Những Nguyên Tắc Thiết Yếu Trong Phẫu Thuật Tuyến Vú (Essentials of Breast Surgery)

Upper Extremity Lymphedema—Com-
bining regional radiation therapy with
axillary surgery will increase the risk of
lymphedema; however, this will depend
on the extent of both. Full axillary radia-
tion after a complete axillary dissection
will result in the highest risk of lymph-
edema and should be discouraged. When
patients
undergo
breast
surgery
along
with an ALND without radiation, they
have a 2% to 10% rate of moderate to
severe arm edema. When radiation ther-
apy is added, just to the breast, the rate
increases to 4% to 13% of patients. This
number jumps to 25% to 30% with nodal
irradiation. The incidence also increases
with
obesity
and
chemotherapy.
It
is
important to note that patients who had
an SLN biopsy also have a risk of lymph-
edema, between 5% and 7%.
Brachial Plexopathy—Permanent plexo-
pathy is primarily seen in women who
receive regional nodal radiation. Women
will present with the new onset of numb-
ness, pain, or weakness in the affected
arm. Most women will have complete
resolution of their symptoms by 1 to
2 years; however, 0.25% will have perma-
nent brachial plexopathy.
Pneumonitis—Approximately 1% to 5%
of women receiving breast or chest wall
radiation will have transient lung inflam-
mation and symptomatic pneumonitis.
The risk will increase with increasing lung
volume in the tangent fields. Increased
lung irradiation (and an increased risk of
pneumonitis) will occur when fields are
extended to include the supraclavicular,
axillary, and internal mammary lymph
nodes. In addition, concurrent chemo-
therapy will increase the risk of pneumo-
nitis.
The
incidence
of
radiation
pneumonitis will increase to 8% to 20%
for women receiving nodal radiation and
adjuvant chemotherapy. Women typically
present with cough, low-grade fever, and
dyspnea beginning about 2 to 3 months
after radiation and persisting for several
weeks. In most women these symptoms
will be self-limiting, although in rare cases
steroids may be necessary. Chest x-ray will
show changes confined to the radiation
therapy field. Pulmonary fibrosis typically
follows in the affected portion.
Rib fracture—Rib fracture is rare after
standard
radiation.
The
incidence
is
approximately 1%, and most rib fractures
are seen about 1 year after radiation. Treat-
ment is simple, primarily supportive until
healing is completed, however, it is impor-
tant to differentiate between a rib fracture
and a bone metastasis. In patients with
preexisting collagen vascular disease, they
may develop severe soft tissue ulcera-
tion or bone necrosis, and this is one rea-
son why this is a contraindication to
radiation.
Cardiovascular morbidity—The risk of
late cardiovascular events is dependent on
tumor location, technique, and dose. The
excess mortality observed in early trials of
radiation therapy was largely the result
of cardiovascular toxicity; however, more
modern techniques have minimized this
effect. Women with left-sided breast can-
cers are at increased risk as they have more
myocardium included in the treatment
field.
Secondary malignancies—Potential treat-
ment-induced secondary malignancies fol-
lowing
locoregional
radiation
include
contralateral breast cancers, sarcomas, lung
cancers, and leukemias, all of which are
rare.
Sarcoma—Angiosarcoma, a relatively rare
tumor, can occur in the breast or chest
wall after irradiation. These tumors usu-
ally present as multiple reddish, bluish,
and purple nodules or areas of skin discol-
oration (see Chapter 23).
Lung cancer—Radiation therapy for breast
cancer has been described as a risk factor
for the development of lung cancer, with
relative risks between two and three. This
is dependent on the volume of lung in
the
irradiated
field.
This
risk
is
also
increased by smoking, so women under-
going
breast
or
chest
wall
irradiation
should be strongly encouraged to quit
smoking.
Acute leukemia—In women undergoing
chest wall radiation therapy, the risk of
acute nonlymphocytic leukemias (ANLL)
appears to be increased. This is related to
the volume of bone marrow in the field,
the total radiation therapy dose, and the
concomitant
use
of
chemotherapy.
Though increased compared to controls,
the absolute risk is quite low, especially
with limited bone marrow in the radiation
therapy field.
Contralateral
breast
cancer—Limited
data suggest a slight excess of contralateral
breast cancers following breast or chest
241
15—PRINCIPLES OF RADIATION THERAPY FOR PRIMARY BREAST CANCER

wall radiation therapy. The risk may be
higher with younger age at treatment.
Although the risk of radiation-associated
contralateral breast cancer is extremely
low, measures to reduce scatter to the
opposite breast are encouraged.
Finally, there is clearly an impact of both
radiation therapy and surgery on cosmetic out-
come. Although cosmesis takes a backseat to
oncologic principles and patient safety, clearly
it cannot be completely overlooked as the
driving force for breast conservation therapy
is in part cosmetic. Overall, the overwhelming
majority of patients and their doctors rate the
cosmetic
outcome
as
good
to
excellent,
although both groups are slightly biased. How-
ever, there are several factors that will impact
the cosmetic outcome.
Most factors contributing to cosmetic out-
come are predetermined and include the size
of the tumor, the location of the tumor and
the preoperative breast size. Tumors in the
upper inner quadrant will leave more notice-
able defects than the upper outer quadrant,
where there is more tissue. The use of chemo-
therapy and the dose and treatment plan of
the radiation therapy will also impact cosm-
esis, but these are driven by oncologic princi-
ples. Other factors, such as the amount of
tissue that must be removed to achieve nega-
tive margins, the size of the scar, and the
location of the scar are controllable by the sur-
geon, but not at the cost of inadequate sur-
gery. It is believed that the higher local
recurrence rate seen among younger women
is not the result of biology but rather surgeons
compromising their oncologic operation in
the name of cosmetic outcome. The surgeon
has some maneuverability as to where the inci-
sion is placed, but excessive tunneling to
remove
a
cancer
is
discouraged,
and
the
trade-off for scar location is the excess tissue
that needs to be removed. If possible, incisions
in the cleavage line should be avoided. Exces-
sively large lumpectomies or quadrantectomies
will compromise cosmetic outcome and are not
necessary for most tumors. Lesions inferior to
the nipple-areolar complex can cause disparity
between the two breasts and lead to excessive
downturning of the nipple. Radial incisions
may help avoid this. Other oncoplastic tech-
niques can further optimize the cosmetic out-
come after radiation therapy (Chapter 14).
Finally placing radio opaque clips will help the
radiation oncologist accurately plan the boost,
minimizing its amount.
Partial Breast Irradiation
Although whole breast irradiation after lumpec-
tomy has well-documented, excellent results, it
can often add additional inconvenience and
cost to both the patient and the health care
system. Not every patient lives in close proxim-
ity to a radiation oncology center, so the time
and travel involved in coming every Monday
through Friday for 5 to 6 weeks can be over-
whelming for some women. For this reason,
some women who are candidates for BCT may
opt for mastectomy to avoid not only the
inconvenience, but also the toxicity of whole-
breast irradiation. This has fueled significant
interest in methods to decrease the time needed
for treatment. One such approach is the use of
more rapid fractionation schedules. A rando-
mized trial from Canada demonstrated that a
shorter schedule, in this case 42.5 Gy over 22
days, was equivalent to the standard 45 to
50 Gy over 35 days. But more significant
changes in the radiation component of breast
conservation may be around the corner.
The argument for using whole-breast irradia-
tion after lumpectomy is based on pathologic
studies of mastectomy specimens showing
tumor cells located 2 to 3 cm away from the
primary tumor. However, clinical observa-
tions demonstrate that the overwhelming
majority of local recurrences occur close to
the site of the tumor bed. This is the reason
that many radiation oncologists recommend
a boost to the tumor bed to follow whole-
breast irradiation, but it raises the question
as to whether radiation of the entire breast is
necessary. It is feasible that patients may
receive the same benefit from irradiating only
the tumor bed, sparing the remainder of the
breast. This may not only improve the cos-
metic outcome, but also would shorten the
costs associated with treatment and the time
necessary to complete therapy. Several tech-
niques for delivering accelerated partial breast
irradiation (APBI) have been evaluated in
appropriately selected patients (Table 15–2,
Box 15–3).
Interstitial Brachytherapy
The concept of irradiating only the region of
the breast near the tumor is not new. Multi-
catheter, interstitial brachytherapy has been
around for some time. This involves the place-
ment of multiple hollow catheters within the
breast tissue around the lumpectomy cavity.
242
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

A radioactive source is then placed within the
catheters. It is somewhat ironic that the first
use
of
radiation
to
avoid
mastectomy,
by English surgeon Keynes in the 1920s, used
interstitial radium needles to treat the pri-
mary tumor, with or without surgery, so APBI
is not so much a new approach as much as
the field of breast radiation oncology coming
full circle.
There are two approaches for delivering the
radiation, which is typically done by automated
technology to limit the potential radiation
exposure of health care providers. Low-dose
rate (LDR) brachytherapy involves a continu-
ous exposure to a low dose of radiation (45 to
50 Gy at a rate of about 30 to 70 cGy/h). This
typically takes 96 hours, so one drawback to
LDR brachytherapy is that this requires admis-
sion to hospital rooms specifically designed
to shield radiation. The other approach is
high-dose rate (HDR) brachytherapy. A total
dose of 34 Gy is delivered in twice daily
fractions of 3.4 Gy. This can be performed on
an outpatient basis and can be completed
over 5 days.
Balloon-Catheter Brachytherapy
A significant drawback to interstitial brachy-
therapy is the complexity of placing the 10 to
25 catheters. In addition, many patients are dis-
suaded away from multi-catheter brachyther-
apy when they see pictures of patients with
the multiple catheters in place, which can be
quite intimidating. This has limited the use of
brachytherapy and generated interest in alter-
nate methods for delivering radiation directly
to within the lumpectomy cavity. The Mammo-
Site (MammoSite RTS; Proxima Therapeutics,
Alpharetta, GA) is a balloon catheter device that
greatly simplifies brachytherapy. A catheter sits
centrally in a distally located balloon, resem-
bling a Foley catheter. This is placed in the
lumpectomy cavity, either at the time of surgery
or as a second procedure, and inflated. This
catheter is pliable so it can easily be worn within
a bra. Treatment is then delivered with a single,
centralized HDR.
The MammoSite does have some drawbacks.
An adequate distance between the lumpec-
tomy cavity and the skin is needed or skin
injury can result. It is also possible that a large
(50 ml or more) or irregularly shaped lumpec-
tomy cavity can negatively impact the effective-
ness of the MammoSite, limiting the number of
patients who would be ideal candidates. How-
ever, early results with MammoSite, though
highly selective, have been promising.
External Beam Radiation
As opposed to brachytherapy, external beam
radiation can be used to deliver PBI. Recent
TABLE 15–2
Relative Advantages and Disadvantages of Methods to Deliver
Accelerated Partial Breast Irradiation
Advantages
Disadvantages
Multi-catheter interstitial
brachytherapy
Well tolerated
Short treatment time
More clinical experience than other
modalities
Can be used for any size, shape, or
location of cavity
Catheter placement and dosimetry can be
technically complex
May require hospitalization (low-dose rate)
Limited number of clinicians who are
familiar with this technique
Multiple (10 to 25) catheters are disturbing
to patients
Balloon-catheter
brachytherapy
Technically simple
Well tolerated by patients
Limited by shape of lumpectomy and
distance to skin
External beam radiation
Uses technology most facilities
already have
May need to radiate larger area than other
methods
Intraoperative radiation
Greatly decreases the time needed
for therapy
Requires special equipment in the operating
room
Skin and chest wall complications
BOX 15–3 CRITERIA OFTEN USED
TO SELECT PATIENTS FOR PARTIAL
BREAST IRRADIATION
Patient age
>45
Tumor size
<2.0 cm
Nodal status
Node negative
Distance from cavity to skin
>5 to 7 mm
243
15—PRINCIPLES OF RADIATION THERAPY FOR PRIMARY BREAST CANCER

