Breast cancer will develop in one of eight American women. Next
to skin cancer, breast cancer is the most common cancer in women;
it is second only to lung cancer as a cause of death. The probability
of developing breast cancer increases throughout life. The mean
age and the median age of women with breast cancer are between 60
and 61 years.
There are about 178,000 new cases of breast cancer annually and
about 41,000 deaths from this disease in women in the United States.
An additional 62,000 cases of ductal carcinoma in situ (DCIS) will
be detected, principally by screening mammography. The incidence
of breast cancer has slightly decreased, presumably because of decreased
use of postmenopausal hormone replacement therapy. Mortality has
also decreased slightly due to early detection and increased use
of systemic therapy.
Although more than 75% of women in whom breast cancer
has been diagnosed do not have an obvious risk factor, there are
several that play a role in breast cancer development. Breast cancer
is three to four times more likely to develop in women with a first-degree
relative (mother, daughter, or sister) who had breast cancer than
in those without a family history. Risk is further increased in
patients whose mothers’ or sisters’ breast cancers
occurred before menopause or were bilateral and in those with a
family history of breast cancer in two or more first-degree relatives
as well as in women of Ashkenazi Jewish descent. Nulliparous women
and women whose first full-term pregnancy was after age 35 have
a 1.5 times higher incidence of breast cancer than multiparous women.
Late menarche and artificial menopause are associated with a lower
incidence, whereas early menarche (under age 12) and late natural
menopause (after age 50) are associated with a slight increase in
risk. Fibrocystic condition, when accompanied by proliferative changes,
papillomatosis, or atypical epithelial hyperplasia, and increased
breast density on mammogram are also associated with an increased
incidence. A woman who had cancer in one breast is at increased risk
for cancer developing in the other breast. In these women, a contralateral
cancer develops at the rate of 1% or 2% per year.
Women with cancer of the uterine corpus have a risk of breast cancer
significantly higher than that of the general population, and women
with breast cancer have a comparably increased risk for endometrial
cancer. In the United States, breast cancer is more common in white
women. The incidence of the disease among nonwhite (mostly black)
women is increasing, especially in younger women. In general, rates reported
from developing countries are low, whereas rates are high in developed
countries, with the notable exception of Japan. Some of the variability
may be due to underreporting in the developing countries, but a
real difference probably exists. Dietary factors, particularly increased
fat consumption, may account for some differences in incidence.
Oral contraceptives do not appear to increase the risk of breast
cancer. There is evidence that administration of estrogens to postmenopausal
women may result in a slightly increased risk of breast cancer,
but only with higher, long-term doses of estrogens. Concomitant
administration of progesterone and estrogen may markedly increase
the incidence of breast cancer compared with the use of estrogen
alone. The Women’s Health Initiative prospective randomized
study of hormone replacement therapy stopped treatment with estrogen
and progesterone early because of an increased risk of breast cancer
compared with untreated controls or women treated with estrogen
alone. With decreasing use of these hormones, breast cancer rates
may continue to decrease. Alcohol consumption increases the risk
Some inherited breast cancers have been found to be associated
with a gene on chromosome 17. This gene, BRCA1, is
mutated in families with early-onset breast and ovarian cancer.
Breast cancer will develop in approximately 85% of women
with BRCA1 gene mutations during their lifetime.
Other genes are associated with increased risk of breast and other
cancers, such as BRCA2 (associated with a gene
on chromosome 13), ataxia-telangiectasia mutation, and mutation
of TP53, the tumor suppressor gene. Mutations to TP53 have
been found in approximately 1% of breast cancers in women
under 40 years of age. Genetic testing is commercially available
for women at high risk for breast cancer. Women with genetic mutations
in whom breast cancer develops may be treated in the same way as women
who do not have mutations (ie, lumpectomy), though there is an increased
ipsilateral and contralateral recurrence rate after lumpectomy for these
women. Such women with mutations often elect bilateral mastectomy
as treatment. Some states have enacted legislation to prevent insurance
companies from considering mutations as “preexisting conditions,” preventing insurability.
Women at greater than normal risk for developing breast cancer
(Table 17–1) should be identified
by their practitioners and monitored carefully. Those with an exceptional
family history should be counseled about the option of genetic testing.
Some of these high-risk women may consider prophylactic mastectomy, oophorectomy,
or tamoxifen, an FDA-approved preventive agent.
Table 17–1. Factors Associated with Increased Risk of Breast Cancer. |Favorite Table|Download (.pdf)
Table 17–1. Factors Associated with Increased Risk of Breast Cancer.
|Family history||Breast cancer in mother, sister, or daughter (especially
bilateral or premenopausal)|
|Genetics||BRCA1 or BRCA2 mutation|
|Previous medical history|
- Endometrial cancer
- Proliferative forms of fibrocystic disease
in other breast
- Early menarche (under age 12)
- Late menopause (after age 50)
|Reproductive history ||Nulliparous or late first pregnancy|
The National Surgical Adjuvant Breast Project (NSABP) conducted
the first Breast Cancer Prevention Trial (BCPT) P-1, which evaluated
tamoxifen as a preventive agent in women with no personal history
of breast cancer but at high risk for developing the disease. Women
who received tamoxifen for 5 years had about a 50% reduction
in noninvasive and invasive cancers compared with women taking placebo.
However, women over age 50 who received the drug had an increased
incidence of endometrial cancer and deep venous thrombosis. Unfortunately,
no survival data will be produced from this trial because it was stopped.
The selective estrogen receptor modulator (SERM) raloxifene,
effective in preventing osteoporosis, is also effective in
preventing breast cancer. The initial study, Multiple Outcomes of
Raloxifene Evaluations (MORE) trial, aimed at determining the effect
of raloxifene on bone, demonstrated that raloxifene also reduced breast
cancer risk in women being given the drug. After 8 years, raloxifene
demonstrated an overall reduction of invasive breast cancer of 66%.
Because this study was designed to determine the effect of raloxifene
on bone density, it was conducted in women at lower risk for breast
cancer. To better understand the preventive effect of raloxifene
in the high-risk population, a randomized study comparing raloxifene
with tamoxifen was conducted.
The Study of Tamoxifen and Raloxifene (STAR) P-2 trial, conducted
by the National Surgical Adjuvant Breast and Bowel Project (NSABP)
and completed in 2006, demonstrated that raloxifene and tamoxifen
are equivalent in preventing invasive breast cancer in the high-risk
population. Many of the side effects of raloxifene are the same
as tamoxifen with a slight decrease in cataracts and thromboembolic
events in the raloxifene group. Surprisingly, noninvasive cancer (DCIS)
occurred more commonly in women treated with raloxifene.
Similar to SERMs, aromatase inhibitors (AIs) have shown great
success in treating breast cancer with fewer side effects, although
bone loss is a significant side effect of this long-term treatment.
Several large multicenter studies (eg, International Breast Cancer
Intervention Study II [IBIS-II] and National Cancer Institute
of Canada Clinical Trials Group [NCIC CTG]) are
underway to determine whether AIs have a role in preventing breast
In addition to pharmaceutical therapy, patients continue to seek
a way to prevent breast cancer. There has been considerable research
on incorporating diet and exercise into the lifestyle of women who
may be at risk for cancer. The Women’s Intervention Nutrition
Study was conducted to determine whether decreasing dietary fat
intake would reduce the incidence of breast cancer recurrence after
initial treatment. Although the trial demonstrated a decrease in
recurrence in the follow-up period, it did not reach statistical
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of Breast Cancer
A number of large screening programs have been conducted over
the years. Such programs, consisting of physical and mammographic
examination of asymptomatic women, identify about 10 cancers per
1000 women over the age of 50 and about 2 cancers per 1000 women under
the age of 50. These studies show the increased survival benefit
of screening programs, as screening detects cancer before it has
spread to the lymph nodes in about 80% of the women evaluated.
This increases the chance of survival to about 85% at 5
Both physical examination and mammography are necessary for maximum yield
in screening programs, since about 35–50% of early
breast cancers can be discovered only by mammography and another
40% can be detected only by palpation. About one third
of the abnormalities detected on screening mammograms will be found
to be malignant when biopsy is performed. The probability of cancer
on a screening mammogram is directly related to the Breast Imaging
and Reporting Data System (BIRADS) assessment, and workup should
be performed based on this classification. Women 20–40
years of age should have a breast examination as part of routine
medical care every 2–3 years. Women over age 40 years should
have annual breast examinations. The sensitivity of mammography
varies from approximately 60% to 90%. This sensitivity
depends on several factors, including patient age (breast density)
and tumor size, location, and mammographic appearance. In young
women with dense breasts, mammography is less sensitive than in
older women with fatty breasts, in whom mammography can detect at
least 90% of malignancies. Smaller tumors, particularly
those without calcifications, are more difficult to detect, especially
in dense breasts. The lack of sensitivity and the low incidence of
breast cancer in young women have led to questions concerning the
value of mammography for screening in women 40–50 years
of age. The specificity of mammography in women under 50 years varies
from about 30% to 40% for nonpalpable mammographic
abnormalities to 85% to 90% for clinically evident malignancies.
Screening recommendations for women in their 40s are based, in
part, on trials from Sweden. Two trials showed a statistical advantage
for screening women in their 40s, and a meta-analysis similarly revealed
a statistical survival advantage for screened women with longer
follow-up. The National Cancer Advisory Board recommended that women
in their 40s with average risk factors have screening mammography
every 1–2 years and that women at higher risk seek medical advice
on when to begin screening. Studies continue to support the value
of screening mammography in women over 40 years. Such women should
have annual mammography and physical examination.
The beneficial effect of screening in women aged 50–69
years is undisputed and has been confirmed by all clinical trials.
The efficacy of screening in older women—those older than
70 years—is inconclusive and is difficult to determine because
few studies have examined this population.
Breast self-exam (BSE) has not been shown to improve survival.
Because of the lack of strong evidence demonstrating value, the
American Cancer Society no longer recommends monthly BSE beginning
at age 20 years. The recommendation is that patients be made aware
of the potential benefits, limitations, and harms (increased biopsies
or false-positive results) associated with BSE. Women who choose
to perform BSE should be advised regarding the proper technique.
