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Breast Cancer Risk Assessment

A Step-Wise Approach for Primary Care Providers on the Front Lines of Shared Decision Making
  • Adelaide H. McClintock
    Correspondence
    Correspondence: Address to Adelaide McClintock, MD, 4245 Roosevelt Way NE, Box 354765, Seattle, WA 98105.
    Affiliations
    Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, Washington

    Women’s Health Care Center, Seattle, Washington
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  • Anna L. Golob
    Affiliations
    Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, Washington

    Seattle Veterans Affairs Medical Center, Seattle, Washington
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  • Mary B. Laya
    Affiliations
    Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, Washington

    Women’s Health Care Center, Seattle, Washington
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      Abstract

      Breast cancer-screening guidelines increasingly recommend that clinicians perform a risk assessment for breast cancer to inform shared decision making for screening. Precision medicine is quickly becoming the preferred approach to cancer screening, with the aim of increased surveillance in high-risk women, while sparing lower-risk women the burden of unnecessary imaging. Risk assessment also informs clinical care by refining screening recommendations for younger women, identifying women who should be referred to genetic counseling, and identifying candidates for risk-reducing medications. Several breast cancer risk-assessment models are currently available to help clinicians categorize a woman’s risk for breast cancer. However, choosing the appropriate model for a given patient requires a working knowledge of the strengths, weaknesses, and performance characteristics of each. The aim of this article is to provide a stepwise approach for clinicians to assess an individual woman’s risk for breast cancer and describe the features, appropriate use, and performance characteristics of commonly encountered risk-prediction models. This approach will help primary care providers engage in shared decision making by efficiently generating an accurate risk assessment and make clear, evidence-based screening and prevention recommendations that are appropriately matched to a woman's risk for breast cancer.
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      Learning Objectives: On completion of this article, you should be able to (1) obtain a complete family history of cancer and identify women in your primary care practice that meet criteria for referral to genetics for testing for Hereditary Cancer Syndromes, (2) articulate the strengths and limitations of The NCI-Gail model, the BCSC Model, and the Tyrer-Cuzick/IBISv8 models for breast cancer risk assessment, (3) choose a breast cancer risk model that is appropriately matched to a patient's history and risk factors, (4) interpret breast cancer risk assessment results and make a recommendation for or against additional breast cancer screening with MRI for high risk women, and (5) use breast cancer risk calculators to inform shared decision making about screening interval for women at average and intermediate risk of developing breast cancer.
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      In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Jenna M. Pederson, have control of the content of this program but have no relevant financial relationship(s) with industry.
      The authors report no competing interests.
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      Breast cancer-screening guidelines increasingly recommend that clinicians perform a risk assessment for breast cancer to inform shared decision making for screening.
      • Siu A.L.
      US Preventive Services Force
      Screening for Breast Cancer: U.S. Preventive Services Task Force recommendation statement.
      Precision medicine is quickly becoming the preferred approach to cancer screening, with the aim of increased surveillance in high-risk women, while sparing lower-risk women the burden of unnecessary imaging.
      • Shieh Y.
      • Eklund M.
      • Madlensky L.
      • et al.
      Breast cancer screening in the precision medicine era: risk-based screening in a population-based trial.
      Risk assessment also informs clinical care by refining screening recommendations for younger women, in whom shared decision making is particularly recommended, as well as identifying women who should be referred to genetic counseling or who may be candidates for risk-reducing medications.
      Several breast cancer risk-assessment models are currently available to help clinicians categorize a woman’s risk for breast cancer. However, choosing the appropriate model for a given patient requires a working knowledge of the strengths, weaknesses, and performance characteristics of each. Unfortunately, current guidelines lack detailed recommendations for how to perform and interpret a breast cancer risk assessment.
      The aim of this article is to provide a stepwise approach for clinicians to assess an individual woman’s risk for breast cancer (Figure) and describe the features, appropriate use, and performance characteristics of commonly encountered risk-prediction models (Table 1). This approach will help primary care providers efficiently generate accurate risk assessments and make clear, evidence-based screening and prevention recommendations that are appropriately matched to an individual’s risk for breast cancer.
      Figure thumbnail gr1
      FigureStepwise approach to breast cancer risk assessment for women without a history of breast cancer, ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), or atypical ductal hyperplasia, high-dose chest radiation between the ages of 10 and 30, or known high-risk genetic mutation.
      Table 1Input Variables, Prediction Horizons, and Best Uses for Commonly Used Breast Cancer Risk-Prediction Models
      ModelFirst- degree relativesSecond- degree relativesOvarian cancerAge at onset of cancerBreast densityBiopsies with proliferative disease or atypiaHormonal factorsPrediction horizonBest use
      NCI Gail++Limited5-yearTo determine if a patient is a candidate for risk-reducing medications
      Lifetime
      BCSC+++None5-yearBreast cancer risk prediction for most patients except for those with significant family history (see Tyrer-Cuzick best uses below)
      10-year
      Tyrer-Cuzick v8++++++Comprehensive5-yearBreast cancer risk prediction for patients with family history of:
      10-year ○ Young age (<50) at diagnosis of cancer
      Lifetime ○ Second-degree relatives with breast or ovarian cancers
       ○ Male breast cancers
       ○ Ovarian cancer
      Can also be used to determine if a patient is a candidate for risk-reducing medications.
      These calculators can be accessed at the following sites:
      BCSC = Breast Cancer Surveillance Consortium; NCI = National Cancer Institute
      Importantly, this approach does NOT apply to women who are already known to be carriers of a high- or moderate-risk genetic mutation, have personal histories of breast cancer or other high-risk lesions such as atypical ductal hyperplasia or lobular carcinoma in situ, or who have had high-dose chest radiation between the ages of 10 and 30. Women in these groups are already considered to be at high risk for breast cancer, on the order or someone with a high-risk mutation,
      • Hartmann L.C.
      • Degnim A.C.
      • Santen R.J.
      • Dupont W.D.
      • Ghosh K.
      Atypical hyperplasia of the breast: risk assessment and management options.
      and should be offered high-risk screening or surveillance protocols without further risk stratification (Figure).