technologic advances in CT-based planning
have allowed the introduction of three-dimen-
sional conformal external beam APBI. This
allows for improved dose homogeneity within
the target volume and does not require addi-
tional technology beyond what most radiation
facilities already have. One disadvantage is
that a larger area of normal breast tissue may
need to be irradiated than with other PBI tech-
niques because the breast is a moving target.
One way to improve on this is the use of
intensity-modulated radiation therapy (IMRT),
which delivers radiation using a variable-
intensity pattern that is determined with the
aid of a computerized optimization algorithm
(Figure
15–6).
Although
more
costly
and
labor-intensive than three-dimensional con-
formal APBI, IMRT delivers a more uniform
and
standardized
radiation
dose
without
excessive treatment of the surrounding tissue.
Intraoperative Radiation Therapy
The most efficient method of limiting the time
necessary to deliver the radiation is to do so in
the operating room following lumpectomy.
Initially intraoperative radiation therapy (IORT)
was proposed as an adjunct to whole-breast irra-
diation, as a more accurate method of delivering
the boost. More recently, it has been examined
as a sole method of radiation treatment. Several
methods exist for delivering the radiation intrao-
peratively. One method uses a portable, dedi-
cated linear accelerator. After completion of the
lumpectomy, the skin is dissected off of the sur-
rounding breast parenchyma around the cavity,
and the parenchyma is dissected off of the pec-
toralis major muscle. This allows adequate
retraction of the skin and the placement of an
aluminum-lead disk to protect the chest wall.
Once this is completed, 21 Gy are delivered. An
alternative approach uses electrons generated
by a mobile linear accelerator.
All of these technologies seem promising, but
clinical experience is limited and long-term
follow-up
is
not
available
for
the
newer
approaches (see Table 15–2). In addition, these
trials are highly selective, and for the most part,
from single institutions. Participation is lim-
ited to a patient population with an expected
excellent cosmetic outcome and low risk of
recurrence with whole-breast irradiation (older
patients, node-negative, smaller tumors). PBI is
presently being directly compared to whole-
breast irradiation in a randomized trial, which
will hopefully secure the role of PBI in breast
conservation therapy.
Suggested Readings
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randomized trial comparing breast conservation
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the
use
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after
mastectomy
in
breast
cancer.
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2002;7:539–546.
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cancer. N Engl J Med 2002;347(16):1233–1241.
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results of a randomized clinical trial comparing
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ifen with or without breast irradiation in women
50 years of age or older with early breast cancer.
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Figure 15–6. Intensity modulated radiation treat-
ment (IMRT) delivers radiation using a variable-
intensity pattern that is determined with the aid of a
computerized optimization algorithm. IMRT delivers
a more uniform and standardized radiation dose with-
out excessive treatment of the surrounding tissue.
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SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

8. Jacobson JA, Danforth DN, Cowan KH, et al. Ten-
year results of a comparison of conservation with
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segmental mastectomy or segmental mastectomy
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Trial. Cancer 2003;98:697–702.
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radiotherapy: clinical practice guidelines of the
American Society
of
Clinical
Onology.
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Clin
Orthod 2001;19:1539–1569.
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ated partial breast irradiation in early-stage breast
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245
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16
Principles of Adjuvant
Chemotherapy for
Breast Cancer
INTRODUCTION
PRINCIPLES OF ADJUVANT
CHEMOTHERAPY
BENEFITS OF ADJUVANT
CHEMOTHERAPY IN BREAST
CANCER
SELECTION OF PATIENTS FOR
ADJUVANT CHEMOTHERAPY
Consensus Groups
Adjuvant Online
CHEMOTHERAPEUTIC
AGENTS USED IN BREAST
CANCER
Anthracycline-Based Regimens
Taxanes
Herceptin
Dose-Dense Chemotherapy
High-Dose Chemotherapy with
Autologous Stem Cell
Support
SIDE EFFECTS OF
CHEMOTHERAPY
Short-Term Toxicity
Long-Term Effects
ON THE HORIZON
Principles of Adjuvant Chemotherapy for Breast
Cancer: Key Points
Be familiar with the principles of how cytotoxic chemotherapy
kills cancer cells.
Describe the benefits of adjuvant chemotherapy after surgery and the data
from the EBCTCG.
Understand the important factors in determining the benefits of adjuvant
chemotherapy and the present guidelines clinicians use to guide these
decisions.
Know how to use Adjuvant Online to assess the benefit of adjuvant
chemotherapy for the individual patient.
247

Understand the potential benefit and unanswered questions of using
microarray analysis for making decisions regarding adjuvant therapy.
Be familiar with the various agents used in breast cancer chemotherapy and
the possible side effects.
Understand the mechanism of action and potential benefit of Herceptin in
the adjuvant setting.
Appreciate the future potential of targeted therapies in the systemic
treatment of breast cancer.
Introduction
Breast cancer can essentially be thought of as
two simultaneous problems. The first is the
locoregional disease, the known cancer within
the breast and regional lymph nodes. This is
directly addressed through the use of surgery
and radiation therapy. The second disease is
the possible presence of micrometastatic dis-
ease elsewhere in the body. These cells will be
unaffected by local therapies, and so the only
way to eradicate them (and prevent recur-
rence) is through the use of adjuvant systemic
therapies. These two problems are obviously
not mutually exclusive. Systemic therapies will
have an impact not only on distant recur-
rence, but locoregional recurrence as well.
Likewise, adequate local control will help min-
imize the secondary spread of micrometastases
and decrease distant recurrence.
Adjuvant systemic therapy refers to the
administration of chemotherapy or hormonal
therapy following primary surgery for early
stage breast cancer to eliminate or delay the
subsequent appearance of clinically occult
micrometastatic disease. Two observations in
the late 1800s led to the concept of using sys-
temic therapy after surgery. The first was the
realization that even with aggressive surgical
therapy, 20% of patients who were node nega-
tive would recur within 5 years, as would 70%
of patients with positive nodes. The second
was the observation of blood-borne tumor
cells post mortem. These led to the awareness
that the only way to improve the outcome
for patients with breast cancer would be
control of the distant micrometastases with
systemic therapies.
The first adjuvant therapy for breast cancer
was hormonal therapy, which will be dis-
cussed in the next chapter. The first clinical
trial investigating chemotherapy began in
1958 and was conducted by the National Sur-
gical
Adjuvant
Breast
and
Bowel
Project
(NSABP).
Adjuvant chemotherapy trials in the late 1960s
and early 1970s focused on single agents in
patients with axillary nodal metastases. With a
clear demonstration of improved survival, trials
of adjuvant chemotherapy have continued to
try to build on these results, examining combina-
tion chemotherapy, different treatment dura-
tions and schedules, and new agents as they are
discovered. This chapter will focus on the use of
systemic chemotherapy following surgery.
Principles of Adjuvant
Chemotherapy
Chemotherapeutic agents inhibit cell growth
and cause apoptosis through interference with
normal cellular functions, primarily progres-
sion through the cell cycle (Box 16–1). As such,
they tend to be more effective in treating rapidly
dividing cells. A considerably smaller proportion
of cells in a slowly growing tumor are progres-
sing through the cell cycle when chemother-
apy is given. Unfortunately, while aggressive,
BOX 16–1 PRINCIPLES
OF ADJUVANT CHEMOTHERAPY


Chemotherapy kills a constant
fraction of tumor cells (first-order
kinetics) rather than a constant number of
cells (log kill hypothesis). Thus, repetitive
cycles of therapy are necessary.


Combination therapy is superior to
single-agent therapy by overcoming drug
resistance. This will, however, increase
toxicity.


A dose-response effect exists, thus
requiring adequate doses of drug.


