Download Treatment of Invasive Breast Cancer

Breast Cancer
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Author: Rachel Swart, MD, PhD; Chief Editor: Jules E Harris, MD
Background
Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women
and the leading cause of cancer death among women.
Many early breast carcinomas may be asymptomatic; pain or discomfort is not usually a
symptom of breast cancer. Breast cancer is often first detected as an abnormality on a
mammogram before it is felt by the patient or healthcare provider. The general approach to
evaluation of breast cancer has become formalized as triple assessment: clinical examination,
imaging (usually mammography and/or ultrasonography), and needle biopsy. (See Workup.)
Increased public awareness and improved screening have led to earlier diagnosis, at stages
amenable to complete surgical resection and curative therapies. Consequently, survival rates
for breast cancer have improved significantly, particularly in younger women.
Surgery is considered primary treatment for breast cancer. Many patients with early-stage
breast cancer are cured with surgery alone. (See Treatment and Management.)
Adjuvant treatment of breast cancer is designed to treat micrometastatic disease, or breast
cancer cells that have escaped the breast and regional lymph nodes but which have not yet
had an established identifiable metastasis. Depending on the model of risk reduction,
adjuvant therapy has been estimated to be responsible for 35-72% of the reduction in
mortality rate. Over the last 2 decades, breast cancer research has led to extraordinary
progress in our understanding of the disease, resulting in more efficient and less toxic
treatments. (See Treatment and Management.)
Anatomy
The breasts of an adult woman are milk-producing glands situated on the front of the chest
wall. They rest on the pectoralis major muscle and are supported by and attached to the front
of the chest wall on either side of the sternum by ligaments. Each breast contains 15-20 lobes
arranged in a circular fashion. The fat that covers the lobes gives the breast its size and shape.
Each lobe comprises many lobules, at the end of which are glands where milk is produced in
response to hormones (see the image below).
Anatomy of the breast.
Pathophysiology
The current understanding of breast tumorigenesis is that invasive cancers arise through a
series of molecular alterations at the cellular level, resulting in the outgrowth and spread of
breast epithelial cells with immortal features and uncontrolled growth.
Genomic profiling has demonstrated the presence of discrete breast tumor subtypes with
distinct clinical behavior (eg, 4 subclasses: luminal A, luminal B, basal, and human epidermal
growth factor receptor 2 [HER2]-positive). The exact number of disease subtypes and
molecular alterations from which these subtypes derive remains to be fully elucidated, but
they generally align closely with the presence or absence of hormone receptor and mammary
epithelial cell type (luminal or basal).
The figure below summarizes the current general understanding of breast tumor subtypes,
prevalence, and the major associated molecular alterations. This view of breast cancer--not as
a set of stochastic molecular events, but as a limited set of separable diseases of distinct
molecular and cellular origins--has altered thinking about breast cancer etiology, typespecific risk factors, prevention, and treatment strategies.
Intrinsic subtypes of breast cancer.
Etiology
Epidemiologic studies have identified many risk factors that increase the chance of a woman
developing breast cancer.
Epidemiology
Over the past 25 years, breast cancer incidence rates have risen globally, with the highest
rates in Westernized countries. Reasons for this trend include change in reproductive patterns,
increased screening, dietary changes, and decreased activity.
Although breast cancer incidence is on the rise globally, breast cancer mortality has been
decreasing, especially in industrialized countries. The 2002 international female breast cancer
incidence rates varied by more than 25-fold, ranging from 3.9 cases per 100,000 in
Mozambique to 101.1 cases per 100,000 in the United States. In 2008, the American Cancer
Society (ACS) estimated there were nearly 1.4 million new cases of invasive breast cancer
worldwide.
In the US, approximately 207,090 new cases of female invasive breast cancer were predicted
to occur in 2010, along with 1,970 cases in men.[1] In addition to invasive breast cancer,
54,010 new cases of in situ breast cancer were expected to occur among women, of which
approximately 85% were expected to be ductal carcinoma in situ (DCIS).
After 2 decades of increasing incidence rates, the number of new female breast cancers
decreased by 2.2% per year from 1999 to 2005. This decrease is thought to reflect reduced
use of HRT following the publication of the WHI findings in 2002, which linked HRT use to
an increased risk of heart disease and breast cancer. Rates of DCIS have stabilized since
2000.[2]
The current lifetime risk of breast cancer in the US is estimated at 12.7% for all women,
13.3% for non-Hispanic whites, and 9.98% for black women. Overall, the annual incidence
rates in black women (119.4/100,000) and Hispanic/Latina women (89.9/100,000) have been
stable since the early 1990s, and they are lower than the annual incidence of breast cancer in
white women (141.1/100,000). However, black women are more likely than white women to
be diagnosed with larger, advanced-stage tumors (>5 cm).
Although incidence rates among Asian and Pacific Islander women have continued to
increase at 1.5% per year (89/100,000), they are still significantly lower than the rates in
white women. Japanese and Taiwanese woman have one fifth the risk of US women.[3]
The various types of breast cancers are listed below by percentage of cases:
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Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor and has a
tendency to metastasize via lymphatics; this lesion accounts for 75% of breast cancers
Approximately 64,000 cases of DCIS are diagnosed annually in the US
Over the last 25 years, lobular carcinoma in situ (LCIS) incidence has doubled and is currently
2.8 per 100,000 women; the peak incidence is in women aged 40-50 years
Infiltrating lobular carcinoma comprises less than 15% of invasive breast cancers
Medullary carcinoma accounts for about 5% of cases and generally occurs in younger
women
Mucinous (colloid) carcinoma is seen in fewer than 5% of invasive breast cancer cases.
Tubular carcinoma of the breast is comprises 1-2% of all breast cancers
Papillary carcinoma is usually seen in women older than 60 years and accounts for
approximately 1-2% of all breast cancers
Metaplastic breast cancer accounts for less than 1% of breast cancer cases, tends to occur in
older women (average age of onset in the sixth decade), and has a higher incidence in blacks
Mammary Paget disease comprises 1-4% of all breast cancers and has a peak incidence in
the sixth decade of life (mean age, 57 y)
Prognosis
Death rates from breast cancer in the United States have decreased steadily in women since
1990. The breast cancer mortality rate fell 24% between the years 1990 and 2000 for women
aged 30-79 years. The largest decrease in mortality has been seen in women younger than 50
years (3.3% per year) compared with those aged 50 years and older (2.0% per year).
The decrease in breast cancer death rates is thought to represent progress in both earlier
detection and improved treatment modalities.[1] The 2010 estimates were 40,230 expected
breast cancer deaths (39,840 women, 390 men).[1]
Prognostic and Predictive Factors
Numerous prognostic and predictive factors for breast cancer have been identified by the
College of American Pathologists (CAP) to guide the clinical management of women with
breast cancer.
Breast cancer prognostic factors include the following:
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Axillary lymph node status
Tumor size
Lymphatic/vascular invasion
Patient age
Histologic grade
Histologic subtypes (eg, tubular, mucinous [colloid], papillary)
Response to neoadjuvant therapy
ER/ PR status
HER2 gene amplification and/or overexpression (see below)
Breast cancer predictive factors include the following:
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ER/PR status
HER2 gene amplification and/or overexpression
Cancerous involvement of the lymph nodes in the axilla is an indication of the likelihood that
the breast cancer has spread to other organs. Survival and recurrence are independent of level
of involvement but directly related to the number of involved nodes.
Patients with node-negative disease have an overall 10-year survival rate of 70% and a 5-year
recurrence rate of 19%. In patients with lymph nodes that are positive for cancer, the
recurrence rates at 5 years are as follows:
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1-3 positive nodes: 30-40%
4-9 positive nodes: 44-70%
More than 10 positive nodes: 72-82%
Hormone-positive tumors have a more indolent course and are responsive to hormone
therapy. ER and PR assays are routinely performed on tumor material by pathologists, and
immunohistochemistry (IHC) is a semiquantitative technique that is observer and antibody
dependent.
Five-year survival rates are highly correlated with tumor stage, as follows:
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Stage 0: 99-100%
Stage I: 95-100%
Stage II: 86%
Stage III: 57%
Stage IV: 20%
This prognostic information can guide physicians in making therapeutic decisions. Pathologic
review of the tumor tissue for histological grade along with the determination of
estrogen/progesterone receptor status and HER2 status is necessary for determining
prognosis. Evaluation of lymph node involvement by sentinel lymph node biopsy or axillary
lymph node dissection is generally[18] necessary as well. (See Staging.)
HER2
Before the routine use of trastuzumab (Herceptin, a monoclonal antibody) in adjuvant
therapy, HER2 overexpression was associated with a more aggressive tumor phenotype and
worse prognosis (higher rate of recurrence and mortality), independent of other clinical
features (eg, age, stage, tumor grade), especially in patients who did not receive adjuvant
chemotherapy.
Additionally, HER2 status has been shown to be predictive for response to certain
chemotherapeutic agents (ie, doxorubicin [Adriamycin]; and HER2-targeted therapies
trastuzumab and lapatinib [Tykerb, a small-molecule oral tyrosine kinase inhibitor directed
specifically to the HER2 receptor]).
