NCCN does not recommend universal germline genetic testing for all
patients with breast cancer, although the ASBrS does recommend offering genetic
testing to all patients with breast cancer, recognizing insurance coverage may not
consistently support this universal approach. The NCCN guidelines describe criteria
for genetic testing based on a family history of several different cancers with associ-
ated ages at diagnosis for the affected family members. If patients do not meet the
criteria set forth by the NCCN but do have a greater than 5% probability of a
BRCA1/2 mutation based on risk models, testing may still be indicated, and it may
even be considered for those patients with a 2.5% to 5% probability of a BRCA1/2
mutation based on these models.10 Although there are many models, this article de-
scribes several of the most relevant and validated (Table 1).

MODELS: BREAST CANCER AND GENETIC RISK

Family History Assessment Tool
The Family History Assessment Tool (FHAT) is a validated scoring tool initially devel-
oped to help clinicians identify which patients would most benefit from a referral to ge-
netic counseling based on family cancer history.11 As expected with a first-pass
screening tool, FHAT has high sensitivity (94%; specificity 51%), and as such does
typically identify several false-positives.12 Unlike the other models discussed later,
this tool does not provide a percent likelihood of developing breast cancer but rather
has a scoring threshold after which genetic counseling is recommended.
Breast Cancer Risk Assessment Tool
One of the earliest breast cancer risk models, Breast Cancer Risk Assessment Tool
(BCRAT), based on the Gail Model, estimates the risk of developing invasive breast
cancer in the next 5 years and through age 90 years (lifetime risk) for women older
than 35 years using personal reproductive history and family history of first-degree rel-
atives.13 This model uses hormonal risk factors (age at menarche, age at first live birth)
and pathologic (personal history of breast disease and breast biopsy). This model was
initially developed on 280,000 white women aged 35 to 74 years in the Breast Cancer
Detection Demonstration Project and Surveillance, Epidemiology, and End Results
Program as a joint National Cancer Institute and American Society of Breast Cancer
screening study.14 Later, it was extended via smaller studies (ranging from 1563–
3244 patients) to include risk assessment for black, Asian, Pacific Islander, and His-
panic women.15–17 However, it is thought to underestimate risk for black women.18
Table 1
Selected breast cancer risk assessment models: model outputs, included personal and family risk factors, excluded populations

Tyrer-
Model FHAT11 BCRAT13 Claus Model20,23 BRCAPRO66 BOADICEA27,67,68 Cuzick69
Risk evaluation
Evaluates risk of developing U U U U U
breast cancer
Evaluates risk of having BRCA1 U U U
or BRCA2
Personal risk factor inclusion
Age U U U U U
Race/ethnicity U U U
BMI U
Age at menarche U U
Age at first live birth U U
Age at menopause U
Hormone replacement therapy U
use
Breast density U
History of prior breast biopsy U U
History of atypical ductal U Ua

Genetics of Breast Cancer

hyperplasia
History of lobular carcinoma Ua
in situ
Family history inclusion
First-degree relatives U U U U U U
Second-degree relatives U U U U U
Third-degree relatives U U

(continued on next page)

37
 38
Rooney et al
Table 1
(continued )
Tyrer-
Model FHAT11 BCRAT13 Claus Model20,23 BRCAPRO66 BOADICEA27,67,68 Cuzick69
Age at onset of breast cancer U U U U U
Bilateral breast cancer U U U U
Ovarian cancer U U U U
Male breast cancer U U
Excluded populations  Personal history of breast  Patients without a
cancer, DCIS, LCIS family history of
 Known BRCA1/2 mutation breast cancer
 Past chest radiation

Abbreviations: BCRAT, Breast Cancer Risk Assessment Tool; BMI, body mass index; BOADICEA, Breast and Ovarian Analysis of Disease Incidence and Carrier Esti-
mation Algorithm; DCIS, ductal carcinoma in situ; FHAT, Family History Assessment Tool; LCIS, lobular carcinoma in situ.
a
May overestimate risk in this population and therefore not be appropriate for use.
 Genetics of Breast Cancer 39

This model has also been demonstrated to underestimate the risk for women with
atypical hyperplasia.19

