Breast cancer is the most frequently diagnosed cancer in women in the United States, accounting

for an estimated 226,870 new cases (163,570 invasive cancers and 63,300 in situ carcinomas) and
39,510 deaths in 2012.

 In the United States, the age-specific incidence of breast cancer increases with age, to a
lifetime risk of breast cancer of 1 in 8 (to 110 years of age); by age 40 years, approximately
1 in 203 women will have been diagnosed with breast cancer annually; at 60 years of age,
the figure is 1 in 28 women.
 Age, family history, and both endogenous and exogenous ovarian hormone exposure have
an important effect on risk and have been incorporated into models that predict individual
risk of breast cancer; diet, alcohol use, and other factors play a smaller role.
 Inherited mutations in BRCA1, BRCA2, PTEN, and TP53 play a role in the development of
breast cancer and can be directly tested in individuals.
 Although breast cancer is the leading cause of cancer for women in the United States
(overall incidence 121 per 100,000 women) fol- lowed by lung cancer (overall incidence
55.8 per 100,000 women), lung cancer was the leading cause of cancer death (40.1 per
100,000 women) followed by breast cancer (23.5 per 100,000 women) between 2004 and

2008.5 Around the world, there are large variations in incidence, mortality, and survival,
which may be a result of several underlying complex factors, including age, ethnicity, diet,

and lifestyles (including reproductive issues such as age at first birth and breastfeeding).1
Breast cancer is increasing in less-developed coun- tries, supposedly related to changes in
lifestyle factors.

Despite a lifetime probability currently estimated as 1 in 8 (in women who live to be 110 years of
age) for breast cancer, only 30% of all women have one or more identifiable risk factors. Although
these risk factors affect the parameters for breast cancer screening, current screening and education
programs must include all women. The goal of breast cancer screening is early detection that will
lead to a reduc- tion in mortality.
During the last 40 years, an intense effort has been mounted to evaluate the efficacy of
mammography, clinical breast examination, and patient self-examination as tools for breast cancer
screening.

‘Triple assessment’ comprises physical examina- tion, mammography and ultrasonography.

Mammography

This comprises radiographic examination of the breasts using low energy X-rays to allow defini-
tion of the soft tissue detail and breast architec- ture. Two views are taken of each breast, usually
in craniocaudal and oblique projections. These may substantiate the clinical diagnosis of carci-
noma, detect ductal carcinoma in situ in both

the affected and contralateral breast, and local- ize the tumour, to assist the planning of a biopsy
or definitive surgical procedure. Carci- noma is suggested by an irregular mass lesion containing
areas of microcalcification, some- times with distortion of the surrounding breast architecture (Fig.
8.13).

Breast ultrasound

This enables the radiologist to determine whether a lump is solid or cystic, the former being more
likely to be malignant, and facili- tates fine needle aspiration or needle biopsy of small lumps under
direct vision, reducing the risk of a geographical miss and thereby increas- ing the sensitivity of
the procedure. It provides images that are complementary to those obtained by mammography

Magnetic resonance imaging

This is reserved for the investigation of more difficult cases, e.g. a suspicious lump arising in a
breast augmented with a tissue expander or sil- icon implant, where mammography can be
impractical. It is also useful in excluding multi- focal disease in mammographically dense breasts
and in excluding occult contralateral breast cancer in those with invasive lobular carcinoma.

Fine needle aspiration (FNA) cytology

This is a rapid, safe, relatively non-traumatic procedure which can be performed at an outpa- tient
consultation and can provide a tissue diag- nosis within hours. It should be performed whenever a
palpable lump or suspicious area of induration is found, and is applicable to the pri- mary tumour,
regional lymph nodes or suspi- cious skin lesions. Small, impalpable lesions might have to be
localized by stereotactic mam- mogram or ultrasound. It cannot, however, dis- tinguish a focus of
in situ carcinoma from invasive carcinoma, and does not allow accurate grading of the tumour.

Figure 8.15 Specimen radiograph showing the tumour excised with a good margin of clearance all
round. The radio-opaque markers allow the pathologist to orientate the specimen.

Needle biopsy

This is performed under local anaesthetic and is a little more traumatic than FNA but gives a
core(s) of tissue for histological analysis. This may allow a preoperative diagnosis of in situ versus
invasive carcinoma, a preliminary grad- ing and determination of hormone receptor status.

Nipple discharge cytology

This is useful in women presenting with a bloody nipple discharge in the absence of a pal- pable
lump.

Excision biopsy

An excision biopsy is mandatory when it is not possible to obtain a tissue diagnosis by FNA or
core biopsy. The procedure is usually performed under general anaesthetic and the specimen can
be sent for instant frozen section so that, if a more radical operation is deemed necessary, it can be
performed immediately. Small, impalpa- ble lesions are first localized with a ‘guidewire’ under
radiological control, which can be used to determine which piece of tissue should be excised. A
specimen radiograph (Fig. 8.15) is useful to confirm peroperatively that the area under suspicion
has been fully excised.

Exclusion of metastatic disease

The results of these investigations may influ- ence the treatment planned, offer useful prog- nostic
information and provide a valuable baseline assessment, which may be of assistance in the future
care of the patient.

 CT scan of the brain, thorax, abdomen and pelvis

 isotope bone scan
 serum CA 15-3 breast cancer tumour marker assay. A very high preoperative level or
persistently high level after surgery may suggest distant metastatic disease.

There is, however, little evidence that rou- tinely performing such screening investigations
in asymptomatic patients is either clinically useful or cost effective, but they should be per-
formed if there is any clinical suspicion of metastases at these sites and should be consid-
ered in high-risk individuals (e.g. T3/T4 cancers, or those with four or more axillary lymph
nodes).

Screening

Screening should permit the diagnosis of a higher proportion of early stages of the disease. As
early stage at diagnosis is an important favourable prognostic factor, and breast cancer has a
defined non-invasive phase that is readily detectable by imaging; this should translate into a
reduction in mortality from invasive breast cancer.

Breast self-examination (BSE) should be rou- tinely practised by women at the same time each
month to take account of the variation in breast size and consistency with the menstrual cycle.
However, to date BSE has not conclusively been shown to have decreased breast cancer mortality
and there has been concern as to the stress of such a practice, together with the inevitably high
false positive rate and false negative rate.

Mammography is a sensitive means of detect- ing carcinomas, often before the lump is palpable
by the patient or clinician, thereby facilitating the detection of early breast cancers with a par-
ticularly good prognosis. In the United Kingdom the National Breast Screening Programme
screens all women aged 50–70 with 3-yearly mammograms. This age range will be extended to
47–73 over the next few years. Women older than this can be screened on request. Such a pro-
gramme should result in a mortality reduction of 20–30 per cent. There is at present no consensus
as to what age premenopausal women should be included in a screening programme, as they tend
to have dense breasts, which can obscure the radiological signs of early breast cancers; studies to
date have indicated a much smaller impact on survival than in the >50 years age group. How- ever,
young women with a family history of breast cancer should be offered regular clinical assessments
and mammographic screening at an earlier age. Digital mammography seems to lead to fewer false
positive results that traditional film-based mammography and is superior for young women with
dense breasts. Ultrasonogra- phy is a poor substitute for mammography. In younger women with
dense breasts, particularly those with BRCA gene mutations, magnetic res- onance mammography
is the optimum screening modality.

