Figure 74-20. Benefits of radiation therapy and tamoxifen in ductal carcinoma in situ. The cumulative incidence of breast cancer

events in the ipsilateral and contralateral breasts for patients treated in the National Surgical Adjuvant Breast and Bowel Project B17 and B-24 trials is shown. The reduction in recurrence is greatest for patients receiving radiotherapy and tamoxifen.

AJCC TNM Staging

The seventh edition of the AJCC TNM staging system for breast cancer is an internationally accepted

system used to characterize the extent of disease, predict prognosis, and facilitate medical decisionmaking (Table 74-10).176 In this system, breast cancer is classified on the basis of the primary tumor

type (invasive or in situ) and size (T), the presence or absence of regional lymph node involvement (N),

and the presence or absence of distant metastases (M).

Noninvasive breast cancers are noted as Tis and further classified into Tis (DCIS), Tis (LCIS), and Tis

(Paget). T1 tumors are invasive cancers ≤20 mm; T2 tumors are >20 mm but ≤50 mm; whereas T3

tumors are >50 mm. T4 tumors are of any size with direct extension to the chest wall and or the skin,

resulting in nodules or ulcerations. Invasion of cancer into the dermis alone does not qualify as T4.

Lymph node classification criteria differ depending on whether the lymph nodes were clinically or

pathologically assessed and as such are designated as cN or pN, respectively. When possible, pathologic

classification is preferred. Regional lymph nodes are defined as those of the ipsilateral axilla, ipsilateral

intramammary, internal mammary nodes, and supraclavicular nodes. Metastasis to any other lymph

node, including cervical or to the contralateral axillary lymph node, is classified as distant disease (M1).

In regard to the clinical classification of the regional lymph nodes, cN0 refers to no regional lymph node

metastases. Mobile level I and II axillary lymph nodes containing metastases are considered cN1,

whereas fixed or matted nodes are cN2. When metastases occur in the infraclavicular lymph nodes,

ipsilateral internal mammary lymph nodes and axillary lymph nodes, or to the ipsilateral supraclavicular

lymph nodes, it is classified as cN3.

In order to discuss the pathologic classification of regional lymph nodes, it is important to note that

breast cancer metastases must be greater than 0.2 mm and exceed 200 cells in a single histologic lymph

node cross-section to be considered clinically relevant. As such, pN0 refers to no regional lymph node

metastases, pN1mi is used to describe micrometastases (>0.2 mm or >200 cells, but none >2.0 mm),

and pN1 is used to describe metastases in one to three lymph nodes and/or internal mammary nodes

with metastases detected by SLN biopsy but not clinically detected. pN2 disease occurs when metastases

are present in four to nine axillary lymph nodes or in clinically detected internal mammary lymph nodes

in the absence of axillary lymph node metastases. pN3 disease includes metastases in 10 or more

axillary lymph nodes, metastases to the infraclavicular (level III axillary) lymph nodes, in clinically

detected ipsilateral internal mammary lymph nodes in the presence of one or more positive level I or II

axillary lymph nodes, in more than three axillary lymph nodes and in internal mammary lymph nodes

with micrometastases or macrometastases detected by SLN biopsy but not clinically detected, or in

ipsilateral supraclavicular lymph nodes.

Distant metastasis (M1) is defined as detectable metastases as determined by classical clinical and

radiographic means and/or histologically proven larger than 0.2 mm. When no clinical or radiographic

evidence of distant metastases is present but deposits of molecularly or microscopically detected tumor

cells are found in circulating blood, bone marrow, or other nonregional nodal tissue that is no larger

than 0.2 mm in a patient with no symptoms of metastases, the designation used is cMO(i+).

The particular combination of the T, N, and M characteristics defines the overall breast cancer stage.

Although the TNM staging system estimates predicted survival, it should not be used alone to dictate

treatment.