Claus model
The Claus model was developed using a population-based, case-control study (Can-
cer and Steroid Hormone Study [CASH]), conducted by the Centers for Disease Con-
trol and Prevention.20,21 This model does not include nonhereditary risk factors in
determining lifetime risk of breast cancer and should be used only for women with
at least 1 female first- or second-degree relative with breast cancer, based on the
assumption that breast cancer is transmitted in an autosomal dominant manner.12,22
There are 2 versions of the Claus model: risk tables (“Claus tables”), which are based
on the model, and the model itself.23

MODELS: BREAST CANCER AND GENETIC RISK

BRCAPRO
BRCAPRO predicts a patient’s probability of carrying a BRCA1 or BRCA2 mutation,
the probability of developing invasive breast cancer or ovarian cancer (if not diag-
nosed with breast cancer), and the probability of developing a contralateral breast
cancer (if breast cancer is present).24,25 The model relies on family history (including
relation, age at diagnosis, pathologic markers, race, ethnicity, and treatment), as
well as prevalence and penetrance of BRCA1 and BRCA2 and baseline breast cancer
rates in the population. The model then applies Bayes theorem.

Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm
Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm
(BOADICEA) is intended for women with a family history that may suggest an
increased risk of breast or ovarian cancer, to predict the probability of a BRCA1 or
BRCA2 mutation and risk of developing breast cancer.26,27 BOADICEA uses family
history of breast and ovarian cancer to calculate risk.

Tyrer-Cuzick Model (International Breast Cancer Study)

The Tyrer-Cuzick model estimates a patient’s risk of a BRCA1 or BRCA2 mutation and
risk of developing an invasive or in situ cancer over time by using genetic and hormon-
al risk factors. Tyrer-Cuzick is particularly useful in populations that are at high risk
based on family history where models such as the BCRAT are not as effective.13 In
addition, it predicts the risk of both invasive and in situ cancers rather than just inva-
sive cancers. Importantly, this model has been demonstrated to overestimate invasive
cancer risk in women with lobular carcinoma in situ and atypical hyperplasia, and other
models may be more accurate for these patient populations.28,29

GERMLINE GENETIC TESTING

Genetic testing for breast cancer has grown considerably in recent history. When ge-
netic testing for breast cancer was first available, only limited gene panels, typically
evaluating only BRCA1 and BRCA2, were available. However, only up to 30% of
genetically linked breast cancers are driven by germline BRCA1/2 mutations.6 Now,
multigene assays evaluating for high-, moderate-, and low-penetrance genes beyond
just BRCA1/2 are available. Therefore, there is a potential group of patients who
received limited or single-gene genetic testing before 2014 who may benefit from
repeat/expanded testing.30
40 Rooney et al

Although expanding the criteria for germline genetic testing is gaining popularity and
the NCCN guidelines become more inclusive every year, there remain several obstacles
to testing. One of the main concerns is who will perform the genetic counseling and
testing. Although there were an estimated 4700 genetic counselors in the United States
in 2019, 17 states had 20 or fewer genetic counselors in the entire state, and 4 states
had 5 or less.31 Furthermore, many genetic counselors are not involved in direct patient
care, opting instead to work for companies in industry or pharma; and of those seeing
patients, many work in noncancer areas, such as prenatal genetics. To combat this
problem, some have advocated for physicians to perform their own counseling and
testing,32 which is supported by several organizations in official statements and by
providing education.7,9,32 Beyond those limitations, cost also remains a concern. After
identifying the association of BRCA1 and BRCA2 with breast cancer in the 1990s,33,34 1
company was performing all BRCA1/2 testing. However, in 2013, the supreme court
invalidated the gene patents for that company,35 thus opening the door for new com-
panies to offer genetic testing related to cancer; this ultimately led to the rapid decline
in the cost of genetic testing from more than $4000 for BRCA1/2 testing alone to now
offering multigene panels for $250.36 Although still not free or feasible for some patients,
it is certainly much more attainable for many. It is also worth noting that direct-to-
consumer testing is available, but it has not been validated for clinical use, and any
“positive” results from these tests should be confirmed in a clinically approved labora-
tory certified by the Clinical Laboratory Improvement Amendments.10
Of the numerous clinically approved testing companies currently offering germline
genetic testing, options include both limited and expanded panels. Some favor a
more limited approach, testing for only those genes that are most likely to be related
to the history presented. However, others prefer to test all genes that may have impli-
cations for the patient, even if the risk of harboring such a mutation is low, particularly
given the decreasing cost and minimal difference in risk to the patient. Once a test is
selected, patient samples can now be provided via multiple methods, such as blood
draws and buccal swabs, or even saliva samples, although blood samples tend to be
the most reliable (ie, adequate for testing).
When the results from a test return, 5 possible outcomes may be reported for any
given variant identified: benign, likely benign, pathogenic, likely pathogenic, or variant
of uncertain significance (VUS). As the names imply, benign and likely benign variants
are considered “negative,” and no further recommendations are typically required. In
contrast, pathogenic and likely pathogenic variants are considered “positive” test re-
sults, and providers can refer to national guidelines, such as those published by the
NCCN, for management recommendations.10 For VUS findings, it is important to
remember that these are actually considered “negative” as well, meaning that no inter-
vention or management decision should be altered based on this finding. Although
VUS rates for BRCA1 and BRCA2 have steadily declined as more patients have
been tested, the expansion of testing to many other genes has yielded a notable in-
crease in overall VUS rates.37 However, this should similarly decline as again more pa-
tients, and particularly more diverse patient populations, are tested.
In addition, racial and ethnic disparities exist in access to and uptake of genetic
testing for all cancers and in breast cancer in particular, with previous work demon-
strating racial and ethnic disparities in genetic testing for solid tumor malig-
nancies.38,39 In breast cancer, previous work has shown how contributing factors
such as decreased provider referrals, access, and awareness has led to lower rates
of genetic testing for black women compared with their white counterparts.40–44 As
genetic testing becomes more and more common, it will be critical to make sure
that all patients from diverse ethnic backgrounds have equal access to testing and
 Genetics of Breast Cancer 41