Outcome is dependent on the number of
malignant cells present when therapy is
initiated. Even a single metastatic cancer
cell, left alive, can lead to death.
248
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

rapidly growing tumors may have more cells in
the cell cycle, they are also more likely to
acquire resistance to chemotherapy. Chemo-
therapy not only kills cancer cells, but normal
cells progressing through the cell cycle are
susceptible, and this is what leads to the
significant toxicity associated with adjuvant
chemotherapy.
The principles of adjuvant chemotherapy
follow several principles that led to the pres-
ent dosing regimens used. The first is that
chemotherapy works by first-order kinetics.
This means that the drugs kill a fixed fraction
of cells with each cycle and not a fixed num-
ber of cells (referred to as log kill hypothesis).
If the latter were true, then a large enough
single dose could potentially be effective (if
tolerated). However, because the drugs kill
only a fraction of cells, repetitive cycles are
necessary. The effectiveness of adjuvant ther-
apy is therefore related to how efficacious
the drug is (how large is that fraction of cells
killed), how many cells are there to begin
with, how many cycles are used, and how
quickly the remaining cells grow between
cycles.
There are several other barriers to the efficacy
of adjuvant chemotherapy. The first is resis-
tance. Some cancer cells are inherently resistant
to particular agents; others will gain resis-
tance via mutation. To some degree, resistance
is countered through the use of combination
chemotherapy rather than single agents. In gen-
eral, using agents in combination is more effec-
tive and the more common approach when
there is a curative intent, as in the adjuvant
setting. The best combinations include agents
that act synergistically, which are most likely
to occur when they have different mechanisms
of action and resistance. When combining che-
motherapy, however, one must also consider
the potential overlapping side effects to avoid
excessive toxicity.
When discussing adjuvant chemotherapy,
there are several endpoints that are relevant
(Box 16–2). Two of the most important end-
points are disease-free survival (DFS) and over-
all
survival
(OS).
DFS
is
the
time
from
treatment to the first evidence of recurrence
or death, whichever comes first. OS is defined
as the time from treatment to death, regardless
of disease recurrence. Although this is rela-
tively straightforward, there are several points
that bear mentioning. DFS and OS are not
linked to the degree that one might expect.
For a disease where recurrence is strongly
linked to inevitable death, then DFS will
parallel OS. However, if local recurrence is
common, but highly curable, this would trans-
late to a low DFS but high OS. For this reason,
some studies tend to ignore local recurrences
and focus only on distant disease-free survival
(DDFS).
One might also assume that improving DFS
would improve OS, but this is also not neces-
sarily the case. If a new agent decreases recur-
rence,
but
makes
subsequent
recurrences
more aggressive and less susceptible to treat-
ment, then an improvement in DFS might
have no effect on OS. It is for this reason that
some might argue that OS is the only mean-
ingful endpoint. On the other hand, a delay
in recurrence, even in the absence of an OS
benefit, may be of significant benefit to
patients, and justify the use of an adjuvant
therapy.
The benefits of adjuvant chemotherapy are
often described in terms of reductions in the
odds of disease recurrence or death. It is
important to understand the concept of abso-
lute versus proportional reductions when dis-
cussing
the
benefits
of
systemic
therapy.
A proportional reduction of 25% is described
as an odds reduction of 25%, an odds ratio of
0.75, or a hazard ratio of 0.75. But the absolute
benefit of the therapy depends on what the
risk of recurrence or death was without treat-
ment. Therefore, let us say that without adju-
vant therapy, the likelihood of death was
40% (an overall survival of 60%). If you start
with 100 patients, 60 will live regardless of
adjuvant treatment. Of the other 40, a 25%
proportional reduction would mean that 10
will now survive and 30 will die. Thus, the
absolute benefit was 10%. If the risk of death
decreases, the proportional benefit stays the
same, but the absolute benefit decreases. If
the likelihood of death is only 20%, the pro-
portional benefit stays the same at 25%, but
the absolute benefit drops to 5%.
BOX 16–2 MEASUREMENTS
OF SURVIVAL
Disease-free survival (DFS): Time from
treatment to first evidence of recurrence
or death.
Overall survival (OS): Time from treatment
to death.
Distant disease-free survival (DDFS): Time
from treatment to first evidence of
distant recurrence.
249
16—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER

Benefits of Adjuvant
Chemotherapy in Breast
Cancer
A lengthy discussion of the early trials and
multiple studies examining adjuvant chemo-
therapy is well beyond the scope of this book.
The impact of adjuvant chemotherapy on
breast cancer is best demonstrated in the Early
Breast Cancer Trialists’ Collaborative Group
(EBCTCG) data. The EBCTCG is an interna-
tional group that meets every 5 years to review
the collective data on breast cancer trials. The
1995 overview analysis summarized the results
of randomized chemotherapy trials beginning
before 1990. The analysis involved 18,000
women participating in 47 trials of adjuvant
chemotherapy and revealed several key points
regarding the efficacy of adjuvant chemother-
apy in breast cancer.
1. Compared to no adjuvant therapy, poly-
chemotherapy significantly improved OS.
The proportional risk reductions are shown
in
Table
16–1
and
broken
down
by
age. Overall, combination chemotherapy
reduces the risk of recurrence by 23.5%
and the risk of death by 15.3%. This
translated to an overall 7% to 11% abso-
lute increase in 10 year OS in women
under age 50, and a 2% to 3% absolute
increase in women aged 50 to 69. There
was no significant difference in either
recurrence or survival for women 70 years
of age or older, however, it should be
mentioned that only a small percentage
of women in the randomized trials were
older than 70.
2. The benefits are true for patients who
are both node negative and node positive.
When first introduced into clinical prac-
tice, adjuvant chemotherapy was limited
to patients who were node positive (hence
the importance of the axillary lymph
node
dissection
[ALND]
even
in
the
absence of a direct survival benefit, as
described in Chapter 13). However, the
Oxford overview clearly shows that the
proportional
reductions
in
recurrence
and death are similar for patients who
are node negative and those who are node
positive. What changes are the risks of
recurrence and death, so that although
the proportional benefit stays the same,
the absolute benefit changes. Thus, the
selection of appropriate patients for adju-
vant chemotherapy is based on a more
complex calculation of the patient’s risk
of recurrence rather than node positive
versus node negative.
3. Anthracycline-based
chemotherapy
is
superior to non-anthracycline based regi-
mens. Initially, one of the most common
regimens used was cyclophosphamide,
methotrexate, and fluorouracil (CMF).
In the Oxford Overview, they identified
11 trials (over 6900 patients) in which
CMF was compared with regimens con-
taining doxorubicin (such as FAC or AC)
or epirubicin (such as FEC). There was a
12% reduction in the odds of recurrence
and an 11% reduction in the odds of
death with the use of an anthracycline
regimen. These benefits were seen in
patients who were both node positive
and node negative. Anthracycline-based
regimens are now the most common regi-
mens in the adjuvant setting, although
CMF is still a reasonable option for some
women.
TABLE 16–1
Proportional Risk Reductions Associated with Adjuvant Chemotherapy
in the 1995 EBCTCG Systematic Review on Polychemotherapy
Proportional Reduction in
Recurrence (%)
Proportional Reduction in
Mortality (%)
Polychemotherapy vs.
None- All Ages
23.8
15.2
<40
37
27
40 to 49
34
27
50 to 59
22
14
60 to 69
18
8
70 or older
—
—
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Selection of Patients for
Adjuvant Chemotherapy
Several factors have been identified that can help
select which patients are most likely to benefit
from adjuvant therapy. Factors can be categor-
ized as either prognostic or predictive. A prognos-
tic factor correlates with the clinical outcome at
the time of diagnosis, independent of therapy.
Examples include tumor size and lymph node
status. Larger tumor size and the presence of
nodal metastases correlate with the likelihood of
distant recurrence and death. Prognostic factors
are important because they can help determine
the absolute benefit of chemotherapy. As stated,
if a drug can reduce the chance of dying of breast
cancer by 25%, it is important to know what the
chance of dying of breast cancer is, based on
prognostic factors. If the chance of dying is only
4%, then the absolute benefit of the drug is
only 1% (meaning 100 women need to be treated
for 1 woman to survive). On the other hand,
if the prognostic signs suggest a 40% chance of
dying, the absolute benefit is 10% (10 women
need to be treated for 1 woman to survive).
A pure prognostic factor, however, does not
give information about the likelihood of a
treatment working. Predictive factors provide
information on the likelihood of a response
to a given modality. These factors are usually
the target of the therapy or related to the
method by which the treatment works.
Many factors may be both predictive and
prognostic. One example is the overexpression
of human epidermal growth factor receptor
2 (Her-2/neu). Her-2 neu status is clearly pre-
dictive. Women who are Her-2/neu positive are
likely tobenefit from Herceptin, whereas women
who are negative will see no benefit. Her-2 neu
status may also predict the response to certain
chemotherapeuticregimens.However,Her-2 neu
status is also prognostic because women with
Her-2 neu overexpressing cancers tend to have
a
worse
outcome
than
patients
who
are
Her-2 neu negative, regardless of treatment.
Although many prognostic and predictive
factors have been examined, only a handful
are used clinically (Box 16–3). The primary fac-
tors presently in use include both those factors
that are patient related (age and comorbidities)
and those that are tumor related (size, nodal sta-
tus, grade, histology, angiolymphatic invasion,
hormone receptors, and HER2/neu status).
Although the standard approach to systemic
therapy is the use of these prognostic and pre-
dictive factors, it is an interesting time in cancer
therapy, with a shift away from using tumor,
node, and metastasis (TNM) staging for adju-
vant therapy decision making and toward
using more detailed genetic information from
the primary tumor. With the introduction of
Onco Type DX, the first foray into more selec-
tive targeting of systemic therapy has been
seen. As more research is done and validated,
this is likely to dramatically change how we
approach adjuvant chemotherapy.
Consensus Groups
Adjuvant hormonal therapy, with a favorable
risk-benefit ratio, is generally recommended to
all hormone receptor positive patients (see
Chapter 17). The decision to administer adju-
vant systemic therapy must take into account
not only the individual patient’s risk of relapse,
but also the absolute benefits of treatment,
the potential short-term and long-term compli-
cations, and the patient’s comorbidities and life
expectancy. This has made the creation of gen-
eral guidelines for adjuvant chemotherapy use
a challenging problem. One method of addres-
sing the complexities has been through groups
of experts reviewing the available data and
making recommendations.
BOX 16–3 AMERICAN SOCIETY
OF CLINICAL ONCOLOGY TUMOR
MARKER GUIDELINES


ER and PgR expression should be
evaluated on every breast cancer to
guide the decision to use hormonal
therapy.


Her-2/neu overexpression should be
evaluated on every breast cancer to help
guide the selection of trastuzumab
(Herceptin) for adjuvant therapy.