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Histologic Subtype and Tumor Grade

Most invasive breast cancers arise from epithelial elements and are categorized as carcinomas,

consisting of several histologic subtypes. Based on the Surveillance, Epidemiology, and End Results

(SEER) database of the National Cancer Institute between 1992 and 2001, estimated percentages of each

histologic subtype of breast cancer in a series involving 135,157 women showed infiltrating ductal

carcinoma (IDC) as the most common (76%), followed by invasive lobular (8%), ductal/lobular (7%),

mucinous/colloid (2.4%), tubular (1.5%), medullary (1.2%), and then papillary (1%).211

Infiltrating ductal carcinoma is the most common type of invasive breast cancer. On gross pathologic

evaluation, these lesions are typically firm, gray–white, gritty masses. Cytologic features of these cells

range from low grade to highly malignant. Microscopically, these cancers are characterized by cords

and nests of tumors cells with varying amounts of gland formation. As these cancer cells infiltrate the

breast parenchyma, they induce a fibrous response, resulting in their characteristic irregular, stellate

shape. Often, IDC is associated with a variable amount of DCIS.

STAGING

Table 74-10 Tumor, Node, Metastasis (TNM) Classification for Breast Cancer

Staging

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Infiltrating lobular carcinomas (ILCs) are the second most common type of breast cancer. The

incidence rate of lobular carcinoma is rising faster than the rate of ductal carcinoma in the United

States. Furthermore, postmenopausal hormone therapy use may be more strongly associated with

lobular carcinoma than with ductal carcinoma. Although some ILCs may appear similar to IDC

macroscopically, others may not show a mass lesion with the excised tissue appearing normal or having

only a slightly firm consistency. As such, the microscopic size of ILC may be much greater than what is

measured grossly. Unlike IDC, ILC induces only a minimal fibrous reaction. Microscopically, these

tumors are characterized by small cells that insidiously infiltrate the mammary stroma and adipose

tissue individually and in a single file pattern, often growing in a target-like configuration around

normal breast ducts. LCIS or DCIS may be present with ILC. There is a higher frequency of bilateral and

multicentric disease with ILC than with IDC.212,213 Infiltrating lobular carcinomas are more common in

older women and are typically larger but more differentiated than IDC. Infiltrating lobular carcinomas

are almost always ER-positive. The prognosis for ILC and IDC appears to be similar; however, recent

reports suggest that the short-term prognosis for ILC may be more favorable.214,215 Infiltrating lobular

carcinomas tend to metastasize later than IDC and spread to unusual locations such as the peritoneum,

meninges, and the gastrointestinal tract.216 Furthermore, lobular breast cancers have been observed in

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families that carry germline mutations in CDH1, the gene that encodes for the E-cadherin protein. The

lack of E-cadherin can be used to distinguish ILC from IDC.217,218

Mucinous (colloid) carcinoma is a less common histologic subtype that is more common in older

patients. On gross examination, these tumors have a soft gelatinous appearance and tend to be well

circumscribed. Microscopically, they are characterized by nests of tumor cells, with uniform and lowgrade nuclei, dispersed in large pools of extracellular mucus. These lesions have a favorable

prognosis.219,220 Another histologic subtype with favorable prognosis is tubular carcinoma, which is

characterized by the presence of well-formed tubular or glandular structures infiltrating the stroma. The

tumor cells are low grade and are often associated with low-grade DCIS. Metastatic disease is rare with

tubular carcinoma.221

Medullary carcinomas are well-circumscribed, soft, tan masses with areas of hemorrhage and necrosis.

Microscopically, the tumor cells are poorly differentiated, grow in a syncytial pattern, and have an

intense lymphoplasmacytic infiltrate.222 These cancers occur more frequently in younger patients and

are more frequent in women with BRCA1 mutations, although the majority of breast cancers in patients

with BRCA1 mutation are not medullary.223 Despite their aggressive histologic appearance, medullary

carcinomas are associated with a more favorable prognosis than IDC.224,225

Other breast cancer subtypes include macropapillary carcinomas that are highly aggressive and have a

tendency for lymph node metastasis even when small in size.226 Also likely associated with a worse

prognosis, metaplastic carcinomas are well-circumscribed tumors that contain various combinations of

poorly differentiated ductal adenocarcinoma, mesenchymal (sarcomatous), and other epithelial (e.g.,