Retrospectively analyzed results from clinical trials have shown that HER2-positive patients
benefit from anthracycline-based regimens secondary to the coamplification of topoisomerase
II with HER2. Preliminary data also suggest that HER2 may predict response to and benefit
from paclitaxel in the adjuvant setting.
Ductal carcinoma in situ
DCIS is divided into comedo (ie, cribriform, micropapillary, solid) and noncomedo subtypes,
which provides additional prognostic information on the likelihood of progression or local
recurrence, as shown in Table 1, below.
Table 1. Ductal Carcinoma in Situ Subtypes (Open Table in a new window)
DCIS Characteristic
Comedo Noncomedo
Nuclear grade
High
Low
Estrogen receptor
Negative
Positive
HER2 overexpression Present
Absent
Distribution
Continuous Multifocal
Necrosis
Present
Absent
Local recurrence
High
Low
Prognosis
Worse
Better
Lobular carcinoma in situ
Approximately, 10-20% of women with LCIS develop invasive breast cancer within 15 years
after their LCIS diagnosis. Thus, LCIS is considered a biomarker of increased breast cancer
risk.
Infiltrating ductal carcinoma
Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor and has a
tendency to metastasize via lymphatics.
Infiltrating lobular carcinoma
Like ductal carcinoma, infiltrating lobular carcinoma typically metastasizes to axillary lymph
nodes first. However, it also has a tendency to be more multifocal. Despite this, the prognosis
is comparable to that of ductal carcinoma.
Medullary carcinoma
Roughly 30% of patients have lymph node metastasis. Typical or classic medullary
carcinomas are often associated with a good prognosis despite the unfavorable prognostic
features associated with this type of breast cancer. However, an analysis of 609 medullary
breast cancer specimens from various stage I and II National Surgical Adjuvant Breast and
Bowel Project (NSABP) protocols indicates that overall survival and prognosis are not as
good as previously reported.
Mucinous carcinoma
Overall, patients with mucinous carcinoma have an excellent prognosis, with a greater than
80% 10-year survival.
Tubular carcinoma
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
Cystic papillary carcinoma has a low mitotic activity, which results in a more indolent course
and good prognosis. However, invasive micropapillary ductal carcinoma has a more
aggressive phenotype, even though approximately 70% of cases are ER-positive.
A retrospective review of 1,400 cases of invasive carcinoma identified 83 cases (6%) with at
least one component of invasive micropapillary ductal carcinoma. Additionally, lymph node
metastasis is seen frequently in this subtype (70-90% incidence), and the number of lymph
nodes involved appears to correlate with survival.
Metaplastic breast cancer
The majority of published case series have demonstrated a worse prognosis for MBC as
compared with infiltrating ductal carcinoma, even when adjusted for stage, with a 3-year
overall survival rate of 48-71% and 3-year disease-free survival rate of 15-60%. In most case
series, large tumor size and advanced stage have emerged as predictors of poor overall
survival and prognosis. Nodal status does not appear to impact survival in metaplastic breast
cancer.
Mammary Paget disease
MPD is associated with an underlying breast cancer in 75% of cases. Breast-conserving
surgery can achieve satisfactory results, but at the risk of local recurrence. Adjuvant
chemotherapy with tamoxifen may increase survival in premenopausal patients with lymph
node metastasis. Poor prognostic factors include a palpable breast tumor, lymph node
involvement, histologic type, and patient younger than 60 years. The overall 5-year and 10year survival rates are 59% and 44%, respectively.
History
Many early breast carcinomas are asymptomatic, particularly if they were discovered during
a breast-screening program. Larger tumors may present as a painless mass. Pain or
discomfort is not usually a symptom of breast cancer; only 5% of patients with a malignant
mass present with breast pain.
Often, the purpose of the history is not diagnosis but risk assessment. A family history of
breast cancer in a first-degree relative is the most widely recognized breast cancer risk factor.
The lifetime risk is up to 4 times higher if a mother and sister are affected; the risk is
approximately 5 times greater in women with 2 or more first-degree relatives with breast
cancer; and it is also greater among women with breast cancer in a single first-degree relative,
particularly if the relative was diagnosed at an early age (50 y or younger).
A family history of ovarian cancer in a first-degree relative, especially if the disease occurred
at an early age (< 50 y), has been associated with a doubling of breast cancer risk.
The family history characteristics that suggest increased risk of cancer are summarized as
follows:
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Two or more relatives with breast or ovarian cancer
Breast cancer occurring in an affected relative younger than 50 years
Relatives with both breast cancer and ovarian cancer
One or more relatives with 2 cancers (breast and ovarian cancer or 2 independent breast
cancers)
Male relatives with breast cancer
BRCA1 and BRCA2 mutations
Ataxia telangiectasia heterozygotes (4-times increased risk)
Ashkenazi Jewish descent (2-times greater risk)
Neoplastic conditions that increase the risk of breast cancer include the following:
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Previous breast cancer
Ovarian cancer
Endometrial cancer
Ductal carcinoma in situ (DCIS)
Lobular carcinoma in situ (LCIS)
Benign breast conditions that increase the risk of breast cancer include the following:
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Hyperplasia (unless mild)
Complex fibroadenoma
Radial scar
Papillomatosis
Sclerosing adenosis
Microglandular adenosis
Cervical cancer is associated with a decreased risk of breast cancer.
Physical Examination
If the patient has not noticed a lump, then signs and symptoms indicating the possible
presence of breast cancer may include the following:
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Change in breast size or shape
Skin dimpling or skin changes (eg, thickening, swelling, redness)
Recent nipple inversion or skin change, or nipple abnormalities (eg, ulceration, retraction,
spontaneous bloody discharge)
Single-duct discharge, particularly if bloodstained
Axillary lump
To detect subtle changes in breast contour and skin tethering, the examination must include
an assessment of the breasts with the patient upright with arms raised. The following findings
should raise concern:
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Lump or contour change
Skin tethering
Nipple inversion
Dilated veins
Ulceration
Paget disease
Edema or peau d'orange
The nature of palpable lumps is often difficult to determine clinically, but the following
features should raise concern:
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Hardness
Irregularity
Focal nodularity
Asymmetry with the other breast
Fixation to skin or muscle (assess fixation to muscle by moving the lump in the line of the
pectoral muscle fibers with the patient bracing her arms against her hips)
A complete examination includes assessment of the axillae and supraclavicular fossae,
examination of the chest and sites of skeletal pain, and an abdominal and neurologic
examination. The clinician should be alert to symptoms of metastatic spread, such as the
following:
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Breathing difficulties
Bone pain
Symptoms of hypercalcemia
Abdominal distention
Jaundice
Localizing neurologic signs
Altered cognitive function
The clinical evaluation should include a thorough assessment of specific risk factors for
breast cancer.
Diagnostic Considerations
The differential diagnosis includes the following:
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Circumscribed breast lesions: benign breast disease (eg, fibroadenomas, cysts), breast
cancer, breast lymphoma, and metastasis to the breast from other primary sites
Skin thickening: inflammatory carcinoma and mastitis
Stellate lesions: breast cancer, traumatic fat necrosis, a radial scar, and a hyalinized
fibroadenoma
Dilated ducts with or without nipple discharge: papilloma, ductal carcinoma, duct ectasia,
and fibrocystic disease
Approach Considerations
Breast cancer evaluation should be approached with an ordered inquiry beginning with
symptoms and general clinical history, followed by clinical examination and, finally,
investigation, which may include imaging and biopsy.
This approach naturally lends itself to a gradually increasing degree of invasiveness, so that a
diagnosis can be obtained with the minimum amount of invasion and, consequently,
minimum 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.
The general approach to evaluation of breast cancer has become formalized as triple
assessment: clinical examination, imaging (usually mammography and/or ultrasonography),
and needle biopsy. However, this should always be performed as part of a more general
assessment beginning with clinical history.
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, a mass, or architectural distortion. If any of these features are
identified, a diagnostic mammogram along with a breast ultrasound should be performed
before obtaining a biopsy. In certain cases, breast magnetic resonance imaging (MRI) may be
warranted.
Breast Cancer Screening
Early detection remains the primary defense available to patients in preventing the
development of life-threatening breast cancer. Breast tumors that are smaller or nonpalpable
are more treatable when detected and thus have a more favorable prognosis.
Screening modalities for breast cancer include breast self-examination, clinical breast
examination, mammography, ultrasonography, and magnetic resonance imaging. Go to
Breast Cancer Screening for more information on this topic.
Mammography
Mammography is a special type of low-dose x-ray imaging used to create detailed images of
the breast. Mammography can demonstrate microcalcifications smaller than 100 µm; it often
reveals a lesion before it is palpable by CBE and, on average, 1-2 years before noted by BSE.
There are 2 types of mammography examinations: screening and diagnostic. Screening
mammography is done in asymptomatic women.