Premenopausal women should perform the examination 7–8
days after the start of the menstrual period. First, breasts should
be inspected before a mirror with the hands at the sides, overhead,
and pressed firmly on the hips to contract the pectoralis muscles
causing masses, asymmetry of breasts, and slight dimpling of the
skin to become apparent. Next, in a supine position, each breast
should be carefully palpated with the fingers of the opposite hand.
Some women discover small breast lumps more readily when their skin
is moist while bathing or showering. While BSE is not a recommended
practice, patients should recognize and report any breast changes
to their practitioners as it remains an important facet of proactive
Mammography is the most reliable means of detecting breast cancer
before a mass can be palpated. Slowly growing cancers can be identified
by mammography at least 2 years before reaching a size detectable
by palpation. Film screen mammography delivers less than 0.4 cGy
to the midbreast per view. Although full-field digital mammography
provides an easier method to maintain and review mammograms, it
has not been proven that it provides better images or increases
detection rates more than film mammography. In subset analysis of
a large study, digital mammography seemed slightly superior in women
with dense breasts. Computer-assisted detection (CAD) has not shown
any increase in detection of cancers and is not routinely performed
at centers with experienced mammographers.
Calcifications are the most easily recognized mammographic abnormality.
The most common findings associated with carcinoma of the breast
are clustered polymorphic microcalcifications. Such calcifications
are usually at least five to eight in number, aggregated in one
part of the breast and differing from each other in size and shape,
often including branched or V- or Y-shaped configurations. There
may be an associated mammographic mass density or, at times, only
a mass density with no calcifications. Such a density usually has
irregular or ill-defined borders and may lead to architectural distortion
within the breast but may be subtle and difficult to detect.
Indications for mammography are as follows: (1) to screen at
regular intervals asymptomatic women at high risk for developing
breast cancer (see above); (2) to evaluate each breast when a diagnosis
of potentially curable breast cancer has been made and at yearly
intervals thereafter; (3) to evaluate a questionable or ill-defined
breast mass or other suspicious change in the breast; (4) to search for
an occult breast cancer in a woman with metastatic disease in axillary
nodes or elsewhere from an unknown primary; (5) to screen women
prior to cosmetic operations or prior to biopsy of a mass, to examine
for an unsuspected cancer; (6) to monitor those women with breast cancer
who have been treated with breast-conserving surgery and radiation; and
(7) to monitor the contralateral breast in those women with breast
cancer treated with mastectomy.
Patients with a dominant or suspicious mass must undergo biopsy
despite mammographic findings. The mammogram should be obtained
prior to biopsy so that other suspicious areas can be noted and the
contralateral breast can be evaluated. Mammography is never a substitute
for biopsy because it may not reveal clinical cancer, especially
in a very dense breast, as may be seen in young women with fibrocystic
changes, and may not reveal medullary cancers.
Communication and documentation among the patient, the referring
practitioner, and the interpreting physician are critical for high-quality
screening and diagnostic mammography. The patient should be told
about how she will receive timely results of her
mammogram, that mammography does not “rule out” cancer,
and that she may receive a correlative examination such as ultrasound
at the mammography facility if referred for a suspicious lesion.
She should also be aware of the technique and need for breast compression
and that this may be uncomfortable. The mammography facility should
be informed in writing by the clinician of abnormal
physical examination findings. The Agency for Health Care Policy and
Research (AHCPR) Clinical Practice Guidelines strongly recommend
that all mammography reports be communicated in writing to the patient
and referring practitioner. MRI and ultrasound may be useful screening
modalities in women who are at high risk for breast cancer but not
for the general population. The sensitivity of MRI is much higher
than mammography; however, the specificity is significantly lower,
which results in multiple unnecessary biopsies. The increased sensitivity
despite decreased specificity may be considered a reasonable trade-off
for those at increased risk for developing breast cancer but not
for normal-risk population. MRI is useful in women with breast implants
to determine the character of a lesion present in the breast and
to search for implant rupture and at times is helpful in patients
with prior lumpectomy and radiation. In addition, positron emission
tomography (PET) may play a role in imaging atypical lesions but
is less sensitive for early breast cancer than is MRI or mammography.
The primary role remains evaluation of metastatic deposits.
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40 to 49 years of age: a systematic review for the American College
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cancer and breast self-examination in women aged 40 and over. J Cancer
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and future directions. Am Fam Physician 2007;75:1660.
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technique, image interpretation, diagnostic accuracy, and transfer
to clinical practice. Radiology 2007;244:356.
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Investigators Group: Diagnostic performance of digital versus film
mammography for breast cancer screening. N Engl J Med 2005;353:1773.
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management. Curr Treat Options Oncol 2005;6:135.
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Associated with Early Detection of Breast Cancer
The presenting complaint in about 70% of patients with
breast cancer is a lump (usually painless) in the breast. About 90% of
these breast masses are discovered by the patient. Less frequent
symptoms are breast pain; nipple discharge; erosion, retraction,
enlargement, or itching of the nipple; and redness, generalized
hardness, enlargement, or shrinking of the breast. Rarely, an axillary
mass or swelling of the arm may be the first symptom. Back or bone
pain, jaundice, or weight loss may be the result of systemic metastases,
but these symptoms are rarely seen on initial presentation.
The relative frequency of carcinoma in various anatomic sites
in the breast is shown in Figure 17–1.
Frequency of breast carcinoma at various anatomic sites.
Inspection of the breast is the first step in physical examination
and should be carried out with the patient sitting, arms at her
sides and then overhead. Abnormal variations in breast size and
contour, minimal nipple retraction, and slight edema, redness, or
retraction of the skin can be identified. Asymmetry of the breasts
and retraction or dimpling of the skin can often be accentuated
by having the patient raise her arms overhead or press her hands
on her hips to contract the pectoralis muscles. Axillary and supraclavicular
areas should be thoroughly palpated for enlarged nodes with the patient
sitting (Figure 17–2). Palpation
of the breast for masses or other changes should be performed with the
patient both seated and supine with the arm abducted (Figure
17–3). Palpation with a rotary
motion of the examiner’s fingers as well as a horizontal
stripping motion has been recommended.
Palpation of axillary region for enlarged lymph
Palpation of breasts. Palpation is performed with the
patient supine and arm abducted.
Breast cancer usually consists of a nontender, firm or hard mass
with poorly delineated margins (caused by local infiltration). Very
small (1–2 mm) erosions of the nipple epithelium may be
the only manifestation of Paget carcinoma. Watery, serous, or bloody
discharge from the nipple is an occasional early sign but is more
often associated with benign disease.
A small lesion, less than 1 cm in diameter, may be difficult
or impossible for the examiner to feel but may be discovered by
the patient. She should always be asked to demonstrate the location
of the mass; if the practitioner fails to confirm the patient’s
suspicions and imaging studies are normal, the examination should
be repeated in 2–3 months, preferably 1–2 weeks
after the onset of menses. During the premenstrual phase of the
cycle, increased innocuous nodularity may suggest neoplasm or may obscure
an underlying lesion. If there is any question regarding
the nature of an abnormality under these circumstances, the patient should
be asked to return after her period. Ultrasound is often valuable
and mammography essential when an area is felt by the patient to
be abnormal but the physician feels no mass. MRI may be considered,
but the lack of specificity should be discussed by the practitioner and
the patient. MRI should not be used to rule out cancer because MRI
has a false-negative rate of about 3–5%. Although
lower than mammography, this false-negative rate cannot permit safe elimination
of the possibility of cancer. False negatives are more likely seen
in infiltrating lobular carcinomas and DCIS.
Metastases tend to involve regional lymph nodes, which may be
palpable. One or two movable, nontender, not particularly firm axillary
lymph nodes 5 mm or less in diameter
are frequently present and are generally of no significance. Firm or
hard nodes larger than 1 cm are typical of metastases. Axillary
nodes that are matted or fixed to skin or deep structures indicate
advanced disease (at least stage III). On the other hand, if the
examiner thinks that the axillary nodes are involved, that impression
will be borne out by histologic section in about 85% of cases.
The incidence of positive axillary nodes increases with the size
of the primary tumor. Noninvasive cancers (in situ) do not metastasize.
Metastases are present in about 30% of patients with clinically
In most cases, no nodes are palpable in the supraclavicular fossa.
Firm or hard nodes of any size in this location or just beneath
the clavicle are suggestive of metastatic cancer and should be biopsied.
Ipsilateral supraclavicular or infraclavicular nodes containing
cancer indicate that the tumor is in an advanced stage (stage III
or IV). Edema of the ipsilateral arm, commonly caused by metastatic
infiltration of regional lymphatics, is also a sign of advanced
A consistently elevated sedimentation rate may be the result
of disseminated cancer. Liver or bone metastases may be associated
with elevation of serum alkaline phosphatase. Hypercalcemia is an occasional
important finding in advanced cancer of the breast. Carcinoembryonic antigen
(CEA) and CA 15-3 or CA 27-29 may be used as markers for recurrent breast
cancer but are not helpful in diagnosing early lesions. Many scientists
are further investigating breast cancer markers through proteomics
and hormone assays. These studies are ongoing and may prove to be
helpful in early detection or evaluation of prognosis.
Chest radiographs may show pulmonary metastases. CT scanning
of the liver and brain is of value only when metastases are suspected
in these areas. Bone scans utilizing 99mTc-labeled phosphates
or phosphonates are more sensitive than skeletal radiographs in
detecting metastatic breast cancer. Bone scanning has not proved
to be of clinical value as a routine preoperative test in the absence
of symptoms, physical findings, or abnormal alkaline phosphatase
or calcium levels. The frequency of abnormal findings on bone scan
parallels the status of the axillary lymph nodes on pathologic examination. PET
scanning is less useful than a bone scan to identify metastatic
bone lesions. It is effective in soft tissue or visceral metastases
in patients with signs or symptoms of metastatic disease. PET scanning
combined with CT (PET-CT) is an effective screening method for detecting
soft tissue metastases and is replacing CT scans.
The diagnosis of breast cancer depends ultimately on examination
of tissue or cells removed by biopsy. Treatment should never be
undertaken without an unequivocal histologic or cytologic diagnosis
of cancer. The safest course is biopsy examination of all suspicious
lesions found on physical examination or mammography, or both. About
60% of lesions clinically thought to be cancer prove on
biopsy to be benign, while about 30% of clinically benign
lesions are found to be malignant. These findings demonstrate the
fallibility of clinical judgment and the necessity for biopsy.