      Step 1: Assess Family History

      The first step in performing a risk assessment is to review family history. The United States Preventive Services Task Force (USPSTF),
      • Hartmann L.C.
      • Degnim A.C.
      • Santen R.J.
      • Dupont W.D.
      • Ghosh K.
      Atypical hyperplasia of the breast: risk assessment and management options.
      National Comprehensive Cancer Network (NCCN),
      • Owens D.K.
      • Davidson K.W.
      • Krist A.H.
      • et al.
      Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement.
      ,
      • Daly M.
      • Pilarski R.
      • Berry M.
      • et al.
      Genetic/familial high-risk assessment: breast and ovarian.
      and American College of Obstetricians and Gynecologists (ACOG)
      ACOG Committee Opinion Summary
      Hereditary Cancer Syndromes and Risk Assessment: Number 793.
      guidelines all recommend screening women for family histories of cancer but differ on which cancers should prompt referral for genetic counseling. USPSTF advocates asking women about personal or family histories of only BRCA-related cancers (breast, ovarian, tubal, and peritoneal cancer) or ancestry associated with BRCA mutations, and further screening only for women with these cancers in their histories, using one of several validated screening tools (eg, Family History Screen 7 [FHS-7] or Breast Referral Screening Tool [BRST]) to determine who should be referred for genetic counseling.
      • Owens D.K.
      • Davidson K.W.
      • Krist A.H.
      • et al.
      Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement.
      By contrast, NCCN and ACOG advise that clinicians ask patients about all cancer diagnoses in first- and second-degree relatives, including age of diagnosis,
      • Daly M.
      • Pilarski R.
      • Berry M.
      • et al.
      Genetic/familial high-risk assessment: breast and ovarian.
      allowing for identification of BRCA1/2 as well as other actionable mutations.
      If the family-history screening is positive using either approach, the patient should first be referred for genetic counseling and consideration of genetic testing before proceeding with further risk assessment. Patients found to have pathogenic mutations in high penetrance genes— such as BRCA1 and 2, TP53, PTEN, and several others (see Supplemental Table)
      • Daly M.B.
      • Pilarski R.
      • Yurgelun M.B.
      • et al.
      NCCN Guidelines Insights: Genetic/familial high-risk assessment: breast, ovarian, and pancreatic cancer, version 1.2020.
      —are automatically considered high risk and should be offered a high-risk screening protocol and consideration of prophylaxis.
      If the family-history screen does not identify an indication for a genetics referral, the patient declines genetic counseling, or is found to have negative or uninformative testing, clinicians can move to step 2. If wait times are especially long for genetics evaluation, or it is unavailable to the patient, it is reasonable to proceed to step 2, so as not to delay screening that may be indicated.