Diagnostic mammography is performed in symptomatic women (eg, when a breast lump or
nipple discharge is found during self-examination or an abnormality is found during
screening mammography). This examination is more involved, time-consuming, and
expensive than screening mammography and is used to determine the exact size and location
of breast abnormalities and to image the surrounding tissue and lymph nodes. Women with
breast implants or a personal history of breast cancer will usually require the additional views
used in diagnostic mammography.
Other uses of mammography in breast cancer
A ductogram, or galactogram, is sometimes helpful for determining the cause of nipple
discharge. In this specialized examination, a fine plastic tube is placed into the opening of the
duct in the nipple. A small amount of contrast medium is injected, which outlines the shape
of the duct on a mammogram and shows whether a mass is present inside the duct.
Ultrasonography
Ultrasonography has become a widely available and useful adjunct to mammography in the
clinical setting. Ultrasound is generally used to assist the clinical examination of a suspicious
lesion detected on mammography or physical examination. As a screening device, ultrasound
is limited by a number of factors, most notably by the failure to detect microcalcifications and
by poor specificity (34%).
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 that 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.
This imaging technique is also useful in the guidance of biopsies and therapeutic procedures;
research is currently under way to evaluate its role in cancer screening.
Magnetic Resonance Imaging
In an effort to overcome the limitations of mammography and ultrasonography, MRI has
been explored as a modality for detecting breast cancer in women at high risk and in younger
women. A combination of T1, T2, and 3-D contrast-enhanced MRI techniques has been
found to be highly sensitive (approximating 99% when combined with mammogram and
CBE) to malignant changes in the breast. Go to Magnetic Resonance Mammography for
more information on this topic.
Indications for MRI
The high cost and limited availability of MRI, as well as the difficulties inherent in
performing and interpreting the studies, require careful recommendations for its use. The
following are common agreed-upon and useful indications for MRI:
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Characterization of an indeterminate lesion after a full assessment with physical
examination, mammography, and ultrasonography
Detection of occult breast carcinoma in a patient with carcinoma in an axillary lymph node
Evaluation of suspected multifocal or bilateral tumor
Evaluation of invasive lobular carcinoma, which has a high incidence of multifocality
Evaluation of suspected, extensive, high-grade intraductal carcinoma
Detection of occult primary breast carcinoma in the presence of metastatic adenocarcinoma
of unknown origin
Monitoring of the response to neoadjuvant chemotherapy
Detection of recurrent breast cancer
Contraindications to MRI
Conversely, in a number of situations, MRI is essentially contraindicated, usually because of
physical constraints that prevent adequate patient positioning. These constraints include the
following:
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Contraindication to gadolinium-based contrast media (eg, allergy, pregnancy)
Patient's inability to lie prone
Marked kyphosis or kyphoscoliosis
Marked obesity
Extremely large breasts
Severe claustrophobia
Relative contraindications also exist. These are essentially based on the high sensitivity but
limited specificity of the technique. MRI may not be useful for the following:
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Cancer-phobic patients
Assessment of mammographically detected microcalcifications
Nuclear Imaging
Three radiotracers are commonly used for breast imaging or scintimammography in either
clinical practice or research: technetium-99m (99m Tc)-sestamibi and99m Tc-tetrofosmin (both
used for myocardial perfusion imaging), as well as99m Tc-methylene diphosphonate (MDP)
(used for bone scintigraphy).99m Tc-sestamibi was the first radiopharmaceutical agent to be
approved by the FDA for use in scintimammography.[4]
Although not indicated as a screening procedure for the detection of breast cancer,
scintimammography may play a useful and significant 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 of99m Tc-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
for99m Tc-tetrofosmin and99m Tc-MDP scintimammography.[4]
Positron Emission Tomography Scanning
PET scanning is the most sensitive and specific of all the imaging modalities for breast
disease, but it is also one of the most expensive and least widely available. Using a wide
range of labeled metabolites (eg, fluorinated glucose [18 FDG]), changes in metabolic
activity, vascularization, oxygen consumption, and tumor receptor status can be detected. At
present, its main use may be to help detect recurrences in scarred breasts, but it is also useful
in multifocal disease, in detecting axillary involvement, and in equivocal cases of systemic
metastases.[5]
PET/computed tomography (CT) scans may be appropriate to assist in identification of
nonaxillary lymph node metastasis (ie, internal mammary or supraclavicular lymph nodes)
for staging locally advanced and inflammatory breast cancer before starting neoadjuvant
therapy.
Accuracy of Breast Imaging Modalities
Table 2, below, summarizes the accuracy of various techniques used in breast imaging. In
nonfatty breasts, ultrasonography and MRI are more sensitive than mammography for
invasive cancer but may overestimate tumor extent. Combined mammography, clinical
examination, and MRI are more sensitive than any other individual test or combination of
tests. Table 2. Accuracy of Breast Imaging Modalities (Open Table in a new window)
Modality
Sensitivity
Mammography 63-95%
Specificity
14-90%
Positive
predictive
value
10-50%
Indications
Initial investigation for
symptomatic breast in women
(>95% palpable,
older than 35 years and for
screening; investigation of choice
for microcalcification
(90%
palpable)
(94%
palpable)
Ultrasonography 68-97% (palpable)
74-94%
(palpable)
92%
(palpable)
Initial investigation for palpable
lesions in women younger than
35 years
MRI
21-97%
52%
Scarred breast, implants,
multifocal lesions, and borderline
lesions for breast conservation;
may be useful in screening highrisk women
70-83%
Lesions larger than 1 cm and
axilla assessment; may help
predict drug resistance
50% impalpable,
83-92% in women
older than 50 y)
(decreases to 35%
in dense breasts)
86-100%
(< 40%
primary
cancer)
Scintigraphy
76-95% (palpable)
62-94%
52-91%
(impalpable)
(94%
(83%
impalpable) palpable,
79%
impalpable)
PET scanning
96%
100%
Axilla assessment, scarred breast,
and multifocal lesions
(90% axillary
metastases)
Breast Biopsy
Percutaneous vacuum-assisted large-gauge core biopsy (VACNB) with image guidance is the
recommended diagnostic approach for newly diagnosed breast cancers. Core biopsies spare
the need for operative intervention (and subsequent scarring), often providing pathologic
results more quickly than surgical excisions.
Additionally, excisional biopsy, as the initial operative approach, has been shown to increase
the rate of positive margins. Thus, core biopsies for diagnosing breast cancer can eliminate
the need for additional surgeries for definitive margin control and assessment of nodal status.
The ultimate diagnostic biopsy is open excisional biopsy of a lesion, normally performed
under general anesthesia. Open excisional biopsy should be reserved for lesions where the
diagnosis remains equivocal despite imaging and less invasive assessment, or the procedure
should be used for benign lesions that the patient chooses to have removed. A wide clearance
of the lesion is usually not the goal in diagnostic biopsies, thus avoiding unnecessary
distortion of the breast. Ongoing audit is essential to help reduce an excessive benign-tomalignant biopsy ratio.
Histology
Breast cancers usually are epithelial tumors of ductal or lobular origin (see the images
below). The following features are all important in deciding on a course of treatment for any
breast tumor:
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Size
Status of surgical margin
Presence or absence of estrogen receptors and progesterone receptors
Nuclear and histologic grade
DNA content
S-phase fraction
Vascular invasion
Tumor necrosis
Quantity of intraductal component
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. Grade I tumors are
associated with a 10-year survival rate of 85%, whereas the survival rate falls to 45% for
grade III tumors. Microscopic criteria for grading are shown in Table 3, below.
Table 3. Grading System in Invasive Breast Cancer (Modified Bloom and Richardson) (Open
Table in a new window)
Score
A. Tubule formation
1
2
3
>75%
10-75%
< 10%
7-12
>12
Slightly enlarged
Markedly enlarged
B. Mitotic count per high-power field < 7
(microscope- and field-dependent)
C. Nuclear size and pleomorphism
Near normal
Little variation Moderate variation Marked variation
Grade I cancer if the total score (A + B + C) is 3-5
Grade II cancer if the total score (A + B + C) is 6 or 7
Grade III cancer if the total score (A + B + C) is 8 or 9
Ductal carcinoma in situ
Increased use of screening mammography has resulted in a dramatic increase in the detection
of DCIS. Approximately 64,000 cases of DCIS are diagnosed annually in the US. Ninety
percent of DCIS cases are identified on mammography as suspicious calcifications, linear,
clustered, segmental, focal, or mixed distribution. DCIS is divided into comedo (ie,
cribriform, micropapillary, solid) and noncomedo subtypes, which provides additional
prognostic information on the likelihood of progression or local recurrence (see the images
and Table 4 below).
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.
Table 4. Ductal Carcinoma in Situ Subtypes (Open Table in a new window)
DCIS Characteristic
Comedo Noncomedo
Nuclear grade
High
Low
Estrogen receptor
Negative
Positive
HER2 overexpression Present
Absent
Distribution
Continuous Multifocal
Necrosis
Present
Absent
Local recurrence
High
Low
Prognosis
Worse
Better
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 2 images below). Over the last 25 years, LCIS incidence has doubled and is currently
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.