All breast masses require a histologic diagnosis with one probable
exception, a nonsuspicious, presumably fibrocystic mass, in a premenopausal
woman. Rather, these masses can be observed through one or two menstrual
cycles. However, if the mass is not cystic and does not completely
resolve during this time, it must be biopsied. Figures
17–4 and 17–5 present
algorithms for management of breast masses in premenopausal and postmenopausal
Evaluation of breast masses in premenopausal women.(Adapted,
with permission, from Giuliano AE: Breast disease. In: Practical
Gynecologic Oncology, 3rd ed. Berek JS, Hacker NF [editors], Lippincott
Williams & Wilkins, 2000.)
Evaluation of breast masses in postmenopausal women.(Adapted,
with permission, from Giuliano AE: Breast disease. In: Practical
Gynecologic Oncology, 3rd ed. Berek JS, Hacker NF [editors], Lippincott
Williams & Wilkins, 2000.)
The simplest biopsy method is needle biopsy, either by aspiration
of tumor cells (FNA cytology) or by obtaining a small core of tissue
with a hollow needle (core biopsy).
FNA cytology is a useful technique whereby cells
are aspirated with a small needle and examined cytologically. This technique
can be performed easily with virtually no morbidity and is much
less expensive than excisional or open biopsy. The main disadvantages
are that it requires a pathologist skilled in the cytologic diagnosis
of breast cancer and that it is subject to sampling problems, particularly
because deep lesions may be missed. Furthermore, noninvasive cancers
usually cannot be distinguished from invasive cancers. The incidence
of false-positive diagnoses is extremely low, perhaps 1–2%.
The false-negative rate is as high as 10%. Most experienced clinicians
would not leave a suspicious dominant
mass in the breast even when FNA cytology is negative unless the
clinical diagnosis, breast imaging studies, and cytologic studies were
all in agreement, such as a fibrocystic lesion or fibroadenoma.
Large-needle (core needle) biopsy removes a core
of tissue with a large cutting needle. Handheld biopsy devices make
large-core needle biopsy of a palpable mass easy and cost effective
in the office with local anesthesia. As in the case of any needle
biopsy, the main problem is sampling error due to improper positioning
of the needle, giving rise to a false-negative test result. Core biopsy
has the advantage that tumor markers, such as estrogen receptor (ER),
progesterone receptor (PR), and HER-2/neu overexpression
can be performed on cores of tissue.
Open biopsy under local anesthesia as a separate
procedure prior to deciding upon definitive treatment is the most
reliable means of diagnosis. Needle biopsy or aspiration, when positive,
offers a more rapid approach with less expense and morbidity, but
when nondiagnostic it must be followed by open biopsy. It generally
consists of an excisional biopsy, which is done through an incision
with the intent to remove the entire abnormality, not simply a sample.
Additional evaluation for metastatic disease and therapeutic options
can be discussed with the patient after the histologic or cytologic
diagnosis of cancer has been established. In situ cancers are not
easily diagnosed cytologically and usually require excisional biopsy.
As an alternative in highly suspicious circumstances, the diagnosis
may be made on frozen section of tissue obtained by open biopsy
under general anesthesia. If the frozen section is positive, the
surgeon can proceed immediately with the definitive operation. This
one-step method is rarely used today except when a cytologic study
has suggested cancer but is not diagnostic and there is a high clinical
suspicion of malignancy in a patient well prepared for the diagnosis
of cancer and its treatment options.
In general, the two-step approach—outpatient biopsy
followed by definitive operation at a later date—is preferred
in the diagnosis and treatment of breast cancer, because patients
can be given time to adjust to the diagnosis of cancer, can consider
alternative forms of therapy, and can seek a second opinion if they wish.
There is no adverse effect from the short delay of the two-step
Ultrasonography is performed primarily to differentiate cystic
from solid lesions but may show signs suggestive of carcinoma. Ultrasonography
may show an irregular mass within a cyst in the rare case of intracystic
carcinoma. If a tumor is palpable and feels like a cyst, an 18-gauge
needle can be used to aspirate the fluid and make the diagnosis
of cyst. If a cyst is aspirated and the fluid is nonbloody, it does
not have to be examined cytologically. If the mass does not recur, no
further diagnostic test is necessary. Nonpalpable mammographic densities that
appear benign should be investigated with ultrasound to determine whether
the lesion is cystic or solid. These may even be needle biopsied
with ultrasound guidance.
When a suspicious abnormality is identified by mammography alone
and cannot be palpated by the clinician, the lesion should be biopsied
under mammographic guidance. In the computerized stereotactic
guided core needle technique, a biopsy needle is inserted into
the lesion with mammographic guidance, and a core of tissue for
histologic examination can then be examined. Vacuum assistance increases
the amount of tissue obtained and improves diagnosis.
Mammographic localization biopsy is performed by
obtaining a mammogram in two perpendicular views and placing a needle
or hook-wire near the abnormality so that the surgeon can use the
metal needle or wire as a guide during operation to locate the lesion.
After mammography confirms the position of the needle in relation
to the lesion, an incision is made and the subcutaneous tissue is
dissected until the needle is identified. Often, the abnormality
cannot even be palpated through the incision—as is the
case with microcalcifications—and thus it is essential
to obtain a mammogram of the specimen to document that the lesion
was excised. At that time, a second marker needle can further localize
the lesion for the pathologist. Stereotactic core needle biopsies
have proved equivalent to mammographic localization biopsies. Core
biopsy is preferable to mammographic localization for accessible
lesions, since an operation can be avoided. A metal clip should
be placed after any image-guided core biopsy to facilitate finding
the site of the lesion if subsequent treatment is necessary.
Other modalities of breast imaging have been investigated for
diagnostic purposes. Automated breast ultrasonography is useful
in distinguishing cystic from solid lesions but should be used only
as a supplement to physical examination and mammography. Ductography
may be useful to define the site of a lesion causing a bloody discharge,
but since biopsy is almost always indicated, ductography may be
omitted and the blood-filled nipple system excised. Ductoscopy has
shown some promise in identifying intraductal lesions, especially
in the case of pathologic nipple discharge, but in practice, this
technique is rarely used. MRI is highly sensitive but not specific and
should not be used for screening except in highly selective cases.
For example, MRI is useful in differentiating scar from recurrence
postlumpectomy and may be valuable to screen high-risk women (eg,
women with BRCA mutations). It may also be of value
to examine for multicentricity when there is a known primary cancer;
to examine the contralateral breast in women with cancer; to examine
the extent of cancer, especially lobular carcinomas; or to determine
the response to neoadjuvant chemotherapy. PET scanning does not appear
useful in evaluating the breast itself but is valuable to examine
regional lymphatics and distant metastases.
Cytologic examination of nipple discharge or cyst fluid may be
helpful on rare occasions. As a rule, mammography (or ductography)
and breast biopsy are required when nipple discharge or cyst fluid
is bloody or cytologically questionable. Ductal lavage, a technique
that washes individual duct systems with saline and loosens epithelial
cells for cytologic evaluation, is being evaluated as a risk assessment
tool but appears to be of little value.
The lesions to be considered most often in the differential diagnosis
of breast cancer are the following, in descending order of frequency:
fibrocystic condition of the breast, fibroadenoma, intraductal papilloma,
lipoma, and fat necrosis.
The American Joint Committee on Cancer and the International
Union Against Cancer have agreed on a TNM (tumor, regional lymph
nodes, distant metastases) staging system for breast cancer. Using
the TNM staging system enhances communication between researchers
and clinicians. Table 17–2 outlines
the TNM classification.
Table 17–2. TNM Staging for Breast Cancer. |Favorite Table|Download (.pdf)
Table 17–2. TNM Staging for Breast Cancer.
