Diseases of the Breast

Normal Development and Physiology

In utero, the milk bud develops from the ectodermal thickening in the pectoral area and extends as the milk streak (mammary ridge) from the axilla to the inguinal area. At 9 weeks of gestation, the milk streak begins to atrophy to normally form a single pair of bilateral glands. When less than the normal atrophy of the milk streak occurs, then polymastia and/or polythelia occurs. Rarely, congenital amastia occurs as a result of failure of the milk bud.

Ninety percent of newborns will have a breast secretion that is commonly referred to as “witches milk” that is the result of elevated maternal hormones and prolactin levels. If the secretion sequesters within the nipple, it can cause a mass or lactocele that will resolve on its own in 3 to 4 weeks, as will the discharge.

Before puberty, the breast is composed primarily of dense fibrous stroma and scattered ducts lined with epithelium. In the United States, puberty, as measured by breast development and the growth of pubic hair, begins between the ages of 9 and 12 years, and menarche (onset of menstrual cycles) begins at approximately 11 to 14 years of age. These events are initiated by low-amplitude pulses of pituitary gonadotropins, which increase serum estradiol concentrations. In the breast, this hormone-dependent maturation (thelarche) entails increased deposition of fat, the formation of new ducts by branching and elongation, and the first appearance of lobular units. This process of growth and cell division is under the control of estrogen, progesterone, adrenal hormones, pituitary hormones, and the trophic effects of insulin and thyroid hormone. There is evidence that local growth factor networks are also important. The exact timing of these events and the coordinated development of both breast buds may vary from the average in individual patients. The term prepubertal gynecomastia refers to symmetrical enlargement and projection of the breast bud in a girl before the average age of 12 years, unaccompanied by the other changes of puberty. This process, which may be unilateral, should not be confused with neoplastic growth and is not an indication for biopsy.

The postpubertal mature or resting breast contains fat, stroma, lactiferous ducts, and lobular units. During phases of the menstrual cycle or in response to exogenous hormones, the breast epithelium and lobular stroma undergo cyclic stimulation. The dominant process appears to be hypertrophy and alteration of morphology rather than hyperplasia. In the late luteal (premenstrual) phase, there is an accumulation of fluid and intralobular edema. This edema can produce pain and breast engorgement.

These physiologic changes can lead to increased nodularity and may be mistaken for a malignant tumor. Ill-defined masses in premenopausal women are generally observed through the course of the menstrual cycle before any intervention is undertaken. With pregnancy, there is diminution of the fibrous stroma and the formation of new acini or lobules, termed adenosis of pregnancy. After birth, there is a sudden loss of placental hormones, which, combined with continued high levels of prolactin, is the principal trigger for lactation. The actual expulsion of milk is under hormonal control and is caused by contraction of the myoepithelial cells that surround the breast ducts and terminal ductules. There is no evidence for innervation of these myoepithelial cells; their contraction appears to occur in response to the pituitary-derived peptide oxytocin. Stimulation of the nipple appears to be the physiologic signal for continued pituitary secretion of prolactin and acute release of oxytocin. When breastfeeding ceases, the prolactin level decreases and there is no stimulus for release of oxytocin. The breast returns to a resting state and to the cyclic changes induced when menstruation resumes.

Menopause is defined by cessation in menstrual flow for at least 1 year; in the United States, it usually occurs between the ages of 40 and 55 years, with a median age of 51 years. Menopause may be accompanied by symptoms such as vasomotor disturbances (hot flashes), vaginal dryness, urinary tract infections, and cognitive impairment (possibly secondary to interruption of sleep by hot flashes). Menopause results in involution and a general decrease in the epithelial elements of the resting breast. These changes include increased fat deposition, diminished connective tissue, and the disappearance of lobular units. The persistence of lobules, hyperplasia of the ductal epithelium, and cyst formation all can occur under the influence of exogenous ovarian hormones, usually in the form of postmenopausal hormone replacement therapy (HRT). Physicians should inquire about the menstrual history, age at onset of menses, and cessation of menses and record the use of HRT because all of these factors can influence a woman’s risk of developing breast cancer. HRT can lead to increased breast density, which may decrease the sensitivity of mammography.

