Breast Cancer
Worldwide, breast cancer is the most frequently diagnosed
life-threatening cancer in women and the leading cause of
cancer death among women. Over the last two decades,
breast cancer research has lead to extraordinary progress in
our understanding of the disease, resulting in more efficient
and less toxic treatments. Increased public awareness and
improved screening have led to earlier diagnosis at stages
amenable to complete surgical resection and curative
therapies. Consequently, survival rates for breast cancer have
improved significantly, particularly in younger women. This
article addresses the etiology, clinical presentation, diagnosis,
surgical and medical treatment, and prognosis of breast
cancer.
For patient education resources, visit eMedicine's Cancer and
Tumors Center, Women's Health Center, and Imaging Center.
eMedicine also has pertinent patient education articles
on Breast
Cancer, Mastectomy, Breast
Lumps
and
Pain, Breast Self-Exam, Mammogram, and OvarianCancer.
Epidemiology
The American Cancer Society estimated nearly 1.4 million
new cases of invasive breast cancer worldwide in 2008.
Female breast cancer incidence rates for 2002 varied
internationally by more than 2.5-fold, ranging from 3.9 cases
per 100,000 in Mozambique to 101.1 cases per 100,000 in
the United States. Over the past 25 years, breast cancer
incidence rates have risen globally, with the highest rates
occurring in the westernized countries. Reasons for this trend
include change in reproductive patterns, increased screening,
dietary changes, and decreased activity. Although breast
cancer incidence is on the rise globally, breast cancer
mortality has been decreasing, especially in industrialized
countries.
In the United States, an estimated 192,370 new cases of
invasive breast cancer will occur in women in 2009, along
with 1,910 cases in men. After two decades of increasing
incidence rates, the number of new female breast cancers
decreased by 2.2% per year from 1999 to 2005. This decrease
is thought to reflect reduced use of hormone replacement
therapy (HRT) following the publication of the Women’s
Health Initiative in 2002, which linked HRT use to an
increased risk of heart disease and breast cancer. In addition
to invasive breast cancer, 62,280 new cases of in situ breast
cancer are expected to occur among women in 2009.
Approximately 85% of these are expected to be ductal
carcinoma in situ (DCIS). Rates of DCIS have stabilized since
2000.1
The current lifetime risk of breast cancer in the United States
is estimated at 12.7% for all women, 13.3% for non-Hispanic
whites, and 9.98% for African American women. Overall, the
annual incidence rates in African American women (119.4 out
of every 100,000) and Hispanic/Latina women (89.9 out of
every 100,000) have been stable since the early 1990s and
are lower than the annual incidence of breast cancer in white
women (141.1 out of every 100,000). However, African
American women are more likely than white women to be
diagnosed with larger, advanced stage tumors (>5 cm).
Incidence rates among Asian and Pacific Islander women
have continued to increase at 1.5% per year (89 out of every
100,000) but are still significantly lower than white women.
Death rates from breast cancer have steadily decreased in
women since 1990. An estimated 40,610 breast cancer
deaths (40,170 women, 440 men) are expected in 2009. The
largest decrease in mortality has been seen in women
younger than 50 years (3.3% per year) versus those aged 50
years and older (2.0% per year). The decrease in breast
cancer death rates is thought to represent progress in both
earlier detection and improved treatment modalities. 2
Etiology
The current understanding of breast tumorigenesis is that
invasive cancers arise through a series of molecular
alterations at the cellular level, resulting in the outgrowth
and spread of breast epithelial cells with immortal features
and uncontrolled growth. Genomic profiling has
demonstrated the presence of discrete breast tumor
subtypes with distinct clinical behavior (eg, 4 subclasses:
luminal A, luminal B, basal, and HER2+). The exact number of
disease subtypes and molecular alterations from which these
subtypes derive remains to be fully elucidated, but they
generally align closely with the presence or absence of
hormone receptor and mammary epithelial cell type (luminal
or basal).
The figure below summarizes the current general
understanding of breast tumor subtypes, prevalence, and the
major associated molecular alterations. This view of breast
cancer, not as a set of stochastic molecular events, but as a
limited set of separable diseases of distinct molecular and
cellular origins, has altered thinking about breast cancer
etiology, type-specific risk factors, prevention, and treatment
strategies.
Risk factors
Epidemiological studies have identified many risk factors,
which increase the chance of a woman developing breast
cancer (see Table 1, below). Many of these factors form the
basis for breast cancer risk assessment tools. The common
denominator for many of these risk factors is their effect on
the level and duration of exposure to endogenous estrogen.
Early menarche, nulliparity, and late menopause increase
lifetime exposure to estrogen in premenopausal women,
while obesity and hormone replacement therapy increase
estrogen
levels
in
postmenopausal
women.
A family history of breast cancer in a first-degree relative is
the most widely recognized breast cancer risk factor. Risk is
approximately 5 times greater in women with 2 or more firstdegree relatives with breast cancer and is also greater among
women with a single first-degree relative, particularly if
diagnosed at an early age (age 50 years or younger). A family
history of ovarian cancer in a first-degree relative, especially
if the disease occurred at an early age (< 50 years old), has
also been associated with a doubling of risk of breast cancer.
One of the most widely studied risk factors in breast cancer is
the use of exogenous hormones in the form of oral
contraceptives (OCs) and hormone replacement therapy
(HRT). The overall evidence suggests a modest 1.25 increased
risk among current users of oral contraceptives. The risk
appears to decrease with age and time from oral
contraceptive discontinuation. Breast cancer risk returns to
that of the average population after approximately 10 years
following cessation of oral contraceptives.
Consistent epidemiologic data support an increased risk of
breast cancer incidence and mortality (2003) with the use of
postmenopausal HRT. Risk is directly associated with length
of exposure, with the greatest risk observed for the
development of hormonally responsive lobular (relative risk
[RR]=2.25, 95% confidence interval [CI]= 2.00-2.52), mixed
ductal–lobular (RR=2.13, 95% CI= 1.68-2.70), and tubular
cancers (RR=2.66, 95% CI= 2.16-3.28).
The risk is greater in women taking combination estrogen
plus progestin formulations compared to estrogen-only
formulations (HR 0.77 for unopposed estrogen vs placebo),
but missed statistical significance (p=0.06). Published results
of a randomized trial, the Women’s Health Initiative (WHI), of
estrogen-only and combination-HRT for the prevention of
chronic disease indicate that the adverse outcomes
associated with long-term use outweigh the potential disease
prevention benefits particularly for women older than 65
years. Conversely, late menarche, anovulation, and early
menopause (spontaneous or induced) are protective, owing
to their effect on lowering endogenous estrogen levels or
shortening the duration of estrogenic exposure.
Table 1. Risk Factors for Breast Cancer
Risk Factors
Estimated
Relative
Risk
Advanced age
>4
Family history
Two or more relatives (mother, sister)
One first-degree relative
Family history of ovarian cancer in women
<50y
>5
>2
>2
Personal history
Personal history
Positive BRCA1/BRCA2 mutation
Breast biopsy with atypical hyperplasia
Breast biopsy with LCIS or DCIS
3-4
>4
4-5
8-10
Reproductive history
Early age at menarche (<12 y)
Late age of menopause
2
1.5-2
Late age of first term pregnancy (>30
y)/nulliparity
Use of combined estrogen/progesterone HRT
Current or recent use of oral contraceptives
Lifestyle factors
Adult weight gain
Sedentary lifestyle
Alcohol consumption
2
1.5-2
1.25
1.5-2
1.3-1.5
1.5
Risk assessment models
There has been a concerted effort by several groups to
develop multivariate methods to derive a Breast Cancer Risk
Assessment Tool using sets of risk factors (genetic and other)
that are informative for estimating the risk of breast cancer.
Two types of risk models have been developed that are
clinically relevant—those that estimate a woman’s absolute
risk of developing breast cancer over time and those that
determine the likelihood that an individual is a carrier of
a BRCA1,BRCA2,
or
unknown
gene
mutation
(ie, BRCA1/2 probability models).
The most commonly used BRCAPRO model identifies
approximately 50% of mutation-negative families but fails to
screen 10% of mutation carriers. The BRCAPRO model, along
with others (ie, Myriad I and II, Manchester, Breast and
Ovarian Analysis of Disease Incidence and Carrier Estimation
Algorithm[BOADICEA], and Ontario Family History
Assessment Tool [FHAT]) were developed using mutation
rates in Ashkenazi Jewish families and families of European
descent but have recently been validated in African American
and Hispanic populations. The U.S. Preventive Services Task
Force (USPSTF) does not specifically endorse any of these
genetic risk assessment models because of insufficient data
to evaluate their applicability to asymptomatic, cancer-free
women. The USPSTF does support the use of a greater than
10% risk probability for recommending further evaluation
with an experienced genetic counselor for decisions
regarding genetic testing.
In contrast to BRCA probability tools, risk prediction models
are designed to derive individual risk estimates for the
development of breast cancer over time. The Gail Model was
originally developed in 1989 from data derived from the
Breast Cancer Detection and Demonstration Project (BCDDP).
It was developed to estimate the probability of developing
breast cancer over a defined age interval and was originally
intended to improve screening guidelines. The model was
subsequently revised (Gail Model 2) and validated to predict
risk of invasive breast cancer including information on the
history of first-degree affected family members. The Gail
Model 2 has been used extensively in clinical practice and has
served as the basis of eligibility for a number of the breast
cancer prevention trials.
At present, the U.S. FDA guidelines use the National Surgical
Adjuvant Breast and Bowel Project’s (NSABP) modified Gail
model as the basis for eligibility for the prophylactic use of
tamoxifen. Tamoxifen is approved for women aged 35 years
and older who have a 5-year Gail risk of breast cancer of
1.67% or more. The Gail Model 2 also forms the basis of the
U.S.National Cancer Institute’s Breast Cancer Risk
Assessment Tool.
The Gail Model 2 is most accurate for non-Hispanic White
women who receive annual mammograms, but the model
tends to overestimate risk in younger women who do not
receive annual mammograms. The model also demonstrates
reduced accuracy in populations with demographics (age,
race, screening habits) that differ from the population on
which it was built. At the individual level, the model lacks
adequate discrimination in predicting risk and has been
challenged on its generalizability across populations.
To address concerns regarding applicability of the Gail Model
to African American women, Gail and colleagues have
derived a CARE Model using data from a large case control
study of African American women participating in the
Women’s Contraceptive and Reproductive Experiences
(CARE) Study. The CARE Model demonstrated high
concordance between the numbers of breast cancer
predicted and the number of breast cancers observed among
African American women when validated in the WHI cohort.
Improvements in risk prediction and clinical tools are likely to
emerge in the next few years with the addition of such
factors as breast density, mammographic density change
across exams, use of HRT, and a variety of other factors such
as weight, age at birth of first live child, and number of firstdegree relatives with breast cancer. Going forward, it is likely
that there will be models specifically for risks of
premenopausal versus postmenopausal cancers and for
specific breast cancer subtypes (luminal versus basal).
Genetic factors
While 20-30% of women with breast cancer have at least one
relative with a history of breast cancer, only 5-10% of women
with breast cancer have an identifiable hereditary
predisposition. BRCA1 and BRCA2 mutations are responsible
for 3-8% of all cases of breast cancer and 15-20% of familial
cases. Rare mutations are seen in the PTEN, TP53, MLH1,
MLH2,and STK11 genes.
The BRCA1 and BRCA2 gene mutations, on chromosome 17
and 13, respectively, account for the majority of autosomal
dominant inherited breast cancers. Both genes are believed
to be tumor suppressor genes whose products are involved
with maintaining DNA integrity and transcriptional
regulation.
Mutation rates may vary by ethnic and racial groups.
For BRCA1 mutations, the highest rates occur among
Ashkenazi Jewish women (8.3%) followed by Hispanic women
(3.5%), non-Hispanic white women (2.2%), African American
women (1.3%), and Asian American women (0.5%).
Moreover, 95% of Ashkenazi Jews with a BRCA gene
mutation will have one of the 3 founder mutations
(185delAG, 538insC in BRCA1 and 6174delT in BRCA2).
Women who inherit a mutation in theBRCA1 or BRCA2 gene
have an estimated 50-80% lifetime risk of developing breast
cancer.
Specifically, BRCA1 mutations are seen in 7% of families with
multiple breast cancers and 40% of families with breast
andovarian cancer. People with a BRCA1 mutation have a
lifetime risk of 40% for developing ovarian cancer and are
also at a higher risk of colon cancer and prostate cancer.
Breast cancer that develops in BRCA1 mutation carriers are
more likely to be high-grade, and ER, PR, and HER-2/neu
negative (triple negative) or basal-like subtype.
BRCA2 mutations are identified in 10-20% of families at high
risk for breast and ovarian cancers and in only 2.7% of
women with early-onset breast cancer. Women with
a BRCA2 mutation have approximately 10% lifetime risk of
ovarian cancer. BRCA2 mutation carriers who develop breast
cancer are more likely to have a high grade, ER+/PR+, and
HER-2/neu negative cancer (luminal type). BRCA2 is also a
risk factor for male breast cancer.
Other cancers associated with BRCA2 mutations include
prostate, pancreatic, fallopian
tube, bladder, non-Hodgkin
lymphoma, and basal cell carcinoma.
Li-Fraumeni syndrome, caused by TP53 mutations , is
associated with multiple cancers, including the SBLLA
syndrome (sarcoma, breast and brain tumors, leukemia, and
laryngeal and lung cancer). Cancer susceptibility is
transmitted in an autosomal dominant pattern, with a
lifetime risk of breast cancer of 90%. Li-Fraumeni syndrome is
responsible for approximately 1% of cases of familial breast
cancer. Bilateral breast cancer is noted in up to 25% of
patients.
Cowden disease is a rare genetic syndrome caused
by PTEN mutations. It is associated with intestinal
hamartoma, cutaneous lesions, and thyroid cancer. The
prevalence rate of breast cancer in women with this disease
is approximately 30%. Benign mammary abnormalities (eg,
fibroadenomas, fibrocystic lesions, ductal epithelial
hyperplasia, and nipple malformations) are also common.
Other rare genetic disorders, such as Peutz-Jeghers and
hereditary nonpolyposis colorectal carcinoma (HNPCC), are
associated with an increased risk of breast cancer.
Breast cancer screening
Early detection remains the primary defense available to
patients in preventing the development of life-threatening
breast cancer. Breast tumors that are smaller or nonpalpable
are more treatable when detected and thus have a more
favorable prognosis. The survival benefit of early detection
with mammography screening has been demonstrated.
Therefore, early detection is widely endorsed by
organizations that issue clinical recommendations for breast
cancer care. For women younger than 40 years, monthly
breast self-examination practices and clinical breast exams
every 3 years are recommended, beginning at age 20 years.
The most widely recommended approach in the United
States has been annual screening mammography beginning
at age 40 years.3 In November 2009, however, the U.S.
Preventive Services Task Force (USPSTF) issued updated
breast cancer screening guidelines that recommend against
routine mammography before age 50 years. Instead, for
women 40 to 49 years of age, the USPSTF suggests that the
decision to start regular screening mammography be
individualized and should include the patient's values
regarding specific benefits and harms (Grade C
recommendation).4
In addition, rather than annual screening, the USPSTF
guidelines recommend that screening mammography be
performed biennially (Grade B recommendation). The
USPSTF concludes that there is currently insufficient evidence
to assess the additional benefits and harms of screening
mammography in women 75 years or older and thus
recommends stopping screening at age 74 years.4
In response, the American College of Obstetricians and
Gynecologists (ACOG) has stated that while it is evaluating
the USPSTF guidelines in detail, for the present it continues
to recommend adherence to current ACOG guidelines. These
include screening mammography every 1-2 years for women
aged 40-49 years and screening mammography every year
for women age 50 or older.5 The ACOG notes, however, that
because of the USPSTF downgrading, some insurers may no
longer
cover
some
of
these
studies.
Breast self-examination (BSE) and clinical breast
examination (CBE)
Both breast self-examination and clinical breast examination
involve inexpensive and noninvasive procedures for the
regular examination of breasts (ie, monthly for breast selfexamination and annually for clinical breast examination).
Evidence supporting the effectiveness of breast selfexamination and clinical breast examination are controversial
and
largely
inferred.