Breast cancer. Lobular carcinoma in situ. Enlargement and
expansion of lobule with monotonous population of neoplastic cells.
Infiltrating ductal carcinoma
Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor and has a
tendency to metastasize via lymphatics. This lesion, which accounts for 75% of breast
cancers, has no specific histologic characteristics other than invasion through the basement
membrane, as seen in 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 the fibrous stroma.
Infiltrating lobular carcinoma
Infiltrating lobular carcinoma has a much lower incidence and comprises less than 15% of
invasive breast cancer. It is characterized histologically by the “Indian 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 more multifocal. Despite
this, the prognosis is comparable to that of ductal carcinoma.
Medullary carcinoma
Medullary carcinoma is relatively uncommon (5%) and generally occurs in younger women.
Most patients present with a bulky palpable mass with axillary lymphadenopathy. Diagnosis
of this type of breast cancer depends on the following histologic triad:
1. Sheets of anaplastic tumor cells with scant stroma
2. Moderate or marked stromal lymphoid infiltrate
3. Histologic circumscription or a pushing border
DCIS may be observed in the surrounding normal tissues. ER, PR, and HER2 are typically
negative, and TP53 is commonly mutated.
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 with 2 main forms, type 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 following image), whereas type
B is a distinct variant with endocrine differentiation.
DCIS is not a frequent occurrence, although it may be found. Most cases are ER- and PRpositive, but HER2 overexpression is rare. Additionally, these carcinomas predominantly
express glycoproteins MUC2 and MUC6. Overall, patients with mucinous carcinoma have an
excellent prognosis (>80% 10-year survival).
Breast cancer. Colloid (mucinous) carcinoma. Nests of tumor cells
in pool of extracellular mucin.
Tubular carcinoma
Tubular carcinoma of the breast is an uncommon histologic type involving 1-2% of all breast
cancers. Characteristic features of this type include a single layer of epithelial cells with lowgrade nuclei and apical cytoplasmic snoutings arranged in well-formed tubules and glands.
Tubular components comprise 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 encompasses a spectrum of histologic subtypes (see the
image below). 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.
Cystic papillary carcinoma has a low mitotic activity, which results in a more indolent course
and good prognosis. However, invasive micropapillary ductal carcinoma has a more
aggressive phenotype, even though approximately 70% of cases are ER-positive. A
retrospective review of 1,400 cases of invasive carcinoma identified 83 cases (6%) with at
least one component of invasive micropapillary ductal carcinoma.
Additionally, lymph node metastasis is seen frequently in this subtype (70-90% incidence),
and the number of lymph nodes involved appears to correlate with survival.
Breast cancer. Papillary carcinoma. Solid papillary growth pattern
with early cribriform and well-developed thin papillary fronds.
Metaplastic breast cancer
MBC accounts for less than 1% of breast cancer cases, tends to occur in older women
(average age of onset in the sixth decade), and has a higher incidence in blacks. 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 based on a similarity in
clinical behavior. When compared with infiltrating ductal carcinoma, MBC tumors are larger;
more rapidly growing; commonly node-negative; and typically ER-, PR-, and HER2negative.
Mammary Paget disease
MPD is relatively rare, comprising 1-4% of all breast cancers. Peak incidence is seen in the
sixth decade of life (mean age, 57 y).
This adenocarcinoma is localized within the epidermis of the nipple-areola complex and
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.
Staging
The American Joint Committee on Cancer (AJCC) staging system groups patients into 4
stages based on tumor size (T), lymph node status (N), and distant metastasis (M). See Table
5, below.
Primary tumor (T)
Tumor size definitions are as follows:

















Tx: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: (DCIS) Carcinoma in situ
Tis: (LCIS) Carcinoma in situ
Tis: Paget disease of the nipple with no tumor (Paget disease associated with a tumor is
classified according to the size of the tumor.)
T1: Tumor 2 cm or smaller in greatest diameter
T1mic: Microinvasion 0.1 cm or less in greatest dimension
T1a: Tumor >0.1 but not >0.5 cm in greatest diameter
T1b: Tumor >0.5 but not >1 cm in greatest diameter
T1c: Tumor >1 cm but not >2 cm in greatest diameter
T2: Tumor >2 cm but not >5 cm in greatest diameter
T3: Tumor >5 cm in greatest diameter
T4: Tumor of any size, with direct extension to (a) the chest wall or (b) skin only, as described
below
T4a: Extension to the chest wall, not including the pectoralis muscle
T4b: Edema (including peau d’orange) or ulceration of the skin of the breast or satellite skin
nodules confined to the same breast
T4c: Both T4a and T4b
T4d: Inflammatory disease
Regional lymph nodes (N)
Regional lymph node definitions are as follows:





Nx: Regional lymph nodes cannot be assessed (eg, previously removed)
N0: No regional lymph node metastasis
N1: Metastasis in movable ipsilateral axillary lymph node(s)
N2: Metastasis in ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent
ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node
metastasis
N2a: Metastasis in ipsilateral axillary lymph nodes fixed to one another or to other
structures





N2b: Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the
absence of clinically evident axillary lymph nodes
N3: Metastasis in ipsilateral infraclavicular or supraclavicular lymph node(s) with or without
axillary lymph node involvement, or clinically apparent ipsilateral internal mammary lymph
node(s) and in the presence of axillary lymph node
N3a: Metastasis in ipsilateral infraclavicular lymph node(s)
N3b: Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
N3c: Metastasis in ipsilateral supraclavicular lymph node(s)
Distant metastasis
Metastases are defined as follows:



Mx: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
Table 5. TNM Staging System for Breast Cancer (Open Table in a new window)
Stage
Tumor Node Metastases
Stage 0
Tis
N0
M0
Stage I
T1
N0
M0
Stage IIA T0
N1
M0
T1
N1
M0
T2
N0
M0
Stage IIB T2
N1
M0
T3
N0
M0
Stage IIIA T0
N2
M0
T1
N2
M0
T2
N2
M0
T3
N1-2 M0
Stage IIIB T4
N0
M0
T4
N1
M0
T4
N2
M0
Stage IIIC Any T N3
M0
Stage IV Any T Any N M1
Five-year survival rates are highly correlated with tumor stage, as follows:





Stage 0: 99-100%
Stage I: 95-100%
Stage II: 86%
Stage III: 57%
Stage IV: 20%
This prognostic information can guide physicians in making therapeutic decisions. Pathologic
review of the tumor tissue for histological grade along with the determination of
estrogen/progesterone receptor status and HER2 status is necessary for determining
prognosis.
Evaluation of lymph node involvement by sentinel lymph node biopsy or axillary lymph node
dissection has also been considered necessary for staging and prognosis, as recommended in
the 2009 edition of the National Comprehensive Cancer Network (NCCN) breast cancer
guidelines, but the 2011 update modifies this recommendation. The 2011 NCCN breast
cancer guidelines state that lymph node evaluation is optional in the following cases:




Strongly favorable tumors
When no result would affect the choice of adjuvant systemic therapy
Elderly patients
Patients with comorbid conditions
The 2011 NCCN guidelines state that for staging, sentinel lymph node biopsy is preferred
over axillary lymph node dissection.[6, 18] .
Additional Testing
The 2011 NCCN guidelines, like the 2009 version, recommends the following laboratory
studies for all asymptomatic women with early-stage breast cancer (stages I and II):




Complete blood cell (CBC) count with differential
Liver function tests (LFTs)
Renal function tests
Serum calcium
In addition, women with stage III (locally advanced or inflammatory breast cancer) or
symptomatic disease should have a chest x-ray or CT scan of the chest, CT scan of the
abdomen and pelvis, and bone scan for evaluation of distant metastasis. Tumor markers
(carcinoembryonic antigen [CEA] and CA15.3 or CA27.29) may also be obtained in these
patients.[6, 18]
Genetic testing for BRCA1 and BRCA2 can be performed in selected high-risk patients with a
strong family history of breast or ovarian carcinoma. However, genetic counseling and
discussion of subsequent management and treatment options should be performed before
testing.
HER2 testing
Although several methods for HER2 testing have been developed, approximately 20% of
current HER2 testing may be inaccurate; therefore, the American Society of Clinical
Oncology (ASCO) and CAP have recommended guidelines in HER2 testing to ensure
accuracy. Breast cancer specimens should initially undergo HER2 testing by a validated
immunohistochemistry (IHC) assay (ie, HercepTest, Dako, Glostrup, Denmark) for HER2
protein expression.[7] The scoring method for HER2 expression is based on the cell membrane
staining pattern and is as follows:



3+: Positive HER2 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
0 or 1+: Negative for HER2 protein expression
Breast cancer specimens with equivocal IHC should undergo validation using 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 less than 3% of invasive breast cancer specimens and those
that had previously been considered HER2 positive. Discordant results (IHC 3+/FISH
negative or IHC less than 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 not
yet been validated. The interpretation for HER2 FISH testing (HER2/CEP17 ratio and gene
copy number) is given below:



Positive HER2 amplification: FISH ratio is greater than 2.2 or HER2 gene copy is greater than
6.0
Equivocal HER2 amplification: FISH ratio of 1.8-2.2 or HER2 gene copy of 4.0-6.0
Negative HER2 amplification: FISH ratio is less than 1.8 or HER2 gene copy of less than 4.0
Go to Breast Cancer and HER2 for complete information on this topic.
