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Workup

Approach Considerations

Breast cancer evaluation should be an ordered inquiry that begins with symptoms and a general clinical history. This is followed by a sequence that has become formalized as triple assessment, which includes the following components:

Clinical examination
Imaging (usually mammography, ultrasonography, or both)
Needle biopsy

This approach naturally lends itself to a gradually increasing degree of invasiveness, so that a diagnosis can be obtained with the minimum degree of invasiveness and, consequently, the minimum amount of discomfort to the patient. Because the more invasive investigations also tend to be the most expensive, this approach is usually the most economical.

The aims of evaluation of a breast lesion are to judge whether surgery is required and, if so, to plan the most appropriate surgery. The ultimate goal of surgery is to achieve the most appropriate degree of breast conservation while minimizing the need for reoperation.

Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient or healthcare provider. Mammographic features suggestive of malignancy include asymmetry, microcalcifications, and a mass or architectural distortion. If any of these features are identified, diagnostic mammography along with breast ultrasonography should be performed before a biopsy is obtained. In certain cases, breast magnetic resonance imaging (MRI) may be warranted.

Breast Cancer Screening

Whereas early detection has been advocated as a primary defense against the development of life-threatening breast cancer, questions have been raised regarding the age at which to initiate, the modality to use, the interval between screenings, whether to screen older women, and even the impact on breast cancer−related deaths. It is widely believed that breast tumors that are smaller or nonpalpable and that present with a favorable tumor marker profile are more treatable when detected early.

A survival benefit of early detection with mammography screening has been demonstrated.^{[82, 83]}A review that used seven statistical models determined that the use of screening mammography reduced the rate of death from breast cancer by 28–65% (median, 46%).^[82]A meta-analysis found that screening mammography reduces breast cancer mortality by about 20–35% in women 50–69 years old and slightly less in women 40–49 years old at 14 years of follow-up.^[83]

In the UK Age trial, breast cancer mortality in the first 10 years after diagnosis was significantly lower (rate ratio [RR] 0.75) in women who received annual screening mammography from age 40-49 years than in those invited for screening at age 50 years and every 3 years thereafter. During the remainder of the 17-year follow-up period, however, reduction in breast cancer mortality was not evident (RR 1.02).^[84]

In contrast, 25-year follow-up of 89,835 women in the Canadian National Breast Screening Study found that annual mammography in women aged 40-59 did not reduce mortality from breast cancer beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available. Findings for women aged 40-49 and 50-59 were almost identical. Moreover, 22% (106/484) of invasive breast cancers detected by screening mammography were over-diagnosed, representing one over-diagnosed breast cancer for every 424 women who received mammography screening in the trial.^[85]

A large-scale, population-based, observational study by García-Albéniz et al concluded that continuing annual breast cancer screening past age 75 years did not result in substantial reductions in 8-year breast cancer mortality compared with stopping screening. The study used data from 1,058,013 women enrolled in Medicare across the United States during 2000-2008.^[86]

In women aged 70 to 74 years, continued screening resulted in a slightly reduced 8-year rate of breast cancer death: 2.7 deaths per 1,000 women, compared with 3.7 for those who stopped screening. In those aged 75 to 84 years, comparable figures were 3.8 versus 3.7 deaths per 1,000 women (hazard ratio, 1.00 [CI, 0.83 to 1.19]).^[86]Although breast cancer was diagnosed more often in women who continued screening, that did not translate to a significant reduction in deaths because breast cancer is less successful treatment in older women.^[87]

A number of screening modalities exist for breast cancer, including clinical breast examination, mammography, ultrasonography, and MRI. (See Breast Cancer Screening.)

Mammography

Mammography is a low-dose x-ray–based modality used to image the breast. It is currently the best available population-based method for detecting breast cancer at an early stage.^{[83, 88, 89]}

Mammography is used both for screening to detect a cancer and for diagnostic workup of patients after a tumor is detected. Screening mammography is performed in asymptomatic women, whereas diagnostic mammography is performed in symptomatic women (ie, when a breast lump or nipple discharge is present or when an abnormality is found during screening mammography).

Mammography is sensitive to microcalcifications that develop in breast tumors with sensitivity at less than 100 µm. Mammography often detects a lesion before it is palpable by clinical breast examination and, on average, 1 to 2 years before noted by breast self-examination.

Advances in mammography include the development of digital mammography and the increased use of computer-aided diagnosis (CAD) systems.^[90]CAD systems have been developed to help the radiologist identify mammographic abnormalities.

Digital mammography allows the image to be recorded and stored. With computer technology, digital mammogram images can be magnified and the image modified to improve evaluation of specific areas in question. Digital images can be transmitted electronically, decreasing the time to second opinion without the risk of losing the film.

In a cohort study of women aged 50-74 years, which used data from the Ontario Breast Screening Program, computed radiography (CR) was 21% less effective than digital direct radiography (DR) for breast cancer detection; however, DR was equivalent to screen-film mammography (SFM).^[91]

The US Preventive Services Task Force (USPSTF) reports that reduction in breast cancer mortality due to screening mammography varies with patient age. With screening mammography, relative risk (RR) of breast cancer mortality was 0.92 for women aged 39 to 49 years, 0.86 for those aged 50 to 59 years, 0.67 for those aged 60 to 69 years, and 0.80 for those aged 70 to 74 years. Risk of advanced breast cancer was reduced for women aged 50 years or older (RR 0.62) but not those aged 39 to 49 years (RR 0.98).^[92]

Screening mammography

Although mammography guidelines have been in place for more than 30 years, 20-30% of women still do not undergo screening as indicated. The 2 most significant factors governing a woman’s decision to undergo mammography are physician recommendation and access to health insurance. Nonwhite women and those of lower socioeconomic status remain less likely to obtain mammography services and more likely to present with life-threatening, advanced-stage disease.^{[93, 94]}

At present, the most widely accepted recommendations in the United States come from the American Cancer Society (ACS). In October 2015, the ACS updated its guidelines, which had previously recommended annual screening mammography, beginning at age 40 years for all women and continuing for as long as a woman is in good health, along with clinical breast examinations about every 3 years for women in their 20s and 30s and every year for women 40 and over, with monthly breast self-examination as an option for women starting in their 20s.^{[95, 96]}

The 2015 ACS recommendations for women at average risk of breast cancer are as follows^[96]:

Women should have the opportunity to begin annual screening at 40-44 years of age (qualified recommendation)
Women should begin regular screening mammography at age 45 years (strong recommendation)
Women aged 45-54 years should be screened annually (qualified recommendation)
Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation)
Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation)
Clinical breast examination is not recommended for breast cancer screening in average-risk women at any age

Since 2009 the USPSTF has recommended biennial screening mammography for women aged 50-74 years (grade B recommendation). The USPSTF has recommended against routine screening mammography in women aged 40-49 years because of high rates of false-negative findings, perceived harm of unnecessary biopsy, and concern for the harm associated with overdiagnosis and overtreatment (grade C recommendation). For women 40-49 years old, the USPSTF has recommended that clinicians provide screening to selected patients, depending on individual circumstances and patient preferences.^[94]

In May 2023, however, the USPTF issued a draft recommendation that all women get screened for breast cancer every other year starting at age 40 (Grade B recommendation).^[97]Lowering of the age for starting screening was prompted by the increase in breast cancer rates in women 40 to 49 years old during the past decade.