Fibrocystic Changes and Breast Pain

The condition previously referred to as fibrocystic disease represents a spectrum of clinical, mammographic, and histologic findings and is common during the fourth and fifth decades of life, generally lasting until menopause. An exaggerated response of breast stroma and epithelium to various circulating and locally produced hormones and growth factors is frequently characterized by the constellation of breast pain, tenderness, and nodularity. Symptomatically, the condition manifests as premenstrual cyclic mastalgia, with pain and tenderness to touch. This mastalgia can be worrisome to many women; however, breast pain is not usually a symptom of breast cancer. Pain without other signs or symptoms of breast cancer is uncommon, occurring in only approximately 7% of patients with breast cancer. In women with breast pain and an associated palpable mass, the presence of the mass is the focus of evaluation and treatment. Normal ovarian hormonal influences on breast glandular elements frequently produce cyclic mastalgia, pain generally in phase with the menstrual cycle. Noncyclic mastalgia is more likely idiopathic and difficult to treat. Women 30 years and older with noncyclic mastalgia should undergo breast imaging with mammography and ultrasonography in addition to a physical examination. If examination reveals a mass, this should become the focus of subsequent evaluation (see “Biopsy” later on). Occasionally, a simple cyst may cause cyclical or noncyclic breast pain, and aspiration of the cyst usually resolves the pain. In the case of large cysts, which will quickly recur after aspiration, percutaneous excision with a vacuum-assisted device will be definitive. Most patients with simple cysts do not require further evaluation. Patients with complex cysts with solid intracystic components require additional evaluation including biopsy of the solid components. Treatment with danocrine, lupron, and tamoxifen are effective but with significant side effects. Referred pain can be a significant cause of breast pain, the most common source of which is scapulothoracic bursitis. It can be cyclical but is most often noncyclical. Because of the confluence of afferent signals from the shoulder and the dorsal horn of the spinal cord, one can get referred pain from the shoulder in the distribution of the intercostal nerves along the axilla, the breast, and the arm. Trigger point injection along the medial scapular border in order to access the scapulothoracic bursa are both diagnostic and therapeutic for this malady. Heat and nonsteroidal antiinflammatory drugs will aid in alleviating the inflammation.

Patients with fibrocystic changes have clinical breast findings that range from mild alterations in texture to dense, firm breast tissue with palpable masses. The appearance of large palpable cysts completes the picture. Fibrocystic changes are usually seen on mammography as diffuse or focal radiologically dense tissue. On ultrasonography, cysts are seen in one-third of all women 35 to 50 years old; most of these cysts are nonpalpable. Palpable cysts or multiple small cysts are typical of fibrocystic disease. Cysts with or without fibrocystic disease are uncommon in postmenopausal women.

Histologically, in addition to macrocysts and microcysts, women with fibrocystic changes may have identified solid elements, including adenosis, sclerosis, apocrine metaplasia, stromal fibrosis, and epithelial metaplasia and hyperplasia. Depending on the presence of epithelial hyperplasia, fibrocystic changes are classified as nonproliferative, proliferative without atypia, or proliferative with atypia. All three types of changes can occur alone or in combination and to a variable degree, and in the absence of epithelial atypia, these changes represent the histologic spectrum of normal breast tissue. However, epithelial atypia (atypical ductal hyperplasia [ADH]) is a risk factor for the development of breast cancer. Atypical proliferations of ductal epithelial cells confer increased risk for breast cancer; however, fibrocystic change is not itself a risk factor for the development of breast malignancy.

Abnormal Development and Physiology

Nipple Discharge

The appearance of discharge from the nipple ( Fig. 35.6A ) of a nonlactating woman is a common condition and is rarely associated with an underlying carcinoma. In one review of 270 subareolar biopsies for discharge from one identifiable duct and without an associated breast mass, carcinoma was found in only 16 patients (5.9%). In these cases, the fluid was bloody or tested strongly positive for occult hemoglobin. In another series of 249 patients with discharge from a single identifiable duct, breast carcinoma was found in 10 patients (4%). In eight of these patients, a mass lesion was identified in addition to the discharge. In the absence of a palpable mass or suspicious findings on mammography, discharge is rarely associated with cancer.