      Step 2: Assess Personal History

      The second step in risk assessment involves careful review of the patient’s personal history. Key risk factors can be divided into distinct groups: demographics (age, ethnicity), hormonal and reproductive (age of menarche and menopause, exogenous hormone use, parity, age of first live birth), radiographic breast density, and personal breast history (biopsies with proliferative disease or atypia) (Figure). As noted, women with histories of atypia do not need further risk assessment, as they are already considered to be at high risk. Of note, we also recommend providers ask all women about a history of chest radiation between the ages of 10 and 30, as this also confers high-risk status and merits a high-risk screening protocol.

      Step 3: Choose an Appropriate Risk-Prediction Model

      There are 3 commonly used risk-assessment tools: The National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool, also called the NCI-Gail Model;
      • Gail M.H.
      • Brinton L.A.
      • Byar D.P.
      • et al.
      Projecting individualized probabilities of developing breast cancer for white females who are being examined annually.
      ,
      • Costantino J.P.
      • Gail M.H.
      • Pee D.
      • et al.
      Validation studies for models projecting the risk of invasive and total breast cancer incidence.
      the Breast Cancer Screening Consortium (BCSC) Model;
      • Tice J.A.
      • Cummings S.R.
      • Smith-Bindman R.
      • Ichikawa L.
      • Barlow W.E.
      • Kerlikowske K.
      Using clinical factors and mammographic breast density to estimate breast cancer risk: development and validation of a new predictive model.
      and the International Breast Cancer Intervention Study (IBIS), also called the Tyrer-Cuzick
      • Tyrer J.
      • Duffy S.W.
      • Cuzick J.
      A breast cancer prediction model incorporating familial and personal risk factors.
      (most recent version 8).
      • Cuzick J.
      • Brentnall A.
      Models for Assessment of Breast Cancer Risk.
      Key information about each model is presented here and in Table 1. More detailed information—including development cohort, performance characteristics, and validation data—are presented in the Supplemental Table.

       National Cancer Institute Gail Model

      The Gail model (updated as NCI-Gail) was the first model developed for breast cancer risk stratification. Although it has been validated in several populations in the United States,
      • 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.
      this model has poor individual discrimination and thus does not predict events as well in individual patients.
      • 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.
      The Gail is also limited in its inputs compared with other available models: it does not include second-degree relatives, considers fewer hormonal risk factors, lacks granularity in delineating grades of breast biopsy abnormalities, and does not include breast density. However, this model was used in studies of risk-reducing medications, and the estimates of risk and benefit of these medications were designed with NCI-Gail model risk thresholds in mind.
      • Freedman A.N.
      • Yu B.
      • Gail M.H.
      • et al.
      Benefit/risk assessment for breast cancer chemoprevention with raloxifene or tamoxifen for women age 50 years or older.
      Although some guidelines do still endorse use of this model,
      • Siu A.L.
      US Preventive Services Force
      Screening for Breast Cancer: U.S. Preventive Services Task Force recommendation statement.
      overall, it is not recommended for use outside the context of risk-reducing medications, given that other models that integrate additional key risk factors are readily available and similarly easy to use.

       Breast Cancer Surveillance Consortium Model

      The BCSC model builds on the methods of the NCI-Gail model but incorporates more recently identified key risk factors, including more detailed breast biopsy results and breast density.
      • Tice J.A.
      • Miglioretti D.L.
      • Li C.S.
      • Vachon C.M.
      • Gard C.C.
      • Kerlikowske K.
      Breast density and benign breast disease: risk assessment to identify women at high risk of breast cancer.
      The BCSC was the first model to include breast density, a well-established and nonmodifiable independent risk for breast cancer, with higher-density categories increasing a woman’s risk by 2- to 4-fold in some studies.
      • Boyd N.F.
      • Guo H.
      • Martin L.J.
      • et al.
      Mammographic density and the risk and detection of breast cancer.
      The BCSC is well calibrated for the diverse US population
      • Tice J.A.
      • Bissell M.C.S.
      • Miglioretti D.L.
      • et al.
      Validation of the breast cancer surveillance consortium model of breast cancer risk.
      and has the advantage of being quick and easy to use (available online or as a phone app). However, this model does not include hormonal risk factors and considers a more limited family history: it includes only first-degree relatives with breast cancer but not age of diagnosis or family history of ovarian cancer. The BCSC model may be particularly useful to women who have questions about the risk impact of breast density, especially given increasing breast-density notification laws. Generally, the BCSC model is appropriate for many women in a primary-care setting, apart from those who have more significant family histories of breast or ovarian cancer that include young age at diagnosis and/or second-degree or male relatives with cancers.