Finally, the USPSTF recommends against teaching breast self-examination and concludes that the current evidence is insufficient to assess the benefits and harms of clinical breast examination in women aged 40 years or older or the benefits and harms of screening mammography in women aged 75 years or older.

Similarly, a 2019 review by the American College of Physicians (ACP) provides the following guidance statements regarding screening of asymptomatic women at average risk and in good health^[98]:

Women 40-49 years of age: Discuss benefits and harms of screening mammography (potential harms outweigh the benefits in most cases).
Women 50-74 years of age: Offer biennial mammography.
Discontinue screening in women ≥75 years of age and in those with a life expectancy of ≤10 years.
Do not use clinical breast examination to screen for breast cancer in women of any age.

Tomosynthesis (3D mammography) has gained a role in breast cancer screening. American College of Radiology (ACR) considers tomosynthesis indicated in woman at low, intermediate, and high risk of breast cancer, and notes that compared with 2D mammography alone, tomosynthesis results in higher cancer detection rates and lower rates of recall for benign findings, and that these advantages may be especially pronounced in women under age 50, and those with dense breasts or certain lesion types (eg, spiculated masses, asymmetries).^[99]

A retrospective review of breast cancer screening in 385,503 women that included 542,945 tomosynthesis screens and 261,359 digital mammography screens demonstrated that in nearly all age groups and races, tomosynthesis is associated with improved patient screening metrics, compared with digital mammography: lower recall rates, higher cancer detection rates, and improved positive predictive value for recall.^[100]

National Comprehensive Cancer Network (NCCN) guidelines recommend considering tomosynthesis as part of screening, although the NCCN notes that studies have yet to determine whether tomosynthesis improves breast cancer–specific mortality.^[101]

In the Screening with Tomosynthesis Or standard Mammography-2 (STORM-2) study—a prospective population-based screening study in 9672 women that compared integrated 3D mammography with 2D mammography—3D mammography detected more cases of breast cancer than 2D mammography but increased the percentage of false-positive recalls in sequential screen-reading.^[102]Thus, the benefit of significantly increased breast cancer detection with tomosynthesis screening must be weighed against the possible risk of overdiagnosis.

For more discussion of tomosynthesis, see Mammography in Breast Cancer.

For women whose mammogram reveals dense breast tissue, 21 US states have laws requiring that the woman be notified and be advised to discuss supplemental imaging with her provider. However, a prospective cohort study found that only a minority of women with dense breasts have high interval cancer rates. Kerlikowske et al reported that women at high risk can be identified by combining 5-year breast cancer risk, as determined with the Breast Cancer Surveillance Consortium (BCSC) risk calculator, with breast density as categorized with the Breast Imaging Reporting and Data System (BI-RADS). High interval cancer rates were observed for women with a 5-year BCSC risk of 1.67% or greater and extremely dense breasts or a 5-year risk of 2.50% or greater and heterogeneously dense breasts. However, study participants who met those criteria accounted for only 24% of all women with dense breasts.^[103]

Ultrasonography

Ultrasonography has become a widely available and useful adjunct to mammography in the clinical setting. Originally, ultrasonography was used primarily as a relatively inexpensive and effective method of differentiating cystic breast masses, which did not require sampling, from solid breast masses, which were usually examined with biopsy; in many cases, the results of these biopsies were benign. However, it is now well established that ultrasonography also provides valuable information about the nature and extent of solid masses and other breast lesions and can often provide useful information regarding the staging of the axilla.

An American College of Radiology practice parameter lists the following as appropriate indications for diagnostic sonography of the breast and axilla^[104]:

Evaluation and characterization of palpable masses and other breast-related signs and/or symptoms
Evaluation of suspected or apparent abnormalities detected on mammography (with or without digital breast tomosynthesis), breast MRI, or other imaging modalities
Initial imaging evaluation of palpable breast masses in patients under 30 years of age who are not at high risk for development of breast cancer
Evaluation of symptoms in lactating and pregnant patients
Evaluation of problems associated with breast implants
Guidance for biopsy and other interventional procedures for breast and axilla
Treatment planning for radiation therapy
Identification of abnormal axillary lymph node(s) in patients with newly diagnosed or recurrent breast cancer, or in patients with findings highly suggestive of malignancy or palpable findings in the axilla

In a systematic review and meta-analysis by Sood et al, data from low- and middle-income countries showed that ultrasound had a diagnostic sensitivity of 89.2% and specificity of 99.1% for detection of breast cancer. These authors concluded that ultrasound has potential use as a primary detection tool for breast cancer in low-resource settings where mammography is unavailable.^[105]

Magnetic Resonance Imaging

The principal indications for MRI of the breast are screening for breast cancer in women at increased risk, staging of known cancer, and evaluation of response to neoadjuvant chemotherapy. Breast MRI is based on T1-weighted contrast-enhanced imaging, but multiparametric assessment, including T2-weighted, ultrafast, and diffusion-weighted imaging, may be used to improve the characterization of lesions.^[106]

MRI is used in conjunction with mammography for breast cancer screening in women at increased risk.^{[101, 107]}For example, guidelines from the American College of Radiology (ACR) recommend supplemental screening with contrast-enhanced breast MRI for women with the following risk factors^[108]:

Genetic predisposition
Calculated lifetime breast cancer risk of 20% or more
History of chest or mantle radiation therapy at a young age
Personal history of breast cancer and dense tissue or diagnosis by age 50

The ACR also recommends consideration of additional surveillance with MRI in women with histories of breast cancer and those with atypia at biopsy, especially if other risk factors are present.

However, in an observational study by Buist et al that included more than 2 million screenings in over 800,000 women, MRI screening for breast cancer was associated with higher rates of subsequent biopsy but a lower yield of cancer findings. In women with a breast cancer history, biopsy rates were more than twofold higher after MRI than after mammography alone; in women with no history of breast cancer, biopsy rates were more than fivefold higher.^[109]

In women with a past history of breast cancer, ductal carcinoma in situ or invasive disease was found in 404.6 per 1000 biopsies following mammography versus 267.7 per 1000 biopsies following MRI, a significant difference. Yield was nonsignificantly higher after mammography in women without a history of breast cancer: 279.3 versus 214.6 per 1000, respectively.^[109]

Breast MRI may be performed when breast cancer is suspected but other imaging studies have yielded equivocal results.^[107]In a study of 1441 women with dense breasts who underwent screening, abbreviated breast MRI was associated with a significantly higher rate of invasive breast cancer detection compared with digital breast tomosynthesis.^[110]

For more information, see Magnetic Resonance Mammography.

Nuclear Imaging

The following 3 radiotracers are commonly used for breast imaging or scintimammography in either clinical practice or research:

Technetium-99m ( ^99mTc)-sestamibi (for myocardial perfusion imaging); this was the first radiopharmaceutical agent to be approved by the US Food and Drug Administration (FDA) for use in scintimammography ^[111]
^99mTc-tetrofosmin (also for myocardial perfusion imaging)
^99mTc-methylene diphosphonate (MDP; for bone scintigraphy)

Scintimammography is not indicated as a screening procedure for the detection of breast cancer. However, it may play a role in various specific clinical indications, as in cases of nondiagnostic or difficult mammography and in the evaluation of high-risk patients, tumor response to chemotherapy, and metastatic involvement of axillary lymph nodes.