It is important to establish whether the discharge comes from one breast or from both breasts, whether it comes from multiple duct orifices or from just one, and whether the discharge is grossly bloody or contains blood. A milky discharge from both breasts is termed galactorrhea . In the absence of lactation or a history of recent lactation, galactorrhea may be associated with increased production of prolactin. Radioimmunoassay for serum prolactin is diagnostic. However, true galactorrhea is rare and is diagnosed only when the discharge is milky (contains lactose, fat, and milk-specific proteins). Unilateral discharge from one duct orifice is often treated surgically when there is a significant amount of discharge. However, the underlying cause is rarely a breast malignancy.

The most common cause of spontaneous nipple discharge from a single duct is a solitary intraductal papilloma (60%–80%) in one of the large subareolar ducts under the nipple. Subareolar duct ectasia producing inflammation and dilatation of large collecting ducts under the nipple is common (20%) and usually involves discharge from multiple ducts. Cancer is a very unusual cause of discharge in the absence of other signs. However, papillomas that are located away from the nipple-areolar complex are at higher risk of malignancy (20%). A papilloma is the most common benign tumor to develop breast cancer, primarily DCIS.

Nipple discharge that is bilateral and comes from multiple ducts is not usually a cause for surgery. Bloody discharge from a single duct often requires surgical excision to establish a diagnosis and control the discharge. Bilateral bloody spontaneous discharge is likely endocrine in nature and is associated with pregnancy and hypothyroidism.

Patient History

In a woman in whom breast disease is suspected, it is important for the examiner to determine the patient’s age and to obtain a reproductive history, including age at menarche, age at menopause, and history of pregnancies including age at first full-term pregnancy. A previous history of breast biopsies should be obtained, including the pathologic findings. If the patient has had a hysterectomy, it is important to determine whether the ovaries were removed. In premenopausal women, a recent history of pregnancy and lactation should be noted. The history should include any use of HRT or use of hormones for contraception. The family history should detail any known genetic abnormalities as well as any cancer, but especially of the breast and ovaries and the menopausal status of any affected relatives.

With respect to the specific breast complaint, the patient should be asked about history of a mass, breast pain, nipple discharge, and any skin changes. If a mass is present, the patient should be asked how long it has been present and whether it has grown or changes with the menstrual cycle. If a cancer diagnosis is suspected, inquiry about constitutional symptoms, bone pain, weight loss, respiratory changes, and similar clinical indications can direct investigations that could reveal evidence of metastatic disease.

Physical Examination

The physical examination begins with the patient in the upright sitting position. The breasts are visually inspected for obvious masses, asymmetries, and skin changes. The nipples are examined and compared for the presence of retraction, nipple inversion, or excoriation of the superficial epidermis such as that seen with Paget disease ( Fig. 35.6B ). The use of indirect lighting can unmask subtle dimpling of the skin or nipple caused by a carcinoma that places Cooper ligaments under tension ( Fig. 35.6C ). Simple maneuvers such as stretching the arms high above the head or tensing the pectoralis muscles may accentuate asymmetries and dimpling. If carefully sought, dimpling of the skin or nipple retraction is a sensitive and specific sign of underlying cancer.

Edema of the skin produces a clinical sign known as peau d’orange ( Fig. 35.6D ). Peau d’orange and tenderness, warmth, and swelling of the breast are the hallmarks of inflammatory carcinoma but may be mistaken for acute mastitis. The inflammatory changes and edema are caused by obstruction of dermal lymphatic channels by emboli of carcinoma cells. Occasionally, a bulky tumor may produce obstruction of lymph channels that results in overlying skin edema. This is not typically the case with inflammatory carcinoma, where there is usually no discrete palpable mass but diffuse changes throughout the breast parenchyma. In 40 patients with inflammatory carcinoma described by Haagensen, erythema and edema of the skin were present in all cases, a palpable mass or localized induration was noted in 19 patients, and no localized tumor was present in 21 patients. Inflammatory cancer also has a rapid onset (less than 3 months) as compared to a similar presentation for locally advanced cancer, which may have been present for years and neglected.

Involvement of the nipple and areola can occur with carcinoma of the breast, especially when the primary tumor is located in the subareolar position. Direct involvement may result in retraction of the nipple. Flattening or inversion of the nipple can be caused by fibrosis in certain benign conditions, especially subareolar duct ectasia. In these cases, the finding is frequently bilateral, and the history confirms that the condition has been present for many years. Unilateral retraction or retraction that develops over weeks or months is more suggestive of carcinoma. Centrally located tumors that go undetected for a long time may directly invade and ulcerate the skin of the areola or nipple. Peripheral tumors may distort the normal symmetry of the nipples by traction on Cooper ligaments.