to ensure the risk models and testing reflect the diversity of potential outcomes and
risks based on racial and ethnic origins.
Genetic testing and risk modeling demonstrate the need for interdisciplinary care for
the patient at high risk for the development of breast cancer. Although access to a ge-
netic counselor allows for increased genetic testing and timely counseling, not all cen-
ters and patients have access.45,46 In this setting, surgeons can play a critical role in
conducting initial risk assessment, identifying patients who may benefit from genetic
counseling, and often recommending and ordering genetic testing.32

IMAGE-BASED SCREENING FOR BREAST CANCER IN HIGH-RISK POPULATIONS

In addition to the general population screening guidelines, the NCCN has screening
guidelines for patients with high- or moderate-risk gene mutations related to breast
cancer. According to the 2022 NCCN guidelines, patients with high-risk gene muta-
tions (ie, 50% absolute lifetime risk of breast cancer [BRCA1, BRCA2, CDH1,
PALB2, PTEN, and TP53]) should follow specific screening guidelines. The NCCN rec-
ommends that for BRCA1 and BRCA2 mutation carriers, breast awareness should
start at age 18 years, with clinical breast examinations every 6 to 12 months starting
at age 25 years. Furthermore, breast cancer imaging/screening for women aged 25 to
29 years should include an annual breast MRI with contrast, or if MRI is unavailable,
annual mammogram, with consideration of tomosynthesis. Women aged 30 to 75
years should receive an annual mammogram with consideration of tomosynthesis
and a breast MRI with contrast; beyond age 75 years, management should be con-
ducted on an individual basis. Notably, these same screening guidelines apply to
women with BRCA1/2 mutations even after a breast cancer diagnosis, if they have re-
sidual breast tissue (underwent lumpectomy or only a unilateral mastectomy). Patients
with a high-risk TP53 mutation have similar recommendations as those patients who
are BRCA1/2 mutation carriers except for clinical breast examinations beginning at an
even earlier age (ie, age 20 years or at the age of the earliest diagnosed breast cancer
in the family if younger than 20 years). The recommendations for those women with
CDH1, PALB2, and PTEN mutations consist of an annual mammogram with consider-
ation of tomosynthesis and breast MRI with contrast starting at age 30 years.47
The NCCN recommends that those patients with moderate-risk mutations (20% to
50% absolute lifetime risk of developing breast cancer, ie, ATM, BARD1, CDH1,
CHEK2, and NF1) undergo annual screening mammography with consideration of
tomosynthesis and breast MRI with contrast. The age of starting this screening de-
pends on the gene mutation. For instance, those with CDH1 and NF1 are recommen-
ded to begin screening mammography and MRI at age 30 years, whereas women with
ATM, CHEK2, and BARD1 mutations are recommended to begin at age 40 years.47
Because women with high-risk genes tend to develop breast cancer at a younger age
when breast tissue is dense, the sensitivity of mammography alone is lower. In high-risk
women, the sensitivity of MRI detecting a breast abnormality ranges from 77% to 100%
with a specificity of 81% to 98.9%; this compares to mammography, which has a sensi-
tivity of 12.5% to 40% and specificity of 93% to 100%. Therefore, mammography in as-
sociation with MRI is the standard screening recommendation in these moderate- to
high-risk women.48 There are certain criteria required for the administration of a high-
quality MRI screening, including regional availability, a radiologist with breast MRI imag-
ing experience, the ability to perform biopsy under MRI guidance, and dedicated breast
coils specific for breast imaging.47 In addition to unavailability, reasons for declining
MRIs for screening purposes include patient claustrophobia, patient time constraints,
financial concerns, referral issues, body habitus, body implants, and frailty.49
42 Rooney et al