In several prospective studies, overall sensitivity of^99mTc-sestamibi scintimammography in the detection of breast cancer was 85%, specificity was 89%, and positive and negative predictive values were 89% and 84%, respectively. Similar numbers have been demonstrated for ^99mTc-tetrofosmin and^99mTc-MDP scintimammography.^[4]

Positron Emission Tomography

Using a wide range of labeled metabolites (eg, fluorinated glucose [¹⁸ FDG]), positron emission tomography (PET) can detect changes in metabolic activity, vascularization, oxygen consumption, and tumor receptor status.

When PET is combined with computed tomography (CT) to assist in anatomic localization (PET-CT), scans can identify axillary and nonaxillary (eg, internal mammary or supraclavicular) lymph node metastasis for the purposes of staging locally advanced and inflammatory breast cancer before initiation of neoadjuvant therapy and restaging high-risk patients for local or distant recurrences.

Accuracy of Breast Imaging Modalities

The different techniques used in breast imaging vary with respect to sensitivity, specificity, and positive predictive value (see Table 1 below).

Table 1. Accuracy of Breast Imaging Modalities (Open Table in a new window)

Modality	Sensitivity	Specificity	PPV	Indications
Mammography	63-95% (>95% palpable, 50% impalpable, 83-92% in women older than 50 y; decreases to 35% in dense breasts)	14-90% (90% palpable)	10-50% (94% palpable)	Initial investigation for symptomatic breast in women older than 35 y and for screening; investigation of choice for microcalcification
Ultrasonography	68-97% palpable	74-94% palpable	92% (palpable)	Initial investigation for palpable lesions in women younger than 35 y
MRI	86-100%	21-97% (< 40% primary cancer)	52%	Scarred breast, implants, multifocal lesions, and borderline lesions for breast conservation; may be useful in screening high-risk women
Scintigraphy	76-95% palpable, 52-91% impalpable	62-94% (94% impalpable)	70-83% (83% palpable, 79% impalpable)	Lesions >1 cm and axilla assessment; may help predict drug resistance
PET	96% (90% axillary metastases)	100%		Axilla assessment, scarred breast, and multifocal lesions
MRI = magnetic resonance imaging; PET = positron emission tomography; PPV = positive predictive value.

Breast Biopsy

Percutaneous vacuum-assisted large-gauge core-needle biopsy (VACNB) with image guidance is the recommended diagnostic approach for newly diagnosed breast tumors. Core biopsies can minimize the need for operative intervention (and subsequent scarring, and provide accurate pathologic diagnosis for appropriate management.

Excisional biopsy, as the initial operative approach, has been shown to increase the rate of positive margins. Open excisional biopsy is reserved for lesions where the diagnosis remains equivocal despite imaging and core biopsy assessment or for benign lesions that the patient chooses to have removed. Because wide clearance of the lesion is usually not the goal in diagnostic biopsies, unnecessary distortion of the breast is thereby avoided. Ongoing audit is essential to help reduce an excessive benign-to-malignant biopsy ratio.

Histology

Breast cancers usually are epithelial tumors of ductal or lobular origin. For full discussion, see Breast Cancer Histology.

All of the following features are important in deciding on a course of treatment for any breast tumor:

Size
Status of surgical margin
Presence or absence of estrogen receptor (ER) and progesterone receptor (PR)
Nuclear and histologic grade
Proliferation
Vascular invasion
Tumor necrosis
Quantity of intraductal component
HER2 status

On the basis of ER and PR (hormone receptor) and HER2 results, breast cancer is classified as one of the following types^[1]:

Hormone receptor positive
HER2 positive
Triple negative (ER, PR, and HER2 negative)

That classification helps guide the selection of drug regimens.

Histologic grade

Histologic grade is the best predictor of disease prognosis in carcinoma in situ, but it is dependent on the grading system used, such as the Van Nuys classification (high-grade, low-grade comedo, low-grade noncomedo). The grading of invasive carcinoma is also important as a prognostic indicator, with higher grades indicating a worse prognosis (see Table 2 below).

Table 2. Grading System in Invasive Breast Cancer (Modified Bloom and Richardson) (Open Table in a new window)

	Score
	1	> 2	> 3
A. Tubule formation	>75%	10-75%	< 10%
B. Mitotic count/HPF (microscope- and field-dependent)	< 7	7-12	>12
C. Nuclear size and pleomorphism	Near normal; little variation	Slightly enlarged; moderate variation	Markedly enlarged; marked variation
Grade I cancer if total score (A + B + C) is 3-5
Grade II cancer if total score (A + B + C) is 6 or 7
Grade III cancer if total score (A + B + C) is 8 or 9
HPF = high-power field.

Ductal carcinoma in situ

Increased use of screening mammography has resulted in a dramatic increase in the detection of ductal carcinoma in situ (DCIS). Approximately 64,000 cases of DCIS are diagnosed annually in the United States. About 90% of DCIS cases are identified on mammography as suspicious calcifications: linear, clustered, segmental, focal, or mixed distribution.

DCIS is broadly divided into 2 subtypes: comedo (ie, cribriform, micropapillary, and solid; see the first image below) and noncomedo (see the second image below). The likelihood of progression or local recurrence, as well as the prognosis, varies in accordance with the DCIS subtype present (see Table 3 below).

Breast cancer. Intraductal carcinoma, comedo type. Distended duct with intact basement membrane and central tumor necrosis.

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Breast cancer. Intraductal carcinoma, noncomedo type. Distended duct with intact basement membrane, micropapillary, and early cribriform growth pattern.

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Table 3. Ductal Carcinoma in Situ Subtypes (Open Table in a new window)

DCIS Characteristic	Comedo	Noncomedo
Nuclear grade	High	Low
Estrogen receptor	Often negative	Positive
Distribution	Continuous	Multifocal
Necrosis	Present	Absent
Local recurrence	High	Low
Prognosis	Worse	Better
DCIS = ductal carcinoma in situ.

Lobular carcinoma in situ

Lobular carcinoma in situ (LCIS) arises from the terminal duct apparatus and shows a rather diffuse distribution throughout the breast, which explains its presentation as a nonpalpable mass in most cases (see the images below). Over the past 25 years, the incidence of LCIS has doubled, currently standing at 2.8 per 100,000 women. The peak incidence is in women aged 40-50 years.

Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.

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Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.

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Infiltrating ductal carcinoma

Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor (accounting for 75% of breast cancers) and has a tendency to metastasize via lymphatic vessels. This lesion has no specific histologic characteristics other than invasion through the basement membrane (see the image below). DCIS is a frequently associated finding on pathologic examination.

Breast cancer. Infiltrating ductal carcinoma. Low-grade carcinoma with well-developed glands invading fibrous stroma.

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Infiltrating lobular carcinoma

Infiltrating lobular carcinoma has a much lower incidence than infiltrating ductal carcinoma, accounting for 15-20% of invasive breast cancers. Histologically, it is characterized by the "single-file" arrangement of small tumor cells. Like ductal carcinoma, infiltrating lobular carcinoma typically metastasizes to axillary lymph nodes first. However, it also has a tendency to be multifocal and have discontinuous areas of involvement, making mammographic and even MRI staging imprecise.

Medullary carcinoma

Medullary carcinoma is relatively uncommon (5%) and generally occurs in younger women. Most patients present with a bulky palpable mass and axillary lymphadenopathy. Diagnosis of this type of breast cancer depends on the following histologic triad:

Sheets of anaplastic tumor cells with scant stroma
Moderate or marked stromal lymphoid infiltrate
Histologic circumscription or a pushing border

DCIS may be observed in the surrounding normal tissues. Medullary carcinomas are typically high-grade lesions that are negative for ER, PR, and HER2 and that commonly demonstrate mutation of TP53.