The present data is insufficient to
recommend the measurement of p53,
cathepsin D, cyclin E, ploidy, or DNA
content or S phase measurements. There
is also insufficient information at this
time to recommend the estimation of the
proliferative rate, including mitotic rate
counts, S-phase fractions, Ki-67,
proliferating cell nuclear antigen (PCNA),
or argyrophilic nucleolar organizer
regions (AgNOR).*
* Although the American Society of Clinical Oncology
(ASCO) guidelines do not recommend the assessment
of cell proliferation, it is recommended by the College
of American Pathologists, and many institutions do
routinely measure Ki-67.
ER, xxxx; Her-2/neu, xxxxx; PgR, xxxx; p53, xxx.***
251
16—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER

National Institutes of Health Consensus
Conference
The National Institutes of Health (NIH) Consen-
sus Panel concluded that several months of poly-
chemotherapy appear to provide benefit in
reducing the risk for recurrence and death and
that anthracycline-containing regimens offer a
small but significant improvement in survival
compared with non-anthracycline regimens.
In regard to selecting the most appropriate
patients for chemotherapy, this consensus group
acknowledged the difficulty in identifying spe-
cific patient groups that might not require adju-
vant chemotherapy. They agreed on the need
to individualize recommendations for node-
negative cancers smaller than 1 cm and state
that the retrospective data indicate that the use
of chemotherapy, in the absence of other worri-
some features, does not appear warranted. They
also emphasize the need for studies designed to
look at women 70 years of age and older and
boosting accrual of these patients to trials because
there is limited evidence regarding adjuvant che-
motherapy in this group (see Chapter 22).
National Comprehensive Cancer
Network
The National Comprehensive Cancer Network
(NCCN) gathers experts in various fields of
oncology to create practice guidelines in oncol-
ogy, which are available to all practitioners in
both published form and on the Internet. Treat-
ment algorithms are presented in flowchart for-
mats based on categories of consensus among
the NCCN committee members (Box 16–4),
and they are available on the Internet at www.
NCCN.org. A sample page from the NCCN
guidelines for the adjuvant therapy of breast
cancer is shown in Figure 16–1. The guidelines
recommendadjuvantchemotherapyforpatients
with lymph node involvement, for those with
hormone receptor negative breast cancer and
tumor size greater than 1 cm, and for those with
hormone receptor and Her-2/neu positive dis-
ease and tumor size greater than 1 cm. They also
recommend consideration of chemotherapy for
patients with tumor size 0.6 to 1.0 cm regardless
of hormone receptor status, and those with hor-
mone receptor positive and Her-2/neu negative
disease and tumor size greater than 1 cm.
St. Gallen International Consensus Panel
The St. Gallen International Consensus Con-
ference gathers a worldwide group of breast
cancer experts on a regular basis to discuss
the latest research in breast cancer and provide
updates on adjuvant therapy recommenda-
tions based on low, intermediate, and high risk
(Table 16–2). They have defined the features
necessary to assess adjuvant therapy needs as
the size of the primary tumor, nodal status, estro-
gen receptor (ER) and progesterone receptor (PR)
expression, and Her-2/neu overexpression (Box
16–5). Additional features that may influence
the decision would be grade, lymphovascular
invasion, and certain histologies. They recom-
mend adjuvant chemotherapy for patients with
hormone receptor positive, high-risk disease,
or hormone receptor negative, intermediate- or
high-risk disease. They also recommend consid-
eration of chemotherapy for patients with
hormone receptor positive, intermediate-risk
disease. High-risk disease is defined as four or
more nodes positive with any Her-2 status, or
one to three nodes positive and Her-2 overex-
pressed. Low-risk is considered age greater than
35, tumor size less than or equal to 2 cm, grade
1,
no
angiolymphatic
invasion,
and
Her-
2 negative.
The St. Gallen guidelines differ slightly from
the NCCN recommendations, being slightly
more conservative. For example, a woman
with a 1.5-cm, node-negative, grade 1 tumor,
ER positive, Her-2 negative has an approxi-
mate 15% 10-year risk of recurrence without
systemic therapy. The NCCN guidelines would
recommend considering adjuvant chemother-
apy in addition to hormonal therapy, whereas
the St. Gallen guidelines would recommend
hormonal therapy only. One can see how this
may lead to confusion for both clinicians and
patients.
BOX 16–4 NATIONAL
COMPREHENSIVE CANCER
NETWORK CATEGORIES OF
CONSENSUS
Category 1: Uniform national
comprehensive cancer network (NCCN)
consensus based on high-level evidence
that the recommendation is appropriate.
Category 2A: There is uniform NCCN
consensus, based on lower-level
evidence including clinical experience,
that the recommendation is appropriate.
Category 2B: There is nonuniform NCCN
consensus (but no major disagreement),
based on lower-level evidence including
clinical experience, that the
recommendation is appropriate.
Category 3: There is major NCCN
disagreement that the recommendation
is appropriate.
252
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

Adjuvant Online
To make it easier for physicians to apply
guidelines to individual patients and help
patients understand the decision they are
making, there are several computer programs
that are now available to assess the risks of
recurrence and death from breast cancer and
the relative and absolute benefits of adjuvant
therapy. These are particularly helpful in
discussing adjuvant therapy decisions with
Figure 16–1. A sample page from the National Comprehensive Cancer Network Guidelines for Adjuvant
Therapy in Breast Cancer. Available at
TABLE 16–2
St. Gallen Systemic Adjuvant Therapy Recommendations
Risk Category
Associated Features
Adjuvant Therapy Options
Low risk

Node-negative, ER/PR positive,
T  1 cm, grade 1, no LVI,
Her-2/neu negative, age  35
1. None
2. Endocrine only
3. Consider Oncotype DX
Intermediate
risk

Node-negative and at least one of the
following: T > 2 cm, grade >1, LVI,
age < 35, Her-2/neu positive

Node-positive (one to three nodes) and
Her/2-neu negative
1. Endocrine only (ER/PRþ)
2. CTX followed by endocrine (ER/PRþ)
3. Consider Oncotype (if node negative and
ER/PRþ)
4. CTX (ER/PR-)
High risk

Node positive (one to three nodes) and
Her-2/neu positive

Node positive ( four nodes)
1. CTX followed by endocrine (ER/PRþ)
2. CTX
CTX, chemotherapy; ER, estrogen receptor; LVI, lymphovascular invasion; PR, progesterone receptor; T, tumor size.
253
16—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER

patients. The most popular program is Adju-
vant! Online (Adjuvant! Inc.), which is easily
accessible to all practitioners via the Internet
at Taking survival
information
derived
mainly
from
surveil-
lance, epidemiology, and end results (SEER)
data combined with the benefits of adjuvant
therapy based on the Oxford overview, this
program uses a Bayesian method to make
estimates for individual patients based on
their demographic and staging information.
After entering the patient age, comorbidities,
menopausal status, tumor size, nodal involve-
ment, grade, and ER status, baseline prognos-
tic
estimates
are
shown.
In
addition,
estimates for the efficacy of endocrine ther-
apy, systemic chemotherapy, and the combi-
nation
(for
both
relapse
and
death)
are
shown
in
both
numerical
and
graphical
forms (Figure 16–2). The user can examine
several chemotherapy regimens and print
out graphs that help patients visualize the
information. Recently, Adjuvant Online has
been updated to include the Oncotype DX
assay in assessing the benefit of adjuvant
therapy.
Figure 16–2. Screen capture from AdjuvantOnline.com.
BOX 16–5 ST. GALLEN
INTERNATIONAL CONSENSUS
CONFERENCE FEATURES
IMPORTANT IN ADJUVANT THERAPY
DECISIONS
Necessary
Tumor size (invasive component)
Nodal status
Hormone receptor expression
Her-2/neu overexpression
Additional
Histologic grade
Angiolymphatic invasion
Primary histology (metaplastic changes
carry increased risk)
254
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

Microarray Analysis and the Oncotype
DX Assay
The present methods for selecting patients for
adjuvant chemotherapy are based on rather
crude measures of the cancer’s likelihood of
returning; tumor size, nodal metastases, tumor
grade, angiolymphatic invasion, etc. The end
result of this is that although chemotherapy
clearly improves overall survival when one
looks at a population of patients with breast can-
cer, for the individual patient the chance that
the chemotherapy is extending their life may
be quite small. For any group of patients with
similar-appearing tumors (similar size, grade,
nodal status), some patients would never have
the cancer return after surgery and radiation,
regardless of whether they take chemotherapy.
However, because we can not differentiate these
patients from those patients likely to recur, we
must offer chemotherapy to the entire group,
to realize the benefit in only a few.
The optimal management of breast cancer
would be to use alternate factors that could pre-
dict the likelihood of cancer recurring regard-
less of the size or grade of the tumor. This
would not only identify those patients with
small, seemingly nonaggressive cancers who
might benefit from chemotherapy, but also
spare women with tumors unlikely to recur
from the morbidity of treatment. For some
time, researchers have used immunohisto-
chemical staining to identify individual tumor
markers expressed on breast cancer cells that
may provide additional prognostic informa-
tion. Although some of these do correlate with
outcome, few provide information above and
beyond size, grade, and nodal status, and thus
do not help to select patients for chemotherapy.
That has changed significantly with micro-
array analysis. Microarray analysis allows for
the measurement of thousands of genes in a
single RNA sample. Although there are a vari-
ety of microarray platforms that have been
developed to accomplish this, the basic idea
is the same. Microarray analysis involves spot-
ting up to 25,000 genes in an ordered “array”
on a glass slide. These genes are then hybri-
dized to RNA from a tumor sample (labeled
with a red fluorophore) or from a reference
sample (labeled with a green fluorophore).
For each gene, if the tumor sample expresses
levels of a particular RNA that are higher than
those of the reference sample (the gene is up
regulated by the tumor), the spot will fluoresce
red. If the reference sample expresses more
RNA than the tumor (the tumor down regu-
lates the gene), the spot will fluoresce green.
If the tumor and reference sample express a
particular transcript at an equal level, the spot
will be yellow (Figure 16–3). The fluorescent
array is scanned, digitized, and analyzed by
computer programs that provide researchers
with a readout of which genes are down regu-
lated and up regulated in the tumor sample.
Tumor
Tumor sample
Labeled tumor RNA or DNA
Labeled control RNA or DNA
Figure 16–3. Microarray anal-
ysis involves spotting genes in
an ordered “array” on a glass
slide. These genes are then
hybridized to RNA or DNA from
a tumor sample (labeled with
a red fluorophore) or from a
reference sample (labeled with
a green fluorophore). For each
gene, if the tumor sample ex-
presses levels of a particular
RNA that are higher than those
of the reference sample (over-
expressed), the spot will fluo-
resce
red.
If
the
reference
sample expresses more RNA
than the tumor (underexpres-
sed), the spot will fluoresce
green. If the tumor and refer-
ence
sample
are
equal,
the
spot will be yellow.
255
16—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER

