Risk stratification can be based on absolute, lifetime, or relative risk for developing breast cancer. Absolute risk is the likelihood of being diagnosed with cancer over a defined period of time. The American Society of Clinical Oncology (ASCO) guidelines defines high risk to be an absolute 5-year risk of 1.66% as calculated by the National Cancer Institute Breast cancer Risk Assessment Tool (BCRAT) or equivalent measures (3,4).

Lifetime risk is the absolute risk of being diagnosed with cancer over the course of a lifetime from birth to death. A woman in the United States has about a 12% chance of being diagnosed with breast cancer in her lifetime (2). In the United States, high lifetime risk for breast cancer is accepted to be a risk greater than 20% as calculated by various risk assessment models.

Relative risk compares the absolute risk of diseases among people with a particular risk factor to the risk among people without that risk factor. If the relative risk is above 1, then risk is higher among those with the risk factor than among those without the factor. Relative risk is useful for comparisons but does not provide information about the absolute risk of the exposed group (2). As shown in Table 4-1, known risk factors can be stratified into three relative risk categories (2). The effects of screening or various intervention measures can be studied based on their impact on relative risk.

The National Comprehensive Cancer Network (NCCN) uses a combination of absolute, lifetime, and relative risk to categorize high-risk groups. It identifies six specific groups that place individuals into the increased risk category: (1) women with a prior history of breast cancer; (2) women greater than 35 years of age with a 5-year risk of invasive breast cancer greater than 1.7% (per Gail model); (3) women who have a lifetime risk greater than 20% based on history of lobular carcinoma in situ (LCIS) or atypical ductal hyperplasia (ADH)/atypical lobular hyperplasia (ALH); (4) women who have a lifetime risk greater than 20% as defined by models that are largely dependent on family history; (5) women between the ages of 10 and 30 years with prior thoracic radiation therapy (e.g., mantle irradiation); and (6) women with a pedigree suggestive of or known genetic predisposition (5). Women with a personal history of breast cancer will be omitted for the purposes of this discussion. A guide to NCCN recommendations for each remaining group for screening and risk reduction strategies is summarized in Table 4-2 (5).

There are multiple risk assessment models available to calculate a woman’s risk for developing breast cancer. The first step in risk assessment should be to identify personal, familial, and genetic factors that may be associated with a patient’s increased breast cancer risk. If these factors are absent, models such as Gail/BCRAT
(Breast Cancer Risk Assessment Tool, NCI) are sufficient. For those individuals with personal, genetic, or familial factors, a more extensive risk assessment needs to be undertaken (5). A recent review of various risk assessment models by the United States Preventive Services Task Force established that each risk assessment tool has advantages and limitation and found insufficient evidence to recommend one over the other (6). Models evaluated included the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, 7-Question Family History Screening Tool, International Breast Cancer Intervention Study Instrument (Tyrer–Cuzick), and brief versions of BRCAPRO. These familial risk assessment tools are primarily intended for use by health care clinicians untrained in genetic cancer risk assessment in order to guide referral to genetic counselors for more definitive evaluation. These familial risk assessment models were found to have sensitivity estimates between 77% and 100% and areas under the receiver operating characteristic curve between 0.68 and 0.96 (7). Clinicians can safely implement any of these risk assessment models into their practice.

Patients who are thought to have a high risk of genetic mutation based on familial risk assessment models should be referred to genetic counseling. Individuals will be identified for testing of specific deleterious mutations, and discussion will ensue regarding benefits and harms of testing, interpretation of results, and management options. Testing for mutations should be performed if personal or family history suggests an inherited cancer susceptibility.

Several societies have established criteria for referral to genetic counseling and testing. These recommendations are summarized in Table 4-3 (8). The outlier in genetic testing referral recommendation is the American Society of Breast Surgeons. In its official statement, the society states that recent data support that genetic testing should be offered to each patient with breast cancer (newly diagnosed or with a personal history). If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2 with other genes as appropriate for the clinical scenario and family history. For patients with newly diagnosed breast cancer, identification of a mutation may impact local treatment recommendations (surgery and potentially radiation) and systemic therapy. Additionally, family members may subsequently be offered testing and tailored risk-reduction strategies (9). The basis of this recommendation was the observation that a significant number of pathogenic mutation carriers remain undetected and undiagnosed. These are largely women with “moderate-penetrance” mutations, but even women with BRCA1/BRCA2 mutations may not be identified (10,11).

Management of the high-risk patient can be undertaken in many different clinical settings. Primary care or surgical offices staffed by clinicians with interest and knowledge for caring for high-risk patients is common.
High-risk clinics have been also been established for screening and management of the high-risk population. These clinics tend to embrace a multidisciplinary approach and often include services such as genetic counseling and testing, nutrition, exercise, and weight control programs. Access is maintained to oncologic and surgical specialties as needed. Regardless of the type of clinical setting, the practical approach to managing the high-risk patient includes the goals summarized in Table 4-4 as per NCCN recommendations (12).