for classifying the primary tumor (T) are the same for clinical
and for pathologic classification. If the measurement is made by
physical examination, the examiner will use the major headings (T1,
T2, or T3). If other measurements, such as mammographic or pathologic
measurements, are used, the subsets of T1 can be used. Tumors should
be measured to the nearest 0.1 cm increment.|
|TX||Primary tumor cannot be assessed|
|T0||No evidence of primary tumor|
|Tis||Carcinoma in situ|
|Tis (DCIS)||Ductal carcinoma in situ|
|Tis (LCIS)||Lobular carcinoma in situ|
|Tis (Paget)||Paget disease of the nipple with no tumor|
disease associated with a tumor is classified according to the size
of the tumor.|
|T1||Tumor ≤ 2 cm in greatest dimension |
|T1mic||Microinvasion ≤ 0.1 cm in greatest dimension |
|T1a||Tumor > 0.1 cm but not > 0.5 cm in greatest dimension |
|T1b||Tumor > 0.5 cm but not > 1 cm in greatest dimension |
|T1c||Tumor > 1 cm but not > 2 cm in greatest dimension |
|T2||Tumor > 2 cm but not > 5 cm in greatest dimension |
|T3||Tumor > 5 cm in greatest dimension |
|T4||Tumor of any size with direct extension to (a) chest wall
or (b) skin, only as described below |
|T4a||Extension to chest wall, not including 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 |
|N2a||Metastasis in ipsilateral
axillary lymph nodes fixed to one another (matted) or to other structures|
in clinically apparent1 ipsilateral internal mammary nodes
and in the absence of clinically evident axillary
lymph node metastasis|
in ipsilateral infraclavicular lymph node(s) with or without axillary
lymph node involvement, or in clinically apparent1 ipsilateral
internal mammary lymph node(s) and in the presence of
clinically evident axillary lymph node metastasis; or metastasis
in ipsilateral supraclavicular lymph node(s) with or without axillary
or internal mammary lymph node involvement |
|N3a||Metastasis in ipsilateral
infraclavicular lymph node(s) |
in ipsilateral internal mammary lymph node(s) and axillary lymph
|N3c||Metastasis in ipsilateral
supraclavicular lymph node(s) |
lymph nodes cannot be assessed (eg, previously removed, or not removed
for pathologic study) |
regional lymph node metastasis histologically, no additional examination
for isolated tumor cells|
tumor cells (ITC) are defined as single tumor cells or small cell
clusters not greater than 0.2 mm, usually detected only by immunohistochemical
(IHC) or molecular methods but which may be verified on hematoxylin
and eosin stains. ITCs do not usually show evidence of malignant
activity, (eg, proliferation or stromal reaction).|
|pN0(i–)||No regional lymph
node metastasis histologically, negative IHC |
|pN0(i+)||No regional lymph
node metastasis histologically, positive IHC, no IHC cluster > 0.2
regional lymph node metastasis histologically, negative molecular
regional lymph node metastasis histologically, positive molecular
|NX||Regional lymph nodes cannot be assessed (eg, previously
|N0||No regional lymph node metastasis |
|N1||Metastasis to movable ipsilateral axillary lymph
|N2||Metastases in ipsilateral axillary lymph nodes fixed
or matted, or in clinically apparent ipsilateral internal mammary
nodes in the absence of clinically evident axillary
lymph node metastasis|
|pN2||Metastasis in 4 to 9 axillary lymph nodes,
or in clinically apparent1 internal mammary lymph nodes
in the absence of axillary lymph node metastasis |
|pN2a||Metastasis in 4 to 9 axillary lymph nodes
(at least one tumor deposit > 2.0 mm) |
|pN2b||Metastasis in clinically apparent1 internal
mammary lymph nodes in the absence of axillary
lymph node metastasis |
|pN3||Metastasis in 10 or more axillary lymph nodes, or
in infraclavicular lymph nodes, or in clinically apparent
ipsilateral internal mammary lymph nodes in the presence of
1 or more positive axillary lymph nodes; or in more than 3 axillary lymph
nodes with clinically negative microscopic metastasis in internal
mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes |
|pN3a||Metastasis in 10 or more
axillary lymph nodes (at least one tumor deposit > 2.0 mm), or metastasis
to the infraclavicular lymph nodes |
|pN3b||Metastasis in clinically apparent
ipsilateral internal mammary lymph nodes in the presence of
1 or more positive axillary lymph nodes; or in more than 3 axillary lymph
nodes and in internal mammary lymph nodes with microscopic disease detected
by sentinel lymph node dissection but not clinically apparent
|pN3c||Metastasis in ipsilateral supraclavicular
in one to three axillary lymph nodes and/or in internal
mammary nodes with microscopic disease detected by sentinel lymph
node dissection but not clinically apparent1|
(> 0.2 mm, none > 2.0 mm) |
|pN1a||Metastasis in 1
to 3 axillary lymph nodes |
in internal mammary nodes with microscopic disease detected by sentinel
lymph node dissection but not clinically apparent1|
in 1 to 3 axillary lymph nodes and in internal mammary lymph nodes
with microscopic disease detected by sentinel lymph node dissection but
not clinically apparent.1 (If associated with > 3 positive
axillary lymph nodes, the internal mammary nodes are classified
as pN3b to reflect increased tumor burden) |
|MX||Distant metastasis cannot be assessed |
|M0||No distant metastasis |
|Stage IIIC||Any T||N3||M0|
|Stage IV||Any T||Any N||M1|
designation may be changed if postsurgical imaging studies reveal
the presence of distant metastases, provided that the studies are carried
out within 4 months of diagnosis in the absence of disease progression
and provided that the patient has not received neoadjuvant therapy.|
Numerous pathologic subtypes of breast cancer can be identified
histologically (Table 17–3).
Table 17–3. Histologic Types of Breast Cancer |Favorite Table|Download (.pdf)
Table 17–3. Histologic Types of Breast Cancer
|Type||Frequency of Occurrence|
|Infiltrating ductal (not otherwise specified)||80–90%|
|Lobular in situ||2–3%|
|Rare cancers||< 1%|
Except for the in situ cancers, the histologic subtypes have
only a slight bearing on prognosis when outcomes are compared after
accurate staging. Various histologic parameters, such as invasion
of blood vessels, tumor differentiation, invasion of breast lymphatics,
and tumor necrosis have been examined, but other than tumor grade
these have little prognostic value. Genetic analysis for certain high-risk
genes in the primary tumor appears to offer prognostic and therapeutic
The noninvasive cancers by definition are confined by the basement
membrane of the ducts and lack the ability to spread. However, in
patients whose biopsies show noninvasive intraductal cancer, associated
invasive ductal cancers metastasize to lymph nodes in about 1–3% of
Forms of Breast Cancer
Paget carcinoma is not common (about 1% of all breast
cancers). It affects the nipple and may or may not be associated with
a breast mass. The basic lesion is usually a well-differentiated
infiltrating ductal carcinoma or a DCIS. The ducts of the nipple
epithelium are infiltrated, but gross nipple changes are often minimal, and
a tumor mass may not be palpable.
Because the nipple changes appear innocuous, the diagnosis is
frequently missed. The first symptom is often itching or burning
of the nipple, with superficial erosion or ulceration. These are
often diagnosed and treated as dermatitis or bacterial infection,
leading to delay or failure in detection. The diagnosis is established
by biopsy of the area of erosion. When the lesion consists of nipple
changes only, the incidence of axillary metastases is less than
5%, and the prognosis is excellent. When a breast mass
is also present, the incidence of axillary metastases rises, with
an associated marked decrease in prospects for cure by surgical
or other treatment.
This is the most malignant form of breast cancer and constitutes
less than 3% of all cases. The clinical findings consist
of a rapidly growing, sometimes painful mass that enlarges the breast.
The overlying skin becomes erythematous, edematous, and warm. Often,
there is no distinct mass, since the tumor infiltrates the involved
breast diffusely. The inflammatory changes, often mistaken for an
infection, are caused by carcinomatous invasion of the subdermal
lymphatics, with resulting edema and hyperemia. If the practitioner
suspects infection but the lesion does not respond rapidly (1–2
weeks) to antibiotics, biopsy should be performed. The diagnosis should
be made when the redness involves more than one-third of the skin
over the breast and biopsy shows infiltrating carcinoma with invasion
of the subdermal lymphatics. Metastases tend to occur early and
widely, and for this reason, inflammatory carcinoma is rarely curable.
Radiation, hormone therapy, and chemotherapy are the measures most likely
to be of value rather than operation. Mastectomy is indicated when
chemotherapy and radiation have resulted in clinical remission with
no evidence of distant metastases. In these cases, residual disease
in the breast may be eradicated.
Occurring during Pregnancy or Lactation
Breast cancer complicates approximately one in 3000 pregnancies.
The diagnosis is frequently delayed, because physiologic changes
in the breast may obscure the lesion. When the cancer is confined
to the breast, the 5-year survival rate is about 70%. In
60–70% of patients, axillary metastases are already present,
conferring a 5-year survival rate of 30–40%. Pregnancy
(or lactation) is not a contraindication to operation or treatment,
and therapy should be based on the stage of the disease as in the
nonpregnant (or nonlactating) woman. Overall survival rates have
improved, since cancers are now diagnosed in pregnant women earlier
than in the past and treatment has improved. Breast-conserving surgery
may be performed—and radiation and chemotherapy given—even during the pregnancy.
Bilateral breast cancer occurs in less than 5% of cases,
but there is as high as a 20–25% incidence of
later occurrence of cancer in the second breast. Bilaterality occurs
more often in familial breast cancer, in women under age 50 years, and
when the tumor in the primary breast is lobular. The incidence of
second breast cancers increases directly with the length of time
the patient is alive after her first cancer—about 1–2% per
In patients with breast cancer, mammography should be performed
before primary treatment and at regular intervals thereafter, to
search for occult cancer in the opposite breast or conserved ipsilateral
breast. MRI may be useful in this high-risk group.
Noninvasive cancer can occur within the ducts (DCIS) or lobules
(lobular carcinoma in situ, LCIS). LCIS, although thought to be
a premalignant lesion or a risk factor for breast cancer, in fact may behave
like DCIS. In a 2004 analysis of multiple NSABP studies, invasive
lobular breast cancer not only developed in patients with LCIS but
it developed in the same breast and indexed location as the original
LCIS. Although more research needs to be done in this area, the
invasive potential of LCIS is being reconsidered. The subtype pleomorphic
LCIS may behave more like DCIS. DCIS tends to be unilateral and
most often progresses to invasive cancer if untreated. In approximately
40–60% of women who have DCIS treated with biopsy
alone, invasive cancer develops within the same breast.
The treatment of intraductal lesions is controversial. DCIS can
be treated by wide excision with or without radiation therapy or
with total mastectomy. Conservative management is advised in patients
with small lesions amenable to lumpectomy. Although research is
defining the malignant potential of LCIS, it can be managed with observation.
Patients unwilling to accept the increased risk of breast cancer
may be offered surgical excision of the area in question or bilateral
total mastectomy. Currently, the accepted standard of care offers
the alternative of chemoprevention, which is effective in preventing
invasive breast cancer in both LCIS and DCIS that has been completely
excised. Axillary metastases from in situ cancers should not occur
unless there is an occult invasive cancer. Sentinel node biopsy
may be indicated in large DCIS treated with mastectomy.
Barnes DM et al: Pregnancy-associated breast cancer:
a literature review. Surg Clin North Am 2007;87:417.
Barni S et al: Locally advanced breast cancer. Curr Opin Obstet Gynecol
Bodner-Adler B et al: Breast cancer diagnosed during pregnancy. Anticancer
Chen CY et al: Paget disease of the breast: changing patterns
of incidence, clinical presentation, and treatment in the U.S. Cancer
Cristofanilli M et al: Inflammatory breast cancer (IBC) and patterns
of recurrence: understanding the biology of a unique disease. Cancer
Dawood S et al: What progress have we made in managing inflammatory
breast cancer? Oncology (Williston Park) 2007;21:673.
Erbas B et al: The natural history of ductal carcinoma in situ
of the breast: a review. Breast Cancer Res Treat 2006;97:135.
Habel KL et al: A population-based study of tumor gene expression
and risk of breast cancer death among lymph node-negative patients.
Breast Cancer Res 2006;8:R25.
Hansen NM et al: Breast cancer: pre- and postoperative imaging for
staging. Surg Oncol Clin N Am 2007;16:447.
Irvine T et al: Biology and treatment of ductal carcinoma in
situ. Expert Rev Anticancer Ther 2007;7:135.
Lakhani SR et al: The management of lobular carcinoma in situ (LCIS).
Is LCIS the same as ductal carcinoma in situ (DCIS)? Eur J Cancer
Schirrmeister H: Detection of bone metastases in breast cancer
by positron emission tomography. Radiol Clin North Am 2007;45:669.
Theriault R et al: Management of breast cancer in pregnancy.
Curr Oncol Rep 2007;9:17.