       Tyrer-Cuzick Version 8

      The Tyrer-Cuzick model (also called IBIS) was developed in 2004 in the United Kingdom and was updated to the most recent version in 2016.
      • Cuzick J.
      • Brentnall A.
      Models for Assessment of Breast Cancer Risk.
      ,
      • Brentnall A.R.
      • Harkness E.F.
      • Astley S.M.
      • et al.
      Mammographic density adds accuracy to both the Tyrer-Cuzick and Gail breast cancer risk models in a prospective UK screening cohort.
      The benefits of this model are that it provides for entry of a more comprehensive family history, allowing for inclusion of second-degree relatives, ovarian cancers, age of diagnosis of family members, family members without cancer, and includes genetic testing information. It also includes hormonal factors, weight, height, and atypia. Version 8 also allows for input of breast density, which was shown to increase the predictive performance of this model.
      • Brentnall A.R.
      • Harkness E.F.
      • Astley S.M.
      • et al.
      Mammographic density adds accuracy to both the Tyrer-Cuzick and Gail breast cancer risk models in a prospective UK screening cohort.
      ,
      • Brentnall A.R.
      • Cuzick J.
      • Buist D.S.M.
      • Bowles E.J.A.
      Long-term accuracy of breast cancer risk assessment combining classic risk factors and breast density.
      It can also be used to determine eligibility for risk-reducing medications, using a 10-year risk threshold of 5% or more.
      • Visvanathan K.
      • Fabian C.J.
      • Bantug E.
      • et al.
      Use of endocrine therapy for breast cancer risk reduction: ASCO clinical practice guideline update.
      However, it is more time consuming to use, and has been shown to over- or underestimate risk in certain groups (Supplemental Table). “User error” can also be introduced if unaffected family members are not entered in the risk model and can lead to an overestimation of risk. In addition, the Tyrer-Cuzik model does not account for competing mortality in the risk assessment, unless selected by the user. This model is most appropriate when there are both first- and second-degree relatives with breast cancer, early-onset breast cancer, male breast cancers, or ovarian cancer in the family. In addition, the Tyrer-Cuzik is the model of choice for evaluating if a patient is a candidate for breast-cancer screening using magnetic resonance imaging (MRI) in addition to mammography, as it is the only model that takes into account “extensive family history” (first- and second-degree relatives) and that can generate a lifetime risk estimate, both of which are current criteria for considering breast MRI.
      • Monticciolo D.L.
      • Newell M.S.
      • Moy L.
      • Niell B.
      • Monsees B.
      • Sickles E.A.
      Breast cancer screening in women at higher-than-average risk: recommendations from the ACR.
      • Saslow D.
      • Boetes C.
      • Burke W.
      • et al.
      American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
      • Bevers T.B.
      • Anderson B.O.
      • Bonaccio E.
      • et al.
      NCCN clinical practice guidelines in oncology: breast cancer screening and diagnosis.

      Step 4: Interpret Risk Assessment

      Using the information generated by the appropriate risk-assessment model, clinicians can counsel women on their individual risk and make recommendations on when to start screening, how often to screen, which modalities to use, and whether risk-reducing medications are indicated. Recommendations for screening based on risk category are shown in Table 2.
      Table 2Breast Cancer Risk Category and Recommended Imaging Strategy
      Risk categoryRisk of developing breast cancerScreening recommendations
      Average<15% lifetimeOffer routine mammography per average risk screening guidelines
      <1.66% 5-year
      Intermediate15% to 20% lifetimeEmphasis on shared decision making, given lack of high-quality data to guide screening in this group
      1.67% to 2.49% 5-yearConsider screening mammography starting at age 40 if “higher than average risk” (USPSTF Grade C).
       • ACOG, ACS, NCCN, and ACR recommend or suggest clinicians “offer” screening mammography starting at 40
       • Most organizations also recommend yearly rather than biennial screening in this group
      For women with intermediate risk of developing breast cancer, based on family history and personal risk factors, NCCN and ACS guidelines agree that there is insufficient evidence to recommend for or against MRI for screening
      For women who have intermediate risk due to breast density alone, without other risk factors, USPSTF, ACS, NCCN, ACOG and ACR do not support routine use of ultrasound or MRI for supplemental screening (either recommend against, believe there is insufficient evidence, or believe it may find more cancer but increase recall and benign biopsies)
      High≥20% lifetimeACS, NCCN, and ACR all recommend offering annual mammography and annual breast MRI starting at 10 years before the age of diagnosis of youngest affected family member, but not before the age 30
      ≥2.5% 5-year
      ACOG = American College of Obstetricians and Gynecologists; ACR = American College of Radiology; ACS = American Cancer Society; MRI = magnetic resonance imaging; NCCN = National Comprehensive Cancer Network; USPSTF = United States Preventive Services Task Force