squamous cell) components.227 When the squamous cell component predominates, the tumors tend to be

more aggressive and are frequently refractory to treatment when compared with IDC.228,229 Unlike IDC,

metaplastic breast cancers tend to have fewer T1 tumors, more node-negative tumors, more poorly

differentiated or undifferentiated tumors, and have fewer ER-positive tumors.227 Metaplastic breast

cancers are treated similarly to other invasive breast cancers.230–232

The grade of a breast cancer is determined by a combination of the architectural and cytologic

features, usually assessed by utilizing the Ellston–Ellis modification of the Scarff–Bloom-Richardson

scoring system. This system is based on three parameters including tubule formation, nuclear

pleomorphism, and mitotic activity. Each category is assigned a score of 1 to 3 and then a summation

score of 3 to 9. The lowest possible score is 3 with scores of 3 to 5 defined as grade 1, 6 or 7 as grade 2,

and 8 or 9 as grade 3. Cells that infiltrate the stroma as solid nests of glands and where the nuclei are

relatively uniform with little or no evidence of mitotic activity are referred to as well differentiated or

grade 1 tumors. When the tumor cells infiltrate as solid nests with some glandular differentiation and

nuclear pleomorphism is present, the tumor is categorized as grade 2 or moderately differentiated. In

addition, the mitotic activity is moderate. In poorly differentiated or grade 3 tumors, solid nests of

neoplastic cells without evidence of gland formation are present. In addition, there is marked nuclear

atypia and high mitotic activity.233

Biomarker Profile (ER, PR, HER2)

As targeted therapies exist against the estrogen receptor (ER), progesterone receptor (PR), and human

epidermal growth factor receptor 2 (HER2), these biomarkers have significant treatment implications.

As such, when an invasive breast cancer is diagnosed, expression of these biomarkers is determined.

Using immunohistochemistry and image analysis, ER and PR are considered positive if 10% of cells or

greater stain positive. The Allred score is another method to quantify ER and PR expression. The Allred

score integrates the percentage of cells that stain positive with the intensity of staining to give a score

of 0–8.234 The goal of the Allred score is to quantify ER expression on the basis of the likelihood that a

patient with breast cancer will respond to endocrine therapy. One of the benefits of the Allred score is

that by integrating both the percentage and intensity of staining, patients with <10% staining may be

identified who benefit from endocrine therapy.235 The receptor tyrosine kinase protein HER2 is a

member of the epidermal growth factor receptor family and its amplification or overexpression has

been shown to contribute to breast cancer development and progression. HER2 can now be targeted

using monoclonal antibodies and small molecule inhibitors. Using immunohistochemistry and image

analysis, HER2 is scored 0, 1+, 2+, and 3+. Positivity is noted as 3+, whereas scores of 0 and 1+ are

considered negative. A score of 2+ is considered indeterminate and further testing for gene

amplification can be performed using either FISH (fluorescence in situ hybridization) or CISH

(chromogenic in situ hybridization). The HER2 FISH assay is based on the gene copy number and the

ratio between the number of HER2 and chromosome enumeration probe 17 (CEP17) sequences, with

2067

positivity defined as a HER2/CEP17 ratio of ≥2.0. Positivity is also defined as HER2 copy number

≥6.0 signals/cell even if the HER2/CEP17 ratio is <2.0.236 Alternatively, a more cost-effective and

comparable method to FISH testing is the HER2 CISH assay.237,238

An emerging biomarker is the Ki-67 index. The Ki-67 antigen is present in all phases of the cell cycle

except for the G0/resting phase and reflects of the proliferative potential of a breast cancer. Ki-67 is

determined by IHC and noted as a percentage, where <10% is considered a low proliferative index,

10% to 20% is considered borderline, and >20% is considered high. The Ki-67 index can also be used to

measure the response to endocrine therapy.