West JG et al: Multidisciplinary management of ductal carcinoma in
situ: a 10-year experience. Am J Surg 2007;194:532.
The ER and PR status and HER-2/neu status
of the tumor should be determined at the time of initial biopsy.
Other studies such as proliferation indices may be performed. These
markers may be obtained on core biopsy specimens, which will be necessary
to institute neoadjuvant therapy.
The presence or absence of ER and PR is a critical element of
breast cancer management. Patients whose primary tumors are receptor-positive
have a more favorable course than those whose tumors are receptor-negative.
Up to 60% of patients with metastatic breast cancer will
respond to hormonal manipulation if their tumors are ER-positive.
Fewer than 5% of patients with metastatic, ER-negative
tumors can be treated successfully in this fashion. Adjuvant hormonal
therapy, with or without chemotherapy, in receptor-positive tumors
and adjuvant chemotherapy alone in receptor-negative tumors improve
survival rates even in the absence of lymph node metastases. Hormone receptors
have no relationship to response to chemotherapy (see discussion
on adjuvant therapy later in chapter).
PR status may be more sensitive than ER status in determining
which patients are likely to respond to hormonal manipulation. Up
to 80% of patients with metastatic PR-positive tumors improve
with hormonal manipulation.
In addition to ER status and PR status, the rate at which tumor
divides and the differentiation of the cells (proliferative indices)
are important. In order to establish the rate of growth and differentiation, the
amount and type of DNA is measured with flow cytometry.
Another key element in determining treatment and prognosis is
the amount of the HER-2/neu oncogene present
in the cancer. HER-2/neu overexpression
is scored using a numerical system: 1+ is not an overexpressor,
2+ is borderline, and 3+ is an overexpressor.
In the case of 2+ expression, fluorescence in situ hybridization
(FISH) is recommended to more accurately assess HER-2/neu amplification
and provide better prognostic information. The presence of HER-2/neu amplification
predicts the response to trastuzumab.
While individually these biomarkers provide insight to appropriate
adjuvant therapy, when combined they provide a great deal of information
regarding risk of recurrence. Several tests now predict relapse
rates for patients treated with tamoxifen or chemotherapy. Oncotype
DX combines 21 genetic markers, including ER, PR, and HER-2/neu expression,
in a tumor specimen to categorize risk of recurrence into three groups:
high risk, intermediate risk, and low risk. The test is able to
identify that the high-risk group is more likely to benefit from
chemotherapy in addition to tamoxifen while the low-risk group does
not. This type of test is quite helpful when the survival advantage
of therapy is difficult to determine. It has been most used for
ER-positive node-negative tumors but now may apply to node-positive
tumors as well.
Another promising biomarker being studied is vascular endothelial
growth factor (VEGF), a protein that stimulates the growth of blood
vessels. Elevated levels of VEGF may be a marker for a tumor that
is more aggressive because of its ability to develop blood vessels
and grow. While researchers look for more specific markers to determine
the presence of breast cancer, these markers also provide insight
to targeted methods of treatment. Other markers being evaluated
are p53, nm23, DNA 5c exceeding rate (DNA 5cER), G-actin, urokinase-type
plasminogen activator (u-PA), and its type-1 inhibitor (PAI-1).
Ferretti G et al: sHER2/neu
in breast cancer: from a prognostic foe to a predictive friend.
Curr Opin Obstet Gynecol 2007; 19:56.
Luadido J et al: HER2 testing: a review of detection methodologies
and their clinical performance. Expert Rev Mol Diagn 2007;7:53.
Nicolini A et al: Biomolecular markers of breast cancer. Front Biosci
Paik S et al: A multigene assay to predict recurrence of tamoxifen
node-negative breast cancer. N Engl J Med 2004;351:2817.
Clearly, not all breast cancer is systemic at the time of diagnosis.
A pessimistic attitude concerning the management of breast cancer
is therefore unwarranted. Most patients with early breast cancer can
Treatment may be curative or palliative. Curative treatment is
advised for clinical stage I, II, and III disease (see Table
17–2). Patients with locally advanced (T3, T4) and
even inflammatory tumors may be cured with multimodality therapy,
but in most, palliation is all that can be expected. Palliative
treatment is appropriate for all patients with stage IV disease
and for previously treated patients in whom distant metastases develop
or who have unresectable local cancers (see Treatment: Palliative
section later in chapter).
The extent of disease and its biologic aggressiveness are the
principal determinants of the outcome of primary therapy. Clinical
and pathologic staging help in assessing extent of disease (see Table 17–2), but each is to some
extent imprecise. Other factors, such as DNA flow cytometry, tumor
grade, hormone receptor assays, and oncogene amplification, may
be of prognostic value but are not important in determining the
type of local therapy.
Controversy has surrounded the choice of primary therapy of stages
I, II, and III breast carcinoma. A number of states require physicians
to inform patients of alternative treatment methods in the management
of breast cancer. Currently, the standard of care for stage I, stage
II, and most stage III cancer is surgical resection followed by adjuvant
radiation or systemic therapy when indicated. Neoadjuvant therapy
is becoming more popular, since large tumors may be shrunk by chemotherapy
prior to surgery, making some patients who require mastectomy candidates for
Multiple, large, randomized studies, including the Milan and
NSABP trials, show that disease-free and overall survival rates
are similar for patients treated with partial mastectomy plus axillary
dissection followed by radiation therapy and for those treated by
modified radical mastectomy (total mastectomy plus axillary dissection).
Twenty years of follow-up of the NSABP trial has shown that lumpectomy
with axillary dissection followed by postoperative radiation therapy
is as effective as modified radical mastectomy for the management
of patients with stage I and stage II breast cancer.
Tumor size is a major consideration in determining the feasibility
of breast conservation. The lumpectomy trial of the NSABP randomized
patients with tumors as large as 4 cm. To achieve an acceptable
cosmetic result, the patient must have a breast of sufficient size
to enable excision of a 4-cm tumor without considerable deformity.
Therefore, large size is only a relative contraindication. Subareolar
tumors, also difficult to excise without deformity, are not contraindications
to breast conservation. Clinically detectable multifocality is a
relative contraindication to breast-conserving surgery, as is fixation
to the chest wall or skin or involvement of the nipple or overlying
skin. The patient—not the surgeon—should be the
judge of what is cosmetically acceptable.
Axillary dissection is valuable in preventing axillary recurrences,
in staging cancer, and in planning therapy. Intraoperative lymphatic
mapping and sentinel node biopsy identify lymph nodes most likely
to harbor metastases if present in the axillary nodes. Sentinel node
biopsy is a reasonable alternative to axillary dissection in selected
patients with invasive cancer.
Breast-conserving surgery with radiation is the preferred form
of treatment for patients with early-stage breast cancer. Despite
the numerous randomized trials showing no survival benefit of mastectomy
over breast-conserving partial mastectomy and irradiation, breast-conserving
surgery still appears underutilized.
Modified radical mastectomy was the standard therapy for most patients
with early-stage breast cancer. This operation removes the entire
breast, overlying skin, nipple, and areolar complex as well as the
underlying pectoralis fascia with the axillary lymph nodes in continuity.
The major advantage of modified radical mastectomy is that radiation therapy
may not be necessary, although radiation may be used when multiple lymph
nodes are involved with cancer. The disadvantage of mastectomy is
the cosmetic and psychological impact associated with breast loss.
Radical mastectomy, which removes the underlying pectoralis muscle,
should be performed rarely, if at all. Axillary node dissection
is not indicated for noninfiltrating cancers because nodal metastases
are rarely present. Skin-sparing mastectomy is currently gaining
favor but is not appropriate for all patients. Breast-conserving
surgery and radiation should be offered whenever possible, since
most patients would prefer to save the breast. Breast reconstruction,
immediate or delayed, should be discussed with patients who choose
or require mastectomy. Patients should have an interview with a
reconstructive plastic surgeon to discuss options prior to making
a decision regarding reconstruction. Time is well spent preoperatively
in educating the patient and family about these matters.
Radiotherapy after partial mastectomy consists of 5–7 weeks
of five daily fractions to a total dose of 5000–6000 cGy.
Most radiation oncologists use a boost dose to the cancer location.
Several studies are underway examining the utility and recurrence
rates after intraoperative radiation or dose dense radiation in
which the time course of radiation is shortened. Accelerated partial
breast irradiation, in which only the portion of the breast from
which the tumor was resected is irradiated for 1–2 weeks,
appears effective in achieving local control. A prospective randomized
trial to examine the efficacy of this technique is underway. Accrual
should be completed this year, but long-term follow-up will be necessary.
Current studies suggest that radiotherapy after mastectomy may improve survival
in a subset of patients and is being further researched in a large
cooperative trial to better identify which subgroups will benefit.
Researchers are also examining the utility of axillary irradiation
as an alternative to axillary dissection in the clinically node-negative
patient with sentinel node micrometastases.
In practice, most medical oncologists are currently using systemic
adjuvant therapy for patients with either node-negative or node-positive
breast cancer. Prognostic factors other than nodal status being used
to determine the patient’s risks are tumor size, ER and
PR status, nuclear grade, histologic type, proliferative rate, and
oncogene expression (Table 17–4).
The assumption is made that all patients with node-negative aggressive tumors
should receive adjuvant therapy except those who have serious coexistent
medical problems. In general, systemic chemotherapy decreases the chance
of recurrence by about 30%. Most patients tolerate at least
Table 17–4. Prognostic Factors in Node-Negative Breast Cancer. |Favorite Table|Download (.pdf)
Table 17–4. Prognostic Factors in Node-Negative Breast Cancer.
|Prognostic Factors||Increased Recurrence||Decreased Recurrence|
|Size||T3, T2||T1, T0|
|DNA flow cytometry||Aneuploid||Diploid|
|Tumor labeling index||< 3%||> 3%|
|S phase fraction||> 5%||< 5%|
|Lymphatic or vascular invasion||Present||Absent|
|Epidermal growth factor receptor||High||Low|
Following surgery and possible radiation therapy, systemic therapy
improves survival and is advocated for most patients with curable
breast cancer. In addition, chemotherapy may decrease local recurrence
in patients treated with breast conservation, whereas hormonal manipulation
decreases contralateral breast cancer occurrence as well as ipsilateral
On the basis of the superiority of anthracycline-containing regimens
in metastatic breast cancer, both doxorubicin and epirubicin have
been studied extensively in the adjuvant setting. Studies comparing Adriamycin
(generic name: doxorubicin) and cyclophosphamide (AC) or epirubicin
and cyclophosphamide (EC) with cyclophosphamide methotrexate fluorouracil
(CMF) have shown that treatments with anthracycline-containing regimens are
at least as effective as, and perhaps more effective than, treatment
with CMF. The NSABP B-23 compared four cycles of AC with six cycles
of CMF and demonstrated the equivalence of these two regimens in
node-negative, ER-negative disease. Whereas four cycles of AC or EC
have not demonstrated improved survival compared with CMF, the use
of six cycles of fluorouracil plus AC (FAC) or fluorouracil plus
EC (FEC) has shown improved survival compared with CMF alone. For
node-negative patients, the results of clinical trials support the
use of four cycles of AC or six cycles of CMF in the adjuvant setting.