Even with appropriate training, breast self-examination has
not been found to reduce breast cancer mortality. However,
with increasing improvements in treatment regimens for
early, localized disease, breast self-examination and clinical
breast examination, particularly among women younger than
40 years, continues to be recommended. Most recently,
randomized clinical trial results support combining clinical
breast examination with mammography to enhance
screening sensitivity, particularly in younger women in whom
mammography may be less effective and in women who
receive mammograms every other year as opposed to
annually.
In 2002, the USPSTF found that there was inadequate
evidence to make a recommendation on teaching or
performing BSE. The 2009 USPSTF guidelines recommend
against teaching women how to perform BSE (Grade D
recommendation), based on studies that found that teaching
BSE did not reduce breast cancer mortality but instead
resulted in additional imaging procedures and biopsies. 4 At
present, however, the ACOG continues to recommend
counseling patients that BSE has the potential to detect
palpable breast cancer and can be performed.5
Mammography
Mammography has been demonstrated to be an effective
tool for the prevention of advanced breast cancer in women
at average risk. Mammography is currently the best available
population-based method to detect breast cancer at an early
stage when treatment is most effective. Mammography
often reveals a lesion before it is palpable by clinical breast
examination and, on average, 1-2 years before noted by
breast self-examination. Recent advances in mammography
include the development of digital mammography and the
increased use of computer-aided diagnosis (CAD) systems.
CAD systems have been developed to help the radiologist
identify mammographic abnormalities. Digital mammography
allows the image to be recorded and stored. Using computer
technology, digital mammogram images can be magnified
and the image modified to improve evaluation of specific
areas in question.
The USPSTF estimates the benefit of mammography in
women aged 50-74 years to be a 30% reduction in risk of
death from breast cancer. For women aged 40-49 years, the
risk of death is decreased by 17%. Although mammography
guidelines have been in place for over 30 years, 20-30% of
women still do not undergo screening as indicated. The two
most significant factors for a woman to undergo
mammography are physician recommendation and access to
health insurance. Non-white women and those of lower
socioeconomic status remain less likely to obtain
mammography services and more likely to present with lifethreatening, advanced-stage disease.
Alternative screening modalities and future directions
While mammography remains the most cost-effective
approach for breast cancer screening, the sensitivity (67.8%)
and specificity (75%) are not ideal. As reported,
mammography combined with clinical breast examination
slightly improves sensitivity (77.4%) with a modest reduction
in specificity (72%). Comparisons between recently
introduced digital mammography and screen-film
mammography suggest that the sensitivity of full-field digital
mammography is superior to screen film mammography in
certain subsets of women. For example, digital
mammography demonstrates improved detection rates for
younger women and for women with more dense breasts.
Improved imaging modalities with greater sensitivity are of
particular benefit for women at the highest risk and for
women whose breast images are difficult to interpret.
Ultrasound has become a widely available and useful adjunct
to mammography in the clinical setting. Ultrasound is
generally used to assist the clinical examination of a
suspicious lesion detected via mammogram or physical
examination. As a screening device, the ultrasound is limited
by a number of factors, but most notably by the failure to
detect microcalcifications and poor specificity (34%).
In an effort to overcome the limitations of mammography
and ultrasound, magnetic resonance imaging (MRI) has been
explored as a modality for detecting breast cancer in women
at high risk and in younger women. A combination of T-1, T-2,
and 3-D contrast-enhanced MRI techniques has been found
to be highly sensitive (approximating 99% when combined
with mammogram and clinical breast examination) to
malignant changes in the breast.
MRI has been demonstrated to be an important adjunct
screening tool for women with BRCA1 or BRCA2 mutations
identifying cancers at earlier stages. However, breast MRI has
limited use as a general screening tool with a 10-fold higher
cost than mammography and poor specificity (26%), resulting
in significantly more false-positive reads that generate
significant additional diagnostic costs and procedures. Below
are the criteria for using breast MRI screening per the
American Cancer Society (ACS).6
1. Recommend annual breast MRI screening (evidence
based, evidence from nonrandomized trials and
observational studies)
 BRCA mutation
 First-degree relative of BRCA carrier, but untested
 Lifetime risk approximately 20-25% or greater as defined
by BRCAPRO or other risk models
2. Recommend annual breast MRI screening (based on
evidence of lifetime risk of breast cancer)
 Radiation to chest when aged 10-30 years
 Li-Fraumeni syndrome and first-degree relatives
 Cowden and Bannayan-Riley-Ruvalcaba syndromes and
first-degree relatives
3. Insufficient evidence to recommend for or against MRI
screening
 Lifetime risk 15-20%, as defined by BRCAPRO or other
risk models
 Lobular carcinoma in situ or atypical lobular hyperplasia
(ALH)
 Atypical ductal hyperplasia (ADH)
 Heterogeneously or extremely dense breast on
mammography
 Women with a personal history of breast cancer,
including ductal carcinoma in situ
The American Cancer Society does not recommend the use of
breast MRI in women who have less than 15% lifetime risk.
Among those with average risk, a combination of clinical
breast examinations and yearly mammograms is
recommended.
Pharmacologic breast cancer risk reduction
Two selective estrogen receptor modulators (SERMs),
tamoxifen and raloxifene, are approved for reduction of
breast cancer risk in high-risk women. Two National Surgical
Adjuvant Breast and Bowel Project (NSABP P1 and P2) trials
showed that tamoxifen reduced the risk of ductal carcinoma
in situ (DCIS) and invasive breast cancer by 30-50%. In the
NSABP P2 prevention trial, raloxifene was as effective as
tamoxifen in reducing the risk of invasive breast cancer but
was 30% less effective than tamoxifen in reducing the risk of
DCIS.
The American Society of Clinical Oncology (ACOG) has
updated their practice guidelines regarding pharmacologic
intervention (eg, tamoxifen, raloxifene, aromatase inhibition)
for breast cancer risk reduction.7 Some of the highlights of
the expert panel's literature review are as follows:
1. Tamoxifen use for 5 years reduces risk for at least 10
years in premenopausal women, particularly estrogen
receptor (ER) – positive invasive tumors.
 Women 50 years or younger have few adverse effects
with tamoxifen.
 Vascular/vasomotor adverse effects do not persist post
treatment.
2. Tamoxifen and raloxifene are equally effective in
reducing risk of ER-positive breast cancer in
postmenopausal women.
 Raloxifene is associated with lower rates of
thromboembolic disease, benign uterine conditions, and
cataracts than tamoxifen.
 Evidence does not exist regarding whether either agent
decreases mortality from breast cancer.
3. Recommendations
 For women with increased risk for breast cancer, offer
tamoxifen (20 mg/d for 5 y) to reduce risk of invasive ERpositive breast cancer.
 In postmenopausal women, raloxifene (60 mg/d for 5 y)
may also be considered.
 Aromatase inhibitors (eg, anastrozole, exemestane,
letrozole), fenretinide, or other SERMs are not
recommended outside of a clinical trial.
Presentation
Breast cancer is often first detected as an abnormality on a
mammogram before it is felt by the patient or health care
provider. Mammographic features suggestive of malignancy
include asymmetry, microcalcifications, a mass, or
architectural distortion. If any of these features are
identified, a diagnostic mammogram along with a breast
ultrasound should be performed prior to obtaining a biopsy.
In certain cases, a breast MRI may be warranted. Larger
tumors may present as a painless mass. Only 5% of patients
with a malignant mass present with breast pain. Other
symptoms include immobility, skin changes (ie, thickening,
swelling, redness) or nipple abnormalities (ie, ulceration,
retraction, spontaneous bloody discharge).
Workup
Diagnostic Procedures
Percutaneous vacuum-assisted large gauge core biopsies with
image guidance are the recommended diagnostic approach
for newly diagnosed breast cancers. Image guided breast
biopsy may be performed with ultrasound, stereotactic, or
MRI guidance. Core biopsies spare the need for operative
intervention (and subsequent scarring), often providing
pathological
results
quicker
than
surgical
excisions. Additionally, excisional biopsy, as the initial
operative approach, has been shown to increase the rate of
positive margins. Thus, core biopsies for diagnosing breast
cancer can eliminate the need for additional surgeries for
definitive margin control and assessment of nodal status.
In some cases, a breast mass may be palpable but not
correlate with imaging by either ultrasound or
mammogram. Under this circumstance, palpation directed
core biopsy, fine needle aspiration, or open excisional biopsy
may be required to diagnose a suspicious palpable breast
mass. Typically, patients who undergo a core needle biopsy,
whether directed by imaging studies or palpation, have a
titanium marker clip placed at the biopsy site. These clips are
particularly helpful when planning a lumpectomy for nonpalpable breast lesions that require preoperative imageguided wire-localization or for patients who undergo
neoadjuvant chemotherapy, resulting in a pathological
complete response. Complications of a diagnostic core or
excisional biopsy include hematoma, infection, scarring, reoperation, and sampling error resulting in inaccurate
diagnosis.
Histologic Findings
Ductal carcinoma in situ (DCIS)
Increased use of screening mammography has resulted in a
dramatic increase in the detection of DCIS. Approximately
64,000 cases of DCIS are diagnosed annually in the United
States. Today, 90% of DCIS cases are identified on
mammography as suspicious calcifications, linear, clustered,
segmental, focal, or mixed distribution. DCIS is divided into
comedo (ie, cribriform, micropapillary, solid) and noncomedo
subtypes, which provides additional prognostic information
regarding likelihood of progression or local recurrence.
Table 3. Ductal Carcinoma in Situ Subtypes
Open table in new window
DCIS Characteristic
Comedo
Noncomedo
Nuclear grade
High
Low
Estrogen receptor
Negative
Positive
HER2/neu overexpression Present
Absent
Distribution
Continuous Multifocal
Necrosis
Present
Absent
Local recurrence
High
Low
Prognosis
Worse
Better
However, mammography often underestimates the
multifocality and extent of DCIS. This has led to the use of
breast MRI for the detection and staging of DCIS. Several
studies, however, have demonstrated high sensitivity and
low specificity for MRI in the detection of DCIS leading to
unnecessary biopsies and more aggressive surgeries.
Currently, the standard treatment of DCIS is surgical
resection with or without radiation. Adjuvant radiation and
hormonal therapies are often reserved for younger women,
patients undergoing lumpectomy, or comedo subtype.
Approximately 30% of women with DCIS in the United States
are treated with mastectomy with or without reconstruction,
30% with conservative surgery alone, and 40% with
conservative surgery followed by whole-breast radiation
therapy. Axillary or sentinel lymph node dissection is not
routinely recommended for patients with DCIS. Current
studies have identified metastatic disease to the axillary node
in 10% of patients. In DCIS, whole-breast radiotherapy is
delivered over 5-6 weeks after surgery, reducing the local
recurrence rate by approximately 60%. Roughly 50% of local
recurrences are invasive breast cancer. Meta-analyses of
randomized controlled trials comparing radiation therapy
versus observation after surgery for DCIS have demonstrated
slightly higher rates of contralateral breast cancer after
radiation therapy (3.85% vs 2.5%). Studies comparing
accelerated partial breast radiation given over 5 days to
standard whole breast radiotherapy are currently underway.
Tamoxifen is the only hormonal therapy currently approved
for adjuvant therapy in patients treated with breastconserving surgery and radiation for DCIS. Currently, a clinical
trial evaluating the role of the aromatase inhibitor
anastrozole as adjuvant therapy in DCIS has met its accrual
and
results
are
anticipated.
Lobular carcinoma in situ (LCIS)
LCIS arises from the terminal duct apparatus and shows a
rather diffuse distribution throughout the breast, which
explains its presentation as a non-palpable mass in most
cases. Over the last 25 years, LCIS incidence has doubled and
is now 2.8% per 100,000 women. The peak incidence is in
women aged 40-50 years. Because LCIS is nonpalpable, it has
no consistent features on breast imaging and is most often
an incidental finding associated with a breast biopsy
performed for an unrelated mammographic abnormality.
Approximately, 10-20% of women with LCIS develop invasive
breast cancer within 15 years from their LCIS diagnosis. Thus,
LCIS is considered a biomarker of increased breast cancer
risk. Treatment options for LCIS include chemoprevention
with a SERM, bilateral mastectomy with or without
reconstruction, and close observation.
Other invasive breast cancer histology
1.
2.
3.
4.

Medullary carcinoma: Medullary carcinoma is relatively
uncommon (5%) and generally occurs in younger
women. Most patients present with a bulky palpable
mass with axillary lymphadenopathy. Diagnosis of this
type of breast cancer depends on a histologic triad of (1)
sheets of anaplastic tumor cells with scant stroma, (2)
moderate or marked stromal lymphoid infiltrate, and (3)
histologic circumscription or a pushing border. DCIS may
be observed in the surrounding normal tissues. ER, PR,
and HER2/neu are typically negative, and TP53 is
commonly mutated. Roughly 30% of patients have lymph
node metastasis. Typical or classic medullary carcinomas
are often associated with a good prognosis despite the
unfavorable prognostic features associated with this
type of breast cancer. However, a recent analysis of 609
medullary breast cancer specimens from various stage I
and II NSABP protocols indicate that overall survival and
prognosis are not as good as previously reported.
Mucinous carcinoma: Mucinous carcinoma is another
rare histologic type seen in fewer than 5% of invasive
breast cancer cases. It usually presents during the
seventh decade of life. It often presents as a palpable
mass or mammographically as a poorly defined tumor
with rare calcifications. Mucin production is the
histologic hallmark with 2 main forms, type A and B, with
AB lesions possessing features of both. Type A mucinous
carcinoma represented the classic variety with larger
quantities of extracellular mucin, whereas type B is a
distinct variant with endocrine differentiation. DCIS is
not a frequent occurrence, though it may be found. Most
cases are ER and PR positive, but HER2/neu
overexpression is rare. Additionally, these carcinomas
predominantly express glycoproteins MUC2 and MUC6.
Overall, patients with mucinous carcinoma have an
excellent prognosis (>80% 10-year survival).
Tubular carcinoma: Tubular carcinoma of the breast is an
uncommon histologic type involving 1-2% of all breast
cancers. Characteristic features of this type include a
single layer of epithelial cells with low-grade nuclei and
apical cytoplasmic snoutings arranged in well-formed
tubules and glands. Tubular components comprise more
than 90% of pure tubular carcinomas and at least 75% of
mixed tubular carcinomas. This type of breast cancer has
a low incidence of lymph node involvement and a very
high overall survival rate. Because of its favorable
prognosis, patients are often treated with only breastconserving surgery and local radiation therapy.
Papillary carcinoma
Papillary carcinoma of the breast encompasses a
spectrum of histological subtypes. There are two
common types: cystic (noninvasive form) and
micropapillary ductal carcinoma (invasive form). This
form of breast cancer is usually seen in women older
than 60 years and accounts for approximately 1-2% of all

5.



6.
breast cancers. Papillary carcinomas are centrally located
in the breast and can present with bloody nipple
discharge. They are strongly ER and PR positive.
Cystic papillary carcinoma has a low mitotic activity,
which results in a more indolent course and good
prognosis. However, invasive micropapillary ductal
carcinoma has a more aggressive phenotype even
though approximately 70% of cases are ER positive. A
retrospective review of 1400 cases of invasive carcinoma
identified 83 cases (6%) with at least one component of
invasive micropapillary ductal carcinoma. Additionally,
lymph node metastasis is frequently seen in this subtype
(70-90% incidence), and the number of lymph nodes
involved appears to correlate with survival.
Metaplastic breast cancer (MBC)
MBC accounts for less than 1% of breast cancer cases. It
is characterized by a combination of adenocarcinoma
plus mesenchymal and epithelial components. A wide
variety of histological patterns include spindle-cell
carcinoma, carcinosarcoma, squamous cell carcinoma of
ductal origin, adenosquamous carcinoma, carcinoma
with pseudosarcomatous metaplasia, and matrixproducing carcinoma. This diverse group of malignancies
is identified as a single entity based on a similarity in
clinical behavior. When compared with infiltrating ductal
carcinoma, metaplastic breast cancer tumors are larger,
more rapidly growing, commonly node negative, and
typically ER, PR, and HER-2 negative. The disease tends
to occur in older women with an average age of onset in
the sixth decade and has a higher incidence in African
Americans.
The majority of published case series have demonstrated
a worse prognosis for metaplastic breast cancer as
compared to infiltrating ductal carcinoma, even when
adjusted for stage, with a 3-year overall survival rate of
48-71% and 3-year disease-free survival rate of 15-60%.
In most case series, large tumor size and advanced stage
have emerged as predictors of poor overall survival and
prognosis. Nodal status does not appear to impact
survival in metaplastic breast cancer.