Patients with a strong family history of breast cancer should be referred to a specialist genetics
clinic for risk assessment, counselling and identi- fication of other susceptible family members.
Those shown (by gene testing or by statistical modelling) to be BRCA gene mutation carriers are
at sufficient lifetime risk of developing breast cancer to be considered for bilateral mastectomy,
which very substantially reduces the risk, although it does not eliminate it completely.

Breast cancer is sufficiently common to make prevention a worthwhile exercise. Any method of
prevention must be easy to comply with, free of short- and long-term adverse effects and be cost
effective. The difference in dietary fat intake between the Western world and Africa and Asia
contributes to the geographical varia- tion in incidence. A reduction in the proportion of daily
calories obtained from dietary fat could make a significant impact on the incidence of breast
cancer. Dietary manipulation has the advantage of being inherently cost effective, and can reduce
morbidity and mortality from cardiovascular and cerebrovascular disease and colorectal cancer.
Uncertainty exists as to when such a dietary adjustment should be instituted and for how long,
although its other advantages make it desirable to make it a lifelong commit-

ment. Reducing body mass index and alcohol consumption, and regular strenuous exercise may
all help prevent breast cancer, although this is yet to be proven in prospective trials.

Breast cancer is one of the few malignant dis- eases for which a large randomized trial has shown
that chemoprevention is not only feasi- ble but also effective. Tamoxifen 20 mg daily as adjuvant
therapy has been conclusively shown to decrease the risk of contralateral breast cancer. This
observation has been extrapolated to the prevention setting where a large (15 000 women) placebo-
controlled, double-blind, ran- domized trial has shown this regimen to signifi- cantly reduce the
risk of developing DCIS and invasive breast cancer. There is an increased risk of thromboembolic
disease and endometrial cancer in women receiving tamoxifen. Tamox- ifen incidentally reduces
cholesterol levels and helps maintain bone mineral density in post- menopausal women, and could
therefore have additional health benefits. The osteoporosis- prevention drug raloxifene has also
been shown to reduce substantially the risk of developing breast cancer, and has the advantage of
not causing hyperstimulation of the endometrium. The aromatase inhibitor anastrozole also
reduces the risk of contralateral breast cancer in women receiving the drug as treatment for
metastatic breast cancer. Anastrozole could therefore be a promising prevention strategy for
postmenopausal women.

Diagnostic Imaging After Screening Mammography Recall

Diagnostic Mammography: Screening mammography consists of 2 standard x-ray images of each

breast, whereas a diagnostic mammogram includes additional views, such as spot compression
views or magnification views, to investigate the finding in question. Diagnostic mammography is
associated with higher sensitivity but lower specificity as compared with screening
mammography. Digital breast tomosynthesis may replace traditional diagnostic mammographic
imaging in certain situations.7-9

Frequently, especially for masses or asymmetries, diagnostic ultrasound is also performed. Each
imaging modality may be positive or negative, which allows 4 outcomes: both imaging modality
results are negative; both are positive; mammogram is positive and ultrasound is negative; and
mammogram is negative and ultrasound is positive. In general, a “final” combined imaging
assessment category is rendered after a “recall' from screening, which is the most suspicious
imaging outcome assessment.

The mammographic final assessments are mandated by the Mammography Quality Standards Act
and Program (MQSA) and are reported using wording similar to the ACR BI-RADS assessment
categories, which classify likelihood of the breast findings into 6 final assessment catergories.10
The BI-RADS assessment categories (which include words and numbers) help to standardize both
the reporting of mammographic findings and the recommendations for further management. The
assessment wording and numbers are often used interchangeably. The definitions of the
mammogram assessment categories are outlined in “Mammographic Assessment Category
Definitions” in the algorithm (available online, in these guidelines, at NCCN.org). Importantly,
the same imaging terms are used for screened (asymptomatic) recalled women and symptomatic
women, which can create confusion regarding recommendations.

NCCN Recommendations for Screening Mammogram BI-RADS Assessment Categories 1–6 are
listed subsequently. The NCCN recommendations following evaluation of symptomatic diagnostic
women can be found in the next section. Importantly, negative or benign BIRADS imaging
assessments, in the setting of symptoms, rely on correlation of clinical findings, which may
indicate need for biopsy even with negative imaging. Conversely, suspicious imaging findings for
women with clinical findings of very low suspicion still warrant biopsy.

For BI-RADS category 1 (negative finding) or category 2 (benign), the panel recommends
resuming routine screening.

For BI-RADS category 3 (probably benign), the panel recommends diagnostic mammograms at 6
months, then every 6 to 12 months for 1 to 2 years as appropriate. If the lesion remains stable or
resolves mammographically, the patient resumes routine screening intervals for mammography. If
in any of the interval mammograms the lesion increases in size or changes its benign
characteristics, a biopsy is then performed. The exception to this approach of short-term follow-
up is when a return visit is uncertain or the patient strongly desires biopsy or has a strong family
history of breast cancer. In those cases, initial biopsy with histologic sampling may be a reasonable
option.

For BI-RADS categories 4 and 5 (suspicious or highly suggestive of malignancy), tissue diagnosis
using core needle biopsy (preferred) or needle localization excisional biopsy with specimen
radiograph is necessary. When a needle biopsy (aspiration or core needle biopsy) is performed,
concordance between the pathology report and the imaging finding must be obtained.11,12 For
example, a negative needle biopsy associated with a spiculated category 5 mass (highly suggestive
of malignancy) is discordant and clearly would not be an acceptable diagnosis. When the pathology
and the imaging are discordant, the breast imaging should be repeated and/or additional tissue
sampled or excised; surgical excision is recommended when pathology and image remain
discordant. Women with a benign result exhibiting pathology/image concordance should be
followed up with mammography every 6 to 12 months for 1 to 2 years before returning to routine
screening.

For BI-RADS category 6 (proven malignancy), the patient should be managed according to the
NCCN Guidelines for Breast Cancer (available at NCCN.org).

Breast Ultrasonography: Imaging by ultrasound is an important adjunct for diagnosing breast

cancer.13 However, breast ultrasonography does not detect most microcalcifications.14–18 The
definitions of the ultrasound assessment categories are outlined in “Ultrasonographic Assessment
Category Definitions” in the algorithm (available online, in these guidelines, at NCCN.org).

Diagnostic Breast MRI: MRI can also play a role in the diagnostic setting. For patients with skin
changes consistent with serious breast disease, consideration of breast MRI is included in the
guidelines for those with benign biopsy of skin or nipple following BIRADS category 1–3
assessment. Since a benign skin punch biopsy in a patient with a clinical suspicion of inflammatory
breast cancer (IBC) does not rule out malignancy, further evaluation is recommended. There is
evidence that certain MRI features may facilitate diagnosis of IBC.19 MRI may be used for
suspicious nipple discharge when mammography and ultrasound are not diagnostic.20–22

Breast Tissue Biopsy

Breast biopsy is recommended if diagnostic imaging findings or clinical findings are suspicious
(BI-RADS 4) or highly suggestive of malignancy (BI-RADS 5).