Paget disease is a condition of the nipple that is commonly associated with an underlying breast cancer. First described by Paget in 1874, Paget disease produces histologically distinct changes within the dermis of the nipple. There is often an underlying intraductal carcinoma in the large sinuses just under the nipple (see Fig. 35.6B ). Carcinoma cells invade across the junction of epidermal and ductal epithelial cells and enter the epidermal layer of the skin of the nipple. Clinically, dermatitis occurs that may appear eczematoid and moist or dry and psoriatic. It begins in the nipple, although it can spread to the skin of the areola. Many benign skin conditions affecting the breast, such as eczema, frequently begin on the areola, whereas Paget disease originates on the nipple and secondarily involves the areola.

Visual inspection should be followed by palpation of the regional lymph nodes and breast tissue. While the patient is still in the sitting position, the examiner supports the patient’s arm and palpates each axilla from a posterior approach to detect the presence of enlarged axillary lymph nodes. The supraclavicular and infraclavicular spaces are similarly palpated for enlarged nodes. Then the patient lies down, and the breast is palpated. Palpation of the breast is always done with the patient lying supine on a solid examining surface, with the arm stretched above the head. Palpation of the breast while the patient is sitting often leads to inaccurate interpretation because the overlapping breast tissue may feel like a mass or a mass may go undetected within the breast tissue. The breast is best examined with compression of the tissue toward the chest wall, with palpation of each quadrant and the tissue under the nipple-areolar complex. Palpable masses are characterized according to their size, shape, consistency, and location and whether they are fixed to the skin or underlying musculature. Benign tumors, such as fibroadenomas and cysts, can be as firm as carcinomas; usually, these benign entities are distinct, well circumscribed, and movable. Carcinoma is typically firm but less circumscribed, and moving a carcinoma produces a drag of adjacent tissue. Cysts and fibrocystic changes can be tender with palpation of the breast; however, tenderness is rarely a helpful diagnostic sign. Most palpable masses are self-discovered by patients during casual or intentional self-examination. Ultrasonography can be used as an extension of your physical exam delineating normal ridges from worrisome masses and cystic from solid (see Ultrasonography section).

Biopsy

Screening Mammography

Screening mammography is performed in asymptomatic women with the goal of detecting occult breast cancer. This approach assumes that breast cancers identified through screening will be smaller, have a better prognosis, and require less aggressive treatment than cancers identified by palpation. The potential benefits of screening are weighed against the cost of screening and the number of false-positive studies that prompt additional workup, biopsies, and patient anxiety.

Eight prospective randomized trials of screening mammography have been performed, with almost 500,000 women participating. In these trials, among women 39 to 49 years old, screening mammography reduced the risk for breast cancer death by 15% (relative risk [RR], 0.85; credible interval [CrI], 0.75–0.96). In the six trials that included women 50 to 59 years old, screening mammography reduced the risk for breast cancer death in this age group by 14% (RR, 0.86; CrI, 0.75–0.99). Two trials included women 60 to 69 years old, and screening mammography reduced the risk for breast cancer death in this age group by 32% (RR, 0.68; CrI, 0.54–0.87). Only one trial included women older than 70 years, and data were insufficient to recommend routine screening in this age group. On the basis of these results, the most recent U.S. Preventive Services Task Force report recommended biennial screening mammography for women 50 to 74 years old and recommended against screening for women 40 to 49 years old or older than 75 years. The recommendations were based on the risk reduction, number of women needed to invite for screening to prevent one breast cancer death, and potential for harm from additional testing and biopsies ( Table 35.1 ).

At the present time, the American Cancer Society continues to recommend annual screening mammography for women older than 40 years and suggests that this practice should continue as long as the woman is in good health. Younger women with a previous breast cancer, significant family history of breast cancer, or histologic risk factors for breast cancer equal to a 20% lifetime risk are recommended for screening with MRI. Although the randomized trials of screening mammography did not enroll women older than 74 years, breast cancer risk increases with age, and the sensitivity and specificity of mammography are highest in older women, whose breast tissue has usually been replaced by fat. It is reasonable to continue mammographic screening in older women who are in good general health who would be considered appropriate candidates for surgery.