Surgery is used to treat up to 95% of women with
metaplastic breast cancer. Few data support the
effectiveness of systemic chemotherapy in patients with
metaplastic breast cancer and its use has been
extrapolated from the treatment of more common types
of breast cancer. A review of chemotherapy and
response in a series of 27 patients with metaplastic
breast cancer found only one partial response with a
doxorubicin-containing regimen in the setting of
metastatic disease. As in soft-tissue sarcomas,
metaplastic breast cancer shows a tendency for local
recurrence and for hematogenous spread to lung, liver,
and bone.
Mammary Paget disease (MPD)

MPD is relatively rare, comprising 1-4% of all breast
cancers. Peak incidence is seen in the sixth decade of life
(mean age 57 y). This adenocarcinoma is localized within
the epidermis of the nipple-areola complex and
composed of the histologic hallmark, Paget cells, within
the basement membrane. Paget cells are large, pale
epithelial cells with hyperchromatic, atypical nucleus,
dispersed between the keratinocytes as a single or
cluster of cells. Lesions are predominantly unilateral
developing insidiously as a scaly, fissured, oozing, or
erythematous nipple-areola complex. Retraction or
ulceration of the nipple is often noted, along with
symptoms of itching, tingling, burning, or pain.
 Mammary Paget disease is associated with an underlying
breast cancer in 75% of cases. Standard treatment of
mammary Paget disease is surgical excision (modified
radical mastectomy with lymph node excision). Breast
conserving surgery can achieve satisfactory results, but
at the risk of local recurrence. Adjuvant chemotherapy
with tamoxifen may increase survival in premenopausal
patients with lymph node metastasis. Poor prognostic
factors include a palpable breast tumor, lymph node
involvement, histological type, and patient younger than
60 years. The overall 5-year and 10-year survival rates
are 59% and 44%, respectively.
Prognostic and predictive factors
Numerous prognostic and predictive factors for breast cancer
have been identified by the College of American Pathologists
to guide the clinical management of women with breast
cancer. Breast cancer prognostic factors include the
following:
 Axillary lymph node status
 Tumor size
 Lymphatic/vascular invasion
 Patient age
 Histologic grade
 Histologic subtypes (eg, tubular, colloid [mucinous],
papillary)
 Response to neoadjuvant therapy
 Estrogen receptor/progesterone receptor status
 Her2/neu gene amplification and/or overexpression
 Breast cancer predictive factors include the following:
 Estrogen receptor/progesterone receptor status
 Her2/neu gene amplification and/or overexpression
 Lymph node status: Fluid from the breast tissue normally
drains into the lymph nodes located in the axilla.
Cancerous involvement of these nodes is an indication of
the likelihood that the breast cancer has spread to other
organs. Axillary nodal involvement and survival have
been evaluated relative to the number and sites in
breast cancer patients. For any given number of positive
nodes, survival was independent of the level of
involvement but directly related to the number of
involved nodes. Patients with node-negative disease


I.
II.
III.
have an overall 10-year survival rate of 70% and 5-year
recurrence rate of 19%. As the number of positive nodes
increase, so does the probability of relapse. With 1-3
positive nodes, the recurrence rate at 5 years is 30-40%.
Four to 9 positive nodes have a recurrence rate of 4470%. Patients with more than 10 positive lymph nodes
have a recurrence rate of 72-82%.
Hormone receptor status: Estrogen receptor (ER) and
progesterone receptor (PR) assays are routinely
performed by pathologists on tumor material.
Immunohistochemistry (IHC) is a semiquantitative
technique that is observer and antibody dependent. In
general, hormone-positive tumors have a more indolent
course and are responsive to hormonal therapy.
HER2
Eighteen to twenty percent of invasive breast cancers
overexpress HER2, which has both prognostic and
predictive implications. Prior to the routine use of
adjuvant trastuzumab therapy, HER2 overexpression was
associated with a more aggressive tumor phenotype and
worse prognosis (higher rate of recurrence and
mortality) especially in patients who do not receive
adjuvant chemotherapy. Additionally, HER2 status has
been shown to be predictive for response to certain
chemotherapeutic agents (ie, doxorubicin, and HER2
targeted therapies, trastuzumab, a monoclonal antibody,
and lapatinib, a small molecule oral tyrosine kinase
inhibitor) directed specifically to the HER2 receptor.
Retrospectively analyzed results from clinical trials have
shown
HER2-positive
patients
benefit
from
anthracycline-based regimens secondary to the coamplification of topoisomerase II with HER2. Preliminary
data also suggest that HER2 may predict response and
benefit from paclitaxel in the adjuvant setting.
A recent phase III, double-blind, randomized study
evaluated the efficacy of lapatinib in HER2-negative and
HER2 uncharacterized metastatic breast cancer. The
study concluded that while patients with HER2-negative
or HER2-untested metastatic breast cancer did not
experience benefit from the addition of lapatinib to
paclitaxel, first-line therapy with paclitaxel-lapatinib
significantly improved clinical outcomes in patients who
were HER2-positive.8
Several methods for HER2 testing have been developed.
Since approximately 20% of current HER2 testing may be
inaccurate, the American Society of Clinical Oncology
and the College of American Pathologists have
recommended guidelines in HER2 testing to ensure
accuracy. Breast cancer specimens should initially
undergo
HER2
testing
by
a
validated
immunohistochemistry assay (ie, DAKO Hercep Test
[DAKO Cytomation]) for HER2 protein expression.9 The
scoring method for HER2 expression is based on the cell
membrane staining pattern and is listed below.
a.
IV.
V.

I.
3+: Positive HER2 expression - Uniform intense
membrane staining of more than 30% of
invasive tumor cells
b. 2+: Equivocal for HER2 protein expression –
Complete membrane staining that is either
nonuniform or weak in intensity but has
circumferential distribution in at least 10% of
cells
c. 0 or 1+: Negative for HER2 protein expression
Breast
cancer
specimens
with
equivocal
immunohistochemistry should undergo validation using
a HER2 gene amplification method (ie, fluorescence in
situ hybridization [FISH]). More centers are relying on
FISH alone for determining HER2 status. In general, FISH
testing is thought to be more reliable, but it is more
expensive
than
immunohistochemistry.
Newer
methodologies for establishing HER2 status including RTPCR and CISH (chromogenic in situ hybridization) have
not yet been validated. Equivocal immunohistochemistry
results can be seen in 15% of invasive breast cancers.
The interpretation for HER2 FISH testing (HER2/CEP17
ratio and gene copy number) is given below.
a. Positive HER2 amplification: FISH ratio greater
than 2.2 or HER2 gene copy greater than 6.0
b. Equivocal HER2 amplification: FISH ratio 1.8-2.2
or HER2 gene copy 4.0-6.0
c. Negative HER2 amplification: FISH less than 1.8
or HER2 gene copy less than 4.0
Discordant results (IHC3+/FISH negative or IHC less than
3+/FISH positive) have been observed in approximately
4%. Equivocal HER2 FISH results are seen in less than 3%
of invasive breast cancer specimens and had previously
been considered HER2 positive. Currently, no data
support excluding this group from treatment with
trastuzumab.
Oncotype DX
The Oncotype Dx assay (Genomic Health, San Francisco,
Calif) is a reverse transcriptase-polymerase chain
reaction (RT-PCR)-based assay of 21 genes (16 cancer
genes and 5 reference genes) performed on paraffinembedded breast tumor tissue. Using a formula based
on the expression of these genes, a recurrence score (RS)
can be calculated that correlates with the likelihood of
distant recurrence at 10 years. Breast tumors with a
recurrence score of less than 18 are considered low risk,
recurrence score of 18-30 intermediate-risk, and more
than 30 are high risk. Currently, Oncotype Dx has been
validated and FDA approved in women with early-stage,
ER-positive, node-negative breast cancer treated with
tamoxifen where the recurrence score correlated with
both relapse-free interval and overall survival.
Furthermore, the Oncotype Dx assay has been shown to
predict benefit from chemotherapy and hormonal
therapy in hormone-sensitive, node-negative tumors
retrospectively in the NSABP B-14 and B-20 studies.
II.
Women with low recurrence score showed a significantly
higher improvement in disease-free survival (DFS) with
the addition of tamoxifen versus chemotherapy.
Whereas, women with a high recurrence score had a
significant improvement in disease-free survival by
adding chemotherapy. Among women with 1-3 nodepositive, hormone receptor-positive disease, the
Oncotype Dx recurrence score was a significant predictor
of recurrence, with a 21% decrease in recurrence risk for
each 10-point drop in recurrence score. In general,
results from these studies would indicate a selective
group of node-positive, hormone receptor-positive
patients with a low recurrence score would not benefit
from an anthracycline based regimen. The benefit of
adding chemotherapy to hormonal therapy in tumors
with an intermediate score is still controversial, and a
large prospective, randomized phase III study (TAILORx
Trial) is addressing this important question.
Staging
The American Joint Committee on Cancer staging system
groups patients based on the tumor size (T), lymph node
status (N), and distant metastasis (M) into 4 stages.
Primary tumor (T)
 Tx: Primary tumor cannot be assessed
 T0: No evidence of primary tumor
 Tis: (DCIS) Carcinoma in situ
 Tis: (LCIS) Carcinoma in situ
 Tis: Paget disease of the nipple with no tumor (Paget
disease associated with a tumor is classified according to
the size of the tumor.)
 T1: Tumor 2 cm or smaller in greatest diameter
T1mic: Microinvasion 0.1 cm or less in greatest
dimension
T1a: Tumor >0.1 but not >0.5 cm in greatest diameter
T1b: Tumor >0.5 but not >1 cm in greatest diameter
T1c: Tumor >1 cm but not >2 cm in greatest diameter
 T2: Tumor >2 cm but not >5 cm in greatest diameter
 T3: Tumor >5 cm in greatest diameter
 T4: Tumor of any size, with direct extension to (a) the
chest wall or (b) skin only, as described below
T4a: Extension to the chest wall, not including the
pectoralis muscle
T4b: Edema (including peau d’orange) or ulceration of
the skin of the breast or satellite skin nodules confined
to the same breast
T4c: Both T4a and T4b
T4d: Inflammatory disease
Regional lymph nodes (N)
 Nx: Regional lymph nodes cannot be assessed (eg,
previously removed)
 N0: No regional lymph node metastasis

N1: Metastasis in movable ipsilateral axillary lymph
node(s)
 N2: Metastasis in ipsilateral axillary lymph node(s) fixed
or matted, or in clinically apparent ipsilateral internal
mammary nodes in the absence of clinically evident
axillary lymph node metastasis
N2a: Metastasis in ipsilateral axillary lymph nodes fixed
to one another or to other structures
N2b: Metastasis only in clinically apparent ipsilateral
internal mammary nodes and in the absence of clinically
evident axillary lymph nodes
 N3: Metastasis in ipsilateral infraclavicular or
supraclavicular lymph node(s) with or without axillary
lymph
node
involvement,
or
clinically apparent ipsilateral internal mammary lymph
node(s) and in the presence of axillary lymph node
N3a: Metastasis in ipsilateral infraclavicular lymph
node(s)
N3b: Metastasis in ipsilateral internal mammary lymph
node(s) and axillary lymph node(s)
N3c: Metastasis in ipsilateral supraclavicular lymph
node(s)
Distant metastasis
o Mx: Distant metastasis cannot be assessed
o M0: No distant metastasis
o M1: Distant metastasis
Table 2. TNM Staging System for Breast Cancer
Stage
Tumor Node Metastases
Stage 0
Tis
N0
M0
Stage I
T1
N0
M0
Stage IIA
T0
T1
T2
N1
N1
N0
M0
M0
M0
Stage IIB
T2
T3
N1
N0
M0
M0
Stage IIIA T0
T1
T2
T3
N2
N2
N2
N1-2
M0
M0
M0
M0
Stage IIIB T4
T4
T4
N0
N1
N2
M0
M0
M0
Stage IIIC Any T
N3
M0
Stage IV
Any N M1
Any T
Five-year survival rates are highly correlated with tumor
stage, 99-100% for stage 0, 95-100% for stage I, 86% for stage
II, 57% for stage III, and 20% for stage IV. This prognostic
information can guide physicians in making therapeutic
decisions. Pathologic review of the tumor tissue for
histological grade along with the determination of
estrogen/progesterone receptor (ER/PR), HER2 status, and
lymph node involvement as determined by sentinel lymph
node biopsy or axillary lymph node dissection is necessary for
determining
prognosis.
See also the Best Evidence rated reference, Trends in survival
over the past two decades among white and black patients
with newly diagnosed stage IV breast cancer.10
The National Cancer Center Network (NCCN) guideline
recommends a history and physical examination followed by
laboratory studies (CBC with differential, liver and renal
function tests, and calcium levels) for all asymptomatic
women with early stage breast cancer (Stage I and II).
Women with stage III (locally advanced or inflammatory
breast cancer) or symptomatic disease should have a chest xray or CT scan of the chest, CT scan of the abdomen and
pelvis, and bone scan for evaluation of distant metastasis.
Tumor markers (CEA and CA15.3 or CA27.29) may also be
obtained in these patients.11
Currently, the use of positron emission tomography (PET) or
PET/CT is not indicated in the staging of clinical stage I, II, or
operable stage III breast cancer; however, the use of PET/CT
scans for staging locally advanced and inflammatory breast
cancer to assist in identification of nonaxillary lymph node
metastasis (ie, internal mammary or supraclavicular lymph
nodes) prior to starting neoadjuvant therapy is appropriate.
Treatment
Medical Therapy
TREATMENT OF INVASIVE BREAST CANCER
Surgery is considered primary treatment for breast cancer, as
many early stage patients are cured with surgery alone. The
goals of breast cancer surgery include complete resection of
the primary tumor with negative margins to reduce the risk
of local recurrences and pathologic staging of the tumor and
axillary lymph nodes for providing necessary prognostic
information. Several different types of operations are
available for the treatment of breast cancer.
Lumpectomy
Lumpectomy is defined as complete surgical resection of a
primary tumor with a goal of achieving widely negative
margins (ideally a 1 cm margin around the lesion). Other
terms synonymous for lumpectomy include partial
mastectomy, segmental mastectomy, and tylectomy. A
quadrantectomy is a type of lumpectomy that is defined as
complete removal of the entire affected breast quadrant.
Lumpectomies may be performed with palpation guidance or
with image guidance.
Variations on the theme of image guidance include 1) wire
localization of nonpalpable image detected lesions via
ultrasound, stereotactic, or MRI guidance; 2) hematoma
ultrasound guidance by the operating surgeon; or 3)
radioactive seed localization. Patients who undergo a
lumpectomy for calcifications should always be advised to
have a mammogram following their lumpectomy to establish
definitively that all calcifications were successfully removed.
This mammogram should occur prior to the administration of
any radiation therapy.
In general, 2 mm or greater is a reasonable definition of a
clear margin. Patients with margin widths less than 2 mm are
often advised to return to the operating room for re-excision
to improve local recurrence rates. The rate of surgical reexcision after lumpectomy ranges from 20-60% in the
published literature. Contraindications to lumpectomy
include multicentric disease, adverse tumor-to-breast ratio,
large primary tumor, repeated positive margins, and inability
to undergo radiation therapy for invasive disease.
The NSABP-B6 was a prospective trial in which 2,163 breast
cancer patients were randomized to modified radical
mastectomy (the standard of care at that time), lumpectomy,
and whole breast radiation therapy, or lumpectomy without
radiation. All patients underwent axillary lymph node
dissection. At 20-year follow-up, no significant difference was
seen in overall survival, disease-free survival, or distant
disease-free survival among the 3 treatment groups.
However, the NSABP-B6 did find a significant difference in
the rate of local recurrence between the 3 treatment arms.
Patients in the lumpectomy alone without radiation therapy
group had a significantly higher local recurrence rate than
patients undergoing lumpectomy plus radiation therapy
(39.2% vs 14.3%, respectively). Patients who underwent
modified radical mastectomy had a 10.2% risk of chest wall
recurrence. This landmark study established breastconserving surgery with radiation therapy to be equivalent to
modified radical mastectomy.