Mucinous carcinoma

Mucinous (colloid) carcinoma is another rare histologic type, seen in fewer than 5% of invasive breast cancer cases. It usually presents during the seventh decade of life as a palpable mass or appears mammographically as a poorly defined tumor with rare calcifications.

Mucin production is the histologic hallmark. There are 2 main types of lesions, A and B, with AB lesions possessing features of both. Type A mucinous carcinoma represents the classic variety, with larger quantities of extracellular mucin (see the image below), whereas type B is a distinct variant with endocrine differentiation.

Breast cancer. Colloid (mucinous) carcinoma. Nests of tumor cells in pool of extracellular mucin.

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DCIS is not a frequent occurrence in this setting, though it may be found. Most cases are ER- and PR-positive, but HER2 overexpression is rare. Additionally, these carcinomas predominantly express glycoproteins MUC2 and MUC6.

Tubular carcinoma

Tubular carcinoma of the breast is an uncommon histologic type, accounting for only 1-2% of all breast cancers. Characteristic features of this type include a single layer of epithelial cells with low-grade nuclei and apical cytoplasmic snoutings arranged in well-formed tubules and glands.

Tubular components make up more than 90% of pure tubular carcinomas and at least 75% of mixed tubular carcinomas. This type of breast cancer has a low incidence of lymph node involvement and a very high overall survival rate. Because of its favorable prognosis, patients are often treated with only breast-conserving surgery and local radiation therapy.

Papillary carcinoma

Papillary carcinoma of the breast (see the image below) encompasses a spectrum of histologic subtypes. There are 2 common types: cystic (noninvasive form) and micropapillary ductal carcinoma (invasive form). This form of breast cancer is usually seen in women older than 60 years and accounts for approximately 1-2% of all breast cancers. Papillary carcinomas are centrally located in the breast and can present as bloody nipple discharge. They are strongly ER- and PR-positive.

Breast cancer. Papillary carcinoma. Solid papillary growth pattern with early cribriform and well-developed thin papillary fronds.

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Cystic papillary carcinoma has a low mitotic activity, which results in a more indolent course and a good prognosis. However, invasive micropapillary ductal carcinoma has a more aggressive phenotype similar to that of infiltrating ductal carcinoma, even though about 70% of cases are ER-positive. A retrospective review of 1400 cases of invasive carcinoma identified 83 cases (6%) with at least 1 component of invasive micropapillary ductal carcinoma. Additionally, lymph node metastasis is seen frequently in this subtype (70-90% of cases).^[112]

Metaplastic breast cancer

Metaplastic breast cancer (MBC) accounts for fewer than 1% of breast cancer cases. It tends to occur in older women (average age of onset in the sixth decade) and has a higher incidence in Black women. It is characterized by a combination of adenocarcinoma plus mesenchymal and epithelial components.

A wide variety of histologic patterns includes the following:

Spindle-cell carcinoma
Carcinosarcoma
Squamous cell carcinoma of ductal origin
Adenosquamous carcinoma
Carcinoma with pseudosarcomatous metaplasia
Matrix-producing carcinoma

This diverse group of malignancies is identified as a single entity on the basis of a similarity in clinical behavior. Compared with infiltrating ductal carcinoma, MBC tumors are larger, faster-growing, commonly node-negative, and typically negative for ER, PR, and HER2.

Mammary Paget disease

Mammary Paget disease is relatively rare, accounting for 1-4% of all breast cancers. The peak incidence is seen in the sixth decade of life. This adenocarcinoma is localized within the epidermis of the nipple-areola complex and is composed of the histologic hallmark Paget cells within the basement membrane. Paget cells are large, pale epithelial cells with hyperchromatic, atypical nuclei, dispersed between the keratinocytes singly or as a cluster of cells.

Lesions are predominantly unilateral, developing insidiously as a scaly, fissured, oozing, or erythematous nipple-areola complex. Retraction or ulceration of the nipple is often noted, along with symptoms of itching, tingling, burning, or pain. In situ or invasive breast cancer is found in approximately 85% of patients with Paget disease. Thus, all diagnosed patients require a careful breast examination and mammographic evaluation, with additional imaging, including breast MRI, if the mammogram is negative.

Breast Cancer Staging

The American Joint Committee on Cancer (AJCC) provides two principal groups for breast cancer staging: anatomic, which is based on extent of cancer as defined by tumor size (T), lymph node status (N), and distant metastasis (M); and prognostic, which includes anatomic TNM plus tumor grade and the status of the biomarkers human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR). The prognostic stage group is preferred for patient care and is to be used for reporting of all cancer patients in the United States.^[113]

In turn, prognostic stages are divided into clinical and pathological groups. Pathological stage applies to patients who have undergone surgery as the initial treatment for breast cancer. It includes all information used for clinical staging plus findings at surgery and pathological findings from surgical resection. Pathological prognostic stage does not apply to patients who received neoadjuvant therapy (systemic agents or radiation prior to surgical resection).^[72]

See the tables below.

Table 4. TNM Classification for Breast Cancer (Open Table in a new window)

Primary tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ
Tis (DCIS)	Ductal carcinoma in situ
Tis (Paget)	Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized on the basis of the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted
T1	Tumor ≤ 20 mm in greatest dimension
T1mi	Tumor ≤ 1 mm in greatest dimension
T1a	Tumor > 1 mm but ≤ 5 mm in greatest dimension (round any measurement >1.0-1.9 mm to 2 mm)
T1b	Tumor > 5 mm but ≤ 10 mm in greatest dimension
T1c	Tumor > 10 mm but ≤ 20 mm in greatest dimension
T2	Tumor > 20 mm but ≤ 50 mm in greatest dimension
T3	Tumor > 50 mm in greatest dimension
T4	Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules), not including invasion of dermis alone
T4a	Extension to chest wall, not including only pectoralis muscle adherence/invasion
T4b	Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d’orange) of the skin, which do not meet the criteria for inflammatory carcinoma
T4c	Both T4a and T4b
T4d	Inflammatory carcinoma
Regional lymph nodes (N)
Clinical
cNX	Regional lymph nodes cannot be assessed (eg, previously removed)
cN0	No regional lymph node metastasis (on imaging or clinical examination)
cN1	Metastasis to movable ipsilateral level I, II axillary lymph node(s)
cN1mi	Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)
cN2	Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases
cN2a	Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures
cN2b	Metastases only in ipsilateral internal mammary nodes and in the absence of axillary lymph node metastases
cN3	Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s), with or without level I, II axillary node involvement, or in ipsilateral internal mammary lymph node(s) with level I, II axillary lymph node metastasis; or metastases in ipsilateral supraclavicular lymph node(s), with or without axillary or internal mammary lymph node involvement
cN3a	Metastasis in ipsilateral infraclavicular lymph node(s)
cN3b	Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
cN3c	Metastasis in ipsilateral supraclavicular lymph node(s)
Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine needle aspiration/core needle biopsy, respectively.
Pathologic (pN)
pNX	Regional lymph nodes cannot be assessed (for example, previously removed, or not removed for pathologic study)
pN0	No regional lymph node metastasis identified histologically, or isolated tumor cell clusters (ITCs) only. Note: ITCs are defined as small clusters of cells ≤ 0.2 mm, or single tumor cells, or a cluster of < 200 cells in a single histologic cross-section; ITCs may be detected by routine histology or by immunohistochemical (IHC) methods; nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated
pN0(i)	No regional lymph node metastases histologically, negative IHC
pN0(i+)	ITCs only in regional lymph node(s)
pN0(mol-)	No regional lymph node metastases histologically, negative molecular findings (reverse transcriptase polymerase chain reaction [RT-PCR])
pN0(mol+)	Positive molecular findings by RT-PCR; no ITCs detected
pN1	Micrometastases; or metastases in 1-3 axillary lymph nodes and/or in internal mammary nodes; and/or in clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsy
pN1mi	Micrometastases (200 cells, > 0.2 mm but none > 2.0 mm)
pN1a	Metastases in 1-3 axillary lymph nodes (at least 1 metastasis > 2.0 mm)
pN1b	Metastases in ipsilateral internal mammary lymph nodes, excluding ITCs, detected by sentinel lymph node biopsy
pN1c	Metastases in 1-3 axillary lymph nodes and in internal mammary sentinel nodes (ie, pN1a and pN1b combined)
pN2	Metastases in 4-9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases
pN2a	Metastases in 4-9 axillary lymph nodes (at least 1 tumor deposit > 2.0 mm)
pN2b	Clinically detected* metastases in internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary lymph nodes
pN3	Metastases in ≥ 10 axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive level I, II axillary lymph nodes; or in > 3 axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes
pN3a	Metastases in ≥ 10 axillary lymph nodes (at least 1 tumor deposit > 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes
pN3b	pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging) or pN2a in the presence of pN1b
pN3c	Metastases in ipsilateral supraclavicular lymph nodes
*"Clinically detected" is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis on the basis of FNA biopsy with cytologic examination.
Distant metastasis (M)
M0	No clinical or radiographic evidence of distant metastasis
cM0(i+)	No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits no larger than 0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastase
cM1	Distant metastases detected by clinical and radiographic means
pM1	Any histologically proven metastases in distant organs; or if in non-regional nodes, metastases > 0.2 mm