Fine-Needle Aspiration (FNA) Biopsy: An FNA biopsy involves use of a smaller bore needle to
obtain cytologic samples from a breast mass. Advantages of FNA biopsy include its minimally
invasive methodology and low cost,23,24 whereas the need for pathologists with specific expertise
in the interpretation of test results and the necessity of performing a follow-up tissue biopsy when
atypia or malignancy is identified are disadvantages of the procedure. FNA of nonpalpable lesions
can be performed under imaging guidance (eg, ultrasound), although there is evidence to indicate
that both core needle biopsy and excisional biopsy are more accurate than FNA in the evaluation
of nonpalpable breast lesions.25,26

Core Needle Biopsy: A core needle biopsy, also called percutaneous core breast biopsy, is a
procedure that typically involves obtaining multiple cores of solid tissue using standard
techniques.27,28 It can be performed under imaging guidance (eg, stereotactic [mammographic]
ultrasound or MRI) or directed by palpation. Advantages of breast core needle biopsy include (1)
increased accuracy over FNA when the procedure is performed in situations where no mass is
palpable; and (2) an ability to obtain tissue samples of sufficient size so as to eliminate the need
for a follow-up biopsy to confirm malignancy.29 In some situations, the core needle biopsy is
performed under vacuum assistance, which can facilitate collection of adequate tissue from a
breast lesion without the need for multiple needle insertions.30–32 Marker clip placement is done at
the time of core needle biopsy so that the radiologist can identify the location of the lesion in the
event that it is entirely removed or disappears during neoadjuvant treatment.33 With a few
exceptions, core needle biopsy is preferred in the NCCN Guidelines over surgical excision when
tissue biopsy is required. Sensitivity for core needle biopsy directed by ultrasound or stereotaxis
is 97% to 99%.34 According to the NCCN panel, surgical excision is appropriate if core needle
biopsy cannot be performed.

Excisional Biopsy: An excisional biopsy involves removal of the entire breast mass or suspicious
area of the breast by a surgeon in an operating room setting. Needle or wire localization is done
by the radiologist immediately before an excisional biopsy of a nonpalpable mammographic or
sonographic finding to direct surgical excision. The wire localization may bracket a lesion that had
a clip placed in it at the time of the core needle biopsy.33 Newer localization methods using
radionucleotide seeds, reflector devices, or magnetic devices are being explored.

Excisional biopsy is included in the NCCN Guidelines as an option when tissue biopsy is required.
Although excisional biopsy is more invasive than core needle biopsy and requires needle
localization when lesions are not palpable, there are situations in which larger tissue samples may
be needed. Excisional biopsy is recommended if the diagnosis by core needle biopsy is an
indeterminate lesion, a benign lesion that is not concordant with imaging, atypical ductal
hyperplasia (ADH) or other specific histologies that require additional tissue, including mucin-
producing lesions, potential phyllodes tumor, papillary lesions, radial scars, or other histologies of
concern to the pathologist.24,29,35,36 Support for this recommendation includes results of studies
showing an underestimation of cancer when atypical hyperplasia and lobular carcinoma in situ
(LCIS) are diagnosed by core needle biopsy.37–42 However, there are situations (eg, select cases of
LCIS or atypical lobular hyperplasia [ALH] such as those concordant with imaging, papillomas,
fibroepithelial lesions, and radial scars) where close observation may be substituted for excisional
biopsy in select patients.24,35,43–50

Diagnostic Evaluation for Symptomatic Findings on Physical Examination

In general, the breast imaging evaluations after physical exam include mammography and
ultrasound. The addition of ultrasound to diagnostic mammography significantly increases cancer
detection and detection of specific benign findings such as cysts. Imaging for women younger than
age 30 begins with ultrasound, whereas older women generally have both studies unless a cyst is
likely.51–56 Combined negative imaging results place a patient in a very low risk of malignancy
(generally less than 3%) category; however, clinical judgment is necessary because some women
with negative imaging may warrant biopsy that may identify a malignant mass. 51,57–59 The
recommendations for subsequent management follow imaging assessments and clinical level of
suspicion. Imaging should precede biopsy in most situations due to potential alteration of imaging
findings by the biopsy. BI-RADS imaging assessments, even if negative, must be correlated with
the clinical findings before final clinical recommendations and do not stand alone as in the
screening situation. There are clinical situations in which biopsy is warranted even with negative
imaging results.

Symptomatic or positive findings on physical examination include palpable mass in the breast,
nipple discharge without a palpable mass, asymmetric thickening or nodularity, skin changes,
axillary mass, and breast pain.

Palpable Mass in the Breast

A palpable mass is a discrete lesion that can be readily identified during a physical exam. The
NCCN Guidelines separate the evaluation of women with a palpable mass into 2 age groups:
women aged 30 years or older and women younger than 30 years of age.

Women with Palpable Mass Aged 30 Years or Older: The main difference in the guidelines for
evaluating a palpable mass in women aged 30 years or older compared with younger women is the
increased degree of suspicion of breast cancer. The initial evaluation begins with a diagnostic
mammogram and ultrasound. Ultrasound should be geographically correlated with the palpable
mass in question. Observation without further evaluation is not an option in these women.
However, in some clinical circumstances, such as a mass with low clinical suspicion or suspected
simple cyst, ultrasound would be preferred and may suffice for women 30 to 39 years of age due
to the high sensitivity of ultrasound alone.54,55,60 After the diagnostic imaging assessment, the
abnormality is placed into one of the following categories: negative or benign; probably benign;
or suspicious or highly suggestive of cancer with management following BIRADS final
assessment recommendations.

If geographic correlation between clinical and imaging findings is lacking, further evaluation is
recommended. Sensitivity of combined mammography and ultrasound for evaluation of palpable
masses is high for cancer detection, although specificity may be relatively low.

For women with mammographic findings that are suspicious or highly suggestive of breast cancer,
the NCCN Panel recommends ultrasound to determine lesion size and to guide tissue biopsy. The
NCCN Panel notes that FNA and core needle biopsy are both valuable. However, FNA requires
cytologic expertise. When a needle biopsy is used, concordance between pathology, imaging, and
clinical findings must be obtained.

Ultrasound Findings:

Solid Mass: If the solid mass found on ultrasound is suspected to be probably benign (ie, BI-RADS
category 3), the options are (1) observation, if clinical suspicion for breast cancer is low; or (2)
tissue (core needle) biopsy, if the mass is clinically suspicious. Observation may be elected for
those with low clinical suspicion; a physical examination follow-up with or without ultrasound or
diagnostic mammogram is recommended every 6 months for 1 to 2 years to assess stability of the
solid mass. The follow-up interval may be variable based on the level of suspicion. Numerous
clinical studies now support the ability of ultrasound to accurately characterize palpable solid
masses as probably benign with risk of malignancy generally less than 2%. However, these same
studies have shown that many such masses will eventually warrant biopsy and compliance with
follow-up may be low.52,54,61–65 Progression of size or suspicion on follow-up studies warrants
tissue biopsy. The NCCN Panel recommends a tissue (core needle) biopsy for solid masses with a
BI-RADS 4 to 5.

Cystic Masses: Breast cysts are classified as simple, complicated, or complex based on the
characteristics identified by ultrasound evaluation (see Table 1 for definitions).

Simple Cyst: A cyst meeting all criteria of a simple cyst is considered to be benign (ie, BI-RADS
2)14,66 if the clinical findings and ultrasonographic results are concordant. A retrospective analysis
of women (n=14,602) with benign breast biopsies developing subsequent breast cancer noted that
simple cysts were not associated with subsequent breast cancer development. 67 Therefore, these
patients then can be followed with routine screening.