Molecular Subtyping

Recent advances in molecular biology, including the development of sophisticated techniques for gene

expression profiling, have established a new taxonomy of breast cancer, defining molecular subtypes of

breast cancer. This new taxonomy has had a profound impact on the clinical management of breast

cancer, as the molecular subtypes differ markedly in prognosis and response to therapy. As gene

expression profiling is not routinely performed on clinical specimens, molecular subtypes have been

approximated on the basis of expression of the ER, PR, HER2 expression, and other biomarkers.

Commonly defined subtypes include luminal A (ER+, PR+, HER2−, Ki-67 <14%), luminal B (ER+

and or PR+, HER2+/−, Ki-67 ≥14%), HER2 (ER and PR−, HER2+), and basal-like (ER, PR, and

HER−).239–241 Luminal A and B subtypes have ER expression; however, the former group has a much

better overall survival.242 Luminal B HER2+ and HER2 subtypes benefit from targeted therapies

against HER2. Furthermore, both HER2 and basal-like breast cancers are known to have higher initial

responses to anthracycline-based chemotherapy than the luminal subtypes but are associated with a

decreased disease-free survival.243

Breast MRI

Although there are no data from prospective randomized trials demonstrating improved outcomes with

the addition of MRI to the diagnostic evaluation of newly diagnosed breast cancers, the NCCN

guidelines suggest that diagnostic MRI should be considered in patients with newly diagnosed breast

cancer (1) when the clinical extent of disease appears larger than what is observed on mammography,

(2) when there is concern about pectoralis muscle involvement, (3) when there is no evidence of a

breast primary in the presence of axillary lymph node metastases, (4) when there is no disease

identified on physical examination or mammography in the presence of PDB, (5) in women at very high

risk for contralateral breast cancers such as those with BRCA1/2 mutations, and (6) to help determine

the extent of disease prior to treatment. Of note, MRI is associated with a high false-positive rate, and

many MRI-detected abnormalities will need to be biopsied in order to meaningfully interpret the results

of the MRI.

Table 74-11 Approach To the Axillary Nodes

Sentinel Lymph Node Biopsy

Breast cancer spread to ipsilateral axillary lymph nodes is common, occurring in 15% to 30% of

patients. The presence of axillary lymph node metastases has important prognostic implications and can

impact medical, surgical, and radiation oncology decision-making. However, axillary lymph node

dissection (ALND) has significant risks, and the therapeutic impact of axillary surgery remains to be

clearly defined.244–246 Currently, SLNB is the procedure of choice for staging of the axilla in breast

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cancer. Axillary ultrasound has also been used and can facilitate evaluation of patients with an equivocal

physical examination (Table 74-11).

6 The SLN hypothesis predicts that breast cancers metastasize to one or a few lymph nodes before

involving other lymph nodes in the corresponding lymph node basin. Prospective studies have

confirmed this hypothesis, demonstrating that the pathology of the SLN accurately predicts the

pathology of the corresponding axillary lymph node basin (Table 74-12). SLNB has significantly fewer

complications than ALND, with the risk of lymphedema being significantly lower (2% after SLNB versus

13% after ALND at 12 months).247

The SLNB procedure begins with localization of the SLN through injection of radioactive colloid

and/or blue dye. Given that the combined use of both tracers appears to be complementary and that

failed SLN identification is minimized when both tracers are used, this is our recommended approach. A

systematic review by an expert panel convened by ASCO concluded that the use of both blue dye and

radioactive colloid was associated with a trend toward a lower false-negative rate.248

Prior to surgery, radioactive technetium sulfur colloid is injected peritumorally, intradermally, or into

the subareolar plexus. Lymphoscintigraphy can be performed to identify areas of increased

radioactivity. Alternatively, a handheld gamma probe can be used to survey the axilla and identify hot

spots. The patient is then brought to the operating room and positioned with the ipsilateral arm

abducted up to 90 degrees. The breast, anterior chest wall, and axilla are prepped and draped in the

usual standard sterile fashion. Five milliliters of blue dye (isosulfan or methylene blue dye) is injected

around the tumor periphery, at the palpable edge of the biopsy cavity, or into the subareolar plexus.