Oncoplastic surgery is a rapidly advancing field that uses local
tissue rearrangement to reconstruct a partial mastectomy
defect. Options include fasciocutaneous local tissue
advancement flaps, breast parenchymal local flaps or
latissimus dorsi myocutaneous flaps. The selection of
aesthetically appropriate incisions also impacts the overall
cosmetic result after lumpectomy. Silverstein et al reported a
variety of options for oncoplastic approaches to breast
conservation.12 Kronowitz et al reported that partial
mastectomy reconstruction produces superior aesthetic
results and lower complication rates when performed prior
to radiation therapy.13
Mastectomy
A total mastectomy is defined as complete removal of all
breast tissue to the clavicle superiorly, the sternum medially,
the inframammary crease inferiorly, and the anterior axillary
line laterally with en bloc resection of the fascia of the
pectoralis major. The nipple-areolar complex (NAC) is
resected along with a skin paddle to achieve a flat chest wall
closure when performing a total mastectomy. A total
mastectomy does not refer to removal of any axillary nodes
but may be performed in conjunction with a sentinel or
axillary node dissection. A modified radical mastectomy is
defined as a total mastectomy with axillary lymph node
dissection. In contrast, a radical mastectomy is defined as a
total mastectomy plus en bloc resection of the pectoralis
major and axillary lymph node dissection. Extended radical
mastectomy refers to a radical mastectomy with resection of
the internal mammary lymph nodes.
Two modern variations of the total mastectomy include the
skin-sparing total mastectomy (SSM) and the nipple-sparing
total mastectomy (NSM). These operations refer to surgical
approaches designed for patients who elect to have
immediate reconstruction. Both SSM and NSM are minimally
invasive surgical approaches that are technically more
difficult and, thus, more time-consuming than traditional
mastectomy. SSM and NSM result in preservation of the
patient’s skin envelope and maintain the position of the
infra-mammary fold. However, both SSM and NSM are
intended to be complete total mastectomies with the same
extent of resection as a traditional total mastectomy.
These operations may not be appropriate for cancers near
the skin or nipple. Additionally, SSM or NSM are not
appropriate for locally advanced or inflammatory breast
cancer. Multiple retrospective single institution studies have
reported excellent results with SSM and NSM. No
randomized clinical trials compare survival results for SSM,
NSM, and total mastectomy. However, most surgical
oncologists accept that as long as SSM and total mastectomy
are carefully performed and patients are carefully selected,
these are reasonable oncologic choices for prophylactic
mastectomy and for the treatment of selected early stage
breast cancers. Complications after total mastectomy include
risk of local recurrence (5-10%), wound infection, seroma,
mastectomy skin flap necrosis, hematoma, chronic pain,
incisional dog ears, lymphedema, and fibrosis.
Breast Reconstruction
Breast reconstruction for mastectomy may be performed in
the immediate or the delayed setting. Most patients
undergoing mastectomies for prophylaxis or early stage
breast cancer are candidates for reconstruction. Immediate
reconstruction, when feasible, generally provides superior
cosmetic results because a SSM or NSM may be offered to
selected patients, resulting in preservation of the native skin
envelope and infra-mammary crease. However, when
postmastectomy radiation is likely or a reconstructive
surgeon is unavailable, delayed reconstruction following all
adjuvant therapies may be recommended.
Reconstruction may be performed via implant-based
methods, autologous tissue-based (termed flaps) method, or
a combination of the two. Implant-based approaches include
tissue expanders and saline or silicone implants. Tissue-based
approaches include the transverse rectus abdominus
myocutaneous flap (TRAM), latissimus dorsi flap, and
the deep inferior epigastric perforator flap (DIEP).
Although federal law protects the rights of patients to have
reconstruction by mandating that insurance companies
support reconstruction, most patients undergoing
mastectomy do not undergo breast reconstruction. Reasons
for this include provider biases, patient preferences and lack
of available specialty services. Patients and physicians should
have realistic expectations for breast reconstruction.
Although excellent results may be achieved, often multiple
operations are required for revisions, symmetry procedures,
and nipple reconstruction. Complications related to
reconstruction include infected prosthetic implant, implant
rupture, capsular contracture, flap necrosis, flap loss, fat
necrosis, asymmetry, and scarring.
Management of the Contralateral Breast
Patients diagnosed with breast cancer that are not known
carriers of a deleterious BRCA mutation are predicted to have
a 0.7% annual risk of contralateral breast cancer. Patients
who are known BRCA mutation carriers have a 3% annual risk
of a contralateral breast cancer. The decision for
contralateral prophylactic mastectomy (CPM) is a personal
decision for the patient and impacted by cancer stage, desire
for symmetry, comorbidities, histologic risk factors, family
history, potential difficult surveillance, and degree of risk
aversion. Patients with locally advanced breast cancers
should be discouraged from a contralateral prophylactic
mastectomy, as potential surgical complications could
compromise their oncologic treatments. Mastopexy and
reduction mammoplasty for the contralateral breast are
potential alternatives to contralateral prophylactic
mastectomy as symmetry procedures.
Sentinel Lymph Node Dissection
Sentinel lymph node (SLN) dissection is a minimally invasive
procedure designed to stage the axilla in breast cancer
patients who have clinically negative nodes. Sentinel nodes
are the first node or first group of nodes that drain from the
breast to the axilla. Lymphatic mapping may be performed
with radioisotope (technetium99 sulfur colloid) alone or
radioisotope plus a patent blue dye (Lymphazurin or
methylene blue). With sentinel lymph node dissection,
typically 1-3 lymph nodes are removed and tested for nodal
metastasis with hematoxylin and eosin (H&E) stain and
immunohistochemistry (IHC) with an anticytokeratin cocktail.
Sentinel lymph nodes may be checked intraoperatively by
imprint touch preparation, frozen section, or RT-PCR.
Intraoperative evaluation allows for immediate axillary lymph
node dissection to be performed if the sentinel lymph node is
unequivocally positive for nodal metastasis. The American
Society
of
Clinical
Oncology
(ASCO)
Guideline
Recommendations for Sentinel Lymph Node Biopsy in early
stage breast cancer recommends axillary lymph node
dissection after detection of a positive sentinel lymph node.
However, isolated tumor cells detected by specialized
techniques such as immunohistochemistry and RT-PCR
remain of uncertain significance. When sentinel lymph node
mapping is not successful, complete axillary lymph node
dissection is recommended. Absolute contraindications for
sentinel lymph node dissection include clinically suspicious
axillary nodes, which should be evaluated by ultrasoundguided (FNA), and biopsy-proven node-positive disease.
A recent study evaluated the accuracy of 4 nomograms in
patients with sentinal lymph node-positive breast cancer. The
authors found the Memorial Sloan-Kettering Cancer Center
nomogram to be more predictive than the other
nomograms.14
Axillary Lymph Node Dissection
Axillary lymph node dissection for breast cancer is a complete
en bloc removal of the level I and II lymph nodes. level I
nodes are lateral to the pectoralis minor, level II are beneath
the pectoralis minor, and level III are medial to the pectoralis
minor. The level III nodes are not removed surgically unless
there is suspicious or palpable adenopathy present. Skip
metastasis to the axillary apex of level III without lower
axillary involvement is very rare. Axillary lymph node
dissection removes all nodal tissue defined by the borders of
the axillary vein superiorly, the latissimus dorsi muscle
laterally, the medial border of the pectoralis minor muscle
medially, and the subscapularis muscle posteriorly.
Care is taken to preserve the long thoracic and thoracodorsal
nerves along their course through the axilla. Injury to the
long thoracic nerve results in a winged scapula, while injury
to the thoracodorsal nerve compromises internal rotation
and abduction of the arm beyond 90 degrees. The median
and lateral pectoral nerves may also be injured during axillary
lymph node dissection. The antecostobrachial nerves run
directly through the resection specimen and are typically
sacrificed, resulting in a predictable pattern of cutaneous
numbness in the inner arm region for most patients after this
procedure.
Axillary lymph node dissection was previously considered to
be the standard of care for all patients diagnosed with
invasive breast cancer. However, axillary lymph node
dissection carries a high rate of surgical morbidity
(lymphedema rates of about 25%, shoulder dysfunction,
wound infection, seroma, nerve damage, numbness, chronic
pain, and, rarely, brachial plexus injury). Lymphedema is the
abnormal accumulation of protein-rich edema fluid in the
upper extremity following axillary lymph node dissection.
This occurs because a portion of the lymphatics that drain
from the breast to the axilla, and those that drain from the
arm are shared within the axilla. Early detection of
lymphedema is paramount as lymphedema is potentially
reversible when treated in its earliest stage. Compression
garments and physical therapy with lymphatic massage are
still the backbone for the treatment of lymphedema.
Patients who have an axillary lymph node dissection should
be cautioned about the risk of lymphedema and should take
precautions to avoid breaks in the skin or infections in the
affected extremity. Lymphedema may develop at any time
after lymph node dissection but most commonly occurs
within the first 2 years of the surgery. Risk factors for
developing lymphedema include obesity and radiation
therapy. Although patients are commonly advised to avoid
taking blood pressures or inserting IV’s in the affected arm
after axillary lymph node dissection, no level I or level II
evidence supports that recommendation.
Breast-Conserving Radiation Therapy (RT)
The purpose of radiation therapy following breast-conserving
surgery is to eradicate local subclinical residual disease while
reducing local recurrence rates by approximately 75%. Based
on results from several randomized controlled studies,
radiation to the intact breast is considered standard of care
even in the lowest risk disease with the most favorable
prognostic features. There are two general approaches used
to deliver radiation therapy: conventional external beam
radiotherapy (EBRT) and partial breast irradiation (PBI).
Whole breast radiotherapy (WBRT) is comprised of EBRT
delivered to the breast at a dose of 50-55 Gy over 5-6 weeks.
This is often followed by a boost dose specifically directed to
the area in the breast where the tumor was removed.
Common side effects of radiation therapy include fatigue,
breast pain, swelling, and skin desquamation. Late toxicity
(lasting 6 mo or longer following treatment) may include
persistent breast edema, pain, fibrosis, and skin
hyperpigmentation. In a quality-of-life study that was part of
the START (Standardisation of Breast Radiotherapy) trials,
Hopwood et al found that at 5 years after radiotherapy for
early breast cancer, up to 40% of women reported moderate
or marked changes to the breast, and arm and shoulder pain
affected up to a third of patients. Breast symptoms and body
image concerns reduced over time. Adverse change in skin
appearance was significantly lower for patients who received
hypofractionated therapy, with 39 Gy delivered in 13
fractions over 5 weeks or 40 Gy in 15 fractions over 3 weeks,
compared with a global standard of 50 Gy in 25
fractions.15 Rare side effects of radiation therapy include rib
fractures, pulmonary fibrosis, cardiac disease (left breast
treatment), andsecondarymalignancies such as radiationinduced sarcoma (0.5%).
Partial breast irradiation is employed in early stage breast
cancer following breast-conserving therapy as a way of
delivering larger fraction sizes while maintaining a low risk of
late effects. Several techniques that can deliver this therapy
include interstitial brachytherapy (multiple catheters placed
through the breast) and intracavitary brachytherapy (a
balloon catheter inserted into the lumpectomy site [ie,
MammoSite]). Treatment is typically for 5 days, twice daily.
These techniques have shown low local recurrence rates
comparable to EBRT in several nonrandomized studies. The
American Society of Breast Surgeons recommends the
following selection criteria when considering patients for
treatment with accelerated partial breast irradiation.
 Age 45 years and older
 Invasive ductal carcinoma or DCIS
 Total tumor size (invasive and DCIS) 3 cm or smaller
 Negative microscopic surgical margins of excision
 Axillary lymph node/sentinel lymph node negative
Potential complications of partial breast irradiation are
catheter placement followed by removal secondary to
inadequate skin spacing, infection, seroma, fibrosis, chronic
pain, or disease recurrence.
Postmastectomy Radiation Therapy
Clinical practice guidelines developed by the American
Society of Clinical Oncology along with several prospective
randomized clinical trials recommend postmastectomy
radiation therapy be performed using the following criteria.
 Positive postmastectomy margins
 Primary tumors larger than 5 cm
 Involvement of 4 or more lymph nodes
Patients with more than 4 positive lymph nodes should also
undergo prophylactic nodal radiation therapy at doses of
4500-5000 cGy to the axillary and supraclavicular regions. For
patients who undergo axillary lymph node dissection and are
found to have no lymph node involvement, axillary radiation
therapy is not recommended. Meta-analyses have shown
postmastectomy combined with regional nodal radiation
therapy significantly decrease the rate of local relapse and
breast cancer mortality. Currently, the benefit of radiation
therapy for women with 1-3 positive axillary lymph nodes is
uncertain and studies are ongoing.
ADJUVANT THERAPY FOR BREAST CANCER
The breast cancer mortality rate fell 24% between the years
1990 and 2000 for women aged 30-79 years. This
improvement in breast cancer mortality is thought to have
resulted from both improvements in early detection through
screening and from advances in adjuvant treatment.
Depending on the model of risk reduction, adjuvant therapy
has been estimated to be responsible for 35-72% of that
reduction. Adjuvant treatment of breast cancer is designed to
treat micro-metastatic disease, or breast cancer cells that
have escaped the breast and regional lymph nodes but have
not yet established an identifiable metastasis. Treatment is
aimed at reducing the risk of future recurrence, thereby
reducing breast cancer-related morbidity and mortality.
Adjuvant Chemotherapy
Combination chemotherapy regimens are standardly
recommended in the adjuvant setting. The most commonly
used regimens are shown below.
Table 4. Adjuvant Chemotherapy Regimens for Breast Cancer
Open table in new window
Regimen
Dose
and Frequency
Schedule
Cycles
TAC (Martin et al, Eur J Cancer 2(suppl):70, 2004)
Taxotere (Docetaxel) 75 mg/m² IV Every
21 6
day 1
Adriamycin
Cyclophosphamide
days
5-FU
50 mg/m² IV
day 1
600 mg/m² IV Every
day 1
days
Adriamycin
500 mg/m² IV
day 1
60 mg/m² IV
day 1
Cyclophosphamide
600 mg/m² IV
day 1
5-FU
500 mg/m² IV Every
days 1 and 8
days
Adriamycin
30 mg/m² IV
days 1 and 8
Cyclophosphamide
100 mg/m² PO
days 1-14
AC => T (conventional regimen) 16
Adriamycin
60 mg/m² IV Every
day 1
days
Cyclophosphamide
600 mg/m² IV
day 1
21 4
Followed by
Paclitaxel
175 mg/m² IV Every
day 1
days
21 4
Dose-Dense
Adriamycin
60 mg/m² IV Every
day 1
days
Cyclophosphamide
600 mg/m² IV
day 1
14 4
Followed by
Paclitaxel
175 mg/m² IV Every
day 1
days
14 4
Adriamycin
20 mg/m² IV Every week
day 1
Cyclophosphamide
50 mg/m² PO
12
CMF (Bonadonna regimen) 21
Cyclophosphamide
100 mg/m² PO Every
days 1-14
days
Methotrexate
40 mg/m² IV
days 1 and 8
5-FU
600 mg/m² IV
days 1 and 8
28 6
80 mg/m² IV Every week
day 1
12
AC => T + H (Trastuzumab) 17
FEC-100 18
500 mg/m² IV Every
day 1
days
Epirubicin
100 mg/m² IV
day 1
Cyclophosphamide
500 mg/m² IV
day 1
50 mg/m² PO Weekly
days 1-7
Methotrexate
15 mg/m² IV
5-FU
300 mg/m² IV
24
Taxotere
75 mg/m² IV Every
day 1
days
Cyclophosphamide
600 mg/m² IV
day 1
21 4
TCH 24
4 mg/kg IV load then 2 mg/kg weekly with Paclitaxel then
give 6 mg/kg IV every 3 weeks for 40 weeks; NOTE
Trastuzumab to be added to a weekly Paclitaxel regimen in
HER2-positive breast cancer patients
5-FU
Cyclophosphamide
TC 23
Every day
Followed by
FAC 19, 20
28 6
Metronomic regimen 22
Metronomic regimen
Paclitaxel
21 4
21 6
Taxotere (Docetaxel) 75 mg/m² IV Every
day 1
days
Carboplatin
AUC 6 IV day 1
Trastuzumab
4
mg/kg
loading dose IV
followed
by
2 mg/kg/wk X
18 then q3wk X
12
21 6
A comparison of major Cancer and Leukemia Group B
(CALGB) chemotherapy clinical trials from the last few
decades including C8541 compared various doses of CAF,
9344 (which added paclitaxel to standard dose AC) and 9741
(which compared q3wk dosing to q2wk dosing in estrogen
receptor-positive and -negative patients). In all cases,
chemotherapy was enormously better in terms of improving
disease-free and overall survival in patients with estrogen
receptor-negative disease.