Table 5. Histologic grade (Open Table in a new window)

Histologic grade (G)
GX	Grade cannot be assessed
G1	Low combined histologic grade (favorable)
G2	Intermediate combined histologic grade (moderately favorable)
G3	High combined histologic grade (unfavorable)

Table 6. Anatomic stage/prognostic groups (Open Table in a new window)

Stage	T	N	M
0	Tis	N0	M0
IA	T1	N0	M0
IB	T0	N1mi	M0
	T1	N1mi	M0
IIA	T0	N1	M0
	T1	N1	M0
	T2	N0	M0
IIB	T2	N1	M0
	T3	N0	M0
IIIA	T0	N2	M0
	T1	N2	M0
	T2	N2	M0
	T3	N1	M0
	T3	N2	M0
IIIB	T4	N0	M0
	T4	N1	M0
	T4	N2	M0
IIIC	Any T	N3	M0
IV	Any T	Any N	M1

Notes:

T1 includes T1mi.
T0 and T1 tumors with nodal micrometastases (N1mi) are staged as Stage IB.
T2, T3, and T4 tumors with nodal micrometastases (N1mi) are staged using the N1 category.
M0 includes M0(i+)
The designation pM0 is not valid; any M0 is clinical.
If a patient presents with M1 disease prior to neoadjuvant systemic therapy, the stage is considered stage IV and remains stage IV regardless of response to neoadjuvant therapy.
Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided the studies are performed within 4 months of diagnosis in the absence of disease progression, and provided the patient has not received neoadjuvant therapy.
Staging following neoadjuvant therapy is designated with “yc” or “yp” prefix to the T and N classification. No anatomic stage group is assigned if there is a complete pathologic response (pCR) to neoadjuvant therapy, for example, ypT0ypN0cM0.

Table 7. Clinical prognostic stage (Open Table in a new window)

TNM	Grade	HER2	ER	PR	Stage
Tis N0 M0	Any	Any	Any	Any	0
T1 N0 M0 T0 N1mi M0 T1 N1mi M0	G1	Positive	Positive	Positive	IA
				Negative
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative
			Negative	Positive
				Negative	IB
	G2	Positive	Positive	Positive	IA
				Negative
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative
			Negative	Positive
				Negative	IB
	G3	Positive	Positive	Positive	IA
				Negative
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative	IB
			Negative	Positive
				Negative
T0 N1 M0 T1 N1 M0 T2 N0 M0	G1	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive
				Negative
		Negative	Positive	Positive	IB
				Negative	IIA
			Negative	Positive
				Negative
	G2	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive
				Negative
		Negative	Positive	Positive	IB
				Negative	IIA
			Negative	Positive
				Negative	IIB
	G3	Positive	Positive	Positive	IB IIA
				Negative
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative	IIB
			Negative	Positive
				Negative
T2 N1 M0 T3 N0 M0	G1	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive
				Negative	IIB
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive
				Negative
	G2	Positive	Positive	Positive	IB
				Negative	IIA
			Negative	Positive
				Negative	IIB
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive
				Negative	IIIB
	G3	Positive	Positive	Positive	IB
				Negative	IIB
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative	IIIA
			Negative	Positive
				Negative	IIIB
T0 N2 M0 T1 N2 M0 T2 N2 M0 T3 N1 M0 T3 N2 M0	G1	Positive	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive
				Negative
		Negative	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive
				Negative	IIIB
	G2	Positive	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive
				Negative
		Negative	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive
				Negative	IIIB
	G3	Positive	Positive	Positive	IIB
				Negative	IIIA
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative	IIIB
			Negative	Positive
				Negative	IIIC
T4 N0 M0 T4 N1 M0 T4 N2 M0 Any T N3 M0	G1	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative
			Negative	Positive
				Negative	IIIC
	G2	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative
			Negative	Positive
				Negative	IIIC
	G3	Positive	Positive	Positive	IIIB
				Negative
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative	IIIC
			Negative	Positive
				Negative
Any T Any N M1	Any	Any	Any	Any	IV
ER=estrogen receptor; PR=progesterone receptor

Table 8. Pathological prognostic stage (Open Table in a new window)