Blue dye should not be injected directly into the tumor itself as the lymphatics may be occluded by

tumor. Likewise, blue dye should not be injected into the seroma cavity following breast surgery as the

seroma cavity may not have sufficient lymphatic drainage. For these reasons, we typically inject into

the subareolar plexus. Breast massage is performed for 5 minutes to dilate the breast lymphatics and

facilitate lymphatic drainage.

Isosulfan blue can be used for SLNB; however, anaphylaxis requiring resuscitation can occur in 0.7%

to 1.1% of cases.249,250 Alternatively, methylene blue can be used. The risks associated with methylene

blue include skin necrosis if injected intradermally, pain secondary to caustic reaction, and pulmonary

edema.251–253 These risks can be minimized by diluting the methylene blue, with common dilutions

ranging from 2:3 (2 mL of methylene blue mixed with 3 mL of saline, injecting 5 mL total) to 1:4 (1 mL

of methylene blue mixed with 4 mL of saline, injecting 5 mL total). In patients taking serotonergic

psychiatric mediations, methylene blue should be used with caution as the dye can prevent the action of

monoamine oxidase A, resulting in toxic levels of serotonin or serotonin syndrome. This is characterized

by mental status changes, muscle twitching, excessive sweating, shivering, diarrhea, trouble with

coordination, and/or fever.254

Using a handheld gamma probe, the axilla is systematically surveyed and the skin is marked at the

location of the hottest spot. A small incision is then made below the hair-bearing area of the axilla and

carried down through the subcutaneous tissue. The clavipectoral fascia is incised with care to visually

identify any blue lymphatics. The blue lymphatics are then followed toward the axilla to identify the

sentinel lymph node(s). Successful SLN identification by blue dye is defined as the identification of any

blue node or non–blue node with a blue afferent lymphatic. These lymph nodes are also evaluated with

the gamma probe and the associated counts are recorded. The dissection is continued until all lymph

nodes associated with a blue afferent lymphatic are removed and any remaining lymph nodes have less

than 10% radioactivity compared to the most radioactive lymph node.259–261 This often results in more

than one SLN being identified and removed. Finally, palpation of the axilla is performed and any

suspicious lymph nodes are also removed as gross tumor involvement can interfere with uptake of both

radioactive colloid and blue dye. In the case of gross tumor involvement, the radioactive colloid and

blue dye may be diverted to a lymph node other than the true SLN, giving rise to a false-negative result

if palpation of the axilla and removal of suspicious lymph nodes is not performed.262,263 Once all SLNs

have been identified and removed, the clavipectoral fascia is reapproximated and the skin is closed in

two layers.

RESULTS

Table 74-12 Results of Prospective, Multi-Institutional Studies of Lymphatic

Mapping and Sentinel Node Biopsy

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TREATMENT OF THE PATIENT WITH BREAST CANCER

Breast cancer is currently treated with a multidisciplinary approach. Most patients benefit from a

combination of therapies that may include surgery, medical therapy, and radiation therapy. This

multidisciplinary approach has resulted in a significant reduction in breast cancer mortality.264 One

important consideration is optimal coordination of surgery with the other treatment modalities. In the

discussion below we will first provide an overview of how the different treatment modalities are

coordinated in early stage, locally advanced, and metastatic breast cancer. After this overview, surgery,

medical therapy, and radiation therapy will be discussed in more detail.

Overview

7 Most patients with newly diagnosed breast cancer have no evidence of metastatic disease and are

diagnosed with early stage breast cancer. This includes patients with clinical stage I (T1N0), IIA (T1N1 or

T2N0), or IIB (T2N1) disease. Local regional management often consists of BCT (partial mastectomy

with radiation therapy) or mastectomy, noting that the choice in locoregional management does not

typically impact the recommendation for adjuvant medical therapy. For patients with clinical T1N0

disease, surgery is typically the first treatment modality. For patients with clinical T2N0 or T2N1

disease, neoadjuvant chemotherapy or endocrine therapy is often the first treatment modality. The goal

of neoadjuvant therapy is to shrink the primary breast cancer prior to surgery, facilitating BCT. For

patients with a clinically suspicious axilla, an ultrasound-guided FNA may be helpful to determine