For node-positive patients and recently selected
node-negative patients, taxanes (paclitaxel and docetaxel)
are frequently combined with anthracycline-based regimens. Initial studies
demonstrated a 20% proportional reduction in recurrence
and a 4% absolute improvement in disease-free survival with
the addition of paclitaxel to an AC regimen. Paclitaxel is FDA-approved
for and increasingly used as adjuvant therapy in node-positive breast
cancer. Taxanes are commonly added to AC for node-positive women.
A trial comparing six cycles of FAC to six cycles of Docetaxel,
doxorubicin, and cyclophosphamide (TAC) showed an improvement in disease-free
survival for patients receiving the addition of docetaxel. This
benefit was most marked for patients with positive nodes and was
seen in both ER-negative and ER-positive tumors. High-risk node-negative
patients are also treated with taxanes. A large study from the Breast
Cancer International Research Group, presented at the San Antonio Breast
Cancer Symposium in December 2007, suggests that anthracyclines
may only be effective in patients with HER-2/neu overexpression.
This remains to be confirmed.
Chemotherapy side effects are now well controlled. Nausea and
vomiting are abated with drugs that directly affect the central
nervous system, such as ondansetron and granisetron. Growth factors
such as erythropoietin (epoetin alfa), which stimulates red blood
cell production and mimics the effect of erythropoietin, and filgrastim
(granulocyte colony-stimulating factor [G-CSF]),
which stimulates proliferation and differentiation of hematopoietic
cells, prevent life-threatening anemia and neutropenia seen commonly
with high doses of chemotherapy. These agents greatly diminish the
incidence of infections that may complicate the use of myelosuppressive chemotherapy.
The overall duration of adjuvant chemotherapy still remains uncertain.
However, based on the meta-analysis performed in the Oxford Overview
(Early Breast Cancer Trialists’ Collaborative Group), the current
recommendation is for 3–6 months of the commonly used regimens. The
addition of taxanes required an additional duration of therapy of
up to 6 months. Increasing the frequency of chemotherapy administration
(dose dense chemotherapy) has been shown to be superior to standard
dosing. It is often used when there is a greater risk of recurrence
or in the younger patient, since it is a difficult regimen to tolerate physically.
Although it is clear that dose intensity to a specific threshold
is essential, there are little to no data supporting the benefit
to high-dose therapy with stem cell support.
Controversy exists about whether patients whose tumors overexpress
the HER-2/neu oncogene benefit more from anthracycline
regimens than from CMF regimens. Trastuzumab (Herceptin), a monoclonal
antibody that binds to the HER-2/neu receptors,
when studied in the metastatic setting, has proved effective in
combination with chemotherapy in patients with HER-2/neu overexpression. A
second monoclonal antibody lapatinib (Tykerb) is effective for metastatic
breast cancer in patients who have received trastuzumab. Cardiac
toxicity is seen from these antibodies. A multicenter trial from
Finland, by the Fin-Her collaborative group, studied the use of
trastuzumab in combination with docetaxel or vinorelbine for patients
with early breast cancer that demonstrated HER-2/neu overexpression.
The 3-year recurrence-free survival was better in those who took
trastuzumab than in those who did not receive the antibody, 89% versus 78%,
respectively. In another study, the HERA trial, a similar disease-free
survival at interim analysis was demonstrated when giving trastuzumab subsequent
to adjuvant chemotherapy in early breast cancer. In several trials,
trastuzumab appears to decrease recurrence by nearly 50% when
used as an adjuvant. It is currently given for 1 year postoperatively.
Vascular Endothelial Growth Factor (VEGF)
Bevacizumab (Avastin) is a monoclonal antibody directed against
VEGF. This growth factor stimulates endothelial proliferation and
neoangiogenesis in cancer. A phase-three randomized trial showed
increased effectiveness of a combination of bevacizumab and paclitaxel
over paclitaxel alone. This antibody is being tested in other phase-three
studies, adjuvant studies, and neoadjuvant studies. Results are
Adjuvant hormonal therapy is highly effective in decreasing recurrence
and mortality by 25% in women with ER-positive tumors regardless
of menopausal status. The standard regimen has been tamoxifen for
5 years. AIs are also effective in the adjuvant setting for postmenopausal
women. The large Arimidex, Tamoxifen, Alone or in Combination (ATAC)
trial in postmenopausal women with ER-positive disease showed improved
disease-free survival in patients treated with anastrozole compared
with those treated with tamoxifen alone or with the combination
of tamoxifen and anastrozole. In addition, anastrozole has shown
a greater than 50% reduction in contralateral breast tumors with
fewer side effects such as endometrial cancers, hot flushes, and
thromboembolic events. However, anastrozole did have an increase
in fractures due to bone loss. Anastrozole is used in the adjuvant
setting in postmenopausal women. Because of the extensive long-term
data supporting the use of tamoxifen, the American Society of Clinical Oncology,
while recommending the use of AI in the appropriate populations,
still encourages the use of tamoxifen for adjuvant hormonal therapy
in the absence of significant contraindications. Tamoxifen should
be used as a systemic agent in all women whose tumors are hormone
receptor–positive, regardless of age, menopausal status,
or other prognostic factors. HER-2/neu status
should not affect the choice of cytotoxic agents or the use of hormone
therapy. Furthermore, anastrozole is being used after completion
of tamoxifen therapy or prior to completing therapy (year 2 or 3)
to further decrease recurrences.
The long-term advantage of systemic therapy has been well established. Selection
of patients for adjuvant treatment should be based on the patient’s axillary
nodal status, tumor size and grade, receptor status, HER-2/neu, and age.
The value of TP53, angiogenesis factors, and vascular
invasion is being investigated, but they remain to be proven prognostic
factors. The use of anthracyclines is superior to combinations without
anthracyclines. Ovarian ablation in premenopausal patients with ER-positive
tumors may produce a benefit similar to that of adjuvant systemic chemotherapy.
Taxanes have demonstrated benefit in patients with metastatic cancer
and are being used in node-negative patients. Adjuvant systemic
therapy should not be given to women who have small node-negative
breast cancers with favorable histologic findings and tumor markers
such as mucinous or tubular carcinoma, ER-positive, low grade, HER-2/neu nonamplified.
The use of chemotherapy or hormonal therapy prior to resection
of the primary tumor (neoadjuvant) is gaining popularity. This enables
the assessment of in vivo chemosensitivity. A complete tumor response
in vivo prior to operation is associated with improvement in survival. Neoadjuvant
chemotherapy also permits breast conservation by shrinking the primary
tumor in women who would otherwise need mastectomy for local control. Survival
after neoadjuvant chemotherapy has not been shown to be superior
to that seen with postoperative adjuvant chemotherapy but is certainly
no worse. There is considerable concern as to the timing of sentinel
lymph node biopsy (SLNB), since the chemotherapy may affect any
cancer present in the lymph nodes. Several studies have shown that sentinel
node biopsy can be done after neoadjuvant therapy. However, a large multicenter
study, NSABP B-27, demonstrated a false-negative rate as high as 10.7%,
well above the false-negative rate outside the neoadjuvant setting
(< 1–5%). Many physicians recommend performing
SLNB before administering the chemotherapy in order to avoid a false-negative
result and to aid in planning subsequent radiation therapy. If a complete
dissection is necessary, this can be performed at the time of the
definitive breast surgery.
Important questions remaining to be answered are the timing and
duration of adjuvant and neoadjuvant chemotherapy, which chemotherapeutic
agents should be applied for which subgroups of patients, the use
of combinations of hormonal therapy and chemotherapy as well as
possibly targeted therapy, and the value of prognostic factors other
than hormone receptors in predicting response to therapy. Adjuvant
systemic therapy is not generally used in patients with small tumors
and those with negative lymph nodes who have favorable tumor markers.
However, a small disease-free survival benefit, even in patients
with small favorable tumors, is seen. It appears that adjuvant systemic therapy
benefits all breast cancer patients, but the clinician and patient must
decide if the benefits outweigh the risks, complications, and expense.
Palliative radiotherapy may be advised for primary treatment
of locally advanced cancers with distant metastases to control ulceration,
pain, and other manifestations in the breast and regional nodes. Irradiation
of the breast and chest wall and the axillary, internal mammary,
and supraclavicular nodes should be undertaken in an attempt to
cure locally advanced and inoperable lesions when there is no evidence
of distant metastases. A small number of patients in this group
are cured in spite of extensive breast and regional node involvement.
Palliative irradiation is of value also in the treatment of certain
bone or soft-tissue metastases to control pain or avoid fracture.
Radiotherapy is especially useful in the treatment of isolated bony metastases,
chest wall recurrences, brain metastases, and acute spinal cord compression.
Disseminated disease may shrink—or grow less rapidly—after
endocrine therapy such as administration of hormones (eg, estrogens,
androgens, progestins; see Table 17–5);
ablation of the ovaries, adrenals, or pituitary; or administration
of drugs that block hormone receptor sites (eg, antiestrogens) or
drugs that block the synthesis of hormones (eg, AIs). Hormonal manipulation
is usually more successful in postmenopausal women even if they have
received estrogen replacement therapy. Treatment should be based
on the ER status of the primary tumor or metastases. The rate of
response is nearly equal in premenopausal and postmenopausal women
with ER-positive tumors. A favorable response to hormonal manipulation
occurs in about one third of patients with metastatic breast cancer.