Oncotype Dx assay
The Onco type Dx assay (Genomic Health, Inc, Redwood City, Calif) has been validated in
and approved by the FDA for women with early-stage, ER-positive, node-negative breast
cancer treated with tamoxifen, where the recurrence score (RS) correlated with both relapsefree 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.
Using a formula based on the expression of these genes, a recurrence score can be calculated
that correlates with the likelihood of distant recurrence at 10 years. Breast tumors with a
recurrence score of less than 18 are considered low risk; a score of 18-30 is considered
intermediate risk; and a score greater than 30 is considered high risk.
Furthermore, the Onco type Dx assay has been shown retrospectively in the National Surgical
Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 studies to predict benefit from
chemotherapy and hormonal therapy in hormone-sensitive, node-negative tumors.
Women with a low recurrence score showed a significantly greater improvement in diseasefree survival (DFS) with the addition of tamoxifen versus chemotherapy, whereas women
with a high recurrence score had a significant improvement in disease-free survival with the
addition of chemotherapy. Among women with 1-3 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 the recurrence score.
In general, results from these studies would indicate that a select group of node-positive,
hormone receptor-positive patients with a low recurrence score would not benefit from an
anthracycline-based regimen. 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] Trial, a large, prospective, randomized phase III study
sponsored by the National Cancer Institute (NCI), is addressing this important question.
Approach Considerations
Surgery is considered primary treatment for breast cancer, as many patients with early-stage
disease are cured with surgery alone. The goals of breast cancer surgery include complete
resection of the primary tumor with negative margins to reduce the risk of local recurrences,
and pathologic staging of the tumor and axillary lymph nodes for providing necessary
prognostic information. Several different types of operations are available for the treatment of
breast cancer.
Adjuvant treatment for breast cancer involves radiation therapy and a variety of
chemotherapeutic and biologic agents.
Treatment of Invasive Breast Cancer
Surgical treatment of invasive breast cancer may consist of lumpectomy or total
mastectomy.In breast cancer patients who have clinically negative nodes, surgery typically
includes sentinel lymph node dissection for staging the axilla. Go to Surgical Treatment of
Breast Cancer for more information on these topics. In addition to surgery, the use of
radiation therapy, chemotherapy, or both may be indicated.
Breast-conserving radiation therapy
The purpose of radiation therapy following breast-conserving surgery is to eradicate local
subclinical residual disease while reducing local recurrence rates by approximately 75%.
Based on results from several randomized controlled studies, radiation to the intact breast is
considered standard of care, even in the lowest-risk disease with the most favorable
prognostic features.
There are 2 general approaches used to deliver radiation therapy: conventional external beam
radiotherapy (EBRT) and partial-breast irradiation (PBI). Whole-breast radiotherapy
(WBRT) consists of EBRT delivered to the breast at a dose of 50-55 Gy over 5-6 weeks. This
is often followed by a boost dose specifically directed to the area in the breast where the
tumor was removed.
Common side effects of radiation therapy include fatigue, breast pain, swelling, and skin
desquamation. Late toxicity (lasting 6 mo or longer following treatment) may include
persistent breast edema, pain, fibrosis, and skin hyperpigmentation. Rare side effects include
rib fractures, pulmonary fibrosis, cardiac disease (left breast treatment), and secondary
malignancies such as radiation-induced sarcoma (0.5%).
Partial-breast irradiation is employed in early stage breast cancer following breast-conserving
surgery as a way of delivering larger fraction sizes while maintaining a low risk of late
effects. Several techniques that can deliver this therapy include interstitial brachytherapy
(multiple catheters placed through the breast) and intracavitary brachytherapy (a balloon
catheter inserted into the lumpectomy site [ie, MammoSite]).
Treatment is typically for 5 days, twice daily. These techniques have shown low local
recurrence rates comparable to EBRT in several nonrandomized studies.
The American Society of Breast Surgeons (ASBrS) recommends the following selection
criteria when considering patients for treatment with accelerated partial breast irradiation:





Age 45 years and older
Invasive ductal carcinoma or DCIS
Total tumor size (invasive and DCIS) 3 cm or smaller
Negative microscopic surgical margins of excision
Axillary lymph node/sentinel lymph node negative
Potential complications of partial-breast irradiation are catheter placement, followed by
removal secondary to inadequate skin spacing, infection, seroma, fibrosis, chronic pain, or
disease recurrence.
Postmastectomy radiation therapy
Clinical practice guidelines developed by ASCO along with several prospective, randomized
clinical trials recommend postmastectomy radiation therapy be performed using the following
criteria:



Positive postmastectomy margins
Primary tumors larger than 5 cm
Involvement of 4 or more lymph nodes
Patients with more than 4 positive lymph nodes should also undergo prophylactic nodal
radiation therapy at doses of 4500-5000 cGy to the axillary and supraclavicular regions. For
patients who undergo axillary lymph node dissection and are found to have no lymph node
involvement, axillary radiation therapy is not recommended.
Meta-analyses have shown postmastectomy radiation therapy combined with regional nodal
radiation therapy significantly decreases the rate of local relapse and breast cancer mortality.
Currently, the benefit of radiation therapy for women with 1-3 positive axillary lymph nodes
is uncertain, and studies are ongoing.
Adjuvant Therapy for Breast Cancer
Depending on the model of risk reduction, adjuvant therapy has been estimated to be
responsible for 35-72% of the reduction in mortality rate. Adjuvant treatment of breast cancer
is designed to treat micrometastatic disease, or breast cancer cells that have escaped the
breast and regional lymph nodes but which have not yet had an established identifiable
metastasis. Treatment is aimed at reducing the risk of future recurrence, thereby reducing
breast cancer-related morbidity and mortality. Go to Adjuvant Therapy for Breast Cancer for
more information on this topic.
Treatment of Carcinoma in Situ
Ductal carcinoma in situ
Currently, the standard treatment of DCIS is surgical resection with or without radiation.
Adjuvant radiation and hormonal therapies are often reserved for younger women, patients
undergoing lumpectomy, or comedo subtype.
Approximately 30% of women with DCIS in the US are treated with mastectomy with or
without reconstruction, 30% with conservative surgery alone, and 40% with conservative
surgery followed by whole-breast radiation therapy. Axillary or sentinel lymph node
dissection is not routinely recommended for patients with DCIS. Studies have identified
metastatic disease to the axillary nodes in 10% of patients.
In DCIS, whole-breast radiotherapy is delivered over 5-6 weeks after surgery, reducing the
local recurrence rate by approximately 60%. Roughly 50% of local recurrences are invasive
breast cancer. Meta-analyses of randomized controlled trials comparing radiation therapy
versus observation after surgery for DCIS have demonstrated slightly higher rates of
contralateral breast cancer after radiation therapy (3.85% vs 2.5%). Studies comparing
accelerated partial breast radiation given over 5 days to standard whole-breast radiotherapy
are currently under way.
Tamoxifen is the only hormonal therapy currently approved for adjuvant therapy in patients
treated with breast-conserving surgery and radiation for DCIS. Currently, a clinical trial
evaluating the role of the aromatase inhibitor anastrozole as adjuvant therapy in DCIS has
met its accrual and results are anticipated.
Lobular carcinoma in situ
The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial prospectively
studied the efficacy of tamoxifen in the prevention of breast cancer and included patients with
LCIS.[8] The researchers found a 55% risk reduction in women treated with tamoxifen.
Overall, treatment options include observation and close follow-up care with or without
tamoxifen, and bilateral mastectomy with or without reconstruction. No evidence exists of
therapeutic benefit from local excision, axillary dissection, radiotherapy, or chemotherapy.
The presence of LCIS in the breast of a woman with ductal or lobular cancer does not require
further immediate surgery on the opposite breast. Mirror biopsy of the contralateral breast,
once advocated in the treatment of LCIS, is mainly of historic interest.
Treatment of Locally Advanced and Inflammatory Breast Cancer
Originally, the reason for grouping LABC and IBC was the recognition that both diseases had
little or no chance of cure from local therapy alone, and they were considered inoperable for
that reason. The definition of locally advanced disease has broadened to include patients who
are technically operable but who have large primary tumors (>5 cm).
It is important to recognize, however, that the reasons for using neoadjuvant therapy are
different in women who have large primary tumors, in which the goal is to increase the
possibility of breast-conserving surgery, than in those who have disease that meets the
original criteria of LABC or IBC, for whom the administration of systemic treatment is
essential to make definitive local treatment possible with the intent of cure.