When the inferior arm of C8541 was compared to the dose
dense arm of C9741, a remarkable 63% (CI 43-76%)
improvement in disease-free and 59% (CI 34-74%)
improvement in overall survival was observed in patients
with estrogen receptor-negative disease compared to 32%
(CI -7-56%) improvement in disease-free and 18% (CI -4153%) improvement in overall survival in patients with
estrogen receptor-positive disease. Overall, the advantages
of chemotherapy, particularly in estrogen receptor-negative
disease, were observed across all 3 trials irrespective of the
chemotherapy regimen used.
Role of taxanes
Taxanes are amongst the most active and commonly used
chemotherapeutic agents used to treat early stage breast
cancer. However, questions have lingered as to whether
taxanes are the most effective chemotherapeutic agent to
use in this setting and if so, what is the best dosing schedule.
A recent Cochrane meta-analysis including 12 studies and
more than 21,000 patients evaluated the role of taxanes in
the adjuvant treatment of operable breast cancer (stage I-III).
The results showed a statistically significant overall survival
(HR 0.81, p< 0.00001) and disease-free survival (HR 0.81, p<
0.00001) for the taxane-containing regimens compared with
the nontaxane regimens. This meta-analysis did not identify
any subgroups of patients within the evaluated studies in
which a taxane-containing regimen would be more
efficacious.
The CALGB 9344 was one of the largest trials evaluating
taxanes in the adjuvant setting for early stage breast cancer,
with more than 3,000 women with node-positive breast
cancer. This study demonstrated a survival benefit for the
sequential use of paclitaxel following AC chemotherapy. In a
recent retrospective analysis of CALGB 9344 testing for HER2
status using 1,322 original participant tumor blocks, HER2
positivity irrespective of estrogen receptor status predicted a
significant benefit from paclitaxel in terms of reduced disease
recurrence (HR 0.59, p= 0.01). Patients with estrogen
receptor-positive, HER2-, node-positive breast cancer did not
seem to benefit from the addition of a taxane.
However, the National Cancer Institute of Canada MA.21 and
UK TACT trials, which used taxane and nontaxane-based
chemotherapeutic regimens in early stage breast cancer
patients, did not demonstrate a benefit in using taxanes.
Although the precise role of adjuvant taxane therapy remains
controversial, the optimal scheduling of taxane
administration
has
been
determined.
The Eastern Coast Oncology Group (ECOG) 1199 randomized
4,950 women with lymph node-positive or high-risk lymph
node-negative early stage breast cancer to 4 cycles of AC
followed by 4 different taxane regimens: 1) paclitaxel at 175
mg/m2 q3wk; 2) paclitaxel at 80 mg/m2 weekly; 3) docetaxel
at 100 mg/m2 q3wk; and 4) docetaxel 35 mg/m2 weekly.
After a 64-month median follow-up, paclitaxel weekly and
docetaxel every 3 weeks were superior to the other two
regimens
in
terms
of
disease-free
survival.
Similarly, the TAX 311 trial performed by the US Oncology
group showed that every 3 week docetaxel at 100
mg/m2improved time to progression (TTP) and overall
survival when compared to paclitaxel at 175 mg/m 2 given
every 3 weeks. Thus, taxane-based regimens still have use in
the treatment of early stage breast cancer and should be
considered in treating women especially with HER2+ disease
using either the weekly paclitaxel or every-3-week docetaxel
dosing schedules.
Role of anthracyclines
Anthracycline-containing adjuvant chemotherapy regimens
have been used in the treatment of early stage breast cancer
for decades, although concerns regarding anthracyclineassociated cardiotoxicity or leukemogenic potential remain.
In the 2000 Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG) overview, anthracycline-based regimens were
associated with an annual risk of cardiac mortality of 0.08%
per year as compared with 0.06% per year in patients treated
with nonanthracycline-based regimens. However, the
question of long-term cardiac safety remains, particularly for
older women with early stage breast cancer.
The US Oncology 9735 trial randomized 1,016 women with
operable breast cancer (stages I-III) to 4 cycles of TC versus 4
cycles of standard dose AC. After a median of 7 years followup, both disease-free survival (81% vs 75%; HR, 0.74; p=
0.033) and overall survival (87% vs 82%; HR 0.69; p= 0.032)
were superior in the TC arm. Grade 5 cardiotoxicity (resulting
in death) was seen in 6 patients treated with AC (4 from
myocardial infarction; 2 from congestive heart failure) versus
2 (myocardial infarction) in the TC group. This trial
established TC as a viable option for treating women with
early stage breast cancer, especially those at high risk of
cardiotoxicity or requiring only 12 weeks of therapy.
Additionally, a recent meta-analysis of 8 trials comprised of
6,564 women with early stage breast cancer to anthracycline
versus nonanthracycline-based regimens suggested a benefit
with anthracycline administration only in patients with
HER2+ disease. Biologically, anthracyclines inhibit
topoisomerase IIa, whose gene (TOP2A) lies adjacent to
the HER2gene on chromosome 17 and is coamplified in
approximately 35% of HER2 -overexpressing breast cancers.
The original trials demonstrating superiority of anthracyclinebased
regimens
over
CMF
did
not
include TOP2A or HER2testing. The BCIRG 006 trial, which
randomized women with HER2+ disease to AC followed by T,
AC
followed
by
TH,
or
TCH,
did
test
for TOP2A and HER2 coamplification.24 This group comprised
only approximately 8% of the total breast cancer population
and may be the only subgroup to benefit from anthracycline
administration. The role of TOP2A as a predictive marker of
response to anthracyclines needs further validation. Until
then, patients should not be deprived anthracycline-based
adjuvant chemotherapy if their risk assessment so
determines it.
A recent study compared the effectiveness of oral uraciltegafur (UFT) with that of CMF given as a postoperative
adjuvant to women with node-negative, high-risk breast
cancer. Risk-free survival and overall survival were similar in
the 2 groups, but the quality of life scores were higher for
patients given UFT than those given CMF. The study
concluded that for women with node-negative, high-risk
breast cancer, UFT is a promising alternative to CMF. 25
An anthracycline followed by or concurrent with a taxane is
the most optimal therapy for "triple-negative" breast cancer
patients with no medical contraindications. However, it
remains unclear what the optimal combination
chemotherapy regimen is for ER+, HER2– tumors. Currently,
CMF, TC, or an anthracycline-based regimen may all be
reasonable options.
Adjuvant
Therapy
for
HER2+
Breast
Cancer
Overexpression of HER2 occurs in approximately 20% of
breast cancers and previously correlated with a more
aggressive phenotype and worse prognosis prior to the
development of HER2 targeted therapies. The advent of
trastuzumab, a monoclonal antibody (mAb) targeting the
extracellular domain of the receptor, has changed the
treatment paradigm for HER2-positive breast cancer.
Trastuzumab has a powerful synergism with a variety of
chemotherapeutics, yet lacks the side-effects (with the
notable exception of cardiotoxicity, which means it should
not
generally
be
given
with
anthracyclines).
To date, results are available from 5 studies (HERA, FinHer,
NSABP B-31, BCIRG006, N9831) that randomized 11,650
women with early-stage HER2+ breast cancer to trastuzumab
versus non-trastuzumab-based adjuvant chemotherapy. All 5
trials have demonstrated that the inclusion of trastuzumab
produces roughly a 50% improvement in disease-free survival
and 33% improvement in overall survival regardless of the
chemotherapy regimen or sequence of trastuzumab delivery.
Based on these trials trastuzumab was FDA approved for the
treatment of HER2+ disease in the adjuvant setting. Whether
the combination of two anti-HER2 targeted therapies with
chemotherapy will prove beneficial in early stage disease is
currently being tested in the phase III ALTTO (Adjuvant
Lapatinib and/or Trastuzumab Treatment Options) trial as
well as the similar NeoALTTO (Neoadjuvant Lapatinib and/or
Trastuzumab
Treatment
Optimization)
trial.
Adjuvant Hormonal Therapy
In estrogen-receptor positive early stage breast cancer,
hormonal therapy plays a main role in adjuvant treatment,
either alone or in combination with chemotherapy. Hormonal
treatments function to decrease estrogen’s ability to
stimulate existing micro-metastases or dormant cancer cells.
Adjuvant hormonal therapy can reduce the relative risk of
distant, ipsilateral, and contralateral breast cancer
recurrence by up to 50% in tumors with high ER expression.
FDA-approved endocrine therapies for adjuvant treatment of
breast cancer includes tamoxifen and the aromatase
inhibitors (anastrozole, letrozole, exemestane26 ).
Tamoxifen
Tamoxifen is a selective estrogen receptor modulator
(SERM), which binds to and inhibits estrogen receptor
signaling in the breast. As a receptor antagonist, it is effective
in both premenopausal and postmenopausal women. It has
ER-stimulating effects in other tissues, including bone
(resulting in preservation of bone density) and endometrium
(leading to a 2- to 4-fold increased risk of endometrial
cancer). Tamoxifen has been approved for breast cancer
treatment since the early 1980s. It has been shown in
multiple studies to decrease breast cancer associated
mortality and recurrence. In an analysis of 55 trials evaluating
tamoxifen versus placebo in the adjuvant treatment of breast
cancer, 5 years of tamoxifen therapy resulted in a 47%
reduction in recurrence and a 22% reduction in mortality.
The EBCTCG meta-analysis demonstrates that the risk
reduction from adjuvant tamoxifen is similar (or even
superior) in older versus younger women, with a relative risk
of recurrence of 0.49 in patients older than 70 years, 0.55 in
patients aged 60-69 years, 0.66 in patients aged 50-59 years,
0.71 in patients aged 40-49 years. Common side effects
associated with tamoxifen use include hot flashes (up to
80%), vaginal bleeding (2-23%), discharge (13-55%) or
dryness (<1%), dyspareunia (3-5%), urinary frequency or
urgency (10%), and mood changes (12-18%) or depression (212%). While many patients attribute postdiagnosis weight
gain to tamoxifen, the literature suggests only a 5% increase
in weight is associated with tamoxifen use.
Tamoxifen is a prodrug that is metabolized primarily by the
cytochrome P450 (CYP2D6) system to its active metabolite,
endoxifen. More than 80 different alleles of the CYP2D6 gene
have been identified with varying activity levels.
Consequently, patients can be categorized by their level
of CYP2D6 activity into high/extensive or low/poor
metabolizers. Up to 7% of the white and African American
populations are poor metabolizers of tamoxifen. Poor
metabolizers have been shown in several retrospective
studies to have lower disease-free survival and higher
recurrence rates compared to extensive metabolizers. Poor
metabolizers also seem to tolerate tamoxifen better as they
have less severe hot flashes and endocrine related toxicities.
Several laboratories now offer CYP2D6 testing for patients
treated with tamoxifen. Recommendation for this testing is
still controversial but is reasonable in women who have
alternative treatment options. Recently, considerable
interest has arisen in inhibitors of CYP2D6 activity. Many
agents, of which the selective serotonin-reuptake inhibitors
fluoxetine (Prozac) and paroxetine (Paxil) are most
prominent, are potent CYP2D6 inhibitors that can also
decrease conversion of tamoxifen to endoxifen.27 Thus, the
use of potent CYP2D6 inhibitors should be avoided if possible
in patients on tamoxifen. Other drugs that are strong
inhibitors of CYP2D6 include quinidine, risperidone, and
tenofovir.
Experts at the American Society of Clinical Oncology 45th
Annual Meeting in 2009 presented contradictory results
regarding the risk of recurrence with use of selective
serotonin reuptake inhibitors in women taking tamoxifen to
reduce their risk of breast cancer recurrence. They concurred
that until more data are available, these patients should
avoid
concomitant
use
of
SSRIs.27,28,29
Aromatase inhibitors (AIs)
AIs function by inhibiting aromatase, the enzyme (found in
body fat, adrenal glands, and breast tissue as well as tumor
cells) responsible for converting other steroid hormones into
estrogen. Aromatase is the sole source of estrogen in
postmenopausal women and likely the underlying reason
that obesity (larger volume of body fat produces more
estrogen) has been associated with a higher risk of breast
cancer in postmenopausal patients. As the AIs have no effect
on ovarian estrogen production, they are only effective in
postmenopausal women. Common side effects of AIs include
hot flashes (12-36%), arthralgia/arthritis (17%), headache (913%), vaginal dryness (2%), and mood changes (19%).
Several large randomized trials including BIG1-98 and ATAC
have shown aromatase inhibitors to be superior to tamoxifen
with regard to disease-free survival in postmenopausal
women with early stage breast cancer. The ATAC trial results
are most mature at 100 months of follow-up and show
anastrozole (Arimidex) to be superior to tamoxifen in
improving disease-free survival (HR 0.90). Significant benefit
was also seen in time to recurrence of contralateral breast
cancer. However, none of the head-to-head comparison trials
have yielded an improvement in overall survival compared to
tamoxifen. Early switching trials in which AIs are initiated
after 2-3 years of tamoxifen have also shown improved
disease-free survival. However, in contrast to the upfront
trials, an improved overall survival is observed when ERnegative patients are excluded and randomization occurs at
the time of switching.
The Canadian lead MA.17 trial randomized patients to an
additional 5 years of AI therapy with letrozole after
completion of 5 years of tamoxifen therapy. The additional 5
years of AI therapy resulted in improved disease-free survival
in all patients randomized and improved overall survival in
the higher risk lymph node-positive subset of patients. This
study was the first to suggest that prolonged hormonal
therapy may be more effective than 5 years of therapy. The
optimal duration and sequence for the use of aromatase
inhibitors has not been clearly defined, but their benefits in
terms of breast cancer recurrence and survival clearly
support their use in all postmenopausal women. Ongoing
trials are now comparing 5 versus 10 years of AI therapy
including a continuation of the MA.17 trial, which will include
patients receiving hormonal therapies for up to 15 years, and
whether the sequence of hormonal agent (ie, tamoxifen
followed by AI versus AI followed by tamoxifen) affects the
efficacy.
The BIG 1-98 Collaborative Group completed a randomized,
double-blind phase 3 trial to evaluate the optimal treatment
strategy with letrozole in postmenopausal women with
endocrine-responsive breast cancer. Patients (n=6182) were
randomly assigned to receive 5 years of tamoxifen, 5 years of
letrozole, letrozole for 2 years followed by tamoxifen for 3
years, or tamoxifen for 2 years followed by letrozole for 3
years. The primary endpoint, disease-free survival, was not
significantly better among either sequential treatment group
compared with letrozole monotherapy (hazard ratio for
tamoxifen followed by letrozole, 1.05; 99% confidence
interval [CI], 0.84-1.32; hazard ratio for letrozole followed by
tamoxifen, 0.96; 99% CI, 0.76-1.21). In addition, overall
survival was not statistically different between monotherapy
with letrozole and monotherapy with tamoxifen when
combined with previous trial data comparing efficacy
(n=4922) (hazard ratio for letrozole, 0.87; 95% CI, 0.751.02;P=0.08).30
Follow-up Guidelines
There is no consensus among oncologists as to the
appropriate and optimal follow-up for long-term breast
cancer survivors. The majority of relapses, both local and
distant, occur within the first 3 years, especially in higher risk
and estrogen receptor-negative patients. The National
Comprehensive Cancer Network (NCCN) recommends the
following guidelines for breast cancer patients in the
adjuvant setting.
Table 5. Follow-up Recommendations for Breast Cancer
Survivors per NCCN* Guidelines
Open table in new window
Intervention†
Year 1
History and q3-4mo
physical
examination
Year 2
Year 3- Year 6+
5
q4mo
q6mo
Annuall
y
Mammograph Annually (or 6 Annuall Annuall Annuall
y
mo
after y
postBCS‡ irradiatio
n)
y
y
CXR
NR§
NR
NR
Pelvic
Annually
||
examination
NR
Annuall Annuall Annuall
y
y
y
Bone density¶ q1-2y
*National
Comprehensive
Cancer
Network
†
Bone scan, blood counts, liver function tests, and tumor
markers are not routinely recommended and should be
performed
if
clinically
indicated.
‡
Breast-conserving
surgery
§
Not
recommended
||
For patients with an intact uterus on tamoxifen
¶
For
patients
at
risk
for
osteoporosis
ASCO guidelines published in 2007 do not support the use of
tumor biomarkers, including CEA, CA 15.3, and CA 27.29 for
monitoring patients for recurrence after primary breast
cancer therapy.