       High-Risk Screening and Recommendations for Prophylaxis

      Several United States-based medical societies, including the American Cancer Society (ACS),
      • Saslow D.
      • Boetes C.
      • Burke W.
      • et al.
      American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
      American College of Radiology (ACR),
      • Monticciolo D.L.
      • Newell M.S.
      • Moy L.
      • Niell B.
      • Monsees B.
      • Sickles E.A.
      Breast cancer screening in women at higher-than-average risk: recommendations from the ACR.
      and NCCN
      • Bevers T.B.
      • Anderson B.O.
      • Bonaccio E.
      • et al.
      NCCN clinical practice guidelines in oncology: breast cancer screening and diagnosis.
      recommend that women with a greater than 20% lifetime risk of developing cancer (calculated using a tool, such as Tyrer-Cuzick, that takes into account extensive family history including first- and second-degree relatives) be offered yearly screening breast MRI scans in addition to yearly mammograms, starting 10 years before onset of breast cancer in the youngest affected family member, although not before the age of 30. Estimates of the sensitivity and specificity of breast MRI for the detection of cancer in high-risk women range from 75% to 91% for sensitivity and 82% to 93% for specificity.
      • Warner E.
      • Messersmith H.
      • Causer P.
      • Eisen A.
      • Shumak R.
      • Plewes D.
      Systematic review: using magnetic resonance imaging to screen women at high risk for breast cancer.
      For comparison, sensitivity of mammography alone for high-risk women ranges from 25% to 59%, and specificity is 91% to 99%.
      • Warner E.
      • Messersmith H.
      • Causer P.
      • Eisen A.
      • Shumak R.
      • Plewes D.
      Systematic review: using magnetic resonance imaging to screen women at high risk for breast cancer.
      When counseling patients on risks and benefits of MRI, providers may also want to note that MRI has not been shown to improve 10-year survival
      • Evans D.G.
      • Kesavan N.
      • Lim Y.
      • et al.
      MRI breast screening in high-risk women: cancer detection and survival analysis.
      or disease-free survival in high-risk women
      • Bae M.S.
      • Sung J.S.
      • Han W.
      • et al.
      Survival outcomes of screening with breast MRI in high-risk women.
      , and that there have been increasing concerns about the impact of gadolinium contrast deposition in brain tissues, with uncertain pathological or clinical correlates.
      • Levine D.
      • McDonald R.J.
      • Kressel H.Y.
      Gadolinium retention after contrast-enhanced MRI.
      Regarding prophylaxis, women with histories of atypical ductal hyperplasia or lobular carcinoma in situ, or who have NCI Gail 5-year risk of 3% or more or a Tyrer-Cuzick 10-year risk of 5% or more, are also candidates for risk-reducing medications including tamoxifen, raloxifene, and aromatase inhibitors
      US Preventive Services Task Force
      Medication use to reduce risk of breast cancer: US Preventive Services Task Force Recommendation Statement.
      ,
      • Vogel V.G.
      • Costantino J.P.
      • Wickerham D.L.
      • et al.
      Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.
      and should be counseled about the risks and benefits of these medications or offered consultation with breast specialists, if they are available.

       Intermediate Risk-Screening Recommendations

      There is less general agreement about how to screen intermediate-risk women. This is especially challenging because of the variability in this group; women may be only slightly above average risk or just barely below the threshold of high risk. For these patients, there are many more decisions to make: whether mammography should begin at age 40 and if mammography should be performed yearly rather than biennially. At present, guidelines do not recommend the use of routine supplemental imaging with ultrasound or MRI for women at intermediate or average risk of breast cancer. Research is ongoing regarding whether supplemental MRI may improve screening outcomes in women with extremely dense breasts.
      • Bakker M.F.
      • de Lange S.V.
      • Pijnappel R.M.
      • et al.
      Supplemental MRI screening for women with extremely dense breast tissue.
      In sum, shared decision-making is the cornerstone of individual screening strategies for women in the intermediate risk category.

      Conclusion

      In this evolving landscape of personalized medicine, shared decision making about breast cancer screening has become increasingly nuanced. The stepwise approach presented here can help busy primary care providers to identify patients who are at higher than average risk of developing breast cancer and who may benefit from a referral to genetic counseling and/or change in screening and prevention strategy that more accurately matches their individual risk of breast cancer.

      Supplemental Online Material

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