Mammography is a low-dose x-ray−based modality used to image the breast. It is currently the
best available population-based method for detecting breast cancer at an early stage. [86, 90, 91]

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

Mammography is sensitive to microcalcifications that develop in breast tumors with sensitivity at

less than 100 µm. Mammography often detects a lesion before it is palpable by clinical breast
examination and, on average, 1 to 2 years before noted by breast self-examination.

Diagnostic mammography is more expensive than screening mammography. It 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 may require
the additional views used in diagnostic mammography as part of their routine screening
examination.

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 has become a widely available and useful adjunct to mammography in the clinical
setting. It is generally employed to assist the clinical examination of a suspicious lesion detected
on mammography or physical examination. As a screening tool, ultrasonography is limited by a
number of factors, most notably its failure to detect microcalcifications and its 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,
which were usually examined with biopsy; in many cases, the results of these biopsies were benign.
However, it is now well established that ultrasonography also provides valuable information about
the nature and extent of solid masses and other breast lesions and can often provide useful
information regarding the staging of the axilla.

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.

Breast masses or thickening: Relevant breast mass characteristics include duration, change in size
over time, relation to menstrual cycle, presence of pain, redness, skin changes, fever or nipple
discharge. A dominant mass is identified as a discrete, solid, palpable finding clearly differentiated
from surrounding tissue, and requires clinical evaluation. An indeterminate mass is not clearly
differentiated, but should be assessed for size, location and other characteristics. Breast ultrasound
is extremely useful in characterizing palpable changes in the breast and especially in distinguishing
simple cysts, benign masses (fibroadenomas), lumpy normal breast tissue and cancers. The follow-
up protocol is dictated by the clinical findings. For example, a mass that varies with menstrual
cycle may be a common cyst, and a diffuse symmetrical lumpiness may be related to hormonal
cycling. If a physical exam and/or ultrasound fails to reveal a dominant mass, then a follow-up
exam in one to two months may be advised to determine the clinical behavior over time and
confirm the benign behavior of the finding. Enlarged lymph nodes (LNs): Many women with
clinically detected breast cancer will have enlarged axillary LNs, although these changes are not
always due to the nodal spread of cancer. The primary significance of nodal spread is its
demonstration that a given cancer has the capacity to spread (metastasize) and is an important
indication for systemic (drug) therapy. Removal of lymph nodes can help control disease in the
nodal bed, but does not itself stop cancer from spreading. More distant lymph node spread (i.e.,
supraclavicular or internal mammary nodes) is an unfavorable prognostic indicator and can suggest
distant metastatic spread to the lung, liver, bone or brain. Although node-positive cancers are
potentially curable with multimodality treatment, cancers that have spread to distant organs are
not considered curable. Breast pain: Pain is a common breast concern but generally is not an
indicator of underlying malignancy or considered a risk factor for breast cancer. There are no
histologic findings that correlate with breast pain. Breast pain can be cyclic (related to the
menstrual cycle) or noncyclic. Cyclic pain is often bilateral, diffuse and radiates to the axilla,
occurring during the premenstrual phase when there is increased breast swelling due to increased
hormone levels. Noncyclic breast pain may be unilateral, focal or generalized. It has been
associated with medications (such as oral contraceptives, psychotropic drugs and some
cardiovascular medications).
Generalized, diffuse breast pain without focal findings should be monitored and does not, of itself,
require imaging studies. Focal breast pain does require additional evaluation, even in the absence
of physical exam findings. It can be associated with a tender breast cyst, acute enlargement of a
cyst, infection (mastitis), trauma, pregnancy, or a general tender area of nodularity. Breast pain is
experienced by the majority of adult women and most cases of breast pain will resolve
spontaneously.Nipple discharge: Assessment of nipple discharge should include evaluation of
color, frequency, laterality (one side versus both sides), spontaneity, persistence, relation to the
menstrual cycle, presence of other health issues, medication changes and association with an
underlying palpable breast mass. The great majority of nipple discharge is associated with benign
disease. The most common causes of pathologic nipple discharge are intraductal papilloma, duct
ectasia, carcinoma and infection. Nipple discharge warrants work-up when it is spontaneous,
unilateral, bloody or watery and/or associated with a mass. Women with pathologic nipple
discharges should be referred to a surgeon to consider surgical excision of the offending duct.
Bilateral milky discharge (galactorrhea) is not considered abnormal and may persist for up to one
year post-partum or after cessation of breastfeeding. If present in women who are not pregnant or
lactating, galactorrhea should be evaluated with a pregnancy test, endocrine work-up and review
of recent medications. Because the absence of malignant cells does not exclude cancer, cytologic
examination of nipple discharge is generally not advised. Nipple inversion: Nipple inversion or
retraction can be unilateral or bilateral, congenital or acquired, and is associated with a wide variety
of diagnoses from infection to cancer. Nipple inversion associated with malignancy tends to be
asymmetric and distorts the areola. Women with an acquired nipple inversion should be evaluated
with diagnostic imaging and possibly biopsy. Breast or skin thickening: Breast thickening can
include breast nodularity, diffuse cystic change, fibrocystic change and breast fullness.
Appropriate diagnostic work-up of skin thickening includes an imaging study (either ultrasound
or mammography) and close follow-up if imaging studies are without focal findings. In the
majority of cases, the finding will be benign, but skin thickening can be a sign of breast cancer in
cases of infiltrating lobular cancer, inflammatory breast cancer, or Paget’s disease of the breast.
Studies suggest that assessing skin thickening can be challenging and may require professional
breast health education, training and experience. Paget’s disease: Paget’s disease of the breast is a
scaly, raw, ulcerated lesion beginning on the nipple generally at the tip, then spreading to the base
of the nipple and then to the areola. Paget’s disease is a process in which cancer from the major
central ducts extrudes at the nipple, generally (but not always) related to an underlying cancer
deeper in the breast. Paget’s disease is unilateral and can be associated with pain, burning and
itching. Women who have a palpable mass with associated nipple erosion are more likely to have
invasive cancer that is extending to and through the nipple. Nipple biopsy is important to
distinguish Paget’s disease from benign skin disorders such as eczema.

Factors associated with the highest risk for development of breast cancer (relative risk [RR] > 4.0)
are as follows [6, 7, 8] :

 Advanced age (65 years and older)

 Atypical hyperplasia of breast (biopsy proven)
  Certain inherited genetic mutations ( BRCA1, BRCA2, TP53, ATM, CDH1); RR 4-8
 Ductal or lobular carcinoma in situ (DCIS/LCIS); RR 8-10
 Family history of early ovarian cancer (age < 50 years)
 Multiple first-degree relatives with breast cancer
 Ionizing radiation exposure before age 30 (RR 22-40)
 Personal history of early breast cancer (age < 40)

Factors associated with RR 2.1-4.0 for breast cancer are as follows [6, 7, 8] :

 High endogenous estrogen or testosterone level (postmenopausal)

 First full-term pregnancy after age 35 years
 Very dense breasts (>50%, compared with 11-25% mammographically)
 One first-degree relative with breast cancer
 Proliferative breast diseases (eg, atypical ductal hyperplasia)
 Certain inherited genetic mutations (eg, CHEK2, PTEN)

Factors associated with RR 1.1-2.0 for breast cancer are as follows [6, 7, 8] :