Locally Advanced and Inflammatory Breast Cancer
Originally, the reason for grouping these categories was the
recognition that both had little or no chance of cure from
local therapy alone and were considered inoperable for that
reason. Today, the definition of locally-advanced disease has
broadened to include patients who are technically operable
but have large primary tumors (>5 cm). It is important to
recognize, however, that the reasons for using neoadjuvant
therapy are different in women who have large primary
tumors, where the goal is to increase the possibility of breast
conserving surgery (BCS), versus those who have disease that
meets the original criteria of locally-advanced breast cancer
(LABC) or inflammatory breast cancer (IBC), for whom the
administration of systemic treatment is essential to make
definitive local treatment possible with the intent of cure.
Since prognosis for women with T3N0 (stage IIB) and T3N1
(stage IIIA) is better overall than it is for those with classically
defined LABC (IIIB, IIIC) or IBC (IIIB, T4d), it is important to
know the relative proportions of patients in each category
when results of a clinical trial are reported. Not only may one
expect better disease-free and overall survival for stage IIB
and IIIA patients, but also the likelihood of achieving a
pathologic complete response (pCR) from neoadjuvant
treatment, a well-recognized surrogate for long-term
outcome, is inversely related to tumor size.
It is also important to recognize that the sixth edition of the
American Joint Committee on Cancer criteria for staging
differs from its predecessors in ways that are relevant to the
patient groups discussed here: women with T3 tumors were
previously considered to have stage III disease and are so
reported in the older literature; women with resectable
tumors who are found to have 4 or more involved axillary
lymph nodes after initial surgery, formerly called stage II, are
now grouped as IIIA. The revised staging system is better for
defining prognostic subgroups, but the practical relevance of
grouping together all patients who typically receive "up
front" chemotherapy remains, since their treatment
outcomes are usually reported as a function of the particular
neoadjuvant program employed.
Inflammatory Breast Cancer (IBC)
Inflammatory breast cancer is a clinical diagnosis that implies
presentation with the cardinal signs of inflammation (calor,
rubor, and tumor) involving the breast, although the calor
(warmth) may be subtle and the tumor (mass) may not be
appreciated as something discrete; indeed, even when a
localized mass is apparent in inflammatory breast cancer, the
true extent of the disease (as shown by performing skin
biopsies from the surrounding, normal-appearing skin) is
usually greater than apparent on physical examination. It was
originally described as having an erysipeloid border, but only
a minority of cases have this component of a raised edge.
In Western countries, the frequency of inflammatory breast
cancer is low, between 1% and 2% of all breast cancers, but it
is much higher in some parts of the world, such as northern
Africa, for reasons that are not known. Inflammatory breast
cancer tends to occur at a younger age than locally advanced
breast cancer. Pathologically, it was originally associated with
the classic finding of involvement of subdermal lymphatics,
although this finding is not in itself diagnostic of
inflammatory breast cancer (it may occur with locally
advanced breast cancer as a secondary phenomenon). It is
more likely to stain negatively by IHC for ER and PR,
somewhat more likely to be positive for HER2/neu
overexpression,
and
both
angiogenesis
and
lymphangiogenesis appear to be increased by microvessel
density or RNA-based gene expression arrays. Within
inflammatory breast cancer, however, may be found the
same molecular subtypes of breast cancer as originally
described for non-inflammatory breast cancer.
Locally Advanced Breast Cancer (LABC)
Locally advanced breast cancer in the United States is more
common than inflammatory breast cancer, and, by the
definition used here, may account for 10-15% of patients
(this drops to about 5% if one uses the stricter definition of
inoperable). Epidemiologically, it is associated with lower
socioeconomic class and, probably for that reason, with
African American ethnicity in the United States. It
encompasses both relatively indolent neglected tumors and
those that have grown rapidly due to their inherent biology.
It is as heterogeneous as invasive breast cancer in general,
and in most series, locally advanced breast cancer has a
better long-term outcome than inflammatory breast cancer,
even when only inoperable cases are considered.
Evaluation of Lymph Nodes and Response
Patients with locally advanced breast cancer or inflammatory
breast cancer with clinically positive nodes should undergo a
core biopsy prior to initiating chemotherapy. Those with
clinically negative nodes may undergo sentinel node biopsy
before they start treatment, or sentinel node determination
may be delayed until after treatment is completed.
Theoretically, it should be preferable to perform sentinel
node sampling up front, because chemotherapy might
eradicate preexistent disease in the sentinel node and result
in a false positive and/or altered lymphatic drainage in large
tumors might affect accuracy of the procedure. However,
data from the NSABP B-27 neoadjuvant trial suggest that the
false-negative rate for sentinel node biopsies performed after
neoadjuvant chemotherapy is about 11%, comparable to the
false-negative rate for patients undergoing initial resection.
In general, the best single test to evaluate the status of
measurable tumor is ultrasound, preferably done by the
same operator to avoid interobserver variability. The mass
often appears larger on physical examination than it does on
ultrasound, which can more effectively discriminate
hypoechoic masses from surrounding stroma and/or
hematoma. In inflammatory breast cancer, MRI may be an
important adjunct to response assessment. The role of PET in
the routine assessment of response remains to be
determined. No present imaging technique appears to be
highly accurate for the prediction of pathologic complete
response. Thus, the purpose of regular size assessment is to
exclude continuation of therapy in a patient with a growing
tumor (seen in <5% with the initial treatment) and to suggest
when maximal response of grossly evident disease has been
achieved, as this may be the optimal time to proceed to
resection.
Neoadjuvant Chemotherapy
Most programs of neoadjuvant therapy used in the United
States have been anthracycline-based, with FAC as the best
historical reference. In inflammatory breast cancer, their
early program of FAC X 4, then surgery followed by FAC X 4,
then irradiation, led to a median survival of about 2 years and
5-year survival in about 30% of patients, which are dramatic
improvements over historical control expectations for local
therapy alone (5-year survival of <5%).
The NSABP B-18 trial proved that preoperative chemotherapy
with 4 cycles of standard-dose AC was equivalent to 4 cycles
of postoperative standard dose AC. This trial also found that
pathologic complete response (pCR) in the primary tumor
predicts excellent overall survival and is an excellent
surrogate for long-term disease-free survival and overall
survival.
In the NSABP B-27 trial, 3 arms compared 4 cycles of
standard-dose AC to 4 cycles of standard dose AC combined
with non-cross-resistant Taxotere at 100 mg/m2, with a third
arm sandwiching primary surgery between the neoadjuvant 4
cycles of AC and the adjuvant 4 cycles of Taxotere. This trial
found that the addition of 4 cycles of Taxotere to standard AC
increased pathologic complete response from 14 to 26% and
that sandwiching surgery in between the chemotherapy
regimens was less effective than administering all
chemotherapy upfront. About 15% of initially node-positive
patients who achieve pCR in the breast have residual disease
in the axilla. Patients who have no residual disease in both
the primary (pCR) and lymph nodes (N0) have the best
overall prognosis with a markedly prolonged disease-free
survival.
To date, no cooperative group trial has attempted to improve
upon the results of neoadjuvant chemotherapy, given as
induction, with administration of alternative treatment after
surgery when the surgical result was suboptimal. A final
important observation made by the MD Anderson group,
from a randomized design, was that weekly paclitaxel X 12
followed by FAC was superior to paclitaxel given every 3
weeks for 4 cycles, followed by the same FAC program,
resulting in a doubling of the pCR rate for locally advanced
breast
cancer
from
14
to
28%
(p=.01).
The pCR in this trial was defined as disappearance of
microscopic evidence of all invasive disease at both the
primary site and the axilla, while much of the other literature
(including trials done by the NSABP) reports on pCR at the
primary site only. About 15% of initially node-positive
patients who achieve pCR in the breast have residual disease
in the axilla. Both criteria, however, predict for markedly
superior long-term disease-free survival, with the pCR N0
criterion having the best outcome.
The Southwest Oncology Group (SWOG) has reported
preliminary results of a prospective, randomized trial in
which "standard" AC, given every 3 weeks at standard doses,
was compared to a schedule of continuous chemotherapy
with the same agents [weekly Adriamycin (A), daily oral
Cyclophosphamide (C)], among patients with locally
advanced breast cancer or inflammatory breast cancer. The
continuous
or
"metronomic"
schedule
required
administration of GCSF as growth factor support. All patients
on the trial, after completing AC, went on to receive weekly
paclitaxel. The pCR rate was higher on the "continuous" arm,
and this effect was most marked in patients with
inflammatory breast cancer, as well as triple negative (ER-PRHER2/neu-) patients with locally advanced breast cancer. This
trial confirmed results of several other neoadjuvant trials
that ER- tumors have a higher pCR compared to ER+ tumors
and that infiltrating ductal histologies have a higher pCR rate
compared to infiltrating lobular histologies.
For patients with Her2/neu overexpression, the value of
adding trastuzumab in the adjuvant setting led to its
incorporation into neoadjuvant therapies for patients with
the Her2+ phenotype. This results in higher rates of pCR for
operable patients, as high as 65% initially reported by the MD
Anderson group, when trastuzumab was given concurrent
with an epirubicin-containing program. One preliminary
report from Europe indicates, in a randomized trial, an
improvement in pCR rate from 13-48% when trastuzumab
was added to standard neoadjuvant chemotherapy.
Though not yet tested on a large scale, it appears likely that
the addition of agents with anti-angiogenesis activity may
also be of value as targeted therapy in inflammatory breast
cancer, given its profile of excessive blood vessel formation.
Preclinical data suggest that metronomic chemotherapy
works through an anti-angiogenic mechanism, which may
explain the apparent benefits seen from the Southwest
Oncology Group (SWOG) trial for that regimen among the
patients with inflammatory breast cancer.
The best candidates for neoadjuvant chemotherapy are ERor Her2+ expressing tumors where pCR rates are generally
above 20% and predict long-term survival. Patients with ER+,
HER2- locally advanced breast cancer are unlikely to achieve
a pCR from presently available chemotherapy and the best
approach for these patients is likely to involve building on a
backbone of hormonal therapy, either alone or in
combination with targeted agents. There has been little
experience in the United States with neoadjuvant hormone
therapy though this approach has been tested in several
clinical trials in Europe. Neoadjuvant hormonal therapies
appear to be very effective in shrinking tumor size to enable
breast-conserving surgery, but pCR is rare.
Local-Regional Therapy
Patients with locally advanced breast cancer and IIB or IIIA
disease who achieve good tumor reduction with neoadjuvant
systemic treatment are good candidates for subsequent
breast-conserving surgery, though their rates of locoregional
relapse may be somewhat higher than those seen with
women who have smaller tumors. Breast-conserving surgery
is certainly feasible among some with locally advanced breast
cancer, which is initially IIIB, but it is not yet clear whether
the rates of locoregional recurrence are unacceptable.
The NSABP B-18 trial examined the clinical question of
whether patients with operable breast cancer randomized to
preoperative or neoadjuvant chemotherapy would have
improved survival over patients treated by surgery first
followed by chemotherapy. This study found no significant
difference in overall survival or disease-free survival between
treatment groups. However, survival advantage was
significant for the 36% of patients who experienced a pCR.
Patients with inflammatory breast cancer are nearly always
best served, given the notorious propensity of this disease for
locoregional as well as systemic recurrence, by having
mastectomy
as
their
definitive
surgery.
following surgery for all patients who do not have a medical
contraindication.
Systemic Treatment of Metastatic Breast Cancer
Marked advancements are being made in the treatment of
early stage breast cancer, but many women still develop
recurrence and metastasis. In addition, 5-10% of breast
cancer patients have metastatic disease at presentation.
While treatments for metastatic breast cancer continue to
improve, there remains no cure once distant metastases
develop. Although occasional patients with metastatic breast
cancer benefit from surgical resection for an isolated
recurrence and many require radiation therapy for palliation
at a specific site (or definitive treatment of brain metastasis),
in general recurrent or metastatic breast cancer must be
approached systemically such that the therapeutic effect
reaches all sites of disease. There are two main interventions:
hormone therapy and chemotherapy.
Hormone therapy
For patients who have hormone receptor (ER and/or PR)
positive disease without a life-threatening component (eg,
massive liver metastases) or systemic symptoms requiring
immediate palliation for comfort, hormone manipulation is in
general the initial treatment of choice. Response rates are
higher with chemotherapy, but so is the incidence of
potentially dangerous toxicity, and there is no evidence that
patients live longer as a result of receiving initial
chemotherapy. A trial of hormone manipulation alone can
assess whether hormone therapy is effective, which is
impossible to determine if given together with cytotoxic
chemotherapy. This is especially important when the patient
has relapsed disease because the benefit of second-line
hormone manipulation is nearly 50%, and failure to benefit
from an initial trial with endocrine therapy correlates with
second-line failure. Common hormonal therapies and
dosages are listed below.
Table 6. Hormonal Agents Used in Breast Cancer
Open table in new window
Agent
Dose and Schedule
Postmenopausal
Tamoxifen
20 mg PO every day
Or
Aromatase inhibitor
Anastrozole 1 mg PO every day
Letrozole
2.5 mg PO every day
Exemestane 25 mg PO every day
Reconstruction is not recommended for locally advanced
(stage IIB or stage III) and inflammatory breast cancer
patients because it may compromise their oncologic care by
interfering with the administration of chemotherapy or
radiation therapy. Radiation therapy is recommended
Or
Fulvestrant
500 mg IM on days 1, 15, 29, then monthly
thereafter (if moderate hepatic impairment,
decrease dose to 250 mg)
Or
Megestrol
bine
pyrimidine
40 mg PO 4 times a day
Premenopausal
Tamoxifen
20 mg PO every day
Or
Aromatase inhibitor + LHRH
Leuprolide
7.5
mg
IM
22.5
mg
30 mg IM q4mo
Goserelin
3.6
mg
10.8 mg SC q3mo
Megestrol
depot
IM
q28d
q3mo
depot
q28d
SC
40 mg PO 4 times a day
Chemotherapy
Cytotoxic chemotherapy for metastatic breast cancer initially
consisted of single agent regimens. Now, combination
therapy is considered upfront depending on the patient’s
performance status due to higher response rates. However,
in the setting of advanced disease, the goal in determining a
treatment regimen should be to prolong survival while
maintaining a good quality of life.
When the patient has life-threatening disease and/or severe
symptoms that require quick relief, combinations of cytotoxic
agents may be preferable because of their high response rate
and early onset of clinical benefit. Randomized trials have
shown a survival advantage for the use of a two-drug
combination versus a single agent, but they have not led to
widespread adoption of this practice, since 1) the
combination is more toxic; and 2) the study designs were
flawed in that patients randomized to receive a single agent
initially were not crossed over to the other drug component
of the initial therapy at the time of relapse. A second
situation, which is becoming increasingly common, is when a
cytotoxic chemotherapeutic agent is combined with a
targeted agent other than hormone therapy. These targeted
agents often have very low response rates when given as
single agents but provide added benefit when given in
combination with cytotoxic chemotherapy.