TNM	Grade	HER2	ER	PR	Stage
Tis N0 M0	Any	Any	Any	Any	0
T1 N0 M0 T0 N1mi M0 T1 N1mi M0	G1	Positive	Positive	Positive	IA
				Negative
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative
			Negative	Positive
				Negative
	G2	Positive	Positive	Positive
				Negative
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative
			Negative	Positive
				Negative	IB
	G3	Positive	Positive	Positive	IA
				Negative
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative
			Negative	Positive
				Negative	IB
T0 N1 M0 T1 N1 M0 T2 N0 M0	G1	Positive	Positive	Positive	IA
				Negative	IB
			Negative	Positive
				Negative	IIA
		Negative	Positive	Positive	IA
				Negative	IB
			Negative	Positive
				Negative	IIA
	G2	Positive	Positive	Positive	IA
				Negative	IB
			Negative	Positive
				Negative	IIA
		Negative	Positive	Positive	IA
				Negative	IIA
			Negative	Positive
				Negative
	G3	Positive	Positive	Positive	IA IIA
				Negative
			Negative	Positive
				Negative
		Negative	Positive	Positive	IB
				Negative	IIA
			Negative	Positive
				Negative
T2 N1 M0 T3 N0 M0	G1	Positive	Positive	Positive	IA
				Negative	IIB
			Negative	Positive
				Negative
		Negative	Positive	Positive	IA
				Negative	IIB
			Negative	Positive
				Negative
	G2	Positive	Positive	Positive	IB
				Negative	IIB
			Negative	Positive
				Negative
		Negative	Positive	Positive	IB
				Negative	IIB
			Negative	Positive
				Negative
	G3	Positive	Positive	Positive	IB
				Negative	IIB
			Negative	Positive
				Negative
		Negative	Positive	Positive	IIA
				Negative	IIB
			Negative	Positive
				Negative	IIIA
T0 N2 M0 T1 N2 M0 T2 N2 M0 T3 N1 M0 T3 N2 M0	G1	Positive	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive
				Negative
		Negative	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive
				Negative
	G2	Positive	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive
				Negative
		Negative	Positive	Positive	IB
				Negative	IIIA
			Negative	Positive
				Negative	IIIB
	G3	Positive	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive
				Negative
		Negative	Positive	Positive	IIA
				Negative	IIIA
			Negative	Positive
				Negative	IIIC
T4 N0 M0 T4 N1 M0 T4 N2 M0 Any T N3 M0	G1	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive
				Negative
		Negative	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive
				Negative
	G2	Positive	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive
				Negative
		Negative	Positive	Positive	IIIA
				Negative	IIIB
			Negative	Positive
				Negative	IIIC
	G3	Positive	Positive	Positive	IIIB
				Negative
			Negative	Positive
				Negative
		Negative	Positive	Positive
				Negative	IIIC
			Negative	Positive
				Negative
Any T Any N M1	Any	Any	Any	Any	IV
ER=estrogen receptor; PR=progesterone receptor

Lymph node assessment

Evaluation of lymph node involvement by means of sentinel lymph node biopsy or axillary lymph node dissection (ALND) has also been considered necessary for staging and prognosis.

A 2014 update on sentinel lymph node biopsy for patients with early-stage breast cancer by the American Society of Clinical Oncology (ASCO) advises that sentinel lymph node biopsy may be offered to the following patients^[114]:

Women with operable breast cancer and multicentric tumors
Women with DCIS who will be undergoing mastectomy
Women who previously underwent breast and/or axillary surgery
Women who received preoperative/neoadjuvant systemic therapy

According to the ASCO guidelines, sentinel lymph node biopsy should not be performed in patients with any of the following:

Large or locally advanced invasive breast cancer (tumor size T3/T4)
Inflammatory breast cancer
DCIS (when breast-conserving surgery is planned)
Pregnancy

ASCO recommendations regarding ALND in patients who have undergone sentinel lymph node biopsy are as follows:

ALND should not be performed in women with no sentinel lymph node (SLN) metastases
In most cases, ALND should not be performed in women with one to two metastatic SLNs who are planning to undergo breast-conserving surgery with whole-breast radiotherapy
ALND should be offered to women with SLN metastases who will be undergoing mastectomy

National Comprehensive Cancer Network (NCCN) recommendations differ from those of ASCO in that the NCCN considers that women with clinical stage as high as IIIA T3, N1, M0 may be candidates for SLN biopsy. In addition, the NCCN concluded that there is insufficient evidence to make recommendations for or against SLN biopsy in pregnant patients; the NCCN recommends that decisions regarding use of SLN biopsy in pregnancy be individualized. However, isosulfan blue or methylene blue dye is contraindicated for SLNB in pregnancy; radiolabeled sulfur colloid appears to be safe.^[72]

The NCCN breast cancer guidelines state that lymph node dissection is optional in the following cases^[72]:

Strongly favorable tumors
When no result would affect the choice of adjuvant systemic therapy
Elderly patients
Patients with comorbid conditions

Also see Breast Cancer Staging for summarized information.

Additional Testing

The NCCN guidelines^[72]recommend the following laboratory studies for all asymptomatic women with early-stage breast cancer (stages I–IIB):

Complete blood count (CBC) with differential
Comprehensive metabolic panel, with liver function tests (LFTs) and alkaline phosphatase

Additional studies indicated in specific settings include the following:

Bone scan, in patients with localized bone pain or alkaline phosphatase elevation
Abdominal ± pelvic diagnostic CT with contrast or MRI with contrast, in patients with elevated alkaline phosphatase, abnormal liver function tests, abdominal symptoms, or abnormal physical examination of the abdomen or pelvis
Chest diagnostic CT with contrast, in patients with pulmonary symptoms

For women with clinical stage lllA (T3, N1, M0) disease, tests to consider are as follows:

CBC
Comprehensive metabolic panel, including LFTs and alkaline phosphatase
Chest diagnostic CT with contrast
Abdominal ± pelvic diagnostic CT with contrast or MRI with contrast
Bone scan or sodium fluoride PET/CT (category 2B)
FDG PET/CT (optional)

HER2 testing

Although several methods for HER2 testing have been developed, approximately 20% of current HER2 testing may be inaccurate; accordingly, the American Society of Clinical Oncology (ASCO) and CAP have recommended guidelines to ensure the accuracy of HER2 testing. Breast cancer specimens should initially undergo HER2 testing by a validated immunohistochemistry (IHC) assay (eg, HercepTest; Dako, Glostrup, Denmark) for HER2 protein expression.^[115](See Breast Cancer and HER2.)

The scoring method for HER2 expression is based on the cell membrane staining pattern and is as follows:

3+ – Positive for HER2 protein expression; uniform intense membrane staining of more than 30% of invasive tumor cells
2+ – Equivocal for HER2 protein expression; complete membrane staining that is either nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells, or uniform intense membrane staining in 30% or less of tumor cells
1+ – Weak or incomplete membrane staining in any tumor cells
0 – Negative for HER2 protein expression; no staining

Breast cancer specimens with equivocal IHC results should undergo validation with a HER2 gene amplification method, such as fluorescence in situ hybridization (FISH). More centers are relying on FISH alone for determining HER2 status.

In general, FISH testing is thought to be more reliable than IHC, but it is more expensive. Equivocal IHC results can be seen in 15% of invasive breast cancers, whereas equivocal HER2 FISH results are seen in fewer than 3% of invasive breast cancer specimens and those that had previously been considered HER2 positive. Discordant results (IHC 3+/FISH negative or IHC < 3+/FISH positive) have been observed in approximately 4% of specimens. Currently, no data support excluding this group from treatment with trastuzumab.

Newer methodologies for establishing HER2 status, including reverse transcriptase–polymerase chain reaction (RT-PCR) and chromogenic in situ hybridization (CISH), have been developed. The HER2 CISH PharmDX Kit (Dako Denmark A/S, Glostrup, Denmark) was approved by the FDA in November 2011. The interpretation for HER2 FISH testing (ratio of HER2 to chromosome 17 centromere [HER2/CEP17] and gene copy number) is as follows:

Positive HER2 amplification – HER2:CEP17 ratio > 2.2 or HER2 gene copy > 6.0
Equivocal HER2 amplification – HER2:CEP17 ratio of 1.8-2.2 or HER2 gene copy of 4.0-6.0
Negative HER2 amplification – HER2:CEP17 ratio < 1.8 or HER2 gene copy < 4.0

Molecular profiling assays

The Onco type Dx assay (Genomic Health, Inc, Redwood City, CA) has been approved by the US Food and Drug Administration (FDA) for women with early-stage ER-positive, node-negative breast cancer treated with tamoxifen, where the recurrence score (RS) correlated with both relapse-free interval and overall survival. This assay is an RT-PCR–based assay of 21 genes (16 cancer genes and 5 reference genes) performed on paraffin-embedded breast tumor tissue.