Of those whose tumors contain ER, the response is about 60% and
perhaps as high as 80% for patients whose tumors contain
PR as well. In addition, women with ER-positive tumors who do not
respond to hormone therapy or experience progression should be placed
on a different form of hormonal manipulation. Because only 5–10% of
women with ER-negative tumors do respond, they should not receive
hormonal therapy except in unusual circumstances (eg, in an older patient
who cannot tolerate chemotherapy). Because the quality of life during
a remission induced by endocrine manipulation is usually superior
to a remission following cytotoxic chemotherapy, it is usually best
to try endocrine manipulation whenever possible. Women who do not
respond to tamoxifen may try a third-generation AI and have an equal
if not better response than those who responded to tamoxifen. However,
when receptor status is unknown and the disease is progressing rapidly
or involves visceral organs, endocrine therapy is rarely successful,
and introducing it may waste valuable time.
Table 17–5. Agents Commonly Used for Hormonal Management of Metastatic Breast Cancer |Favorite Table|Download (.pdf)
Table 17–5. Agents Commonly Used for Hormonal Management of Metastatic Breast Cancer
|Drug||Action||Dose, Route, Frequency||Major Side Effects|
|Tamoxifen citrate (Nolvadex)||SERM||20 mg orally daily||Hot flushes, uterine bleeding, thrombophlebitis, rash |
|Fulvestrant (Faslodex)||Steroidal estrogen receptor antagonist||250 mg intramuscularly monthly||Gastrointestinal upset, headache, back pain, hot flushes,
|Toremifene citrate (Fareston)||SERM||40 mg orally daily||Hot flushes, sweating, nausea, vaginal discharge, dry eyes,
|Diethylstilbestrol (DES)||Estrogen||5 mg orally three times daily||Fluid retention, uterine bleeding, thrombophlebitis, nausea |
|Goserelin (Zoladex)||Synthetic luteinizing hormone-releasing analogue||3.6 mg subcutaneously monthly||Arthralgias, blood pressure changes, hot flushes, headaches,
|Megestrol acetate (Megace)||Progestin||40 mg orally four times daily||Fluid retention |
|Letrozole (Femara)||AI||2.5 mg orally daily||Hot flushes, arthralgia/arthritis, myalgia|
|Anastrozole (Arimidex)||AI||1 mg orally daily||Hot flushes, skin rashes, nausea and vomiting|
|Exemestane (Aromasin)||AI||25 mg orally daily||Hot flushes, increased arthralgia/arthritis, myalgia,
In addition to radiotherapy, bisphosphonate therapy has shown
excellent results in delaying and reducing skeletal events in women
with bony metastases. Bisphosphonates are also sometimes used in conjunction
with AIs to decrease the potential bony events associated with AIs.
Bisphosphonates are routinely given with AIs to patients with bone metastases.
In general, only one type of therapy should be given at a time
unless it is necessary to irradiate a destructive lesion of weight-bearing
bone while the patient is receiving another regimen. The regimen should
be changed only if the disease is clearly progressing. This is especially important
for patients with destructive bone metastases, since changes in the status of
these lesions are difficult to determine radiographically. A plan
of therapy that would simultaneously minimize toxicity and maximize
benefits is often best achieved by hormonal manipulation.
The choice of endocrine therapy depends on the menopausal status
of the patient. Women within 1 year of their last menstrual period
are arbitrarily considered to be premenopausal, whereas women whose
menstruation ceased more than a year ago are postmenopausal. If
endocrine therapy is the initial choice, it is referred to as primary
hormonal manipulation; subsequent endocrine treatment is called
secondary or tertiary hormonal manipulation. In metastatic disease,
for patients with HER-2/neu oncogene overexpression,
trastuzumab has been shown to increase survival.
In addition, the use of an antiangiogenesis drug bevacizumab
in the treatment of metastatic disease is effective to improve survival.
Based on the amount of VEGF detected in the primary tumor, bevacizumab
can increase overall survival and disease-free survival when used
in combination with chemotherapy when metastases are present.
The Premenopausal Patient
The potent SERM tamoxifen is by far the most common and preferred
method of hormonal manipulation in the premenopausal patient. Tamoxifen
is usually given orally in a dose of 20 mg daily. There is no significant
difference in survival or response between tamoxifen therapy and
bilateral oophorectomy. The average remission is about 12 months. Tamoxifen
can be given with little morbidity and few side effects. Toremifene,
a tamoxifen analog, has similar side effects but is less likely
to cause uterine cancer. The response to tamoxifen is predictive of
probable success with other forms of endocrine manipulation in premenopausal
Bilateral oophorectomy is less desirable than tamoxifen in premenopausal women
because tamoxifen is so well tolerated. However, oophorectomy can
be achieved rapidly and safely by surgery or by irradiation of the
ovaries if the patient is a poor surgical candidate. Chemical ovarian
ablation using a gonadotropin-releasing hormone (GnRH) analog can also
be used. Oophorectomy presumably works by eliminating estrogens, progestins,
and androgens, which stimulate growth of the tumor. AIs should not be
used in a patient with functioning ovaries since they do not block
Secondary or Tertiary Hormonal Therapy
Although patients who do not respond to tamoxifen or oophorectomy
should be treated with cytotoxic drugs, those who respond and then
relapse may subsequently respond to another form of endocrine treatment
(Table 17–5). The initial choice
for secondary endocrine manipulation has not been clearly defined.
Patients who improve after oophorectomy but subsequently relapse
should receive tamoxifen or an AI; if one fails, the other may be
tried but is not likely to succeed. Megestrol acetate, a progesterone
agent, may be considered. These drugs cause less morbidity and mortality
than surgical adrenalectomy, can be discontinued once the patient improves,
and are not associated with the many problems of postsurgical hypoadrenalism,
so that patients who require chemotherapy are more easily managed.
Adrenalectomy or hypophysectomy, procedures rarely done today, induced regression
in 30–50% of patients who previously responded to
oophorectomy. Pharmacologic hormonal manipulation has replaced these
invasive procedures. AIs are of value when a tumor responded to
tamoxifen or oophorectomy but then progresses.
Tamoxifen, 20 mg orally daily, or anastrozole, 1 mg orally daily,
is the initial therapy of choice for postmenopausal women with metastatic
breast cancer amenable to endocrine manipulation. Anastrozole (an
AI) has fewer side effects than tamoxifen and may be more effective.
The main side effects of tamoxifen are nausea, vomiting, skin rash,
and hot flushes. Rarely, it may induce hypercalcemia in patients
with bony metastases. The main side effects of anastrozole are similar but
lower in incidence; however, osteoporosis and bone fractures are
significantly higher than tamoxifen. Other AIs are letrozole or
exemestane. They have similar efficacy and side-effect profiles.
Secondary or Tertiary Hormonal Therapy
AIs are also available for the treatment of advanced breast cancer
in postmenopausal women after tamoxifen treatment. In the event
that the patient responds to AI but then has progression of disease, an
antiestrogen, fulvestrant, has shown efficacy with about 20–30% of
women benefiting from use. Postmenopausal patients who do not respond
to SERM or AI should be given cytotoxic drugs. Postmenopausal women
who respond initially to a SERM or AI but later manifest progressive
disease may be crossed over to another hormonal therapy. If they
do not respond, they should receive cytotoxic drugs. Androgens have
many toxicities and should rarely be used. As in premenopausal patients,
neither hypophysectomy nor adrenalectomy should be performed.
Cytotoxic drugs should be considered for the treatment of metastatic
breast cancer (1) if visceral metastases are present (especially
brain or lymphangitic pulmonary), (2) if hormonal treatment is unsuccessful
or the disease has progressed after an initial response to hormonal manipulation,
or (3) if the tumor is ER-negative. Prior adjuvant chemotherapy does
not seem to alter response rates in patients who relapse. The most
useful single chemotherapeutic agent to date is doxorubicin, with
a response rate of 40–50%.
Combination chemotherapy with multiple agents is more effective,
with objectively observed favorable responses achieved in 60–80% of
patients with stage IV disease. Doxorubicin (40 mg/m2 intravenously
on day 1) and cyclophosphamide (200 mg/m2 orally
on days 3–6) produce an objective response in about 85% of
patients so treated. Various combinations of drugs have been used,
and clinical trials are always ongoing to identify a combination to
increase survival and reduce side effects. Other chemotherapeutic
regimens have consisted of various combinations of drugs, including cyclophosphamide,
vincristine, methotrexate, fluorouracil, and taxanes with response
rates ranging up to 60–70%. Researchers continue
to study new drugs and combinations of chemotherapy agents, such
as capecitabine, mitoxantrone, vinorelbine, gemcitabine, irinotecan,
cisplatin, and carboplatin. Many of these agents or combinations are
available to patients in a clinical trial setting or by physician’s
choice. For patients whose tumors have progressed after many therapies
and who are considering additional therapy, clinical trial participation
with experimental drugs in phase I, II, or III testing should be encouraged.
Although infrequent, single-agent use with taxanes (paclitaxel
and docetaxel) has been shown to be very effective for patients
with metastatic breast cancer, with a response rate of 30–40%.
They have usually been given after failure of combination chemotherapy
for metastatic disease or relapse shortly after completion of adjuvant
chemotherapy. They may be especially valuable in treating anthracycline-resistant
tumors. High-dose chemotherapy and autologous bone marrow or stem
cell transplantation aroused widespread interest for the treatment
of metastatic breast cancer. With this technique, the patient receives high
doses of cytotoxic agents, eradicating the marrow, for which the
patient subsequently undergoes autologous bone marrow or stem cell
transplantation. Most randomized trials, however, comparing high-dose
chemotherapy with stem cell support showed no improvement in survival
over conventional chemotherapy. Enthusiasm for high-dose chemotherapy with
stem cell support has waned, and the procedure is rarely performed.
The technique is extremely costly, and the treatment itself is associated
with a mortality rate of about 3–7%.
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for early-stage breast cancer: 100-month analysis of the ATAC trial.
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Carlson RW et al: NCCN Task Force report: adjuvant therapy for
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Chu QD et al: Adjuvant therapy for patients who have node-positive
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Fitzal F et al: Breast conservation: evolution of surgical strategies.
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Gould RE et al: Update on aromatase inhibitors in breast cancer.