Recent advances with breast cancer screening include tomosynthesis (three-dimensional [3D] mammography). Tomosynthesis acquired thin sections of tissue with its main advantage being to separate overlapping breast tissues, decrease callbacks, and find smaller significant disease. The Screening With Tomosynthesis or Standard Mammography-2 (STORM-2) prospective trial compared two-dimensional (2D) and 3D mammography. In this trial, 9672 patients were randomized and showed a significantly higher detection of breast cancer but a slightly higher false positive recall. Tomosynthesis excels in delineating small and multiple masses, microcalcifications, and distortion due to ducts and vessels. The question is whether it should be used for screening in a risk-adjusted manner due to the modest increase in radiation dose to the patient.

Ultrasonography

Ultrasonography is useful in determining whether a lesion detected by mammography is solid or cystic. Ultrasonography can also be useful for discriminating lesions in patients with dense breasts. However, it has not been found to be useful as a breast cancer screening tool because it is highly dependent on the operator performing the freehand screening and there are no standardized screening protocols. The American College of Radiology Imaging Network (ACRIN) performed a trial (ACRIN 6666) in high-risk women in whom mammography and ultrasonography were performed and were randomized in order to compare the sensitivity, specificity, and diagnostic yield of ultrasonography plus mammography compared with mammography alone. The investigators found that the combination of mammography plus ultrasonography resulted in detection of an additional 4.2 cancers per 1000 women. However, the use of ultrasonography resulted in more false-positive events and required more callbacks and biopsies. There are no data available showing that the use of screening ultrasonography can reduce mortality caused by breast cancer. Automated breast ultrasound overcomes some of the issues of free-hand ultrasonography, but randomized trials are forthcoming.

Magnetic Resonance Imaging

MRI is increasingly being used for the evaluation of breast abnormalities. It is useful for identifying the primary tumor in the breast in patients who present with axillary lymph node metastases without mammographic evidence of a primary breast tumor (unknown primary tumor) or in patients with Paget disease of the nipple without radiographic evidence of a primary tumor. MRI may also be useful for assessing the extent of the primary tumor, particularly in young women with dense breast tissue; extent of residual disease after lumpectomy with positive margins; for evaluating for the presence of multifocal or multicentric cancer; for screening of the contralateral breast; and for evaluating invasive lobular cancers. Some surgeons use MRI preoperatively to determine eligibility for breast conservation; however, there are no high-level data showing that use of MRI to guide decision-making about local therapy improves local recurrence rates or survival. Other diagnostic indications include assessment of treatment response after neoadjuvant chemotherapy. It can also be used for assessing implant rupture or assessing the breast when silicone injections have been used.

The sensitivity of MRI is greater than 90% for the detection of invasive cancer but only 60% or less for the detection of DCIS. The specificity of MRI is only moderate as compared to mammography or ultrasound; there is significant overlap in the appearance on MRI of benign and malignant lesions. A meta analysis of 22 studies reporting the detection of contralateral breast cancer by MRI revealed a mean incremental cancer detection rate of 4.1% and a positive predictive value of 47.9%. This high rate of detection may result partly from selection bias; however, it is of significant concern that more than 50% of the abnormalities detected on MRI represented false-positive findings, resulting in the need for additional imaging studies and biopsies.

The Comparative Effectiveness of MRI in Breast Cancer (COMICE) trial was a multicenter trial that recruited 1623 women aged 18 years or older with newly diagnosed breast cancer to assess the clinical efficacy of contrast-enhanced MRI. Patients had standard clinical and radiologic examinations and were randomly assigned to undergo MRI or no further imaging. The primary end point was the proportion of patients undergoing another surgical procedure (reexcision or mastectomy) within 6 months. There was no statistically significant difference in reoperation rates between patients who did or did not undergo MRI. The contralateral breast cancer detection rate in the COMICE trial was 1.6%, significantly lower than that reported in other trials. This trial was criticized because MRI-guided biopsy was not available at all centers to assess suspicious findings identified on MRI. This situation led to numerous mastectomies without pathologic verification that the additional findings were malignancy.

With respect to using MRI for routine screening, the American Cancer Society has recommended a risk-adjusted model. Annual MRI screening is recommended beginning at age 30 years for women at high lifetime risk for breast cancer development (approximately 20%–25% or greater) ( Box 35.1 ). Women at moderately increased lifetime risk (15%–20%) are advised to discuss with their physicians the benefits and limitations of adding MRI screening. MRI is not recommended for women with a lifetime risk of developing breast cancer of less than 15%. When MRI is used for screening, it should be used in addition to screening mammography. Although MRI is more sensitive than mammography, it may still miss some malignancies that a mammogram would detect.