Table 7. Targeted Chemotherapy for Metastatic Breast
Cancer
Open table in new window
Drug
Class
Dose/Sche Overal Toxicity
dule
l
Respo
nse
Rate
Capecita
Oral fluoro- 1250
30%
Rash,
hand-
mg/m²/d
PO for 2
weeks with
1 wk off
foot
syndrome,
diarrhea,
mucositis
Docetaxe Antimicrotu 75-100
30l
bule
mg/m² IV 68%
q3wk
or
40
mg/m²/wk
X IV for 6
wk with 2
wk off
Myelosuppre
ssion,
alopecia,
skin reaction,
mucositis,
and
fluid
retention
Doxorubi
cin
Anthracycli
ne
(antitumor
antibiotic)
45-60
35mg/m² IV 50%
q3wk
or
20 mg/m²
IV
qwk
(not
to
exceed a
cumulative
dose
of 450-500
mg/m²)
Myelosuppre
ssion,
nausea/
vomiting,
mucositis,
diarrhea
cardiotoxicity
, alopecia
Doxil
(liposom
al
encapsul
ated
doxorubi
cin)
Anthracycli
ne
20 mg/m²
IV
q2wk
or
35-40
mg/m² IV
q4wk
Less
cardiotoxicity
,
neutropenia,
alopecia,
stomatitis,
hand-foot
syndrome
Epirubici
n
Anthracycli
ne
90 mg/m² 35IV
q3wk 50%
(not
to exceed
cumulative
dose
of
900
mg/m²)
Myelosuppre
ssion,
mucositis,
nausea,
vomiting,
cardiotoxicity
Gemcitab Antimetabo 725
ine
lite
mg/m²/wk
IV for 3 wk
then 1 wk
off
or
1 g/m²/wk
IV X 2 then
1 wk off
Myelosuppre
ssion,
nausea/
vomiting,
flulike
syndrome,
elevated LFTs
NabAntimicrotu 80-100
58paclitaxel bule
mg/m²/wk 62%
IV X 3 then
1 wk off 33%
or
260 mg/m²
IV q3wk
Less
neuropathy,
and allergic
reaction
Paclitaxel Antimicrotu 80
25bule
mg/m²/wk 50%
IV
or
175 mg/m²
IV over 3
hours
q3wk
Myelosuppre
ssion,
alopecia,
neuropathy,
allergic
reaction
Trastuzu
mab
Monoclonal 4
mg/kg 10antibody
loading
15%
dose, then
2
mg/kg
weekly or
8
mg/kg
loading
dose, then
6
mg/kg
q3wk
Fever, allergic
reaction,
cardiotoxicity
/CHF
Vinca
alkaloid
Myelosuppre
ssion,
nausea/
vomiting,
constipation,
fatigue,
stomatitis,
anorexia
Vinorelbi
ne
20
mg/m²/wk
IV
3545%
Paclitaxel
XN 32
Capecitabine
Navelbine
Carboplatin 34
Paclitaxel
AUC of 6 day 1 Repeat cycle every 21
200 mg/m² day 1
days
Carboplatin 35
Docetaxel
AUC of 6 day 1 Repeat cycle every 21
75 mg/m² day 1
days
Paclitaxel 36
Bevacizumab
90 mg/m² day 1, 8, Repeat cycle every 28
and
15 days
10 mg/kg day 1
and 15
HER2 Positive Metastatic Breast Cancer Regimens 37, 38, 39, 40, 8
Trastuzumab
Paclitaxel
Trastuzumab
Docetaxel
Trastuzumab
Table 8. Combination Regimens for Metastatic Breast Cancer
Open table in new window
Chemotherapy Dose and Schedule Cycle
1250 mg/m² bid Repeat cycle every 21
days
1-14 days
75 mg/m² day 1
May
decrease
capecitabine
dose
to 850-1000 mg/m² to
reduce
toxicity risk
XP 32
825
mg/m²
bid Repeat cycle every 21
4 mg/kg loading
dose
then
2 mg/kg weekly
80
mg/m²
IV
weekly
8 mg/kg loading Repeat cycle every 21
dose
then days
6 mg/kg day 1
100 mg/m² IV day
1
4 mg/kg loading
dose
then
2 mg/kg weekly
25 mg/m² day 1
weekly
Lapatinib
Capecitabine
1250 mg PO daily Repeat cycle every 21
2000 mg/m² daily days
days 1-14
Paclitaxel
Lapatinib
175
mg/m2 Repeat cycle every 3
1500 mg/d
weeks
XT 31
Capecitabine
1000 mg/m² bid Repeat cycle every 21
days
1-14 days
25 mg/m² days 1
and 8
Gemcitabine 33 1250 mg/m² days 1 Repeat cycle every 21
Paclitaxel
and
8 days
175 mg/m² day 1
Vinorelbine
Capecitabine
Docetaxel
days
1-14 days
175 mg/m² day 1
The initial choice of chemotherapy is highly influenced by the
patient’s personal history of prior drug exposure. For
example, if doxorubicin (Adriamycin) was a component of
prior adjuvant therapy, the tumor cells have a higher risk of
developing resistance, and there is a relationship of
cumulative total dose over a lifetime to the risk of potentially
fatal
cardiomyopathy
as
a
result
of
this
drug.
arm
compared
to
paclitaxel
alone.
It is important to realize that if a year or more has elapsed
since completion of adjuvant therapy, a patient’s tumor is
likely to respond to a previously given drug or combination as
though that drug or combination had never been given. Most
patients have been exposed to both an anthracycline (ie,
doxorubicin) and a taxane (docetaxel or paclitaxel) in the
adjuvant setting. Treatment of breast cancer with a taxane in
the metastatic setting after treatment in the adjuvant setting
may be difficult because of residual toxicity. Although
taxanes are not cardiotoxic, they can produce lingering
neuropathy (especially paclitaxel) or problems with edema
(docetaxel especially), which makes further administration
problematic. Substitution of one taxane for the other is
possible, depending on the nature of the chronic toxicity. If
the tumor has recurred quickly after administration of
adjuvant chemotherapy containing a taxane, then changing
the schedule of administration can be effective.
Vinorelbine (Navelbine) is a vinca alkaloid that targets tubulin
in the mitotic spindle and administered IV usually on a
weekly basis. Vinorelbine is often used as a single-agent
following treatment with a taxane or anthracycline yielding
an overall response rate of 25%. However, when used as a
first- or second-line agent, vinorelbine can have overall
response rates of up to 40%.
As with hormone therapy, the chance of benefit from
chemotherapy is related to the success achieved with the
previous regimen. Although there are occasional gratifying
responses to a drug used in the third or fourth line setting of
metastatic breast cancer, they are the exception rather than
the rule. Thus, patient characteristics, previous treatments,
and the expected toxicity of these regimens must be taken
into
account.
At least a third of breast cancer patients with taxaneresistance due to administration of every 3-week paclitaxel
respond when the same drug is administered on a weekly
schedule at a lower dose. The CALGB 9840 trial, reported an
improved overall response rate (ORR) in patients receiving
weekly dosing of paclitaxel compared to every 3-week (40%
vs. 28%, p= .017) and median time to progression (9 mo vs 5
mo). However, care should be taken in watching for
progression of side effects, especially neuropathy.
In addition to the use of taxanes and anthracyclines, a variety
of other chemotherapeutic agents can be used as a single
agent or in combination with taxanes. Capecitabine (Xeloda)
is an oral agent that essentially represents a sustained
release formulation of the older antimetabolite, 5-FU and
provides the convenience of self-administration. Drugs like
capecitabine have very little myelosuppression associated
with them, and are often chosen when the patient’s bone
marrow has been damaged by previous therapy or there is a
desire to coadminister a myelosuppressive agent for more
rapid effect. As a single agent, capecitabine has an overall
response rate of 25-30% with minimal toxicity. When
combined with a taxane, the overall response rate of 40-50%
has been observed along with a median overall survival
benefit of 3-15 months.
Another antimetabolite, gemcitabine (Gemzar), is typically
given in combination with paclitaxel-based results from a
phase III trial comparing paclitaxel to the combination
regimen in locally advanced and metastatic breast cancer
patients. A total of 529 patients were randomized to receive
either paclitaxel 175 mg/m2 on day 1 plus gemcitabine 1250
mg/m2 on days 1 and 8 or the same dose of paclitaxel alone
every 3 weeks. Overall response rate (41% vs 26%, p= .0002)
and overall survival (18.6 mo vs 15.8 mo; HR 0.82, p= .0489)
were significantly improved in the paclitaxel/gemcitabine
In the metastatic setting, a pivotal phase III trial compared
first line chemotherapy (doxorubicin/epirubicin and
cyclophosphamide or paclitaxel) plus trastuzumab versus
chemotherapy alone in HER2+ patients. Trastuzumab plus
chemotherapy was associated with a significant
improvement in time to disease progression (7.4 months vs.
4.6 months), RR (50% vs. 32%), and 1-year survival (25.1
months vs. 20.3 months) compared to chemotherapy alone.
Additionally, there is evidence suggesting that "up front" use
of trastuzumab with chemotherapy, in women with advanced
HER2+ breast cancer, prolongs life compared to sequential
administration, with trastuzumab reserved for the time of
disease progression on an initial chemotherapy regimen.
Based on these results, the US Food and Drug Administration
approved trastuzumab for first line therapy in HER2+
metastatatic breast cancer. However, the question of optimal
duration of trastuzumab therapy remains unresolved.
Clinical evidence to support continued trastuzumab
treatment after initial progression has emerged.
Retrospective studies have described a response to
trastuzumab in multiple lines of therapy, and patients treated
with > 2 trastuzumab-containing regimens appear to have
advantageous OS and TTP outcomes. Recently, a prospective
randomized study of 112 patients with HER2+ metastatic
breast cancer initially progressing on a trastuzumab-based
therapy (GBG-26/BIG 3-05 study) reported that
trastuzumab/capecitabine resulted in a longer PFS (8.2
months vs 5.6 months) and OS (25.5 months vs 20.4 months)
when compare to the capcitabine-only arm. Overall response
rates were also significantly improved in the combination
arm vs the capecitabine alone (48.1% vs 27%, p= 0.0115).
Larger trials are currently ongoing to assess the activity of
trastuzumab
in
multiple
lines
of
treatment.
Treatment
of
HER2+
Metastatic
Breast
Cancer
Another agent used in the treatment of HER2+ metastatic
breast cancer is lapatinib. Lapatinib, a tyrosine kinase
inhibitor (TKI), was approved in 2007 for the treatment of
metastatic breast cancer in HER2+ patients after progression
on trastuzumab. This small molecule is known to block
multiple epithelial growth factor receptors, EGFR (HER-1) and
HER2, and is generally well tolerated with diarrhea, skin rash,
fatigue and nausea as the main toxicities. An analysis of
cardiac toxicity found that 1.7% of patients exposed to
lapatinib experienced a decline in LVEF with 0.2% being
symptomatic, lower than the comparable incidence observed
with trastuzumab. Preclinical data have indicated synergistic
activity between lapatinib and trastuzumab leading to a
randomized study of this combination. A phase III trial
involving 296 heavily pretreated, trastuzumab-refractory
MBC patients randomized to treatment with lapatinib alone
or lapatinib with trastuzumab was recently reported.
Combination therapysignificantlyimproved progression free
survival (PFS) (8.4 wks vs. 12 wks) compared to lapatinib
alone, with a non-significant trend toward improved median
OS. Diarrhea and rash were the most common side effects.
An asymptomatic decline in LVEF was seen in 5% of patients
in the combination arm compared to 2% in the lapatinib
alone
arm.
Antiangiogenic
Therapy
in
Breast
Cancer
Angiogenesis is recognized as a key process in the
progression and metastasis of breast cancer. Bevacizumab
(Avastin) is a humanized mAb directed against VEGF, which
exerts an independent effect on the process of new blood
vessel formation in tumors (angiogenesis). Bevacizumab has
recently been FDA-approved for first-line therapy of HER2metastatic breast cancer patients based on results from the
phase III Eastern Cooperative Trial (ECOG) 2100 trial. In this
trial, the addition of bevacizumab to paclitaxel as first-line
therapy for 347 evaluable patients prolonged progressionfree survival (11.8 mo vs 5.9 mo; p <.001) and increased
objective response rates (36.9% vs 21.2%; p <.001). However,
median overall survival was not significantly changed.
The AVADO study (Avastin and Docetaxel in Metastatic
Breast Cancer) randomized 736 HER2-negative locally
advanced breast cancer patients to receive docetaxel alone
vs docetaxel plus bevacizumab at 7.5 mg/kg or 15 mg/kg
every 3 weeks. At a median follow-up of 10.2 months,
median progression-free survival was statistically improved in
the bevacizumab arms compared to docetaxel alone (8.0 mo
vs 8.7 mo vs 8.8 mo, respectively). One explanation for the
dramatically different degree of improvement in progressionfree survival observed between the control and bevacizumab
containing arms in the E2100 study compared to the AVADO
study (5.9 mo vs 0.8 mo) may be the metronomic dosing of
paclitaxel used in E2100, which may on its own yield
antiangiogenic
effects.
Although the biology behind this remains elusive, the
increased use of adjuvant taxane therapy in patients treated
in the US-sponsored E2100 trial compared to the Europeanled AVADO trial might have contributed to the differences
observed. The most common grade 3/4 adverse events
consisted of sensory neuropathy (23.5%) and hypertension
(15%) in the E2100 study and febrile neutropenia (17%) and
diarrhea
(7%)
in
the
AVADO
study.
Results from a phase II trial XCALIBr (Xeloda in Combination
With Avastin as First-Line Treatment for HER2-Negative
Metastatic Breast Cancer) also demonstrated modest benefit
with the addition of bevacizumab to chemotherapy. An
interim
analysis
of
106
patients
found
capecitabine/bevacizumab to be tolerable and active with an
overall response rate of 38%. After 12.9 months of follow-up,
progression-free survival was a disappointing 5.7 months.
The North Central Cancer Treatment Group (NCCTG) N0432
phase
II
trial
examined
the
docetaxel/capecitabine/bevacizumab as first-line therapy in
45 metastatic breast cancer patients. The 6-month
progression-free survival and overall survival rates were 77%
and 96%, respectively. This regimen, however, had high rates
of grade 3/4 neutropenia (77%). These studies suggest that
achieving maximal efficacy with targeted therapies may be
dependent on appropriately selecting chemotherapy
combinations. Currently larger phase III trials evaluating the
benefit of bevacizumab with any chemotherapy regimen in
first- and second-line therapy of metastatic breast cancer are
ongoing (RIBBON I and II). Because of the promising results
seen in advanced breast cancer, bevacizumab is being added
to adjuvant chemotherapy regimens in patients with
resected, high-risk breast cancer (BETH trial).
Adjunctive Bisphosphonate Therapy in Metastatic Breast
Cancer
Another class of targeted systemic therapy, which is
complimentary to both chemotherapy and hormone therapy,
involves agents that lessen the damage to bone from
metastatic disease. Because of the propensity of breast
cancer to metastasize to the bone, these agents are of
particular importance. One class of agents are the
bisphosphonates (eg, zoledronate, Zometa), which act by
inhibiting osteoclast function and thereby reducing the
resorption of bone, critical to progression of disease within
the cortex. Controlled trials have shown that administration
of a bisphosphonate is associated with a delay in the
development of new skeletal related events, thus reducing or
delaying the need for palliative radiation, orthopedic surgery
to address pathologic fractures, and use of narcotic
analgesics.
In the setting of metastatic disease, bisphosphonates have
little or no survival effect. However, IV bisphosphonates do
appear to provide a continuous effect on bone for the
duration of their use, and for this reason, monthly
administration continues for an indefinite period in breast
cancer
patients
with
bone
metastasis.
A recent study examined the potential role of
bisphosphonates in cancer treatment-induced bone loss and
found that aromatase inhibitors or androgen deprivation can
be risk factors for osteopenia, osteoporosis, and bone
fracture, and that this can be mitigated with appropriate
bisphosphonate therapy.41
The addition of zoledronate to hormonal therapy in the
adjuvant breast cancer setting, however, was recently found
to decrease disease-free survival by 36%. A larger,
randomized phase III (SWOG 0307) trial is currently ongoing
to evaluate further the importance of other bisphosphonates
including zoledronate in the treatment of early stage breast
cancer.
Side effects in general for bisphosphonates include bone,
joint or muscle pain, nausea, vomiting, and diarrhea. Oral
bisphosphonates have a higher risk of heartburn and
esophagitis compared to their intravenously administered
counterparts. Increasingly recognized is the side effect of
osteonecrosis of the jaw (ONJ), a particularly difficult and
unpleasant complication, with an incidence of 3% in
bisphosphonate-treated breast cancer patients. Patients with
underlying oral pathology such as prior radiation to the area,
need for invasive oral procedures, and poor dental hygiene
are
at
a
higher
risk
of
developing
ONJ.
Monitoring
Recommendations for monitoring disease response in the
metastatic setting vary. In general, monthly evaluations
consisting of a history and physical examination to evaluate
progression of disease and toxicities are reasonable. Tumor
markers, such as carcinoembrionic antigen (CEA), CA15.3,
and CA27.29, can be used in conjunction with diagnostic
imaging, history, and physical examination for monitoring
while on active therapy. CA15.3 and CA27.29 correlate with
the course of disease in 60-70% of patients while CEA levels
correlate in 40% of patients. However, data are insufficient to
recommend the use of CEA, CA15.3, or CA27.29 alone for
monitoring response to treatment. Caution should be used
when interpreting a rising CEA, CA15.3, or CA27.29 levels
during the first 4-6 weeks of a new therapy, since spurious
early rises may occur.