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Miller K et al: Paclitaxel plus bevacizumab versus paclitaxel
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Stage of breast cancer is the most reliable indicator of prognosis
(Table 17–6). Patients with disease
localized to the breast with no evidence of pathologic involvement
of the lymph nodes have the most favorable prognosis. Axillary lymph node
status is the best-analyzed prognostic factor and correlates with
survival at all tumor sizes. In addition, increased number of axillary
nodes involved correlates directly with lower survival rates. Biologic
marker status, such as ER, PR, grade, HER-2/neu, aides
in determining the aggressiveness of a tumor and are important prognostic
variables, but no markers are as significant as lymph node metastases
in predicting outcome (see Biomarkers). The histologic subtype of breast
cancer (eg, medullary, lobular, colloid) seems to have little significance
in prognosis of invasive carcinomas. Flow cytometry of tumor cells
to analyze DNA index and S-phase frequency aid in prognosis. Tumors
with marked aneuploidy have a poor prognosis (see Table
17–4). Gene analysis studies, such as Oncotype DX,
can predict survival for some subsets of patients.
Table 17–6. Approximate Survival (%) of Patients with Breast Cancer by TNM Stage. |Favorite Table|Download (.pdf)
Table 17–6. Approximate Survival (%) of Patients with Breast Cancer by TNM Stage.
|TNM Stage||5 Years||10 Years|
The mortality rate of breast cancer patients exceeds that of
age-matched normal controls for nearly 20 years. Thereafter, the
mortality rates are equal, though deaths that occur among breast cancer
patients are often directly the result of tumor. Five-year statistics
do not accurately reflect the final outcome of therapy.
When cancer is localized to the breast, with no evidence of regional spread after pathologic examination,
the clinical cure rate with most accepted methods of therapy is
75% to greater than 90%. Variations to this generalization
may be related to the hormonal receptor content of the tumor, genetic markers,
tumor size, host resistance, or associated illness. Patients with
small mammographically detected biologically favorable tumors and
no evidence of axillary spread have a 5-year survival rate greater
than 95%. When the axillary lymph nodes are involved with
tumor, the survival rate drops to 50–70% at 5
years and probably around 25–40% at 10 years.
In general, breast cancer appears to be somewhat more malignant
in younger than in older women, and this may be related to the fact
that fewer younger women have ER-positive tumors. Adjuvant systemic
chemotherapy, in general, improves survival by about 30% and
adjuvant hormonal therapy by about 25%.
For those patients whose disease progresses despite treatment,
studies suggest supportive group therapy may improve survival. As
they approach the end of life, such patients will require meticulous
efforts at palliative care.
Stuart K et al: Life after breast cancer. Aust
Fam Physician 2006;35:219.
After primary therapy, patients with breast cancer should be
monitored for life in order to detect recurrences and to observe
the opposite breast for a second primary carcinoma. Local and distant recurrences
occur most frequently within the first 2–5 years. During
the first 2 years, most patients should be examined every 6 months,
then annually thereafter. The patient should examine her own breasts
monthly, and a mammogram should be obtained annually. Special attention
is paid to the contralateral breast because a new primary breast malignancy
will develop in 20–25% of patients. In some cases,
metastases are dormant for long periods and may appear 10–15
years or longer after removal of the primary tumor. Although studies
have failed to show an adverse effect of hormonal replacement in
disease-free patients, it is rarely used after breast cancer treatment,
particularly if the tumor was hormone receptor positive. Even pregnancy
has not been clearly associated with shortened survival of patients
rendered disease free—yet most oncologists are reluctant
to advise a young patient with breast cancer that she may become
pregnant, and most are less than enthusiastic about prescribing
hormone replacement for the postmenopausal breast cancer patient. The
use of estrogen replacement for conditions such as osteoporosis
and hot flushes may be considered for a woman with a history of
breast cancer after discussion of the benefits and risks, but it
is not recommended.
The incidence of local recurrence correlates with tumor size, the
presence and number of involved axillary nodes, the histologic type
of tumor, the presence of skin edema or skin and fascia fixation
with the primary tumor, and the type of definitive surgery and local
irradiation. Local recurrence on the chest wall after total mastectomy
and axillary dissection develops in as many as 8% of patients.
When the axillary nodes are not involved, the local recurrence rate
is less than 5%, but the rate is as high as 25% when
they are heavily involved. A similar difference in local recurrence
rate was noted between small and large tumors. Factors such as multifocal
cancer, in situ tumors, positive resection margins, chemotherapy,
and radiotherapy have an effect on local recurrence in patients
treated with breast-conserving surgery.
Chest wall recurrences usually appear within the first several
years but may occur as late as 15 or more years after mastectomy.
All suspicious nodules and skin lesions should be biopsied. Local excision
or localized radiotherapy may be feasible if an isolated nodule
is present. If lesions are multiple or accompanied by evidence of
regional involvement in the internal mammary or supraclavicular
nodes, the disease is best managed by radiation treatment of the
entire chest wall including the parasternal, supraclavicular, and
axillary areas and usually by systemic therapy.
Local recurrence after mastectomy usually signals the presence
of widespread disease and is an indication for studies to search
for evidence of metastases. Distant metastases will develop within
a few years in most patients with locally recurrent tumor after
mastectomy. When there is no evidence of metastases beyond the chest
wall and regional nodes, irradiation for cure after complete local
excision should be attempted. Patients with local recurrence may
be cured with local resection and radiation. After partial mastectomy,
local recurrence does not have as serious a prognostic significance
as after mastectomy. However, those patients in whom a recurrence
develops have a worse prognosis than those who do not. It is speculated
that the ability of a cancer to recur locally after radiotherapy
is a sign of aggressiveness and resistance to therapy. Completion
of the mastectomy should be done for local recurrence after partial
mastectomy; some of these patients will survive for prolonged periods, especially
if the breast recurrence is DCIS or occurs more than 5 years after
initial treatment. Systemic chemotherapy or hormonal treatment should
be used for women in whom disseminated disease develops or those
in whom local recurrence occurs.
Significant edema of the arm occurs in about 10–30% of
patients after axillary dissection with or without mastectomy. It occurs
more commonly if radiotherapy has been given or if there was postoperative
infection. Partial mastectomy with radiation to the axillary lymph
nodes is followed by chronic edema of the arm in 10–20% of
patients. Sentinel lymph node dissection has proved to be a more
accurate form of axillary staging without the side effects of edema
or infection. It does not replace axillary dissection if the sentinel
lymph nodes are involved with metastases. Judicious use of radiotherapy,
with treatment fields carefully planned to spare the axilla as much
as possible, can greatly diminish the incidence of edema, which
will occur in only 5% of patients if no radiotherapy is
given to the axilla after a partial mastectomy and lymph node dissection.
Late or secondary edema of the arm may develop years after treatment,
as a result of axillary recurrence or infection in the hand or arm,
with obliteration of lymphatic channels. When edema develops, a
careful examination of the axilla for recurrence or infection is
performed. Infection in the arm or hand on the dissected side should
be treated with antibiotics, rest, and elevation. If there is no sign
of recurrence or infection, the swollen extremity should be treated
with rest and elevation. A mild diuretic may be helpful. If there
is no improvement, a compressor pump or manual compression decreases
the swelling, and the patient is then fitted with an elastic glove or
sleeve. Most patients are not bothered enough by mild edema to wear
an uncomfortable glove or sleeve and will treat themselves with
elevation or manual compression alone. Benzopyrones have been reported
to decrease lymphedema but are not approved for this use in the
United States. Rarely, edema may be severe enough to interfere with
use of the limb.
Breast reconstruction is usually feasible after total or modified
radical mastectomy. Reconstruction should be discussed with patients
prior to mastectomy, because it offers an important psychological
focal point for recovery. Reconstruction is not an obstacle to the
diagnosis of recurrent cancer. The most common breast reconstruction
has been implantation of a silicone gel or saline prosthesis in
the subpectoral plane between the pectoralis minor and pectoralis
major muscles. Alternatively, autologous tissue can be used for
Autologous tissue flaps are aesthetically superior to implant
reconstruction in most patients. They also have the advantage of
not feeling like a foreign body to the patient. The most popular
autologous technique currently is the transrectus abdominis muscle
flap (TRAM flap), which is done by rotating the rectus abdominis
muscle with attached fat and skin cephalad to make a breast mound. The
free TRAM flap is done by completely removing a small portion of
the rectus with overlying fat and skin and using microvascular surgical
techniques to reconstruct the vascular supply on the chest wall.
A latissimus dorsi flap can be swung from the back but offers less
fullness than the TRAM flap and is therefore less acceptable cosmetically.
An implant often is used to increase the fullness with a latissimus
dorsi flap. Reconstruction may be performed immediately (at the time
of initial mastectomy) or may be delayed until later, usually when
the patient has completed adjuvant therapy. When considering reconstructive options,
concomitant illnesses should be considered, since the ability of
an autologous flap to survive depends on medical comorbidities.
In addition, the need for radiotherapy may affect the choice of reconstruction,
as radiation may increase fibrosis around an implant or decrease the
volume of a flap.
Data are insufficient to determine whether interruption of pregnancy improves
the prognosis of patients who are identified to have potentially
curable breast cancer and who receive definitive treatment during
pregnancy. Theoretically, the increasingly high levels of estrogen
produced by the placenta as the pregnancy progresses could be detrimental
to the patient with occult metastases of hormone-sensitive breast cancer.
Moreover, occult metastases are present in most patients with positive axillary
nodes, and treatment by adjuvant chemotherapy could be potentially
harmful to the fetus early in gestation, although chemotherapy may
be given to pregnant women later. Under these circumstances, interruption
of early pregnancy seems reasonable, with progressively less rationale
for the procedure as term approaches. The decision is affected by
many factors, including the patient’s desire to have the baby
and the prognosis especially when axillary nodes are involved.
Equally important is the advice regarding future pregnancy (or
abortion in case of pregnancy) to be given to women of child-bearing
age who have had definitive treatment for breast cancer. It is assumed
that pregnancy will be harmful if occult metastases are present,
though this has not been demonstrated. Patients whose tumors are
ER negative (most younger women) may not be affected by pregnancy.
To date, no adverse effect of pregnancy on survival of pregnant women
who have had breast cancer has been demonstrated, though most oncologists
advise against it.
In patients with inoperable or metastatic cancer (stage IV disease),
induced abortion is usually advisable because of the possible adverse
effects of hormonal treatment, radiotherapy, or chemotherapy upon
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