 Alcohol consumption
 Age 30-35 at first full-term pregnancy
 Diethylstilbestrol exposure in utero
 Early menarche (age < 12 years)
 Height (> 5 feet 3 inches) [6]
 High socioeconomic class
 Ashkenazi Jewish heritage
 Personal history of breast cancer (age of onset > 40)
 Dense breasts (25-50%, compared with 11-25% mammographically)
 Benign breast conditions: Non-atypical ductal hyperplasia, fibroadenoma, sclerosing
adenosis, microglandular adenosis, papillomatosis, radial scar
 Never breastfed a child
 Nulliparity (no full-term pregnancies)
 Late menopause (age > 55)
  Type II diabetes mellitus
 Obesity (post-menopausal)
 Personal history of uterine, ovarian, or colon cancer
 Recent and long-term use of hormone replacement therapy (HRT) containing estrogen and
progestin
 Recent oral contraceptive use [9]
 Occupation: night shift
 Tobacco abuse
 Sedentary lifestyle
 Inferior cardiovascular health
 High bone mineral density [10]

Factors that reduce risk of breast cancer (RR < 1) include the following [8] :

 Asian, Hispanic, or Pacific islander race

 Breastfeeding
 Age < 20 at first pregnancy
 Tamoxifen use
 Prior risk-reduction breast surgery
 History of cervical cancer
 History of oophorectomy
 Exercise/active lifestyle
 Low bone mineral density

Breast Cancer Facts & Figures 2017-2018. American Cancer Society. Available at https://www.cancer.org/content/dam/cancer-
org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf. Accessed: April 3, 2019.

, 7, 8]
:
[Guideline] National Comprehensive Cancer Network. Breast Cancer Risk Reduction. NCCN Clinical Practice Guidelines in Oncology.
Available at https://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf. Version 1.2019 — December 11, 2018; Accessed: April 3,
2019.

]
:

A family history of breast cancer in a first-degree relative is the most widely recognized breast
cancer risk factor, but only 5-10% of women diagnosed with breast cancer have a known genetic
predisposition. Women with a family history of breast cancer in a mother or sister have a 1.5-3
fold increase in the risk of developing breast cancer.

Family history of breast cancer is a heterogeneous risk factor that depends on the number of family
members affected and the age at diagnosis, as well as the number of unaffected women in the
pedigree. Even in the absence of a known genetic risk factor, the presence of a family history may
suggest the presence of an unknown genetic risk, or a shared environmental risk.

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 an increased risk of breast cancer risk. [12]

Hereditary Breast and Ovarian Cancer: Breast and Ovarian Cancer and Family History Risk
Categories. Centers for Disease Control and Prevention. Available at
https://www.cdc.gov/genomics/resources/diseases/breast_ovarian_cancer/risk_categories.htm.
July 29, 2016; Accessed: November , 2019.
]

The family history characteristics that suggest increased risk of cancer are summarized as
follows [13] :

PDQ Cancer Genetics Editorial Board. Genetics of Breast and Gynecologic Cancers (PDQ®):
Health Professional Version. Updated March 21, 2019. [Medline]. [Full Text].
]
:

 One or more relatives with breast or ovarian cancer

 Breast cancer occurring in an affected relative younger than 50 years
 Male relatives with breast cancer
 BRCA1 and BRCA2 mutations
  Ataxia-telangiectasia heterozygotes (4 times’ increased risk)
 Ashkenazi Jewish descent (2 times’ greater risk; independent of BRCA positivity

Although 20-30% of women with breast cancer have at least one relative with a history of breast
cancer, only 5-10% of women with breast cancer have an identifiable hereditary predisposition.
BRCA1 and BRCA2 mutations are responsible for 3-8% of all cases of breast cancer and 15-20%
of familial cases. Rare mutations include PTEN, TP53, MLH1, MLH2, and STK11 genes, as well
as ATM, BRIP1, CDH1, CHEK2, MRE11A, NBN, PALB2, RAD50, RAD51C, and SEC23B.

The BRCA1 and BRCA2 gene mutations, on chromosomes 17 and 13, respectively, account for the
majority of autosomal dominant inherited breast cancers. Both genes are believed to be tumor
suppressor genes whose transcribed protein products are involved with maintaining DNA integrity
and transcriptional regulation.

Prevalence rates of these mutations vary by ethnic and racial groups. For BRCA1 mutations, the
highest rates occur among Ashkenazi Jewish women (8.3%), followed by Hispanic women (3.5%),
non-Hispanic white women (2.2%), black women (1.3%), and Asian women (0.5%). Moreover,
95% of Ashkenazi Jews with a BRCA gene mutation will have 1 of the 3 founder mutations
(185delAG, 538insC in BRCA1; 6174delT in BRCA2). Women who inherit a mutation in the
BRCA1 or BRCA2 gene have an estimated 50-80% lifetime risk of developing breast cancer.

BRCA1 mutations are seen in 7% of families with multiple breast cancers and 40% of families
with breast and ovarian cancer. Women with a BRCA1 mutation have a 40% lifetime risk of
developing ovarian cancer. Breast cancers that develop in BRCA1 mutation carriers are more
likely to be high grade, as well as estrogen receptor (ER) negative, progesterone receptor (PR)
negative, and HER2-negative (triple negative) or basal-like subtype. BRCA1 mutations are also
associated with a higher risk of colon, pancreatic, and prostate cancer. [14]

Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, et al. Population BRCA1 and
BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J
Natl Cancer Inst. 2006 Dec 6. 98 (23):1694-706. [Medline]. [Full Text].

]
BRCA2 mutations are identified in 10-20% of families at high risk for breast and ovarian cancers
but in only 2.7% of women with early-onset breast cancer. Women with a BRCA2 mutation have
an approximately 10% lifetime risk of ovarian cancer. BRCA2 mutation carriers who develop
breast cancer are more likely to have a high-grade, ER-positive, PR-positive, and HER2-negative
cancer (luminal type). BRCA2 is also a risk factor for male breast cancer. Other cancers associated
with BRCA2 mutations include the following [15] :

 Prostate
 Pancreas
 Gallbladder and bile duct
 Stomach
 Malignant melanoma

The US Preventive Services Task Force (USPSTF) recommends that women who have family
members with breast, ovarian, tubal, or peritoneal cancer should be screened to identify a family
history that may be associated with an increased risk for carriage of BRCA1 or BRCA2. For women
with positive screening results, the USPSTF recommends genetic counseling and, if indicated after
counseling, BRCA testing. [16]

Li-Fraumeni syndrome, caused by TP53 mutations, is responsible for approximately 1% of cases

of familial breast cancer. Bilateral breast cancer is noted in up to 25% of patients. Li-Fraumeni
syndrome is also associated with multiple cancers, including the SBLLA syndrome (sarcoma,
breast and brain tumors, leukemia, and laryngeal and lung cancer). Cancer susceptibility is
transmitted in an autosomal dominant pattern, with a 90% lifetime risk of breast cancer (and a 56%
risk by age 45), necessitating earlier screening in TP53 mutation carriers.) [17]

Cowden disease is a rare genetic syndrome caused by PTEN mutations. It is associated with
intestinal hamartoma, cutaneous lesions, and thyroid cancer. The lifetime risk of breast cancer
ranges from 25-50%. Benign mammary abnormalities (eg, fibroadenomas, fibrocystic breast
disease, ductal epithelial hyperplasia, and nipple malformations) are also common. [17]

Other rare genetic disorders, such as Peutz-Jeghers syndrome and hereditary nonpolyposis
colorectal carcinoma (HNPCC), are associated with an increased risk of breast cancer.
Hereditary syndromes may also affect the response to treatment in breast cancer. A study by
Mangoni et al found an association between MSH2 and MSH3 genetic variants and the
development of radiosensitivity in patients with breast cancer. The authors propose a hypothesis
that mismatch repair mechanisms may be involved in the cellular response to radiotherapy and that
genetic polymorphisms warrant further study as candidates for predicting acute radiosensitivity.