Standardized guidelines for imaging are not yet established
and should be tailored to each patient. In general, CT scans
(chest, abdomen, and pelvis), MRI, bone scan, or PET/CT are
performed when symptoms change or tumor markers rise.
Circulating tumor cells (CTCs)
Circulating tumor cells are cells present in the blood that
possess antigenic or genetic characteristics similar to a
primary tumor type. The Food and Drug Administration (FDA)
has recently approved the CellSearch System (Veridex;
Warren, NJ) for the detection of circulating tumor cells in
patients with metastatic breast cancer. This system captures
circulating tumor cells using an immunomagnetic process
with an epithelial cell adhesion molecule coated with
magnetic beads and cytokeratin antibodies. A circulating
tumor cell is identified when it is cytokeratin and DAPI
positive but CD45 negative. Studies done by Cristofanilli et al
using the CellSearch System have shown a prognostic utility
and predictive use for circulating tumor cells in metastatic
breast cancer patients.42 Circulating tumor cell-positive
patients (>5 CTCs/7.5 mL blood) were shown to have a worse
progression-free survival and overall survival than the
circulating tumor cell-negative patients (17% vs 36%,
respectively).
The presence of more than 5 circulating tumor cells prior to
hormonal or chemotherapy treatment and following the first
cycle of treatment also predict a worse outcome. However,
the studies to date have small sample sizes and no data
support the use of circulating tumor cell testing effects
overall survival or improves on quality of life. Per ASCO
guidelines, the use of circulating tumor cells in breast cancer
is not recommended for the diagnosis of breast cancer or
influencing treatment decisions. Currently, SWOG is
conducting a large prospective trial to address the clinical use
of circulating tumor cells in breast cancer.
Surgery in Metastatic Breast Cancer Treatment
As modern systemic chemotherapy has become more
effective, some metastatic patients with intact primary
tumors can have long-term stable distant disease or even no
evidence of residual metastatic disease following treatment.
Recently, interest has increased in the role of surgical
intervention for the intact primary tumor for these
metastatic breast cancer patients. Several single-institution
cohort, and retrospective studies have examined this
question, concluding that there may be a survival advantage
in undergoing surgical resection of the intact primary tumor.
Currently, it is unknown if a selection bias impacts these
findings of a survival advantage in favor of surgery and a
prospective randomized control trial has never been
performed addressing this question. However, the dogma
never to operate in the setting of metastatic disease certainly
has been dispelled in favor of critical evaluation of whether
surgically achieved local control can lead to improved survival
as a part of multimodal treatment.
Advances in targeted therapy
The first success in targeted therapy of any cancer was first
described in 1896 by Thomas Beatson when he performed a
bilateral oophorectomy for treatment of premenopausal
breast cancer. Since that time, the molecular era in cancer
therapy has flourished and our knowledge of cancer biology
has expanded. As increased numbers of targeted therapies
show promise for the treatment of breast cancer, the goal is
to best optimize these expensive and toxic therapies with
existing anticancer approaches.
Novel HER/ErbB Receptors Agents
Only one in 3 HER2-positive metastatic breast cancer patients
respond to single-agent trastuzumab and most, if not all,
eventually develop resistance. To overcome resistance,
trastuzumab has been modified using a covalent linker to
attach DM1, a derivative of the microtubule destabilizer
maytansine. By exploiting trastuzumab to target the cytotoxic
activity of DM1 to HER2 overexpressing cells, trastuzumabDM1 (TDM-1) offers a novel mechanism for overcoming
trastuzumab resistance. A phase I trial of every-3-week
trastuzumab-DM1 demonstrated a clinical benefit rate of
53% in metastatic breast cancer patients that had progressed
on prior trastuzumab. Additionally, preliminary results from a
phase II trial of TDM-1 reported an overall response rate of
43%. The most common adverse event was transient
thrombocytopenia with no cardiac toxicity observed.
Pertuzumab, a humanized mAb that blocks the activation of
the HER2 receptor by hindering dimerization, is under
investigation and have yielded promising early results in
patients who have progressed on trastuzumab containing
regimens. Two phase II trials involving trastuzumabrefractory, HER2+ metastatic breast cancer have
demonstrated an overall response rate of 18-24% and clinical
benefit of 45-50% when trastuzumab is combined with
pertuzumab. This combination is now moving into phase III
trials including CLEOPATRA (Clinical Evaluation of
Pertuzumab and Trastuzumab) trial, which will compare firstline
trastuzumab/docetaxel/placebo
to
trastuzumab/docetaxel/pertuzumab in HER2+ metastatic
breast cancer.
Neratinib (HKI-272) is an oral irreversible tyrosine kinase
inhibitor of HER2 and EGFR. Preliminary phase I data from 23
HER2+ or EGFR+ advanced breast cancer patients
demonstrated antitumor activity in 7 patients. A phase II
open label study in locally advanced breast cancer showed a
16-week progression-free survival rate of 75% in 36
trastuzumab-naïve patients and 51% in previously treated
disease. Several ongoing phase I/II trials are investigating this
tyrosine kinase inhibitor (TKI) combination with trastuzumab,
paclitaxel, or vinorelbine in patients with trastuzumabrefractory breast cancer. Other EGFR tyrosine kinase
inhibitors such as gefitinib and erlotinib have been studied in
combination with trastuzumab and endocrine therapy with
disappointing results.
Novel Antiangiogenic Agents
Small molecule VEGFR tyrosine kinase inhibitors offer several
potential advantages over antibody therapies including oral
administration, a shorter half life, and multi-targeted effects.
An open label, multicenter phase II study evaluated sunitinib,
an oral multi-targeted kinase inhibitor of VEGFR, and
platelet-derived growth factor receptor, as monotherapy in
64 metastatic breast cancer patients previously treated with
an anthracycline and taxane. Median time to progression and
overall survival were 10 and 38 weeks, respectively, with the
best responses observed in triple-negative and HER2+
disease. Most adverse events were grade 1/2 fatigue,
nausea, and diarrhea, but 56% of patients required dose
reductions.
Sunitinib has also demonstrated activity in combination with
paclitaxel and sequentially with docetaxel as first-line therapy
in metastatic breast cancer with overall response rate of 33%
and 72%, respectively. Axitinib, another oral tyrosine kinase
inhibitors of VEGFRs, showed promising antitumor activity in
combination with docetaxel in a randomized phase II trial of
first-line chemotherapy in 168 patients with locally
recurrent/metastatic breast cancer. The overall response rate
was 40% in the axitinib/docetaxel arm versus 23% in the
docetaxel alone arm, similar to the results from E2100. The
most common adverse events included diarrhea (60%),
nausea (53%), fatigue (49%), and stomatitis (44%) with an
increase in febrile neutropenia with the combination arm
(16%). Other VEGFR tyrosine kinase inhibitors such as
pazopanib, vatalanib, cediranib, and motesanib are under
investigation.
Dual Blockade by Antiangiogenic/HER2 Agents
HER2 targeted therapies have been investigated in
combination with angiogenesis inhibitors with promising
results. HER2 overexpression is associated with an increase in
VEGF levels in primary breast cancers. Combination therapy
targeting HER2, EGFR, and VEGF pathways produces greater
inhibition of human breast cancer cell lines than inhibition of
any single or dual pathway.
The role of HER2 and VEGFR cross-talk has been explored in a
phase II trial combining trastuzumab and bevacizumab in
patients with HER2+ metastatic breast cancer. In 37
evaluable patients, the overall response rate was 54.1% with
a 16% incidence in LVEF decline. Additionally, early data from
a 50-patient single-arm study evaluating lapatinib with
bevacizumab in heavily pretreated HER2+ metastatic breast
cancer patients showed signs of clinical activity with a 12week progression-free survival rate of 62% and negligible
evidence for cardiac toxicity.
Another angiogenesis inhibitor, pazopanib, was investigated
in a randomized phase II study in combination with lapatinib
versus lapatinib alone in chemotherapy-naïve, HER2+
metastatic breast cancer. A 45% response rate was observed
in the combination arm compared to 28% in the lapatinib
alone arm at 12 weeks. Adverse events included diarrhea,
rash, nausea, and elevated liver function tests, with only 5%
experiencing cardiac toxicity in the combination arm.
Additional trials of lapatinib in combination with endocrine
therapy or other targeted agents are ongoing.
Insulin Growth Factor-1 Receptor Inhibitors
Insulin-like growth factor-1 receptor (IGF-1R) overexpression
is associated with the development of breast cancer and
correlates with disease-free survival in patients with primary
breast cancer. IGF-1R-mediated growth and anti-apoptotic
signaling occurs through the phosphatidylinositol 3-kinase
(PI3K)/Akt and mitogen-activated protein kinase (MAPK)
pathways.
To date, drug development targeting the IGF pathway has
focused on IGF-1R mAbs. Studies have shown that these
compounds yield antitumor activity in several breast cancer
models in vitro and in vivo. Breast cancer cell lines with IGF1R overexpression appear to be more resistant to
trastuzumab and ER-targeted therapies, thus clinical trials are
focusing on hormone-refractory and/or HER+ disease. This
strategy of dual targeting is being employed in an ongoing
phase II trial of CP-751,871, a mAb targeting IGF-1R, in
combination with the aromatase inhibitor, Exemestane
compared to Exemestane alone in postmenopausal patients
with hormone receptor-positive advanced breast cancer.
PI3K/AKT/Mammalian Target of Rapamycin (mTor)
Inhibitors
Among signaling pathways, the PI3K/Akt/mammalian target
of rapamycin (mTor) pathway is thought to be highly active in
human breast cancer development and progression. In breast
cancer, this pathway can be activated through PI3K by
membrane protein receptors including the ErbB/HER family
of growth factor receptors, IGF-1R and ER. PI3K activates
downstream Akt, leading to mTor phosphorylation, and
promotion of breast cancer cell survival as well as resistance
to chemotherapy and targeted agents, such as trastuzumab,
and tamoxifen.
Constitutively active mutations of PI3K have been described
in up to 40% of primary breast cancer tumors, implicating a
role for PI3K in breast cancer tumorigenesis. SF1126 is a
chemical conjugate of LY294002, the most studied of the
PI3K inhibitors. This compound has a broad spectrum of
inhibition via Akt and mTor resulting in antitumor and
antiangiogenic activity. The water-soluble SF1126 has a good
pharmacokinetic profile and is well tolerated in murine
systems. Phase I trials are ongoing with this compound and
other novel PI3K inhibitors.
In preclinical breast cancer models, mTor inhibitors
substantially inhibit tumor growth. In 109 heavily pretreated
locally advanced or metastatic breast cancer patients, singleagent activity of the mTor inhibitor, temsirolimus, yielded an
objective response rate of 9%, consisting of 10 partial
responses. Based on preclinical data showing a synergistic
effect between mTor inhibitors and endocrine therapy,
clinical trials have focused on combination therapy. Initial
randomized trials investigating letrozole alone or in
combination with temsirolimus showed no significant clinical
benefit in locally advanced/metastatic breast cancer.
However, a phase I study of letrozole in combination with
daily everolimus (RAD001), another selective mTor inhibitor
with a good safety profile, proved promising with one
complete response and one partial response in 18 patients
with advanced breast cancer. The most common adverse
events included stomatitis (50%), fatigue (44.4%), and
diarrhea (38.9%).
In a recent study by Baselga et al (2009), the addition of
everolimus (10 mg/d) significantly increased letrozole (2.5
mg/d) efficacy (antiproliferative response defined by
reduction of Ki67 expression) compared to letrozole and
placebo (P<0.01). The study included 270 postmenopausal
women with operable ER-positive breast cancer. Biopsies
were obtained at baseline and after 2 weeks of treatment. 43
HSP90 Inhibitors
Heat shock protein 90 (HSP 90) is a molecular chaperone
required for the stability and function of several expressed
and/or activated signaling proteins. By directly inhibiting
HSP90, inactivation, destabilization, and degradation of
numerous chaperone-dependent client proteins occur
resulting in antitumor activity, antiangiogenesis and
apoptosis in cancer cells. A preclinical study reported HER2 is
particularly susceptible to degradation when exposed to the
HSP90
inhibitor,
tanespimycin
(KOS-953).
A phase I study of trastuzumab/tanespimycin in 25 patients
with advanced solid tumors yielded a response in 5 patients
with HER2+ metastatic breast cancer. Furthermore, recently
reported phase II results on trastuzumab/tanespimycin in
trastuzumab-refractory metastatic breast cancer patients
showed an overall response rate of 26% with a clinical
benefit rate of 63%. Drug-related toxicities included fatigue,
diarrhea, dizziness, and headache. Grade 3/4 fatigue,
elevated AST, and headache were observed in 2 patients
each.
PARP Inhibitors
Polyadenosine diphosphate ribose polymerase (ADP)
polymerase (PARP) inhibitors were initially developed to
investigate the role of PARP-1, a nuclear enzyme involved in
DNA repair. However, these agents have also proven to have
antitumor activity in breast cancer cells. BRCA1 and BRCA2 deficient cell lines are defective in homologous
recombination, thus relying on PARP-1 for DNA
repair. BRCA –deficient cells treated with PARP inhibitors
demonstrate an increase in DNA fragmentation and cell
death.
A phase IB study showed BS-201, a PARP inhibitor, was well
tolerated in combination with several chemotherapeutic
agents in patients with advanced solid tumors. Thus, PARP
inhibitors may have the potential to improve the efficacy of
commonly used chemotherapeutics without adding
significant toxicities. Trials of PARP inhibitors in breast cancer
patients are ongoing, including a phase II study of
chemotherapy with or without BSI-201 in patients with triplenegative metastatic breast cancer. The PARP inhibitors
AGO14699 and AZD2281 are also under investigation in
phase I and II trials in patients with advanced breast cancer.
Results with BSI-201 were presented at the American Society
of Clinical Oncology 45th Annual Meeting in 2009. In
combination with conventional chemotherapy, a phase II
study found that with BSI-201, women with metastatic triplenegative breast cancer had significant improvement in overall
and progression-free survival compared with chemotherapy
alone.44,45
Farnesyltransferase Inhibitors
The Ras oncogene family is a key component of the MAPK
signaling pathway, which promotes mitogenic activity.
AberrantRas expression resulting in downstream signaling
has been reported in breast cancer, although Ras mutations
are rare in this malignancy. Farnesyltransferase inhibitors
(FTIs) such as tipifarnib and lonafarnib were developed to
block farnesylation and subsequent membrane localization
of Ras. Initially, early clinical data suggested FTIs may
modulate endocrine response. However, a phase II
randomized clinical trial of letrozole with or without tipifarnib
in advanced breast cancer failed to meet its primary
endpoint. Recently, a phase II trial showed an overall clinical
benefit of 24% in ER- or hormone-refractory breast cancer
patients treated with tipifarnib sparking renewed interest in
these agents. HER-2+ tumors derived the most clinical benefit
from the addition of FTIs suggesting HER2 is upstream of Ras.
Src Kinase Inhibitors
Dasatinib is a novel oral kinase inhibitor that targets the Src
family kinases and BCR-abl. Currently, dasatinib is approved
by the FDA in the treatment of chronic myelogenous
leukemia (CML). A preclinical study revealed a dasatinibsensitive signature in the basal breast cancer subtype.
Additionally, preliminary results from a phase I study of
gemcitabine/dasatinib demonstrated antitumor activity in a
patient with inflammatory breast cancer. Phase I and II
clinical studies of dasatinib as a single agent or in
combination with capecitabine in various breast cancer
subtypes are underway. The combination of dasatinib and AIs
are also underway in hormone receptor positive metastatic
breast cancer.
Future and Controversies
The future of breast cancer therapy is promising, as targeted
therapies focus on regulating pathways necessary for tumor
growth and metastases. However, we are still in the early
stages of learning how best to use these agents and what
patient subsets will benefit most. Unexpected and novel
toxicities have been frequently observed with targeted
agents and are likely to be seen in the future. Thus, carefully
designed and monitored trials are necessary, not only to
document efficacy, but also to document unusual toxicities.
To date, no single targeted agent can successfully cure
metastatic breast cancer. Thus, the paradigm has been to
test targeted agents in combination with chemotherapy or
hormonal therapy to identify regimens with superior clinical
benefit. It is only by better understanding the molecular
mechanisms of breast cancer growth and progression, that
curative and cost effective combinations of antitumor
therapies, whether targeted, chemotherapy, or hormonal
therapy, will be determined and tailored to the individual
needs of each breast cancer patient.