By using a formula based on the expression of these genes, an RS can be calculated that correlates with the likelihood of distant recurrence at 10 years. Breast tumor RSs and risk levels are as follows:

< 18, low risk
18-30, intermediate risk
>30, high risk

Furthermore, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 studies, the Onco type Dx assay was shown retrospectively to predict benefit from chemotherapy and hormonal therapy in hormone-sensitive, node-negative tumors.^[116]Similarly, among women with 1- to 3-node-positive, hormone receptor-positive disease, the Onco type Dx recurrence score was a significant predictor of recurrence, with a 21% decrease in recurrence risk for each 10-point drop in RS.

Women with a low RS showed a significantly greater improvement in disease-free survival (DFS) with the addition of tamoxifen; no additional benefit was derived from the addition of chemotherapy. In contrast, women with a high RS had a significant improvement in DFS with the addition of chemotherapy to hormonal therapy (tamoxifen).

The benefit of adding chemotherapy to hormonal therapy in tumors with an intermediate score is still controversial. The Trial Assigning Individualized Options for Treatment [TAILORx], a large, prospective, randomized phase III study sponsored by the National Cancer Institute (NCI), is addressing this important question.

The MammaPrint assay (Agendia, The Netherlands) is a genetic test that measures the activity of 70 genes to determine the 5- to 10-year relapse risk for women diagnosed with early breast cancer. It was approved for use by the FDA in 2007 and is an alternative platform to Oncotype DX. MammaPrint test results are reported as either a low-risk or a high-risk RS:

A low-risk score means that the cancer has a 10% risk of coming back within 10 years without any additional treatments after surgery
A high-risk score means that the cancer has a 29% risk of coming back within 10 years without any additional treatments after surgery

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Media Gallery

Anatomy of the breast.
Intrinsic subtypes of breast cancer.
Breast cancer. Intraductal carcinoma, comedo type. Distended duct with intact basement membrane and central tumor necrosis.
Breast cancer. Intraductal carcinoma, noncomedo type. Distended duct with intact basement membrane, micropapillary, and early cribriform growth pattern.
Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.
Breast cancer. Lobular carcinoma in situ. Enlargement and expansion of lobule with monotonous population of neoplastic cells.
Breast cancer. Infiltrating ductal carcinoma. Low-grade carcinoma with well-developed glands invading fibrous stroma.
Breast cancer. Colloid (mucinous) carcinoma. Nests of tumor cells in pool of extracellular mucin.
Breast cancer. Papillary carcinoma. Solid papillary growth pattern with early cribriform and well-developed thin papillary fronds.
Anatomy of the breast. Courtesy of Wikimedia Commons (Patrick J Lynch, medical illustrator).

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Author

Pavani Chalasani, MD, MPH Associate Professor of Medicine, Director, Division of Hematology and Oncology, Leader, Breast Cancer Clinical Research Team, Co-Program Leader, Clinical and Translational Oncology Program, George Washington Cancer Center, George Washington University School of Medicine and Health Sciences

Pavani Chalasani, MD, MPH is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, Hemostasis and Thrombosis Research Society, SWOG

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bayer, Heron, Amgen, Athenex, Novartis, Eisai, Eli Lilly, Zentalis <br/>Received research grant from: Pfizer.

Chief Editor

John V Kiluk, MD, FACS Associate Professor, Department of Oncologic Sciences, Department of Surgery (Joint Appointment), University of South Florida Morsani College of Medicine; Clinical Director, Breast Surgical Oncology, Associate Member, Comprehensive Breast Program, Department of Women's Oncology, H Lee Moffitt Cancer Center and Research Institute

John V Kiluk, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society of Breast Surgeons, Moretz Surgical Society, Society of Surgical Oncology, Southeastern Surgical Congress

Disclosure: Nothing to disclose.

Additional Contributors

Alison T Stopeck, MD Professor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center; Director of Clinical Breast Cancer Program, Arizona Cancer Center; Medical Director of Coagulation Laboratory, University Medical Center; Director of Arizona Hemophilia and Thrombosis Center

Alison T Stopeck, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, SWOG, American Society of Clinical Oncology, Hemophilia and Thrombosis Research Society

Disclosure: Received honoraria from Genentech for speaking and teaching; Received honoraria from AstraZeneca for speaking and teaching; Received grant/research funds from AstraZeneca for other.

Patricia A Thompson, PhD Assistant Professor, Department of Pathology, University of Arizona College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Leona Downey, MD Assistant Professor of Internal Medicine, Section of Oncology and Hematology, University of Arizona, Arizona Cancer Center

Leona Downey, MD is a member of the following medical societies: American Geriatrics Society, American Society of Clinical Oncology, and Southwest Oncology Group

Disclosure: Nothing to disclose.

Manjit Singh Gohel, MD, MRCS, MB, ChB Specialist Registrar, Division of Breast and Endocrine Surgery, Northwick Park Hospital

Disclosure: Nothing to disclose.

Harold Harvey, MD Professor, Department of Medicine, Pennsylvania State University

Disclosure: Nothing to disclose.

Kanchan Kaur, MBBS, MS (General Surgery), MRCS (Ed) Consulting Breast and Oncoplastic Surgeon, Medanta, The Medicity, India

Disclosure: Nothing to disclose.

Julie Lang, MD Assistant Professor of Surgery and the BIO5 Institute, Director of Breast Surgical Oncology, University of Arizona College of Medicine

Julie Lang, MD is a member of the following medical societies: American College of Surgeons, American Society of Breast Surgeons, American Society of Clinical Oncology, Association for Academic Surgery, and Society of Surgical Oncology

Disclosure: Genomic Health Grant/research funds Speaking and teaching; Agendia Grant/research funds Speaking and teaching; Surgical Tools Grant/research funds Research; Sysmex Grant/research funds Research

Robert B Livingston, MD Professor of Clinical Medicine and Director, Clinical Research Shared Services, Arizona Cancer Center

Robert B Livingston, MD is a member of the following medical societies: American Association for Cancer Research, American Federation for Clinical Research, and American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Hanan Makhoul, MD Staff Physician, Department of Internal Medicine, University of Arkansas School of Medicine

Disclosure: Nothing to disclose.

Issam Makhoul, MD Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences

Issam Makhoul, MD is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology

Disclosure: Nothing to disclose.

Robert C Shepard, MD, FACP Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International

Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy

Disclosure: Nothing to disclose.

Hemant Singhal, MD, MBBS, FRCSE, FRCS(C) Senior Lecturer, Director of Breast Service, Department of Surgery, Imperial College School of Medicine; Consultant Surgeon, Northwick Park and St Marks Hospitals, UK

Hemant Singhal, MD, MBBS, FRCSE, FRCS(C) is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada and Royal College of Surgeons of Edinburgh

Disclosure: Nothing to disclose.

Carl V Smith, MD The Distinguished Chris J and Marie A Olson Chair of Obstetrics and Gynecology, Professor, Department of Obstetrics and Gynecology, Senior Associate Dean for Clinical Affairs, University of Nebraska Medical Center

Carl V Smith, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Council of University Chairs of Obstetrics and Gynecology, Nebraska Medical Association, and Society for Maternal-Fetal Medicine

Disclosure: Nothing to disclose.

Wiley Souba, MD Chairman, Professor, Department of General Surgery, Pennsylvania State College of Medicine; Chief Surgeon, The Milton S Hershey Medical Center

Disclosure: Nothing to disclose.