Neoplastic conditions that increase the risk of breast cancer include the following:

 Previous breast cancer

 Ovarian cancer
 Endometrial cancer
 Ductal carcinoma in situ (DCIS)
 Lobular carcinoma in situ (LCIS)

Benign breast conditions that slightly increase the risk of breast cancer include the following [20] :

 Hyperplasia (unless mild)

 Complex fibroadenoma
 Radial scar
 Papillomatosis
 Sclerosing adenosis
 Microglandular adenosis

Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, et al. Benign breast
disease and the risk of breast cancer. N Engl J Med. 2005 Jul 21. 353 (3):229-37. [Medline].
[Full Text].

One of the most widely studied risk factors in breast cancer is the use of exogenous
hormones in the form of oral contraceptives (OCs) and hormone replacement therapy
(HRT).
Kubba AA, Breast cancer and the pill.
J R Soc Med. 2003; 96(6):280-3 (ISSN: 0141-0768)

Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal
contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer
and 100 239 women without breast cancer from 54 epidemiological studies. Lancet. 1996 Jun 22.
347 (9017):1713-27. [Medline].
]
The progestin (synthetic progesterone)-o

The progestin (synthetic progesterone)-only pill (“mini pill”) does not seem to be
associated with an increased breast cancer risk, [23] and is commonly prescribed to women
who experienced side effects from combination OCs or those with thrombotic risk, such as
smokers or those with sickle cell disease.

 Consistent epidemiologic data support an increased risk of breast cancer incidence and
mortality with the use of postmenopausal HRT. Risk is increased 1.35 times for 5 or more
years of HRT use, normalizing 5 years after discontinuing. [24] Risk is directly associated
with length of exposure, with the greatest risk observed for the development of hormonally
responsive lobular, mixed ductal-lobular, and tubular cancers. [25]

Studies, including the Women’s Health Initiative (WHI) trial, have shown that the incidence of
breast cancer was greater in women taking combination estrogen plus progestin formulations
than in those taking estrogen-only formulations, and the cancers in women taking combination
HRT were more commonly advanced or node positive. This risk seems to achieve demonstrable
significance at 3 or more years of exposure. Combination HRT also appears to be associated with
increased mortality. [26]

Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, et al. Estrogen plus
progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010 Oct
20. 304 (15):1684-92. [Medline].

 Contemporary Hormonal Contraception

and the Risk of Breast Cancer.
Mørch LS1, Skovlund CW1, Hannaford PC1, Iversen L1, Fielding S1, Lidegaard Ø1. N Engl J
Med. 2017 Dec 7;377(23):2228-2239. doi: 10.1056/NEJMoa1700732.


 Published results of the WHI of estrogen-only and combination-HRT for the prevention of
chronic disease indicate that the adverse outcomes associated with long-term use outweigh
the potential disease prevention benefits, particularly for women older than 65 years.

Factors that increase the number of menstrual cycles also increase the risk of breast cancer,
probably due to increased endogenous estrogen exposure. Such factors include the following:

 Menarche when younger than 13 years (2 times the risk)

 Nulliparity
 First full pregnancy when older than 30 years
 Not breastfeeding
 Menopause when older than 50 years

Conversely, late menarche, anovulation, and early menopause (spontaneous or induced) are
protective, owing to their effect on lowering endogenous estrogen levels or shortening the duration
of estrogenic exposure.

Tobacco smoking

Tobacco abuse portends a 24% higher risk of developing invasive breast cancer. Former smokers
carry a 13% increased risk. Starting smoking at an earlier age has a profound impact. Compared
with never smoking, beginning tobacco use prior to menarche increases breast cancer risk by
61%, and beginning tobacco use 11 or more years prior to parity carries a 45% increased risk. [28]

Gaudet MM, Gapstur SM, Sun J, Diver WR, Hannan LM, Thun MJ. Active smoking and breast
cancer risk: original cohort data and meta-analysis. J Natl Cancer Inst. 2013 Apr 17. 105
(8):515-25. [Medline]. [Full Text].

Diabetes/insulin resistance
Postmenopausal women with type 2 diabetes have a 17% higher risk of developing breast cancer.
In addition, diabetic women with a new breast cancer have a higher incidence of being diagnosed
at a more advanced stage. Diabetics are diagnosed with stage I cancer at about 49% of the
frequency as non-diabetics; they are 21% and 16% more likely to be diagnosed with stage III or
stage IV disease, respectively. This elevated risk was noted specifically in postmenopausal women
with estrogen receptor-positive disease. [29]

Palmer, Julie R et al. “Type II Diabetes and Incidence of Estrogen Receptor Negative Breast
Cancer in African American Women.” Cancer research vol. 77,22 (2017): 6462-6469.
doi:10.1158/0008-5472.CAN-17-1903

Alcohol consumption

Principles and Practice of Modern Radiotherapy Techniques in Breast

Cancer
edited by Ayfer Haydaroglu, Gokhan Ozyigit

A meta-analysis showed that for every 10 grams of alcohol consumed per day, there is a 7%
increase in the risk of breast cancer. Compared with women who never drank, women who drank
35-44 g of alcohol (or, roughly 2-3 alcoholic beverages) per day had a 32% increased risk. [10]

Chen WY, Rosner B, Hankinson SE, Colditz GA, Willett WC. Moderate alcohol consumption
during adult life, drinking patterns, and breast cancer risk. JAMA. 2011 Nov 2. 306 (17):1884-90.
[Medline]. [Full Text].

Irradiation
Radiation, particularly to the chest or in the first decade of life, profoundly increases the risk of
developing breast cancer. Studies involving patients who had received thoracic mantle radiation
for Hodgkin lymphoma have repeatedly corroborated this risk. Jessica Katz, MD, PhD,
FACP Senior Medical Director, Immuno-Oncology, Oncology R&D, GlaxoSmithKline

Socioeconomic class

The incidence of breast cancer is increased in individuals in higher socioeconomic classes.

However, breast cancer survival rates are lower in women from lower socioeconomic classes. This
underscores the benefits of mammography in early detection, which likely contributes to the better
outcomes seen in people with the means to diligently follow cancer screening recommendations.