DNA microarrays have been used to analyze
thousands of genes from fresh frozen tissue
obtained from patients with breast cancer.
Comparing the over- and underexpression of
certain genes with follow-up information on
these patients, researchers can identify the
genes that most strongly correlate with out-
come and create molecular “signatures.” Sev-
eral
reports
now
demonstrate
how
gene
expression profiling can be used to predict
clinical outcome in patients with breast can-
cer, above and beyond standard clinical and
pathologic prognostic features. For example,
tissues from almost 300 patients in the Nether-
lands (all young women with stage I or II
breast cancer) were classified according to a
70-gene prognosis profile. The patients with a
“good” molecular signature had a 10-year over-
all survival of 95%, whereas the women with a
“bad” signature had a 55% survival. In multi-
variate analysis, the molecular signature of
the tumor was a more powerful predictor than
any
clinical
or
histologic
criteria.
Un-
fortunately, efforts to validate these findings
have not been as impressive. Prospective stud-
ies are presently under way. Other drawbacks
to microarray analysis are the cost, and the
fact that fresh tissue is required, so the deci-
sion to use the test must be made at the time
of surgery.
A more clinically feasible method to use
genetic information to select women for che-
motherapy is now available to clinicians. The
Oncotype DX assay is a reverse-transcriptase
polymerase
chain
reaction
(RT-PCR)
based
assay that measures the expression of several
genes that appear to be important in predict-
ing outcome. The advantage of using RT-PCR
is that the test can be performed on paraffin-
embedded tissue. This not only allows the test
to be studied and verified using tissue from
completed adjuvant therapy trials, but allows
the test to be ordered on patients after surgery,
after it has been determined that they are
appropriate candidates.
The
Oncotype
DX
assay
measures
the
expression of 21 genes in patients with node-
negative,
ER-positive
breast
cancer.
Using
tumor blocks from patients that were treated
on NSABP B14, an algorithm was constructed
to predict a recurrence score. This score is based
on the expression of 16 genes relative to 5 refer-
ence genes. Based on this score, patients could
be stratified into three groups based on their
likelihood of recurrence (low, intermediate, or
high risk). In the NSABP B14 data, about half
of the patients were low risk, with a 10-year
recurrence rate of 6.8%. One quarter of the
patients were intermediate risk with a 10-year
recurrence rate of 14.3%, and the remaining
quarter were high risk, with a 30.5% chance of
recurrence. It is important to remember that
because this information was verified on the
patients in NSABP B14, which was limited to
node-negative, ER-positive patients, the results
would only be accurate in this patient popula-
tion. Oncotype DX cannot be used to make che-
motherapy decisions in patients who are node
positive or patients who are ER negative.
The Oncotype DX assay was then evaluated
for its ability to predict which patients would
benefit from adjuvant chemotherapy in addi-
tion to tamoxifen. Using data from both NSABP
B14 and NSABP B20, the benefit of chemother-
apy was assessed for low-, intermediate-, and
high-risk patients. The results suggested that
chemotherapy adds little to tamoxifen alone
for patients with low or intermediate scores,
but
significantly
improves
survival
among
high-risk patients. This was independent of
tumor size or grade.
Thus, the Oncotype DX assay is available to
help women with node-negative, ER-positive
breast cancer decide whether they should be
treated with tamoxifen alone or whether they
should receive adjuvant chemotherapy in addi-
tion to tamoxifen. Women in the low-risk group
would see little added benefit to chemotherapy,
and hormonal therapy alone should be suffi-
cient. On the other hand, women in the high-
risk group should receive chemotherapy in
addition to hormonal therapy. The recommen-
dation for women in the intermediate group is
slightly more controversial. The data suggests
that these women see little benefit to adjuvant
chemotherapy, and hormonal therapy alone
should suffice. However, some medical oncolo-
gists feel that appropriate recommendations
cannot be made for these women based on the
assay. A randomized trial to help answer this
question is underway.
The Oncotype DX assay should only be
ordered in women who are appropriate candi-
dates (node negative, ER positive) and are unsure
as to whether they would take chemotherapy.
If a woman was low risk, but would take the
chemotherapy anyway for a less than 3% benefit
over 10 years, there is no need to order the test.
Likewise, if a woman is not interested in chemo-
therapy regardless of her risk, the test is also
not indicated.
Other gene assays are moving toward clini-
cal use. The MammaPrint assay was recently
cleared for marketing by the U.S. Food and
256
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

Drug Administration (FDA) for women under
the age of 61 with node-negative tumors less
than 5 cm in size. This is a 70-gene signature
developed at the Netherlands Cancer Institute
based on the data previously described. Al-
though this assay can provide additional prog-
nostic information, there is less data regarding
the ability of the MammaPrint assay to improve
patient outcome. This assay is presently being
studied in a randomized trial. Another molecular
signature is being developed in conjunction
with Veridex LLC (San Diego, CA). However, as
previously stated, these latter two assays use
fresh frozen tissue for DNA microarrays, which
may be more difficult to use in the United States,
where immediate fixation of tumor specimens is
more common.
Chemotherapeutic Agents
Used in Breast Cancer
Table 16–3 and Box 16–6 highlight some of
the more common agents used in breast can-
cer treatment.
Anthracycline-Based Regimens
Several different regimens exist for the adjuvant
treatment of breast cancer. Trials in the 1970s
and 1980s demonstrated the efficacy of cyclo-
phosphamide, alone or in combination, in
reducing breast cancer recurrence rates. Cyclo-
phosphamide is an alkylating agent. This class
of agents was one of the first chemotherapies
and includes the nitrogen mustards first used in
the 1940s. All alkylating agents contain an alkyl
group (-CH2C) which covalently binds DNA.
Agents with a single alkyl group damage DNA
bases or cause single-stranded DNA breaks.
Agents with two alkyl groups form DNA cross-
links, which lead to interference with DNA syn-
thesis and transcription and double stranded
DNA breaks. Side effects include myelosuppres-
sion, nausea and vomiting, alopecia, infertility,
hemorrhagic cystitis, and syndrome of inappro-
priate antidiuretic hormone (SIADH).
Ultimately,
two
combination
regimens
involving cyclophosphamide gained accep-
tance, both delivered in 3-week cycles. One
was CMF. Both methotrexate and fluorouracil
fall into the category of antimetabolites. Anti-
metabolites are structural analogues to a vari-
ety of cellular substrates. 5-Fluorouracil (5-FU)
is metabolized to FdUMP, which inhibits the
enzyme thymidylate synthase, necessary for
thymidine synthesis. It is also misincorporated
into RNA, leading to aberrant RNA processing.
FdUMP and another metabolite, FdUTP, are
both misincorporated into DNA, inhibiting
further DNA synthesis. Methotrexate is a folate
analogue that binds to dihydrofolate reductase
(DHFR) and inhibits its ability to reduce folate,
which is necessary for the synthesis of thymi-
dylate, purines, serine, and methionine.
The other popular regimen was cyclophos-
phamide, doxorubicin, and fluorouracil (CAF).
Doxorubicin falls into the class of drugs known
as antitumor antibiotics. Most of these are
derived from the Streptomyces species of fungus.
These drugs work by intercalating into DNA
and inhibiting its synthesis and transcription.
Doxorubicin also inhibits topoisomerase
II
and causes DNA breaks through the forma-
tion of free radicals. Although doxorubicin
is the most commonly used anthracycline in
the United States and Canada, epirubicin
(40-epidoxorubicin) is commonly used else-
where. This is the semisynthetic L-arabino
derivative of doxorubicin in which the amino
sugar daunosamine is replaced with acosa-
mine. It appears to have a better safety pro-
file than doxorubicin on a milligram per
milligram basis, with less nausea and cardio-
toxicity when given at roughly equal myelo-
suppressive doses and with similar response
rates. The FDA did recently approve the use
of epirubicin for adjuvant therapy in breast
cancer. There is little data to support using
one over the other.
The dose-limiting toxicity of all anthracy-
clines is myelosuppression. Neutrophil nadirs
typically occur 10 to 14 days after treatment.
Other common toxicities include alopecia, nau-
sea and vomiting, diarrhea, and mucositis. The
most concerning toxicity of the anthracyclines
is the cardiac toxicity. An acute pericarditis/
myocarditis syndrome with fever, chest pain,
and congestive heart failure can occur, but it is
quite rare. Chronic cardiac toxicity is dose
dependent, and rarely occurs when a cumula-
tive dose of less than or equal to 450 mg/m2 is
given. If it does occur, however, it can lead to
irreversible congestive heart failure. The risk
increases with advanced age, diabetes, a history
of cardiomyopathy, and chest wall radiation,
particularly for left-sided breast cancers.
As previously described, one of the findings of
the Oxford Overview, in reviewing over 6900
patients from 11 trials in which CMF was
compared with regimens containing doxorubi-
cin (such as FAC or AC) or epirubicin (such as
FEC), was that there was an improvement with
the doxorubicin- or epirubicin-based regimens
257
16—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER

TABLE 16–3
Chemotherapeutic Agents Used in Breast Cancer
Agent
Type of Agent
Side Effects
Precautions
Cyclophosphamide
Alkylating agent
Myelosuppression
Nausea/vomiting
Alopecia
Infertility
Hemorrhagic cystitis
Syndrome of inappropriate
antidiuretic hormone
(SIADH)
Second-degree malignancies
-Encourage oral fluids (2–3 L/day)
to prevent hemorrhagic cystitis
-May increase the effects of
anticoagulation
Thiotepa
Alkylating agent
Myelosuppression
Nausea/vomiting
Mucositis
Hypersensitivity
Rash
Hemorrhagic cystitis
Second-degree malignancies
-Have resuscitation supplies nearby
during administration for
hypersensitivity reactions
Paclitaxel
Antimicrotubule
Myelosuppression
Hypersensitivity
Neurotoxicity
Alopecia
Mucositis
Diarrhea
Cardiac arrhythmia
Hepatotoxicity
-Dexamethasone, antihistamines,
and histamine-2 blockers should
be administered before treatment
to avoid hypersensitivity
-Resuscitation supplies should be
available during administration
-Activity reduced by phenytoin and
carbamazepine
Docetaxel
Antimicrotubule
Myelosuppression
Hypersensitivity
Fluid retention
Neurotoxicity
Alopecia
Arthralgias
Myalgias
Mucositis
Diarrhea
Rash
-Administer dexamethasone before
and after treatment to prevent
hypersensitivity and fluid
retention
-Resuscitation supplies should be
available during administration
-Activity reduced by phenytoin and
carbamazepine
5-Fluorouracil
Antimetabolite
Myelosuppression
Blepharitis
Cardiac ischemia
-Severe toxicity in patients with
DPD deficiency
-May increase toxicity of
antiepileptic medications
Capecitabine
Antimetabolite
Mucositis
Hand-foot syndrome
Diarrhea
Nausea/vomiting
Hepatotoxicity
Blepharitis
Cardiac ischemia
-Severe toxicity in patients with
DPD deficiency
-May increase the effects of
Coumadin
Methotrexate
Antimetabolite
Myelosuppression
Mucositis
Hepatotoxicity
Renal failure
Pneumonitis
Arachnoiditis (when given
intrathecally)
-Accumulates in third space fluid
and should not be given to
patients with ascites, pleural
effusions, etc.
-May increase the effects of
Coumadin
-Ineffective if given with folate
-Activity reduced by phenytoin
and carbamazepine
-May decrease activity of
phenytoin or valproic acid
Gemcitabine
Antimetabolite
Myelosuppression
Nausea/vomiting
Flulike syndrome
Hepatotoxicity
Dyspnea
Rash
Hemolytic-uremic syndrome
(Continued)
258
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