Because the prognosis for women with T3N0 (stage IIB) and T3N1 (stage IIIA) breast cancer
is better overall than it is for those with classically defined LABC (IIIB, IIIC) or IBC (IIIB,
T4d), it is important to know the relative proportions of patients in each category when
results of a clinical trial are reported. Not only may one expect better disease-free and overall
survival for stage IIB and IIIA patients, but also the likelihood of achieving a pathologic
complete response (pCR) from neoadjuvant treatment, a well-recognized surrogate for longterm outcome, is inversely related to tumor size.
It is also important to recognize that staging criteria in the sixth edition of the AJCC Cancer
Staging Handbook differs from its predecessors in ways that are relevant to the patient groups
discussed here: women with T3 tumors were previously considered to have stage III disease
and are so reported in the older literature; women with resectable tumors who are found to
have 4 or more involved axillary lymph nodes after initial surgery, formerly called stage II,
are currently grouped as IIIA.
The revised staging system is better for defining prognostic subgroups, but the practical
relevance of grouping together all patients who typically receive "up front" chemotherapy
remains, as their treatment outcomes are usually reported as a function of the particular
neoadjuvant program employed.
Inflammatory breast cancer
IBC is a clinical diagnosis that implies presentation with the cardinal signs of inflammation
(calor, rubor, and tumor) involving the breast, although the calor (warmth) may be subtle and
the tumor (mass) may not be appreciated as something discrete. Indeed, even when a
localized mass is apparent in IBC, the true extent of the disease (as shown by performing skin
biopsies from the surrounding, normal-appearing skin) is usually greater than apparent on
physical examination. It was originally described as having an erysipeloid border, but only a
minority of cases have this component of a raised edge.
In Western countries, the frequency of IBC is low, between 1% and 2% of all breast cancers,
but it is much higher in some parts of the world, such as northern Africa, for reasons that are
not known. IBC tends to occur at a younger age than LABC. Pathologically, it was originally
associated with the classic finding of involvement of subdermal lymphatics, although this
finding is not in itself diagnostic of IBC (it may occur with LABC as a secondary
phenomenon).
This disease is more likely to stain negatively by IHC for ER and PR, somewhat more likely
to be positive for HER2 overexpression, and both angiogenesis and lymphangiogenesis
appear to be increased by microvessel density or RNA-based gene expression arrays. Within
IBC, however, may be found the same molecular subtypes of breast cancer as originally
described for non-inflammatory breast cancer.
Locally advanced breast cancer
LABC is more common in the US than is IBC, and, by the definition used here, may account
for 10-15% of patients (this drops to about 5% if one uses the stricter definition of
inoperable). Epidemiologically, LABC is associated with lower socioeconomic class and,
probably for that reason, with black race in the US.
LABC encompasses both relatively indolent neglected tumors and those that have grown
rapidly as a result of their inherent biology. It is as heterogeneous as invasive breast cancer in
general, and, in most case series, LABC has a better long-term outcome than IBC, even when
only inoperable cases are considered.
Evaluation of lymph nodes and response
Patients with LABC or IBC with clinically positive nodes should undergo a core biopsy
before initiating chemotherapy. Those with clinically negative nodes may undergo sentinel
node biopsy before they start treatment, or sentinel node determination may be delayed until
after treatment is completed.
Theoretically, it should be preferable to perform sentinel node sampling up front, because
chemotherapy might eradicate preexistent disease in the sentinel node and result in a false
negative, and/or altered lymphatic drainage in large tumors might affect accuracy of the
procedure. However, data from the NSABP B-27 neoadjuvant trial suggest that the falsenegative rate for sentinel node biopsies performed after neoadjuvant chemotherapy is about
11%, comparable to the false-negative rate for patients undergoing initial resection.[9]
In general, the best single test to evaluate the status of measurable tumor is ultrasonography,
preferably done by the same operator to avoid interobserver variability. The mass often
appears larger on physical examination than it does on sonogram, which can more effectively
discriminate hypoechoic masses from surrounding stroma and/or hematoma. In IBC, MRI
may be an important adjunct to response assessment. The role of PET scanning in the routine
assessment of response remains to be determined.
No current imaging technique appears to be highly accurate for the prediction of complete
pathologic response. Thus, the purpose of regular size assessment is to exclude continuation
of therapy in a patient with a growing tumor (seen in < 5% with the initial treatment) and to
suggest when maximal response of grossly evident disease has been achieved, as this may be
the optimal time to proceed to resection.
Systemic Treatment of Metastatic Breast Cancer
Marked advancements are being made in the treatment of early stage breast cancer, but many
women still develop recurrence and metastasis. In addition, 5-10% of breast cancer patients
have metastatic disease at presentation. Although treatments for metastatic breast cancer
continue to improve, there remains no cure once distant metastases develop.
Furthermore, although occasional patients with metastatic breast cancer benefit from surgical
resection for an isolated recurrence and many require radiation therapy for palliation at a
specific site (or definitive treatment of brain metastasis), in general, recurrent or metastatic
breast cancer must be approached systemically such that the therapeutic effect reaches all
sites of disease. There are 2 main interventions: hormone therapy and chemotherapy. Go to
Adjuvant Therapy for Breast Cancer for more information on these topics.
Surgery in Metastatic Breast Cancer Treatment
As modern systemic chemotherapy has become more effective, some patients with intact
primary tumors and metastasis can have long-term stable distant disease or even no evidence
of residual metastatic disease following treatment. Recently, interest has increased in the role
of surgical intervention for the intact primary tumor for these metastatic breast cancer
patients. Several single-institution cohort and retrospective studies have examined this
question, concluding that surgical resection of the intact primary tumor may provide a
survival advantage.
It is still unknown whether a selection bias affects the findings of a survival advantage in
favor of surgery, and no prospective, randomized control trial has ever been performed to
address this question. However, the dogma to never operate in the setting of metastatic
disease has certainly been dispelled in favor of critical evaluation of whether surgically
achieved local control can lead to improved survival as a part of multimodal treatment.
Pharmacologic Breast Cancer Risk Reduction
Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene (Evista), are
approved for reduction of breast cancer risk in high-risk women. Two NSABP trials (NSABP
P1 and P2) showed that tamoxifen reduced the risk of DCIS and invasive breast cancer by 3050%. In the NSABP P2 prevention trial, raloxifene was as effective as tamoxifen in reducing
the risk of invasive breast cancer but was 30% less effective than tamoxifen in reducing the
risk of DCIS.
ACOG has updated its practice guidelines regarding pharmacologic intervention (eg,
tamoxifen, raloxifene, aromatase inhibition) for breast cancer risk reduction.[10] Some of the
highlights of the expert panel's literature review are as follows:
Tamoxifen use for 5 years reduces risk of breast cancer for at least 10 years in premenopausal
women, particularly ER-positive invasive tumors. Women 50 years or younger have few
adverse effects with tamoxifen, and vascular/vasomotor adverse effects do not persist post
treatment.
Tamoxifen and raloxifene are equally effective in reducing risk of ER-positive breast cancer
in postmenopausal women. Raloxifene is associated with lower rates of thromboembolic
disease, benign uterine conditions, and cataracts than tamoxifen. Evidence does not exist on
whether either agent decreases mortality from breast cancer.
Recommendations include the following:



For women with increased risk for breast cancer, offer tamoxifen (20 mg/d for 5 y) to reduce
the risk of invasive ER-positive breast cancer
In postmenopausal women, raloxifene (60 mg/d for 5 y) may also be considered
Aromatase inhibitors (eg, anastrozole, exemestane, letrozole), fenretinide, or other SERMs
are not recommended for use outside of a clinical trial
Long-term Monitoring
Follow-up guidelines
There is no consensus among oncologists as to the appropriate and optimal follow-up for
long-term breast cancer survivors. The majority of relapses, both local and distant, occur
within the first 3 years, especially in higher risk and ER-negative patients. The 2007 ASCO
guidelines do not support the use of tumor biomarkers, including CEA, CA15.3, and
CA27.29, for monitoring patients for recurrence after primary breast cancer therapy.
Table 6, below, lists the NCCN’s recommendations for breast cancer patients in the adjuvant
setting.
Table 6. Follow-up Recommendations for Breast Cancer Survivors per NCCN Guidelines
(Open Table in a new window)
Intervention*
Year 1
History and physical examination q3-4 mo
Mammography
Year 2 Year 3-5 Year 6+
q4 mo
q6 mo
Annually
Annually (or 6 mo after Annually Annually Annually
post-BCS irradiation)
Chest x-ray
NR
NR
NR
NR
Pelvic examination†
Annually
Annually Annually Annually
Bone density‡
q1-2 y
BCS = breast-conserving surgery; NR = not recommended.
*
Bone scan, blood counts, LFTs, and tumor markers are not routinely recommended
and should be performed if clinically indicated.
†
For patients with an intact uterus on tamoxifen.
‡
For patients at risk for osteoporosis.