Night shift work

The International Agency for Research on Cancer and the World Health
Organization (IARC/WHO) have recognized night shift work as a probable carcinogen. A 2005
meta-analysis (including 13 studies of airline cabin attendants and nighttime shift workers )
explored the relationship between night work and breast cancer risk and reported a relative risk
(RR) of 1.48; they noted similar risk levels in female air cabin crew and female night shift workers
(RR of 1.51 vs 1.44, respectively). [31]

Poor cardiovascular health

A review of the American Heart Association cardiovascular health (CVH) score in 161,809
Women's Health Initiative participants followed from 1993 through 2010 found that, compared
with women with the highest (best) CVH scores, those with the lowest (worst) CVH scores had a
52% greater risk of incident cancer, including breast cancer. Fewer minority women and less-
educated women achieved an ideal CVH score. The CVH score is based on smoking, body mass
index, physical activity, diet, total cholesterol, blood pressure, and fasting glucose. [32]

High bone density

High bone density is associated with higher endogenous estrogen levels, which are associated with
a higher risk of breast cancer. Women in the highest hip bone mineral density (BMD) category are
62% more likely to develop breast cancer than are women in the lowest BMD category. Of note,
women of east Asian ethnicity have lower bone density and have a lower incidence of breast cancer
than white and black Americans. [33, 34, 35]

Long-term use of calcium channel blockers

Several studies had previously shown a correlation between use of calcium channel blockers and
breast cancer incidence. [36, 37, 38] More powerful data, however, has emerged recently, showing that
calcium channel blockers do not increase the risk of breast cancer. [39] Given that the newer data is
derived from a larger study, current evidence does not implicate calcium channel blockers as a
significant risk factor.

Hair product use

A study of 4,285 women found a significant increase in breast cancer risk in black women who
used dark shades of hair dye and in white women who used chemical hair relaxers. The risk of
breast cancer was 51% higher in black women who reported using dark hair dye, compared with
those who did not, and was 74% higher in white women who reported using chemical relaxers.
Risk was more than doubled in whites who used both relaxers and hair dyes (odds ratio [OR] =
2.40, 95% confidence index [CI],1.35–4.27). [40, 41]

In white women,the use of dark hair dyes was associated with increased estrogen receptor (ER)–
positive disease (OR = 1.54; 95% CI, 1.01–2.33). Relaxer use was associated with increased ER-
negative disease (OR = 2.56; 95% CI, 1.06–6.16).

BRCA Mutation Testing

The American Congress of Obstetricians and Gynecologists and the Society of Gynecologic
Oncologists recommend genetic risk assessment for women who have more than a 20% to 25%
risk for an inherited predisposition to breast and ovarian cancer, and suggest that it may be
helpful for patients with more than a 5% to 10% risk. [42] Pal, Tuya, and Susan T Vadaparampil.
“Genetic risk assessments in individuals at high risk for inherited breast cancer in the breast
oncology care setting.” Cancer control : journal of the Moffitt Cancer Center vol. 19,4 (2012):
255-66. doi:10.1177/107327481201900402
Pruthi, Sandhya et al. “Identification and Management of Women With BRCA Mutations or
Hereditary Predisposition for Breast and Ovarian Cancer.” Mayo Clinic proceedings vol. 85,12
(2010): 1111-20. doi:10.4065/mcp.2010.0414

The United States Preventive Services Task Force (USPSTF) recommends that women who have
family members with breast, ovarian, tubal, or peritoneal cancer undergo screening with a risk
assessment tool designed to identify increased risk for carriage of BRCA mutations. The USPSTF
recommends that women with positive screening results receive genetic counseling and, if
indicated after counseling, BRCA testing

Breast Biopsy

Percutaneous vacuum-assisted large-gauge core-needle biopsy (VACNB) with image guidance is

the recommended diagnostic approach for newly diagnosed breast tumors. Core biopsies can
minimize the need for operative intervention (and subsequent scarring, and provide accurate
pathologic diagnosis for appropriate management.

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

The American Joint Committee on Cancer (AJCC) provides two principal groups for breast cancer
staging: anatomic, which is based on extent of cancer as defined by tumor size (T), lymph node
status (N), and distant metastasis (M); and prognostic, which includes anatomic TNM plus tumor
grade and the status of the biomarkers human epidermal growth factor receptor 2 (HER2), estrogen
receptor (ER), and progesterone receptor (PR). The prognostic stage group is preferred for patient
care and is to be used for reporting of all cancer patients in the United States. [107]
In turn, prognostic stages are divided into clinical and pathological groups. Pathological
stage applies to patients who have undergone surgery as the initial treatment for breast cancer. It
includes all information used for clinical staging plus findings at surgery and pathological findings
from surgical resection. Pathological prognostic stage does not apply to patients who received
neoadjuvant therapy (systemic agents or radiation prior to surgical resection).

Primary tumor (T)

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

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

Histologic grade (G)

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

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

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

Notes:

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

Lymph node assessment

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

A 2014 update on sentinel lymph node biopsy for patients with early-stage breast cancer by the
American Society of Clinical Oncology (ASCO) advises that sentinel lymph node biopsy may be
offered to the following patients [108] :

 Women with operable breast cancer and multicentric tumors

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

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

 Large or locally advanced invasive breast cancer (tumor size T3/T4)

  Inflammatory breast cancer
 DCIS (when breast-conserving surgery is planned)
 Pregnancy

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

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

National Comprehensive Cancer Network (NCCN) recommendations differ from those of ASCO
in that the NCCN considers that women with clinical stage as high as IIIA T3, N1, M0 may be
candidates for SLN biopsy. In addition, the NCCN concluded that there is insufficient evidence to
make recommendations for or against SLN biopsy in pregnant patients; the NCCN recommends
that decisions regarding use of SLN biopsy in pregnancy be individualized. However, isosulfan
blue or methylene blue dye is contraindicated for SLNB in pregnancy; radiolabeled sulfur colloid
appears to be safe. [75]

The NCCN breast cancer guidelines state that lymph node dissection is optional in the following
cases [75] :

 Strongly favorable tumors

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

[75]
The NCCN guidelines recommend the following laboratory studies for all asymptomatic
women with early-stage breast cancer (stages I–IIB):

 Complete blood count (CBC) with differential

  Comprehensive metabolic panel, with liver function tests (LFTs) and alkaline phosphatase

Additional studies indicated in specific settings include the following:

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

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

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

HER2 testing

Although several methods for HER2 testing have been developed, approximately 20% of current
HER2 testing may be inaccurate; accordingly, the American Society of Clinical Oncology (ASCO)
and CAP have recommended guidelines to ensure the accuracy of HER2 testing. Breast cancer
specimens should initially undergo HER2 testing by a validated immunohistochemistry (IHC)
assay (eg, HercepTest; Dako, Glostrup, Denmark) for HER2 protein expression. [109] (See Breast
Cancer and HER2.)

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

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

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

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

Newer methodologies for establishing HER2 status, including reverse transcriptase–polymerase

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

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

Molecular profiling assays

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

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

 < 18, low risk

 18-30, intermediate risk
 >30, high risk

Furthermore, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-
20 studies, the Onco type Dx assay was shown retrospectively to predict benefit from
chemotherapy and hormonal therapy in hormone-sensitive, node-negative tumors. [110] Similarly,
among women with 1- to 3-node-positive, hormone receptor-positive disease, the Onco type Dx
recurrence score was a significant predictor of recurrence, with a 21% decrease in recurrence risk
for each 10-point drop in RS.