Screening with whole breast ultrasonography (WBUS) is another imaging tool used
for women who cannot or do not wish to undergo MRIs. Overall, this modality is well
tolerated, widely available, relatively inexpensive, and does not require intravenous
contrast or ionizing radiation. WBUS has been shown to detect cancers not seen on
mammography with a greater sensitivity in dense breast. Concerns include the need
for a highly experienced technologist and the inability to detect calcifications.50
Contrast-enhanced mammography (CEM), which uses modified digital mammog-
raphy with the addition of an intravenous contrast agent, is another imaging modality
that is not standard for breast cancer screening, yet shows promise for the future.51 In
a retrospective study by Sung and colleagues,51 904 patients received baseline CEM
screenings with 1-year follow-up. Results showed a breast cancer detection rate of
15.5 of 1000, sensitivity increased from 50% with the standard mammography to
87.5% with CEM (p 5 0.03), and specificity was 93.7% (95% confidence interval,
91.9%–95.3%).51 Other imaging modalities, such as thermography, which detects
localized skin temperature gradients and produces a heat map of the breast (thermo-
gram), have been theorized to identify developing tumors; yet, there is insufficient ev-
idence to support its use in breast cancer screening.52

ROLE OF RISK-REDUCING BREAST SURGERY

According to the NCCN guidelines, bilateral risk-reducing mastectomy (BRRM) may

be considered and discussed with all women with a high-risk pathogenic/likely path-
ogenic germline genetic mutation, which includes BRCA1, BRCA2, CDH1, PALB2,
PTEN, and TP53. Discussions should include the degree of protection, reconstruction
options, and residual breast cancer risk with age and life expectancy.47 Surgical risk-
reducing mastectomies include simple, total, skin-sparing, or nipple-sparing mastec-
tomies, all of which have been shown to be safe and feasible options for women
choosing a risk-reducing surgery. Regardless of the type of mastectomy, the goal is
to remove as much of the breast tissue as possible for the obvious reason of reducing
the risk of developing breast cancer.48 In a review of 201 BRCA1/2 carriers, Yao and
colleagues demonstrated that nipple-sparing mastectomies have a low rate of compli-
cations and locoregional recurrence. Loss of the nipple areolar complex occurred in
1.8% of the patients, flap necrosis in 2.5%, and there were 4 recurrences (none at
the nipple areolar complex and 3 in patients with cancer) over a mean follow-up
time of 32.6 months.53 Reconstruction options using implant-based (silicone or saline)
prepectoral or postpectoral versus autogenous flap grafts should be part of the dis-
cussion with the patient when they are opting for BRRM.48
BRRM reduces the risk of developing breast cancer by more than 90%54; however, the
survival benefit is unclear. According to Heemskerk-Gerritsen and colleagues,55 who
reviewed 2857 BRCA1/2 mutation carriers in the Netherlands, 42% of the BRCA1 and
35% of the BRCA2 mutation carriers received BRRMs. During a mean follow-up of
10 years, breast cancer-specific survival of women at age 65 years with BRCA1 muta-
tions was 93% for patients receiving surveillance versus 99.7% for those who had
BRRM, in contrast to patients with a BRCA2 mutation, for which rates were 98% and
100%, respectively. Overall, they concluded that BRRM for BRCA1 mutation carriers
was associated with lower mortality, but not necessarily for BRCA2 mutation carriers.55
Consideration around unwanted secondary effects such as chronic pain, decreased
body image, and decreased sexual satisfaction also needs to be part of the BRRM dis-
cussion. A 2018 Cochrane review looked at these psychosocial effects, reporting that
generally, patients were satisfied with their decision for BRRM, but their psychological
well-being was impacted.54 In particular, Gahm and colleagues56 demonstrated in their
 Genetics of Breast Cancer 43