whether there is metastatic spread to the axilla. If the FNA is negative, then the patient should undergo

a SLNB at the time of surgery. For patients with a clinically negative axilla, a SLNB should be planned at

the time of surgery with a decision about further management of the axilla, if any, pending the results

of the SLNB. The decision to recommend chemotherapy for patients with early breast cancer is primarily

dependent on tumor characteristics but also integrates the patient’s overall health status and personal

preference. Adjuvant chemotherapy is typically recommended when high-risk features are present such

as high-grade tumor, large tumor size (≥1.0 cm), unfavorable biomarker profile, or lymph node

involvement. In addition, an Oncotype DX can be obtained in patients with ER+/HER2-negative breast

cancers and negative lymph nodes. A score of ≥31 often suggests that adjuvant chemotherapy will be

beneficial. For patients with breast cancers that are hormone receptor-positive, endocrine therapy is

typically recommended postoperatively. If adjuvant chemotherapy is recommended, then endocrine

therapy is given after completion of chemotherapy. For patients with TNBC, adjuvant chemotherapy is

commonly given if the tumor size is ≥0.5 cm. Patients who have HER2-positive breast cancers that are

≥1.0 cm are treated with adjuvant chemotherapy plus HER2-directed therapy. The management of

HER2-positive breast cancers that are <1.0 cm is controversial and should be decided by the patient

and her provider after a discussion of the risks and benefits of treatment. Adjuvant radiation therapy is

typically recommended for all patients who are treated with BCT and a subset of patients who are

treated with mastectomy (see the section on Radiation Therapy).

Patients with locally advanced disease (clinical stage IIB (T3N0) or stage IIIA-IIIC (T1-T3N2 disease, T4

disease)) are at a higher risk for recurrence and distant metastases, and neoadjuvant and/or adjuvant

chemotherapy and radiation therapy are typically recommended (Fig. 74-21). Benefits of neoadjuvant

chemotherapy in this clinical context include the ability to treat any potential systemic disease

immediately and the ability to directly assess the response to treatment by physical examination and

imaging, allowing for suboptimal regimens to be discontinued and other regimens to be prescribed. In

patients with hormone receptor-positive disease, neoadjuvant chemotherapy is associated with a higher

response rate in a shorter period of time than endocrine therapy. Endocrine therapy in the neoadjuvant

setting is often reserved for postmenopausal women who have contraindications to chemotherapy. For

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patients with HER2-positive breast cancer, HER2-directed therapy such as trastuzumab is often given

with pertuzumab along with chemotherapy. If a patient has a limited response or cannot tolerate the

neoadjuvant regimen, she should proceed with surgery. Even if patients have an excellent clinical

response, they should undergo surgery to remove the area of involvement. Although BCT is an option

for patients with locally advanced breast cancer (LABC) who have a significant clinical response to

neoadjuvant chemotherapy, mastectomy is typically recommended for those who initially present with

breast cancers that are greater than 5 cm.

Approximately 5% of patients with newly diagnosed breast cancer will present with stage IV disease,

and up to 30% of patients who present with early stage breast cancer at diagnosis will develop distant

metastatic disease.265 The approach to patients with metastatic breast cancer is focused on prolonging

survival and improving quality of life by minimizing cancer- related symptoms. As such, the treatment

plans for these patients are highly individualized.

Figure 74-21. Locally advanced breast cancer. The breast is lifted and the upper half is bulging because of the large tumor.

Distortion in the inferolateral contour is evident. The medial skin changes are caused by dermal tumor satellites.

TREATMENT

Table 74-13 Recommendations for Adjuvant Therapy

For patients with hormone receptor-positive, HER2- negative disease, the preference is for endocrine

therapy alone. However, for patients with rapidly progressing disease, endocrine-resistant disease, or a

large tumor burden involving visceral organs, chemotherapy should be considered.266,267 For patients

with HER2+ disease, HER2-directed therapies should be administered along with chemotherapy. For

patients with TNBCs, chemotherapy is the only option for the treatment of metastatic disease.

When chemotherapy is indicated, the preference is for sequential single agent therapy, which includes

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