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

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

The MammaPrint assay (Agendia, The Netherlands) is a genetic test that measures the activity of
70 genes to determine the 5- to 10-year relapse risk for women diagnosed with early breast cancer.
It was approved for use by the FDA in 2007 and is an alternative platform to Oncotype DX.
MammaPrint test results are reported as either a low-risk or a high-risk RS:
  A low-risk score means that the cancer has a 10% risk of coming back within 10 years
without any additional treatments after surgery
 A high-risk score means that the cancer has a 29% risk of coming back within 10 years
without any additional treatments after surgery

Tstands for the size of the cancer (meas-ured in centimeters: 2.5 centimeters = 1 inch)and whether
it is growing directly intonearby tissues. Nstands for spread to nearbylymph nodes and Mis for
metastasis (spreadto other parts of the body).
T CategoriesT categories are based on the size of thebreast cancer and whether it has spread
tonearby tissue.Tis:Tis is used only for carcinoma in situor noninvasive breast cancer such as
ductalcarcinoma in situ (DCIS) or lobular carcinomain situ (LCIS).T1:The cancer is 2 cm in
diameter (about3⁄4inch) or smaller.T2:The cancer is more than 2 cm but notmore than 5 cm in
diameter.T3:The cancer is more than 5 cm in diameter.T4:The cancer is any size and has spreadto
the chest wall or the skin.N CategoriesThe N category is based on which of thelymph nodes near
the breast, if any, are affectedby the cancer. There are 2 classifications used todescribe N. One is
clinical—before surgery—i.e. what the doctor can feel or see on imagingstudies. The other is
pathological—what thepathologist can see in lymph nodes removedat surgery. N0 Clinical:The
cancer has not spread tolymph nodes, based on clinical exam.N0 Pathological:The cancer has
notspread to lymph nodes, based on examiningthem under the microscope. N1 Clinical:The cancer
has spread tolymph nodes under the arm on the same sideas the breast cancer. Lymph nodes are
notattached to one another or to the surroundingtissue.N1 Pathological:The cancer is found in 1to
3 lymph nodes under the arm.N2 Clinical:The cancer has spread tolymph nodes under the arm on
the same sideas the breast cancer and are attached to oneanother or to the surrounding tissue. Or
thecancer can be seen to have spread to theinternal mammary lymph nodes(next to thesternum),
but not to the lymph nodes underthe arm.N2 Pathological:The cancer has spread to4 to 9 lymph
nodes under the arm.N3 Clinical:The cancer has spread tolymph nodes above or just below the
collar-bone on the same side as the cancer, and mayor may not have spread to lymph nodes
underthe arm. Or the cancer has spread to internalmammary lymph nodes and lymph nodesunder
the arm, both on the same side as thecancer.N3 Pathological:The cancer has spread to10 or more
lymph nodes under the arm or alsoinvolves lymph nodes in other areas aroundthe breast.M
CategoriesThe M category depends on whether thecancer has spread to any distant tissues
andorgans. M0:No distant cancer spread.M1:Cancer has spread to distant organs.
Stage Grouping for Breast CancerOnce the T, N, and M categories have beenassigned, this
information is combined toassign an overall stage of 0, I, II, III or IV asseen in the table. The stages
identify tumortypes that have a similar outlook and thus aretreated in a similar way.

The most useful serum markers for breast cancer are CA 15.3 (or BR 27.29) and CEA, but due to
their low sensitivity, they cannot be recommended for screening or early diagnosis, but serial levels
may be useful in the early diagnosis of distant metastases.Prognosis: Preoperatively elevated levels
of either CA 15.3 or CEA are associated with adverse outcome in patients with breast cancer; their
use in combination with established prognostic factors is rec-ommended.Early diagnosis of
recurrence: Serial CA 15.3 and CEA serum de-terminations are recommended for the early
detection of recur-rence in patients with breast cancer and no evidence of disease, if the detection
of recurrent or metastatic disease would alter clinical management. The impact of this lead time
information on patient outcome is not clear.
Therapy monitoring: Markers should be measured prior to every chemotherapy course and at least
every 3 months for patients re-ceiving hormone therapy
tumor marker de-termination may complement patient staging: high levels of CA 15.3 (e.g. 1 50
U/ml) and/or CEA (e.g. 1 20 ng/ml)
While serum markers in breast cancer are mostly used for monitoring patients with diagnosed
disease, tissue-based markers are primarily measured in order to deter-mine prognosis and predict
response to therapy. Clini-cally, the most useful tissue-based markers in breast can-cer are estrogen
receptor (ER), progesterone receptor (PR) and HER-2 (also known as c-erbB-2 or neu).Al-though
not yet in widespread clinical use, urokinase plas-minogen activator (uPA) and plasminogen
activator in-hibitor 1 (PAI-1) are potential markers for determining prognosis in lymph node-
negative breast cancer pa-tients.

Epidemiology of Female Breast Cancer in West Jakarta, Indonesia

J. Agustina1*, D. Sinulingga1, E. Suzanna2, B. Andinata3, R. Ramadhan1, A. Kadir4
Breast cancer was the most common cancer in the world. GLOBOCAN 2012 estimated the
incidence of female breast cancer in Indonesia was 40.3 per 100,000 and the mortality rate was
16.6 per 100,000. In 2016, Dharmais National Cancer Center was appointed as Regional
Population Based Cancer Registry in West Jakarta. West Jakarta was a municipality with
2,281,945 populations, being the 2nd largest population in DKI Jakarta Province

Breast cancer is the most common cancer and cause of cancer-related deaths among women,
accounting for 1.67 million(25.2%) new cases and 521,907 (14.7%) deaths worldwide(Ferlayet
al., 2015). Similarly, in Indonesia, breast cancer hasbecome a great burden. It accounts for 30.5%
of all cancersdiagnosed and 21.5% of cancer-related deaths among females(Ferlayet al., 2013).
Moreover, breast cancer in Indonesia ismostly diagnosed in the advanced stages of the cancer
(Nget al., 2011; Rahmatyaet al., 2015), with increasing rates ofmortality (Ministry of Health
Republic of Indonesia, 2015b).
Delayed presentation among women with breast cancer hasresulted in increased mortality, poor
prognoses, and decreasedsurvival rates, which can be associated to low awareness ofbreast cancer,
as well as non-adherence to recommendedscreening (Stapletonet al., 2011; Iskandarsyah, 2013;
McIntosh,2015)
In particular, womenwith a family history of breast cancer, who are at a moderate-to-high risk of
developing breast cancer, have a 15% or morelifetime risk of developing breast cancer (American
CancerSociety, 2014).
Given the high number of Indonesian womendiagnosed in the advanced stages of breast cancer, to
date, littleevidence has been found regarding the status of breast cancerawareness within the
context of Indonesia, in particular amongwomen at moderate-to-high risk of developing breast
cancer.Therefore, an understanding of this situation in Indonesia is needed.

Breast cancer awareness among Indonesian

women atmoderate-to-high risk
Aira Putri Mardela,MNS,RN,†Khomapak Maneewat,PhD,RNand Hathairat Sangchan,PhD,RNDepartment of
Nursing, Faculty of Nursing, Prince of Songkla University, Hat Yai, Thailand, Journal of Health
Sciences(2017)19,301–306

Komite Nasional Penanggulangan Kanker. Pedoman nasional pelayanan kedokteran kanker payudara. Kementerian
Kesehatan Republik Indonesia (diunduh 10 Desember 2019). Tersedia dari:
http://kanker.kemkes.go.id/guidelines/PPK Payudara.pdf

Breast Cancer Facts & Figures 2017-2018. American Cancer Society. Available at
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-
cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf. Accessed: April 3,
2019.

There is abundance of data linking obesity- related breast cancer to estrogen receptor signal- ing.
As comorbidities of obesity; excessive local production of estrogens in adipose tissue, the
influence of adipokines and inflammatory cyto- kines, finally hypercholesterolemia have also been
established as independent risk factors for breast cancer in postmenopausal women