(12% reduction in the odds of recurrence, 11%
reduction in the odds of death). These benefits
were seen in patients who were both node
positive and node negative, and so anthracy-
cline-based regimens are now the most recom-
mended regimens in the adjuvant setting. CMF
is still a reasonable option, especially if there is
concern regarding the cardiac risk associated
with the anthracycline.
For many years, anthracycline-based regi-
mens dominated the adjuvant breast cancer
landscape. In the late 1990s, three advances
occurred
that
dramatically
changed
the
choices for adjuvant therapy. The first of these
was the emergence of the taxanes as a highly
effective agent against breast cancer. The sec-
ond was the development of tolerable bone
marrow supportive therapy in the form of
granulocyte colony-stimulating factors, allow-
ing dose-dense regimens (higher doses within
shorter time frames) without the risks of severe
neutropenia. Finally, the development of tras-
tuzumab, a monoclonal antibody that targets
the Her-2/neu marker, and proven to be effec-
tive in the metastatic setting, was recently
shown to be extremely effective in the adju-
vant setting as well.
Taxanes
Mechanism of Action
The taxanes (paclitaxel and docetaxel) are
known as antitubulins and bind to dimeric
tubulin, disrupting the microtubule network
by inhibiting tubule disassembly, leading to sta-
ble microtubule bundles to accumulate in the
cell. These cells are incapable of forming normal
mitotic spindles and become blocked in the
G2 and M phases of the cell cycle. The dysfunc-
tional
microtubules
can
also
lead
to
cell
death by interfering with normal microtubule
dynamics. Paclitaxel (Taxol) and docetaxel
(Taxotere) bind to the same site and have a
similar mechanism of action, although there
are some small differences in the pharmaco-
logic characteristics. Paclitaxel was first identi-
fied as the active component of a bark extract
from the Pacific yew Taxus brevifolia. Docetaxel
TABLE 16–3
Chemotherapeutic Agents Used in Breast Cancer
Agent
Type of Agent
Side Effects
Precautions
Doxorubicin
Antitumor
antibiotics
Myelosuppression
Nausea/vomiting
Cardiotoxicity
Alopecia
Mucositis
Diarrhea
Rash (radiation recall)
-Infuse through a central venous
catheter as a result of vesicant
properties
-Obtain baseline left ventricular
ejection fraction (LVEF) and
monitor for cardiotoxicity
-May decrease activity of valproic
acid or carbamazepine
Mitomycin-C
Antitumor
antibiotic
Myelosuppression
Nausea/vomiting
Mucositis
Pulmonary toxicity/ARDS
Renal failure
Hemolytic-uremic syndrome
Cystitis (intravesicular
treatment)
-Avoid FiO2 > 50% that may
worsen pulmonary toxicity
ARDS, adult respiratory distress syndrome; DPD, dihydropyrimidine dehydrogenase.
BOX 16–6 COMMON ADJUVANT
CHEMOTHERAPY REGIMENS
FAC/CAF
Fluorouracil/doxorubicin/
cyclophosphamide
FEC/CEF
Cyclophosphamide/epirubicin/
fluorouracil
AC
Doxorubicin/cyclophosphamide
CMF
Cyclophosphamide/
methotrexate/fluorouracil
ACx4þTx4
Doxorubicin/cyclophosphamide
then paclitaxel
TAC
Docetaxel/doxorubicin/
cyclophosphamide
TC
Docetaxel/cyclophosphamide
AC!TþH
Doxorubicin/cyclophosphamide
then paclitaxel plus trastuzumab
259
16—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER

is a semisynthetic product derived from the
European yew Taxus bacata. Docetaxel has a
longer plasma half-life and longer intracellular
retention. Both taxanes have potent radiosensi-
tizing effects, can induce apoptosis, and have
antiangiogenic properties.
The major dose-limiting toxicity of taxanes
is profound myelosuppression. Another signi-
ficant
side
effect
is
the
hypersensitivity
reaction (HSR). Within a few minutes of the
first or second dose of paclitaxel, patients
may experience hypotension, hives, rash, or
shortness of breath. This typically resolves
after the taxane is discontinued, and antihis-
tamines, steroids, and sometimes vasopres-
sors
are
administered.
With
pretreatment
dexamethasone,
diphenhydramine
and
cimetidine, the incidence of HSR is only 1%
to 3%. Another difficult side effect of the tax-
anes is a peripheral neuropathy characterized
by numbness and paresthesias in a stocking-
and-glove
distribution.
Like
other cytotoxic
agents, the taxanes induce a reversible alopecia.
Urticaria, dermatitis, and reactive erythema can
also occur.
Taxanes in the Adjuvant Setting
With the antitumor activity demonstrated in
studies of metastatic breast cancer, taxanes
were examined in the adjuvant setting. The
first study to demonstrate results was CALGB
9344, which randomized patients with node-
positive breast cancer to Adriamycin/cytoxan
(three dose levels of Adriamycin) followed by
randomization to paclitaxel or no paclitaxel.
Preliminary results at a median follow-up of
21 months showed significant reductions in
both recurrence (22%) and mortality (26%).
Based
on
these
results,
paclitaxel
was
approved by the FDA for adjuvant therapy in
node-positive breast cancer. After 5 years of
follow-up, results show a 17% reduction in
recurrence (DFS 70% versus 65%) and approx-
imately 4% OS advantage (OS 80% versus
77%) with the addition of taxanes. A retro-
spective subset analysis of CALGB 9344 sug-
gests the benefit to DFS and OS are primarily
among the patients who were ER negative,
with little benefit seen in patients who were
ER positive. NSABP B-28 also evaluated adju-
vant taxanes in patients who were node posi-
tive. Over 3000 patients were randomized to
AC with or without paclitaxel. Early results
demonstrated
no
benefit
to
DFS
or
OS,
although as with the CALGB 9344 trial, sub-
set analysis suggested a trend toward benefit
for patients who were ER negative. However,
the data was updated in 2003 and the addi-
tion of paclitaxel to AC resulted in a signifi-
cant improvement in DFS (relative risk [RR]
0.83, p ¼ 0.008). There was still no benefit
to OS (RR 0.94, p ¼ 0.46). This magnitude of
benefit is approximately similar to that seen
in CALGB 9344.
A third trial, a single institution trial from
MD Anderson, randomized patients to eight
cycles of FAC versus four cycles of FAC and
four cycles of paclitaxel. After 4 years, the pac-
litaxel group had a nonsignificant 3% absolute
improvement in DFS (86% versus 83%), but
no better OS.
The Breast Cancer International Research
Group (BCIRG) study 001 randomly assigned
1491 women with node-positive breast cancer
to six cycles of 5-FU, doxorubicin, and cyclo-
phosphamide (FAC) or six cycles of docetaxel,
doxorubicin, and cyclophosphamide (TAC).
After a median follow-up of 5 years, the TAC
group had a reduction in both the risk of
recurrence (DFS 75% versus 68% and death
(OS 87% versus 81%). Based on these results,
docetaxel was approved by the FDA for the
adjuvant treatment of node-positive breast
cancer in combination with AC.
Herceptin
The epidermal growth factor receptor (EGFR)
family of tyrosine kinases regulates a complex
signaling cascade that controls the prolifera-
tion, survival, adhesion, migration, and differ-
entiation of cells. This pathway is tightly
regulated in normal cells because when there
is dysregulation of EGFR signaling, the result
can be abnormal cell proliferation and other
tumor-promoting activities.
There are four distinct receptors in the EGFR
family: EGFR (ErbB-1), Her-2 (Her-2/neu or
ErbB-2), Her-3 (ErbB-3), and Her-4 (ErbB-4).
Each of these receptors consists of an extra-
cellular binding domain, a transmembrane
lipophilic segment, and (with the exception
of Her-3), a functional intracellular tyrosine
kinase domain. When ligand binding occurs,
the tyrosine kinase domains are activated by
homo- and heterodimerization. Abnormalities
of these receptors can be associated with sev-
eral types of human cancer. In contrast to the
260
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