Postsurgical imaging
Women who have had surgery for breast cancer may still require breast cancer screening with
mammography. If a woman had a total mastectomy, then the other breast requires yearly
follow-up, because she is still at higher risk of developing cancer in the remaining breast. If
she had subcutaneous mastectomy, partial mastectomy, or lumpectomy, then that breast itself
requires follow-up mammography.
The first mammogram is best performed 6 months postoperatively to provide a baseline for
the new postoperative and radiation changes. Thereafter, mammography may be performed
every 6-12 months for screening and follow-up. Go to Postsurgical Breast Imaging for more
information on this topic.
Monitoring of metastatic disease
Recommendations for monitoring disease response in the metastatic setting vary. In general,
monthly evaluations consisting of a history and physical examination to evaluate progression
of disease and toxicities are reasonable.
Tumor markers, such as CEA, CA15.3, and CA27.29, can be used in conjunction with
diagnostic imaging, history, and physical examination for monitoring while on active therapy.
CA15.3 and CA27.29 levels correlate with the course of disease in 60-70% of patients,
whereas CEA levels correlate in 40% of patients.
However, data are insufficient to recommend the use of CEA, CA15.3, or CA27.29 alone for
monitoring response to treatment. Caution should be used when interpreting rising CEA,
CA15.3, or CA27.29 levels during the first 4-6 weeks of a new therapy, as spurious early
rises may occur.
Standardized guidelines for imaging are not yet established and should be tailored to each
patient. In general, CT scanning (chest, abdomen, and pelvis), MRI, bone scanning, or
PET/CT scanning are performed when symptoms change or tumor markers rise.
Circulating tumor cells are cells present in the blood that possess antigenic or genetic
characteristics similar to a primary tumor type. The FDA has recently approved the
CellSearch System (Veridex, Raritan, NJ) for the detection of circulating tumor cells in
patients with metastatic breast cancer. This system captures circulating tumor cells using an
immunomagnetic process with an epithelial cell adhesion molecule coated with magnetic
beads and cytokeratin antibodies.
A circulating tumor cell is identified when it is cytokeratin- and DAPI-positive but CD45negative. Studies done by Cristofanilli using the CellSearch System have shown a prognostic
utility and predictive use for circulating tumor cells in metastatic breast cancer patients.[11]
Circulating tumor cell–positive patients (>5 CTCs/7.5 mL blood) were shown to have a
worse progression-free survival (17%) and overall survival than the circulating tumor cell–
negative patients (36%).
The presence of more than 5 circulating tumor cells before hormonal or chemotherapy
treatment and following the first cycle of treatment also predict a worse outcome. However,
studies to date have used small sample sizes, and no data have shown that use of circulating
tumor cell testing affects overall survival or improves on quality of life.
Per ASCO guidelines, the use of circulating tumor cell testing in breast cancer is not
recommended for the diagnosis of breast cancer, nor should test results influence treatment
decisions. The Southwest Oncology Group (SWOG) is conducting a large, prospective trial to
address the clinical use of circulating tumor cells in breast cancer.
Medication Summary
Adjuvant treatment for breast cancer involves radiation therapy and a variety of
chemotherapeutic and biologic agents. Adjuvant treatment of breast cancer is designed to
treat micrometastatic disease, or breast cancer cells that have escaped the breast and regional
lymph nodes but which have not yet had an established identifiable metastasis. Treatment is
aimed at reducing the risk of future recurrence, thereby reducing breast cancer-related
morbidity and mortality.
The 2011 NCCN guidelines include recommendations for the use of two new drugs,
denosumab and eribulin, both of which received FDA approval in 2010. The 2011 guidelines
support the use of biologic denosumab for the prevention of skeletal events. When compared
with zoledronic acid, denosumab, which is administered subcutaneously, delayed the onset of
skeletal events by 8% and the time to multiple skeletal events by 23%. In addition, toxicities,
such as hypercalcemia and renal failure, were less frequent. The guidelines recommend
eribulin, an antimicrotubular drug, as the "preferred single agent" in chemotherapy treatment
for women with advanced disease. Trials have shown significant improvement in survival
when compared with patients receiving "treatment by physician's choice."[18]
In June 2011, an FDA panel recommended that bevacizumab (Avastin) no longer be used to
treat breast cancer, and in November officially rescinded its approval.
Antineoplastic Agents
Class Summary
Various chemotherapy regimens are recommended for the treatment of breast cancer.
Common regimens include docetaxel, cyclophosphamide, doxorubicin, carboplatin,
methotrexate, and trastuzumab, among others.
View full drug information
Docetaxel (Taxotere)
Docetaxel is indicated for use in combination with doxorubicin and cyclophosphamide for
adjuvant treatment of operable node-positive breast cancer. It is also indicated for locally
advanced or metastatic breast cancer after failure of prior chemotherapy. It is a semisynthetic
taxane, a class of drugs that inhibits cancer cell growth by promoting assembly and blocking
the disassembly of microtubules, thereby preventing cancer cell division, leading to cell
death.
View full drug information
Carboplatin
Carboplatin is an analog of cisplatin. This is a heavy metal coordination complex that exerts
its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to
interstrand and intrastrand DNA cross-links and inhibition of DNA replication. It binds to
protein and other compounds containing the SH group. Cytotoxicity can occur at any stage of
the cell cycle, but the cell is most vulnerable to the action of these drugs in the G1 and S
phases. It has the same efficacy as cisplatin, but with a better toxicity profile. The main
advantages over cisplatin include less nephrotoxicity and ototoxicity, not requiring extensive
prehydration, and less likelihood of inducing nausea and vomiting; however, it is more likely
to induce myelotoxicity.
View full drug information
Doxorubicin (Liposomal)
Doxorubicin is a cytotoxic anthracycline that inhibits topoisomerase II and produces free
radicals, which may cause destruction of DNA. It blocks DNA and RNA synthesis by
inserting between adjacent base pairs and binding to the sugar-phosphate backbone of DNA,
which causes DNA polymerase inhibition. It binds to nucleic acids, presumably by specific
intercalation of the anthracycline nucleus with the DNA double helix. It is also a powerful
iron chelator. The iron-doxorubicin complex induces production of free radicals that can
destroy DNA and cancer cells. Maximum toxicity occurs during the S phase of the cell cycle.
View full drug information
Capecitabine (Xeloda)
Capecitabine is a pyrimidine analog, which, in combination with docetaxel, is indicated for
metastatic breast cancer after the failure of prior anthracycline-containing chemotherapy.
Monotherapy with capecitabine is indicated for the treatment of patients with metastatic
breast cancer resistant to both paclitaxel and an anthracycline–containing chemotherapy
regimen or resistant to paclitaxel and for whom further anthracycline therapy is not
indicated.[12]
View full drug information
Paclitaxel
Paclitaxel is indicated for adjuvant treatment of node-positive breast cancer (ie, administered
sequentially to doxorubicin-containing combination chemotherapy). Dose-dense regimens
(ie, more frequent administration) are currently being studied and resulting disease-free
interval examined. Mechanisms of action are tubulin polymerization and microtubule
stabilization, which, in turn, inhibit mitosis and may result in the breakage of chromosomes.
View full drug information
Gemcitabine (Gemzar)
Gemcitabine is a pyrimidine analog that is metabolized intracellularly to an active nucleotide.
It inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for
incorporation into DNA. It is cell-cycle specific for the S phase. Gemcitabine, in combination
with paclitaxel, is indicated as a first-line treatment for metastatic breast cancer after the
failure of prior anthracycline-containing adjuvant chemotherapy (unless anthracyclines were
clinically contraindicated).
View full drug information
Cyclophosphamide
Cyclophosphamide is chemically related to nitrogen mustards. It is indicated for use in
patients with carcinoma of the breast. It is activated in the liver to its active metabolite, 4hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-ornone type of reaction. As an alkylating agent, the mechanism of action of the active
metabolites may involve cross-linking of DNA, which may interfere with the growth of
normal and neoplastic cells.
View full drug information
Methotrexate (Trexall)
Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, thereby hindering
DNA synthesis and cell reproduction in malignant cells. Methotrexate is indicated alone or in
combination with other anticancer agents for the treatment of breast cancer.
View full drug information
Epirubicin (Ellence)
Epirubicin is indicated as a part of adjuvant therapy in patients with evidence of axillary-node
tumor involvement following resection of primary breast cancer.[13] It is a cell cycle phase
inhibitor–nonspecific anthracycline derivative of doxorubicin with maximum cytotoxic
effects on the S and G2 phases of the cell cycle.
View full drug information
Vinorelbine (Navelbine)
Vinorelbine is a semisynthetic vinca alkaloid that inhibits tubulin polymerization during the
G2 phase of cell division, thereby inhibiting mitosis.
Monoclonal Antibodies
Class Summary
Monoclonal antibodies have been engineered to react against specific antigens on cancer
cells, which can help to enhance the patient’s immune response and prevent cancer cell
growth.