Nonpalpable Mammographic Abnormalities

Mammographic abnormalities that cannot be detected by physical examination include clustered microcalcifications and areas of abnormal density (e.g., masses, architectural distortions, asymmetries) that have not produced a palpable finding ( Fig. 35.7 ). The Breast Imaging Reporting and Data System (BI-RADS) is used to categorize the degree of suspicion of malignancy for a mammographic abnormality ( Table 35.2 ). To avoid unnecessary biopsies for low-suspicion mammographic findings, probably benign lesions are designated BI-RADS 3 and are monitored with 6-month interval mammograms over a 2-year period. Biopsy is performed only for lesions that progress during follow-up. Because 75% to 80% of patients for whom diagnostic biopsy of a nonpalpable mammographic lesion is recommended have benign findings, the less invasive and less costly image-guided CNB approach is preferred whenever feasible.

Image-Localized Surgical Excision of Nonpalpable Breast Lesions

Nonpalpable breast lesions should be assessed with image-guided CNB, as appropriate, according to the type of abnormality. If the diagnosis is not concordant with imaging findings or there is ADH in a field of microcalcifications that may represent DCIS, most patients should proceed to excisional biopsy for definitive diagnosis.

To ensure that the abnormality is completely excised, it should be localized with any of a number of different methods. If visible with ultrasonography, then intraoperative ultrasonography can avoid the preoperative pain, vasovagal events and delays of the old standard needle localization breast biopsy. If a wire is used to localize the lesion, it is placed through an introducer needle and has a hook that engages within the breast parenchyma at or near the abnormality to hold it in position after the introducer is withdrawn. Images with the wire in place are made available in the operating room to guide the surgeon. Depending on the size of the breast and length of the localization wire, the hook may be a long distance from the skin entry site. The surgical excision can be performed directly over the lesion or via a number of oncoplastic techniques for better cosmesis. Depending on the size of the lesion and the degree of suspicion of malignancy, some surgeons will excise shaved margins around the resection cavity to ensure a better chance of complete removal with a negative margin. After excision, a specimen radiography confirms that the targeted lesion has been excised. Patients who have a diagnosis of benign findings on excision should undergo new baseline mammogram 4 to 6 months after the surgical procedure.

Other techniques have been developed to facilitate resection of nonpalpable lesions, including radioactive seed localization, which involves positioning a 4.5-mm ¹²⁵ I seed in the breast tissue, most of which require a second procedure. Radioactive seeds are preloaded into needles that are advanced under mammographic or ultrasound guidance into the lesion of interest, after which the seeds are deployed. Images with the seed in place are made available in the operating room to guide the surgeon. In the operating room, a gamma probe, which detects technetium-99m ( ^99m Tc), commonly used for sentinel lymph node dissection (SLND), and ¹²⁵ I can be used to guide the breast resection. After excision, the specimen is sent for specimen radiography to confirm that the targeted lesion and radioactive seed have been excised. A newer technique, fluoroscopic intraoperative neoplasm or node detection, utilizes fluoroscopy to find the radio-opaque clip placed at the time of the original CNB. It avoids any other procedures while the patient is awake and can be used interactively at the time of surgery.

Risk Factors for Breast Cancer

Identification of factors associated with an increased incidence of breast cancer development is important in general health screening for women ( Box 35.2 ). Risk factors for breast cancer can be divided into seven broad categories—age and gender, personal history of breast cancer, histologic risk factors, family history of breast cancer and genetic risk factors, reproductive risk factors, and exogenous hormone use.

Risk Assessment

A model for assessing breast cancer risk, known as the Gail model , was developed from case-control data in the Breast Cancer Detection Demonstration Project. (This model is available for clinical use at http://www.cancer.gov/bcrisktool .) In developing the model, factors influencing the risk for breast cancer were identified as age, race, age at menarche, age at first live birth, number of previous breast biopsies, presence of proliferative disease with atypia, and number of first-degree female relatives with breast cancer. The model does not include detailed information about genetic factors and may underestimate the risk for BRCA1 or BRCA2 mutation carriers and overestimate the risk for noncarriers. The model should not be used in women with a diagnosis of LCIS or DCIS. The Gail model for breast cancer risk was used in the design of the Breast Cancer Prevention Trial, which randomly assigned women at high risk (>1.67%) to receive tamoxifen or a placebo, and in the design of Study of Tamoxifen and Raloxifene (STAR), which randomly assigned women at high risk to receive tamoxifen or raloxifene.