review of 59 women post-BRRM that 69% reported chronic pain, 71% reported discom-
fort in their breasts, and 85% had reduced sexual sensations, which all negatively
impacted their enjoyment of sex. However, their quality of life and feelings of regret
were not a factor.56 An additional Cochrane review specifically focused on the psychoso-
cial interventions and the effect these had on the quality of life and emotional well-being in
female BRCA mutation carriers who underwent BRRM. Unfortunately, only 2 studies with
small sample sizes fit the review criteria and no conclusions could be drawn from the data.
These findings (or lack thereof) further emphasize the importance of supporting women
when they choose this type of elective risk-reducing surgery and the need for further
research in this area of long-term outcomes for risk-reducing surgery.57

TREATMENT OF BREAST CANCER IN HIGH-RISK PATIENTS

For women with a genetic predisposition to breast cancer who develop breast can-
cer, survival outcomes may vary. However, a systematic review and meta-analysis of
66 studies of patients with breast cancer and BRCA1/2 mutations noted that the ev-
idence was inconclusive, because some studies suggested worse outcomes,
whereas others demonstrated relatively more favorable survival outcomes.58 Given
no clear difference in survival outcomes, patients with BRCA1/2 mutations and
breast cancer may still be eligible for breast-conserving therapy (lumpectomy and
radiation), similar to those patients with breast cancer and no BRCA1/2 mutation.59
However, patients with BRCA1/2 mutations do have an increased risk of developing
a contralateral (or second primary) breast cancer, potentially as high as greater than
30%, depending on the age at diagnosis of the first breast cancer.60 As such, many
women with BRCA1/2 mutations and breast cancer may opt for bilateral mastec-
tomies (1 therapeutic and 1 prophylactic) to reduce that risk of a second breast
cancer.61
Beyond surgery, there are now systemic therapy options that are specific to women
with a genetic predisposition to breast cancer. For example, the recently published
OlympiA trial demonstrated that women with BRCA1/2 mutations and early breast
cancer may benefit from 1 year of an adjuvant poly(adenosine diphosphate-ribose) po-
lymerase inhibitor (PARPi).62 Similar benefits were previously demonstrated for
women with BRCA1/2 mutations and metastatic/advanced breast cancer as
well.63,64 In addition to its impact on systemic therapy options, the results of genetic
testing may also impact radiation therapy recommendations, because women with
TP53 mutations or homozygous ATM mutations are generally advised to avoid thera-
peutic radiation.65 As more women with a genetic predisposition to (breast) cancer are
identified, more research will undoubtedly reveal additional areas where we can
personalize treatment recommendations for our patients.

SUMMARY

Genetic testing plays an important role in assessing breast cancer risk and often the
risk of other types of cancers. Accurate risk assessment and stratification represents a
critical element of identifying who is best served by increased surveillance and consid-
eration of other prevention or treatment options while also limiting overtreatment and
unnecessary testing. Given the implications of these types of genetic test results, the
indications for testing will likely continue to expand, and ideally, more women with a
genetic predisposition to breast cancer will be identified before they are diagnosed
with breast cancer and thus have the option to consider effective screening and pre-
vention management strategies.
44 Rooney et al

CLINICS CARE POINTS

 Women aged 25 years or older should undergo breast cancer risk assessment, particularly
those with a family history of cancer.
 Multiple risk models exist to help evaluate a patient’s risk of developing breast cancer, and
they differ based on the risk factors included and the types of risk calculations provided.
 Not all risk models are appropriate for assessing breast cancer risk for every patient.
 The indications for germline genetic testing are continually expanding.
 Depending on the risk level or known genetic mutation, increased imaging surveillance may
be recommended.
 Depending on the risk level or known genetic mutation, BRRM may be considered.

DISCLOSURE
 The authors report no proprietary or commercial interest in any product
mentioned or concept.
 Dr J.K. Plichta is a recipient of research funding by the Color Foundation (PI: J.K.
Plichta). She serves on the National Comprehensive Cancer Network (NCCN)
Breast Cancer Screening Committee.

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