Rachel Swart, MD, PhD Assistant Professor of Medicine, Department of Hematology and Oncology, Arizona Cancer Center, University of Arizona

Rachel Swart, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, Arizona Medical Association, and Southwest Oncology Group

Disclosure: Roche Grant/research funds Other

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Simon Thomson, MB, BCh, MD, FRCS Specialist Registrar, Department of Breast and Endocrine Surgery, Northwick Park Hospital, UK

Simon Thomson, MB, BCh, MD, FRCS is a member of the following medical societies: British Medical Association

Disclosure: Nothing to disclose.

Agent	Dose and Schedule
Postmenopausal
Tamoxifen	20 mg PO every day
Elacestrant	345 mg PO every day
Or
Aromatase inhibitor
Anastrozole	1 mg PO every day
Letrozole	2.5 mg PO every day
Exemestane	25 mg PO every day
Or
Fulvestrant	500 mg IM on days 1, 15, 29, and once monthly thereafter
Or
Megestrol	40 mg PO 4 times a day
Premenopausal
Tamoxifen	20 mg PO every day
Or
Aromatase inhibitor + LHRH*
Leuprolide	7.5 mg IM depot q28d 22.5 mg IM q3mo 30 mg IM q4mo
Goserelin	3.6 mg SC depot q28d 10.8 mg SC q3mo
Megestrol	40 mg PO 4 times a day
*LHRH = luteinizing hormone–releasing hormone.

Drug	Class	Dose/Schedule	Overall Response Rate (ORR)	Toxicity
Abemaciclib	CDK inhibitor	200 mg PO BID continue until disease progression	19.7%	Diarrhea, fatigue, neutropenia and nausea
Capecitabine	Oral fluoro-pyrimidine	1250 mg/m²/d PO for 2 weeks with 1 wk off	30%	Rash, hand-foot syndrome, diarrhea, mucositis
Docetaxel	Antimicrotubule	75-100 mg/m² IV q3wk or 40 mg/m²/wk X IV for 6 wk with 2 wk off	30-68%	Myelosuppression, alopecia, skin reaction, mucositis, and fluid retention
Doxorubicin	Anthracycline (antitumor antibiotic)	45-60 mg/m² IV q3wk or 20 mg/m² IV qwk (not to exceed a cumulative dose of 450-500 mg/m²)	35-50%	Myelosuppression, nausea/ vomiting, mucositis, diarrhea cardiotoxicity, alopecia
Doxil (liposomal encapsulated doxorubicin)	Anthracycline	20 mg/m² IV q2wk or 35-40 mg/m² IV q4wk		Less cardiotoxicity, neutropenia, alopecia, stomatitis, hand-foot syndrome
Epirubicin	Anthracycline	90 mg/m² IV q3wk (not to exceed cumulative dose of 900 mg/m²)	35-50%	Myelosuppression, mucositis, nausea, vomiting, cardiotoxicity
Gemcitabine	Antimetabolite	725 mg/m²/wk IV for 3 wk then 1 wk off or 1 g/m²/wk IV X 2 then 1 wk off		Myelosuppression, nausea/ vomiting, flulike syndrome, elevated LFTs
Nab-paclitaxel	Antimicrotubule	80-100 mg/m²/wk IV X 3 then 1 wk off or 260 mg/m² IV q3wk	58-62% 33%	Less neuropathy, and allergic reaction
Olaparib	PARP inhibitor	300 mg PO BID	59.9%	Anemia, fatigue, nausea, and vomiting
Paclitaxel	Antimicrotubule	80 mg/m²/wk IV or 175 mg/m² IV over 3 hours q3wk	25-50%	Myelosuppression, alopecia, neuropathy, allergic reaction
Pertuzumab	Monoclonal antibody	840 mg IV loading dose, then 420 mg q3wk Give with trastuzumab and docetaxel	80.2% (objective response rate)	Fever, allergic reaction, cardiotoxicity/congestive heart failure
Palbociclib	CDK inhibitor	125 mg/day PO for 3 weeks with 1 wk off Give with letrozole	Data are not available for ORR Mean PFS was 10.2 months in the letrozole group and 20.2 months for palbociclib plus letrozole group	Neutropenia, leukopenia, thrombocytopenia, anemia, stomatitis
Ribociclib	CDK inhibitor	600 mg/day PO for 3 weeks with 1 wk off Give with letrozole	Mean PFS was 16 months in the letrozole group and 25.3 months for ribociclib	QT prolongation, hepatobiliary toxicity, neutropenia, alopecia, diarrhea, vomiting, constipation, fatigue, anorexia
Sacituzumab govitecan	Monoclonal antibody	10 mg/kg IV on Days 1 and 8 with 2 wk off	33.3%	Nausea, neutropenia, diarrhea, fatigue, anemia, vomiting
Talazoparib	PARP inhibitor	1 mg PO qDay	62.6%	Fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, and decreased appetite
Trastuzumab or biosimilars of trastuzumab	Monoclonal antibody	Combination therapy: 4 mg/kg IV once, then 2 mg/kg weekly for 12-18 weeks, then 6 mg/kg q3weeks to total 52 weeks Single agent: 8 mg/kg IV once, then 6 mg/kg q3weeks to total 52 weeks	10-15%	Fever, allergic reaction, cardiotoxicity/congestive heart failure
Trastuzumab deruxtecan^[155]	Monoclonal antibody conjugate	5.4 mg/kg IV q3weeks	60.3%	Interstitial lung disease and pneumonitis; neutropenia; left ventricular dysfunction
Tucatinib^[156]	Tyrosine kinase inhibitor of HER2	300 mg PO BID	40.6%	Diarrhea, hand-foot syndrome, nausea, fatigue, hepatotoxicity
Vinorelbine	Vinca alkaloid	20 mg/m²/wk IV	35-45%	Myelosuppression, nausea/ vomiting, constipation, fatigue, stomatitis, anorexia

	NCCN	ASCO
History and physical examination	Year 1, every 3-4 mo Year 2, every 4 mo Year 3-5, every 6 mo Year 6+, annually	Year 1-3, every 3-6 mo Year 4-5, every 6-12 mo Year 6+, annually
Breast self-examination	No recommendation	Counseled to perform monthly breast self-examination
Mammography	6 mo after post-BCS radiation therapy Annually thereafter	6 mo after definitive radiation therapy Every 6-12 mo for surveillance of abnormalities Annually if stability of abnormalities is achieved
Pelvic examination	Annually, for women on tamoxifen Annual exam if uterus present	Regular gynecologic follow-up Patients on tamoxifen should be advised to report any vaginal bleeding
Routine blood tests	Not recommended	Not recommended
Imaging studies	Not recommended	Not recommended
Tumor marker testing	Not recommended	Not recommended

Breast Cancer Workup

Approach Considerations

Breast Cancer Screening

Mammography

Ultrasonography

Magnetic Resonance Imaging

Nuclear Imaging

Positron Emission Tomography

Accuracy of Breast Imaging Modalities

Breast Biopsy

Histology

Histologic grade

Ductal carcinoma in situ

Lobular carcinoma in situ

Infiltrating ductal carcinoma

Infiltrating lobular carcinoma

Medullary carcinoma

Mucinous carcinoma

Tubular carcinoma

Papillary carcinoma

Metaplastic breast cancer

Mammary Paget disease

Breast Cancer Staging

Lymph node assessment

Additional Testing

HER2 testing

Molecular profiling assays

References

Tables

Contributor Information and Disclosures

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