The Gail model assesses population risk using nongenetic factors, whereas hereditary and familial models assess genetic and familial factors of breast cancer. The Gail model is not accurate for African Americans and a specific model, CARE, was developed. The Claus model is based on assumptions about the prevalence of high-penetrance breast cancer susceptibility genes. The Claus model provides individual estimates of breast cancer risk according to decade of life based on knowledge of first-degree and second-degree relatives with breast cancer and their ages at diagnosis. Many other models have been developed for specific populations, all with similar discriminatory power as compared with the nonspecific traditional models. Mammographic density is associated with high risk for breast cancer. However, models including breast density have only minimal discriminatory power. Other well-known risk factors not included in most if not all risk assessment tools are alcohol consumption, body weight, and physical activity.

Several models have been designed to assess the risk for harboring a mutation in BRCA1 or BRCA2 . These models can be useful in determining whether genetic testing is needed. The Couch model predicts risk for a mutation in the BRCA1 gene. The BRCAPro model, developed by Myriad Genetics Laboratories, estimates the risk of BRCA1 and BRCA2 mutations. The Tyrer-Cuzick model incorporates personal risk factors and genetic analysis to give a more comprehensive and individual risk assessment. Such models have estimated that the incidence of clinically significant BRCA1 or BRCA2 mutations in the general population is approximately 1 in 300 to 500. Indications for consideration of genetic testing include breast cancer diagnosed before age 50, bilateral breast cancer, breast and ovarian cancer in the same individual, and breast cancer in men. Other factors that may be indications for testing are a family history (maternal or paternal) of two or more individuals with breast and ovarian cancer, a close male relative with breast cancer, a close relative with early-onset (<50 years) breast or ovarian cancer, and known BRCA1 or BRCA2 mutation in the family. Online risk calculators are available.

In addition to BRCA1 and 2, there are many other recognized genes and familial syndromes with lesser but significant risk of breast cancer. The development and reduced cost of multiple gene panel testing make screening for these other genes meaningful. These include evaluation for Li-Fraumeni syndrome (TP53 mutation), Cowden syndrome (PTEN mutation), and PALB2, CHEK2, CDH1, STK-11, NF1, and ATM carriers. The American Society of Breast Surgeons developed recommendations for screening and treatment of the lesser-known genes in the Consensus Guidelines on Hereditary Genetic Testing for Patients With and Without Breast Cancer ( https://www.breastsurgeons.org/docs/statements/Consensus-Guideline-on-Genetic-Testing-for-Hereditary-Breast-Cancer.pdf , accessed December 27, 2018). In the process of genetic testing, individuals with Variant of Uncertain Significance will be identified but should not be acted upon.

Care of High-Risk Patients

In practice, clinicians assess risk factors and consider the factors that are important to individual patients in making recommendations about breast cancer screening and prevention. Increased risk for breast cancer is defined as a 5-year calculated risk of 1.66% or higher using the National Cancer Institute (NCI) risk calculator, which is based on the Gail model. This is the average risk for a woman who is 60 years old; it has been used in the design of the U.S. prevention trials. This risk calculator is not applicable to women with a history of invasive breast cancer, DCIS, or LCIS or African-Americans. The model does not make adjustments for a first-degree relative with premenopausal or bilateral breast cancer and does not consider genetic mutations. The clinician must understand that risk may be significantly underestimated if these factors are present, and risk should be calculated within the context of the patient’s overall personal and family history. However, even with these limitations, the Gail model provides a valuable starting point for the evaluation of breast cancer risk assessment. This risk assessment can provide a context for recommendations for primary prevention strategies and screening appropriate to the individual’s risk level. For women found to be at high risk for the development of breast cancer, options include close surveillance with clinical breast examination, mammography, and breast MRI (with a lifetime risk of >20%) and interventions to reduce risk, such as chemoprevention or a bilateral prophylactic mastectomy and/or salpingo-oophorectomy.