View full drug information
Denosumab
Monoclonal antibody that specifically targets RANK ligand, an essential regulator of
osteoclasts. Indicated to prevent SREs (ie, bone fractures and pain) in patients with bone
metastases from solid tumors.
View full drug information
Trastuzumab (Herceptin)
Trastuzumab is a monoclonal antibody that binds to the extracellular human epidermal
growth receptor 2 (HER2). It mediates antibody-dependent cellular cytotoxicity against cells
that overproduce HER2. It is indicated for adjuvant treatment of HER2-overexpressing, nodepositive or node-negative (ER/PR negative or with one high-risk feature) breast cancer, as
part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either
paclitaxel or docetaxel; with docetaxel and carboplatin; or as a single agent following
multimodality anthracycline-based therapy. It is also used in combination with paclitaxel for
first-line treatment of HER2-overexpressing metastatic breast cancer and as a single agent for
treatment of HER2-overexpressing breast cancer in patients who have received one or more
chemotherapy regimens for metastatic disease.[14]
Tyrosine Kinase Inhibitors
Class Summary
Tyrosine kinase inhibitors play an important role in the modulation of growth factor
signaling. They are commonly combined with other forms of chemotherapy or radiation
therapy.
View full drug information
Lapatinib (Tykerb)
Lapatinib is a 4-anilinoquinazoline kinase that inhibits intracellular tyrosine kinase domains
of epidermal growth factor receptors (EGFR [ErbB1]) and HER2 (ErbB2). It is indicated in
combination with capecitabine for advanced or metastatic breast cancer with tumors that
over-express HER2 for which previous therapy (ie, anthracycline, taxane, and trastuzumab)
was not effective. It is also used in combination with letrozole for the treatment of
postmenopausal women with hormone receptor–positive metastatic breast cancer tumors that
over expresses the HER2 receptor for whom hormonal therapy is indicated.[15]
Aromatase Inhibitors
Class Summary
Aromatase inhibitors play a role in adjuvant therapy in breast cancer. These agents work by
inhibiting aromatase, the enzyme responsible for converting other steroid hormones into
estrogen.
View full drug information
Anastrozole (Arimidex)
Anastrozole significantly lowers serum estradiol concentrations by inhibiting the conversion
of adrenally generated androstenedione to estrone. It is used as first-line treatment of breast
cancer in postmenopausal women with hormone receptor–positive or hormone receptor–
unknown locally advanced or metastatic disease. It is also used to treat advanced breast
cancer in postmenopausal women with disease progression following tamoxifen therapy.
View full drug information
Letrozole (Femara)
Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system. It inhibits
the conversion of androgens to estrogens. Letrozole is indicated for the adjuvant treatment of
postmenopausal women with hormone receptor–positive early breast cancer. It is also used
for first-line treatment of postmenopausal women with hormone receptor–positive or
hormone receptor–unknown locally advanced or metastatic breast cancer. It is also indicated
for the treatment of advanced breast cancer in postmenopausal women with disease
progression following antiestrogen therapy and for the extended adjuvant treatment of early
breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen
therapy.[16]
View full drug information
Exemestane
Exemestane elicits irreversible steroidal aromatase inactivation by acting as a false substrate
for the aromatase enzyme. It binds irreversibly to the aromatase enzyme active site, causing
inactivation (ie, suicide inhibition). It significantly lowers circulating estrogen concentrations
in postmenopausal women. It differs from tamoxifen in that it inhibits estrogen production,
whereas tamoxifen inhibits estrogen at the receptor site. It is indicated for advanced breast
cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.
Bisphosphonate Agents
Class Summary
Bisphosphonates are complementary to chemotherapy and hormone therapy because they
may lessen the damage to bone from metastatic disease. Bisphosphonates inhibit osteoclast
function and reduce the resorption of bone.
View full drug information
Zoledronic Acid (Zometa, Reclast)
Zoledronic acid inhibits bone resorption, possibly by acting on osteoclasts or osteoclast
precursors.
Selective Estrogen Receptor Modulators (SERMs)
Class Summary
SERMs stimulate or inhibit the estrogen receptors of various target tissues. Examples of
SERMs include tamoxifen, raloxifene, and toremifene.
View full drug information
Tamoxifen
SERMs stimulate or inhibit the estrogen receptors of various target tissues. Examples of
SERMs include tamoxifen, raloxifene, and toremifene.
View full drug information
Raloxifene (Evista)
Raloxifene is a selective nonsteroidal benzothiophene, estrogen receptor modulator. It is
indicated for risk reduction for invasive breast cancer in postmenopausal women with
osteoporosis. In addition, it is indicated for risk reduction in invasive breast cancer in
postmenopausal women at high risk of invasive breast cancer.
View full drug information
Toremifene (Fareston)
Toremifene is a nonsteroidal triphenylethylene derivative that binds to estrogen receptors. It
may exert estrogenic activities, antiestrogenic activities, or both activities. It is indicated for
metastatic breast cancer in postmenopausal women with estrogen-receptor–positive or
unknown tumors.[17]
Antimicrotubular agent
Class Summary
May consider use in patients who have received at least 2 chemotherapeutic regimens for
metastatic disease.
View full drug information
Eribulin (Halaven)
Microtubule inhibitor. Inhibits growth phase of microtubules, leading to G2/M cell-cycle
block, disruption of mitotic spindles, and, ultimately, apoptotic cell death.
Indicated for metastatic breast cancer in patients who have previously received at least 2
chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have
included an anthracycline and a taxane in either the adjuvant or metastatic setting.
Antineoplastic Agent, Monoclonal Antibody
Class Summary
The NCCN 2011 guidelines still recommend bevacizumab for targeted therapy[18] despite
concerns expressed by the FDA.[19, 20]
View full drug information
Bevacizumab
Indicated as a first-line treatment for metastatic colorectal cancer. Murine derived
monoclonal antibody that inhibits angiogenesis by targeting and inhibiting vascular
endothelial growth factor (VEGF). Inhibiting new blood vessel formation denies blood,
oxygen, and other nutrients needed for tumor growth. Used in combination with standard
chemotherapy.
References
1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. Sep-Oct
2010;60(5):277-300. [Medline]. [Full Text].
2. American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Available at
http://www5.cancer.org/downloads/STT/F861009_final%209-08-09.pdf. Accessed
January 5, 2010.
3. Dawood S, Broglio K, Gonzalez-Angulo AM, Buzdar AU, Hortobagyi GN, Giordano
SH. Trends in survival over the past two decades among white and black patients with
newly diagnosed stage IV breast cancer. J Clin Oncol. Oct 20 2008;26(30):4891-8.
4. Taillefer R. The role of 99mTc-sestamibi and other conventional
radiopharmaceuticals in breast cancer diagnosis. Semin Nucl Med. Jan 1999;29(1):1640.
5. Weir L, Worsley D, Bernstein V. The value of FDG positron emission tomography in
the management of patients with breast cancer. Breast J. May-Jun 2005;11(3):204-9.
6. [Guideline] National Comprehensive Cancer Network Practice Guidelines. Invasive
Breast Cancer. 2009. (Registered Users Only). [Full Text].
7. [Guideline] Wolff AC, Hammond ME, Schwartz JN, et al. American Society of
Clinical Oncology/College of American Pathologists guideline recommendations for
human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. Jan 1
2007;25(1):118-45.
8. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast
cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.
J Natl Cancer Inst. Sep 16 1998;90(18):1371-88.
9. Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative
docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable
breast cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J
Clin Oncol. May 1 2006;24(13):2019-27. [Medline].
10. [Best Evidence] [Guideline] Visvanathan K, Chlebowski RT, Hurley P, Col NF,
Ropka M, Collyar D, et al. American Society of Clinical Oncology clinical practice
guideline update on the use of pharmacologic interventions including tamoxifen,
raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol. Jul
1 2009;27(19):3235-58.
11. Cristofanilli M. Circulating tumor cells, disease progression, and survival in
metastatic breast cancer. Semin Oncol. Jun 2006;33(3 Suppl 9):S9-14.
12. Xeloda [package insert]. South San Francisco, Calif: Genentech; November 2009.
13. Ellence [package insert]. New York, NY: Pfizer; February 2007.
14. Herceptin [package insert]. South San Francisco, Calif: Genentech; October 2010.
15. Tykerb [package insert]. Research Triangle Park, NC: GlaxoSmithKline; January
2010.
16. Femara [package insert]. East Hanover, NJ: Novartis; April 2010.
17. Fareston [package insert]. Memphis, Tenn: GTX; December 2004.
18. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in
Oncology. Breast Cancer, v.2.2011. Available at
http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed June 3
2011.
19. The U.S. Food and Drug Administration. FDA begins process to remove breast cancer
indication from Avastin label. FDA NEWS RELEASE: Dec. 16, 2010. Available at
http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm237172.htm.
Accessed July 15, 2011.
20. The U.S. Food and Drug Administration. Postmarket Drug Safety Information:
Avastin (bevacizumab) Information, Update, 6/29/2011. Available at
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsa
ndProviders/ucm193900.htm. Accessed July 15, 2011.