other receptors, Her-2 can adopt a fixed con-
formation resembling a ligand-activated state,
permitting it to dimerize in the absence of a
ligand. In addition, overexpression or mutation
can induce dimerization. Overexpression of
Her-2 is found in approximately one third of
breast cancers and is associated with a poor
prognosis in breast cancer. Overexpression of
Her-2 is associated with increased proliferation,
increased properties of metastases (invasion,
angiogenesis), and resistance to therapeutic
agents (chemotherapy and hormonal therapy).
Because the overexpression of Her-2 correlates
with prognosis in breast cancer, it is an important
therapeutic target. The first therapy to specifi-
cally target Her-2 is trastuzumab (Herceptin), a
recombinant humanized monoclonal antibody
to the extracellular domain of Her-2. Herceptin
binds to Her-2 and disrupts the downstream sig-
naling (Figure 16–4 and Box 16–7).
Trastuzumab is an immunoglobulin G (IgG)
antibody that consists of two antigen-specific
sites that bind to the juxta-membrane portion
of the extracellular domain of the Her-2 receptor.
This prevents the activation of its intracellular
tyrosine kinase. This may occur through preven-
tion of dimerization, endocytic destruction of
the receptor, or inhibition of shedding of the
extracellular domain. The IgG does have a con-
served Fc portion, so it can trigger immune rec-
ognition. Although most investigators consider
trastuzumab a “targeted therapy,” it may also
be a form of “immunotherapy” because it is pos-
sible that immune activation plays a role in the
mechanism of action of trastuzumab. There is
some evidence for antibody-dependent cytotox-
icity, including increased tumor infiltration by
lymphoid cells and a loss of function in mice
deficient in immune-cell activating Fc receptors.
Whether trastuzumab may be combined with
other vaccines or immunotherapies is being
investigated.
After several studies demonstrating the effi-
cacy and safety of trastuzumab in the man-
agement of stage IV disease, studies in the
adjuvant setting were initiated. Four large,
multicenter,
randomized
trials
(and
some
smaller studies) reported a significant benefit
EGF
ligand
HER2
MAPK
Nucleus
Trastuzumab
(Herceptin)
Figure 16–4. Herceptin
binding.
BOX 16–7 POTENTIAL
MECHANISMS FOR TRASTUZUMAB
Inhibition of tumor cell proliferation
Reduces signaling through cell-
proliferative pathways (MAPK)
Promotes apoptosis
Reduces signaling through cell survival
pathways (Pt3K/Akt)
Inhibits angiogenesis
Induces G1 arrest
Induces p27 cell cycle inhibitor
Reduces cyclin D1 levels
Initiates ADCC
ADCC, xxxx; G1, xxxx; Pt2K/Akt, xxx; p27, xxx.***
261
16—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER

from the addition of trastuzumab to adjuvant
and neoadjuvant therapy. The use of adjuvant
trastuzumab should be considered for women
with Her-2-positive breast cancer who are either
node positive or have worrisome features despite
being node negative. The benefits to patients
with small, hormone-responsive tumors who
are node negative appear quite modest, so it is
unclear whether trastuzumab is indicated in this
situation, even if patients are Her-2 positive.
One key to the successful use of trastuzumab is
the Her-2 testing. In the trials of trastuzumab,
response was seen only in patients with 3þ stain-
ing or gene amplification on fluorescence in situ
hybridization (FISH). No response was seen in
patients with 2þ staining unless gene amplifica-
tion was present. Therefore, all patients who
are 2þ should undergo FISH testing.
Trastuzumab alone is relatively safe. About
10% of patients may have a hypersensitivity-
like reaction, but this is preventable with
antihistamines, antiinflammatories, and corti-
costeroids. Myelosuppression and nausea and
vomiting are rare, and alopecia does not occur.
The most concerning side effect of trastuzumab
is congestive heart failure, particularly when
used in combination with anthracyclines. It is
not completely understood how trastuzumab
is related to cardiotoxicity, but it appears to be
less severe and more readily reversible than
the cardiac dysfunction associated with anthra-
cyclines. There appear to be few trastuzumab-
related cardiac deaths; however, patients on
trastuzumab must be carefully monitored and
appropriate actions taken in patients with dev-
eloping congestive heart failure.
Dose-Dense Chemotherapy
Dose density refers to a shortened interval
between treatments under the assumption
that more frequent administration may be
more effective. The concept is based on exper-
imental models that a dose of chemotherapy
kills a certain fraction (rather than number)
of exponentially growing cells and tumor
regrowth is faster when the number of viable
cells is lowest. By giving the next dose faster,
there is less time for the cells to regrow. The
problem with this approach had been the
severe neutropenia triggered by dose-dense
chemotherapy. With the introduction of fil-
grastim, however, neutropenia can be avoided
during dose-dense regimens. Filgrastim is an
analog of granulocyte-colony stimulating fac-
tor (G-CSF) which stimulates the bone marrow
to increase the production of neutrophils.
Evidence for the benefit of dose-dense regi-
mens came from CALGB 9741, a trial of
adjuvant chemotherapy
in 2000 patients
with node-positive breast cancer. This study
used a 2-by-2 design, randomizing women
between sequential doxorubicin, paclitaxel,
and cyclophosphamide, and AC for four
cycles followed by paclitaxel for four cycles.
They were also randomized to an every
3-week regimen versus an every 2-week regi-
men with filgrastim. At a median follow-up
of 36 months, dose-dense treatment signifi-
cantly improved DFS (RR 0.74, p ¼ 0.01)
and overall survival (RR 0.69, p ¼ 0.013).
Further
follow-up
suggests
that
although
the DFS remains improved, the OS may have
lost statistical significance. Longer follow-up
is
needed.
There
were
no
differences
between
the
concurrent
and
sequen-
tial regimens. Although this study provides
evidence as to the benefit of dose-dense
schedules, there are still many questions
regarding the appropriate dosing and sched-
uling of Adriamycin- and taxane-based regi-
mens
in
the
adjuvant
setting.
Ongoing
clinical trials will continue to change the
manner in which systemic chemotherapy is
administered (Box 16–8).
High-Dose Chemotherapy with
Autologous Stem Cell Support
It was hypothesized that higher doses of che-
motherapy, beyond what is in standard clini-
cal
use,
would
improve
outcome.
In
preclinical
culture
systems,
the
alkylating
agents exhibit a steep dose response in breast
cancer, meaning that resistance can be over-
come by a fivefold to tenfold higher doses.
However, high doses of chemotherapy are lim-
ited by the myelosuppression. Because the
other side effects of alkylating agents do not
reach dose-limiting levels until the dose is
many times higher than the myelosuppressive
dose, it was felt that if the myelosuppression
could be overcome, much higher doses could
be given and would result in better outcomes.
Thus, extremely high doses were combined
with autologous stem cell support. Initial,
nonrandomized data seemed promising, and
based on public pressure, began to be offered
as a choice for high-risk patients before rando-
mized trial data was available. Unfortunately,
prospective randomized trials failed to demon-
strate a benefit, and this practice has fallen out
of favor. A recent meta-analysis suggests that
there may be a small benefit to high-dose
chemotherapy, although the minimal benefit
compared to the significantly increased toxici-
ties do not appear to justify its use.
262
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

Side Effects of Chemotherapy
Short-Term Toxicity
Hair Loss (Alopecia)
The most common side effect of chemotherapy
for breast cancer, as well as the most visible and
distressing, is hair loss. Alopecia is almost 100%
with regimens including an anthracycline or a
taxane. Alopecia does not always occur with
CMF, with an incidence between 40% and
65% depending on the route and schedule.
Nausea and Vomiting
Nausea and vomiting during chemotherapy are
primarily caused by serotonin release from the
gastrointestinal mucosa, which leads to stimu-
lation of the emesis center of the medulla.
Although severe nausea and vomiting used to
BOX 16–8 SCHEDULES FOR COMMONLY USED ADJUVANT CHEMOTHERAPY REGIMENS
CMF
Cyclophosphamide 100 mg/m2 by mouth days 1 to 14
Methotrexate 40 mg/m2 intravenously days 1 and 8
5-FU 600 mg/m2 intravenously days 1 and 8
Cycled every 28 days for 6 cycles
AC
Doxorubicin 60 mg/m2 intravenous day 1
Cyclophosphamide 600 mg/m2 intravenous day 1
Cycled every 21 days for 4 cycles
CAF
Cyclophosphamide 100 mg/m2 by mouth day 1 to 14
Doxorubicin 30 mg/m2 intravenously day 1 and 8
5-FU 500 mg/m2 intravenously days 1 and 8
Cycled every 28 days for 6 cycles
TC
Docetaxel 75 mg/m2 intravenously day 1
Cyclophosphamide 600 mg/m2 intravenously day 1
Cycled every 21 days for 4 cycles.
AC!T
Doxorubicin 60 mg/m2 intravenously day 1
Cyclophosphamide 600 mg/m2 intravenously day 1
Cycled every 21 days for 4 cycles
FOLLOWED BY
Paclitaxel 175 to 225 mg/m2 intravenously by 3 hours infusion day 1
Cycled every 21 days for 4 cycles
OR
Paclitaxel 80 mg/m2 intravenously by 1 h infusion weekly for 12 weeks
Dose-dense
AC!T
Doxorubicin 60 mg/m2 intravenously day 1
Cyclophosphamide 600 mg/m2 intravenously day 1
Cycled every 14 days for 4 cycles
FOLLOWED BY
Paclitaxel 175 to 225 mg/m2 intravenously by 3 hours infusion day 1
Cycled every 21 days for 4 cycles
All cycles are with filgrastim support.
AC!TþH
Doxorubicin 60 mg/m2 intravenously day 1
Cyclophosphamide 600 mg/m2 intravenously day 1
Cycled every 21 days for 4 cycles
Paclitaxel 175 to 225 mg/m2 intravenously by 3 hours infusion day 1
Cycled every 21 days for 4 cycles OR paclitaxel 80 mg/m2 intravenously by 1 hour
infusion weekly for 12 weeks
WITH
Trastuzumab 4 mg/kg intravenously with first dose of paclitaxel
THEN
Trastuzumab 2 mg/kg intravenously weekly for 1 year
OR
Trastuzumab6 mg/kgintravenously every 3 weeks after completion of paclitaxel for 1 year.
263
16—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER

be a significant side effect of chemotherapy,
the availability of new antiemetic agents has
decreased the severity. The prophylactic use of
antiemetic medications containing 5-hydroxy-
triptamine 3(5-HT3) serotonin antagonists has
dramatically improved the tolerability of adju-
vant chemotherapy. Dexamethasone may fur-
ther
improve
the
response
to
the
5-HT3
serotonin antagonists. Although most women
receiving chemotherapy will develop some nau-
sea, less than 5% will have severe nausea and
vomiting. Metoclopramide or prochlorperazine
may be useful for those cases where nausea
occurs several days after treatment.
Myelosuppression
Myelosuppression is a common side effect of
chemotherapy, and thus patients are carefully
monitored for the development of neutrope-
nia, anemia, or thrombocytopenia. It typically
occurs within 5 to 15 days of treatment.
The management of neutropenia depends
on the severity. Mild neutropenia, defined as
an absolute neutrophil count of less than
1500/mm3, but greater than 1000/mm3 does not
require treatment. It may be prudent to decrease
the dose of chemotherapy. Patients with moder-
ate (500 to 1000) or severe (<500) neutropenia
are at an increased risk of infection and must be
instructed to report any fevers. Fevers should be
thoroughly worked up and antibiotics initiated,
even if no source is found. Granulocyte colony-
stimulating factors should be considered for
any patient who had neutropenic fever, with
prolonged
neutropenia
or
prophylactically
when neutropenia is expected (such as with
dose-dense regimens).
Anemia is treated with erythropoietin, or
rarely, blood transfusion. Symptomatic patients
with hemoglobin counts less than 10 gm/dl are
likely to benefit from erythropoietin. Patients
with thrombocytopenia may require platelet
transfusion.
Neurologic Toxicity
The addition of taxanes (paclitaxel, docetaxel)
to adjuvant chemotherapy carries with it sev-
eral neurologic toxicities. These can take the
form of both motor and sensory neuropathies.
The severity is dose- and schedule-dependent,
and symptoms can be improved by early recog-
nition with subsequent dose reduction. Within
72 hours of receiving paclitaxel, myalgias and
arthralgias may develop. These can be relieved
by either nonsteroidal antiinflammatory drugs
(NSAIDs), or a short course of glucocorticoids.
Weight Gain and Fatigue
As weight loss is commonly associated with
cancer, many women are surprised to learn that
weight gain is a common side effect of chemo-
therapy. On average, women gain between
2 and 6 kg, depending on the regimen. The
cause for the weight gain is multifactorial.
One of the most common complaints dur-
ing chemotherapy is fatigue. As with weight
loss, the reasons are multifactorial. Anemia
should be ruled out, as should other poten-
tially reversible factors, such as sleep distur-
bance, uncontrolled pain, depression, or poor
nutrition. However, in most cases a correctable
condition will not be identified. The fatigue
should resolve after the cessation of treatment.
During therapy, symptomatic relief may be
provided by initiating an exercise regimen,
changing the diet, or through the use of stimu-
lants or antidepressants.
Long-Term Effects
Adjuvant chemotherapy is given with the goal
of improving long-term survival. Therefore,
the long-term effects of chemotherapy must
be considered in addition to the acute toxicity.
Cognitive Dysfunction
A considerable amount of data is now coming
out on the long-term effect of chemotherapy
on cognition. As many as one third of patients
who
receive
adjuvant
chemotherapy
may
develop some dysfunction in memory or the
ability to concentrate, although for many
patients this will eventually return to baseline.
There may be a relationship between the
intensity of the adjuvant therapy and the inci-
dence
of
cognitive
impairment.
Further
research is necessary to better clarify the
impairment and identify ways to avoid or
reverse it.
Ovarian Failure
Premature termination of ovarian function is a
significant concern for younger women receiv-
ing adjuvant chemotherapy for breast cancer.
On one hand, the induction of premature
menopause may be beneficial. Removal of
estrogen may improve DFS and OS in women
with ERþ breast cancer. However, many young
women being treated for breast cancer would
like to maintain reproductive function, hoping
to have children after completing therapy.
264
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

Even in women who no longer desire to have
children, premature ovarian failure can affect
quality of life by heralding menopausal symp-
toms (hot flashes, vaginal dryness, dyspareu-
nia, depression, sleep disturbance) and result
in significant bone loss.
Premature ovarian failure can occur in any
woman, but the risks are higher for older
women, a longer duration of treatment and for
CMF regimens compared to AC. Women receiv-
ing taxanes may actually have a lower incidence
of ovarian failure. It may be possible to reduce
the incidence of ovarian failure by reducing
ovarian function during treatment by using
gonadotropin-releasing hormone (GnRH) ago-
nists or oral contraceptives. This is presently
being studied in a prospective randomized
trial. In women who do suffer ovarian failure,
supplemental calcium, vitamin D and regular
exercise should be used to mitigate bone loss.
Bisphosphonates can treat osteoporosis in
women with premature menopause.
Cardiac Toxicity
Women treated with anthracyclines or with
Herceptin may be at an increased risk of car-
diac toxicities. This may be higher in women
who receive radiation therapy for left-sided
breast cancers. Anthracyclines directly damage
the myocardium and can lead to cardiomyopa-
thy. The risk of cardiac failure greatly increases
after cumulative doses of doxorubicin greater
than 450 mg/m2. The risk is also higher in
older patients and those with a history of car-
diac disease.
Leukemia and Myelodysplastic
Syndromes
Although chemotherapy can lead to the devel-
opment of leukemias and myelodysplastic syn-
dromes, the incidence appears low for regimens
used to treat breast cancer, less than 1% overall.
This may be slightly higher among women
who receive radiation therapy or with the
administration of G-CSF, although the data is
not clear. Two distinct types of treatment-related
leukemic syndromes can occur. The first is typ-
ically associated with alkylating agents and
takes 3 to 7 years to develop, often preceded by
a myelodysplastic syndrome. The second is asso-
ciated with topoisomerase II inhibitors and has
a more rapid onset, within 2 to3 years of therapy.
Unfortunately the treatment-related leukemias
have a poor prognosis and are more refractory
to conventional antileukemic therapies.
On the Horizon
With the success of Herceptin, there is consid-
erable interest in other targeted therapies—
agents that exploit certain characteristics of
the cancer cells rather than relying on more
universal “cytotoxicity” of standard chemo-
therapy. Many of these targeted therapies are
early in their development and evaluation,
but several may soon be in clinical use.
Tyrosine kinase inhibitors (TKIs) are small
molecules that block the intracellular kinase
domain of the transmembrane receptor, pre-
venting its autophosphorylation and subseq-
uent activation. TKIs may be specific for a given
receptor type or have more broad effects against
multiple tyrosine kinases. The less specific they
are, the more side effects they may have. Com-
mon side effects include skin rashes, diarrhea,
and headaches.
Gefitinib (Iressa) and erlotinib (Tarceva) are
TKIs that act by blocking EGFR activation. As
single agents, both have been relatively disap-
pointing against breast cancer, although more
promising results have been obtained by com-
bining these agents with cytotoxic chemother-
apy. Further research is looking into identifying
subsets of patients who may benefit from EGFR
TKIs as the mere presence of EGFR overexpres-
sion does not seem to correlate with response
to treatment.
Lapatinib (Tykerb) is a TKI that inhibits both
EGFR and Her-2/neu. As Her-2 may play a role
in the oncogenic activity of EGFR, blocking
both could provide a better response. This agent
has been studied alone or in combination with
hormonal therapy, chemotherapy, and trastu-
zumab, and several trials in the adjuvant,
neoadjuvant and metastatic settings are ongo-
ing. As previously stated, some TKIs inhibit
multiple kinases. One example is sunitinib
(Sutent), a multiinhibitor vascular endothelial
growth factor (VEGF) receptor; platelet-derived
growth factor receptor; stem cell factor receptor,
Kit; rearranged during transfection (RET) gene;
and fetal liver tyrosine kinase receptor-3 (Flt-
3). Phase II and III trials are ongoing or planned
in patients with breast cancer.
The family of ras proto-oncogenes has been
implicated in the development of breast can-
cer and so it was hypothesized that blocking
this pathway could inhibit tumor growth. Far-
nesyltransferase inhibitors (FTIs) are agents
designed to target ras proteins. One example
is tipifarnib (Zarnestra), which inhibits growth
of several breast cancer cell lines and has
265
16—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER

shown some clinical activity as monotherapy
in clinical studies, particularly when combined
with endocrine therapy. Unfortunately, a large
randomized study of tipifarnib plus letrozole
versus letrozole alone showed no difference
in outcome between the two groups. Ongoing
studies are looking at tipifarnib in combina-
tion with chemotherapy.
Another important pathway in cell growth
and proliferation is the PI3-K/Akt pathway.
Akt may promote breast cancer cell survival
and play a role in resistance to standard thera-
pies. Temsirolimus (CCI-779) and everolimus
(RAD-001) inhibit mTOR, a downstream sub-
strate of Akt, and blocks progression in late
G1/S phase of the cell cycle. Both are being
examined in the treatment of breast cancer.
Crucial to cancer development and growth
is angiogenesis, the formation of new blood
vessels for oxygen and nutrient delivery. The
most potent stimulator driving tumor angio-
genesis is VEGF. Bevacizumab (Avastin) is a
recombinant monoclonal antibody that binds
directly to VEGF, inhibiting angiogenesis and
slowing or stopping tumor growth. It is hoped
that the addition of Avastin to standard che-
motherapy will increase the response rate and
outcome with breast cancer therapy. Rando-
mized trials are ongoing.
Cyclooxygenase-2 (COX-2) is an inducible
enzyme that converts arachidonic acid to pros-
taglandins. Deregulation of COX-2 has been
demonstrated in tumorigenesis, and multiple
tumors (including breast) have elevated COX-
2 levels. COX-2 inhibitors, such as celecoxib
(Celebrex), have shown promising results in
preclinical studies of breast cancer, although
the exact mechanisms of action by which
these drugs slow tumor growth is not well
understood. They may be anti-angiogenic.
COX-2 inhibitors are also presently being stud-
ied in combination with chemotherapy and
hormonal therapy for breast cancer.
Heat shock proteins (HSP) are proteins
responsible for the correct folding of a large
number of proteins, which is essential to
their functional conformation. Cellular stress
leads to an increased production of these
proteins, which allow cells to adapt to nox-
ious environments, such as heat or hypo-
xia, but also chemotherapy or irradiation.
HSP-90 is essential for the conformation of
several protein kinases and transcription fac-
tors involved in cell signaling and prolifera-
tion
(p53,
Erb-B2,
Akt-kinase,
Raf,
etc.).
Thus, targeting HSP-90 may have antitumor
activity or make cells more susceptible to
chemotherapy.
Many
drugs
that
bind
to
HSP-90 are unfortunately too hepatotoxic
for clinical use, but newer analogs are under
development.
Suggested Readings
1. Adjuvant! On Line.
2. Burstein HJ. The distinctive nature of HER2-positive
breast cancers. N Engl J Med 2005;353:1652–1654.
3. Citron ML. Dose density in adjuvant chemother-
apy for breast cancer. Cancer Invest 2004;22(4):
555–568.
4. Early Breast Cancer Trialists’ Collaborative Group.
Effects of chemotherapy and hormonal therapy
for early breast cancer on recurrence and 15-year
survival: an overview of the randomized trials.
Lancet 2005;365(9472):1687–1717.
5. Early Breast Cancer Trialists’ Collaborative Group.
Multi-agent chemotherapy for early breast cancer.
Cochrane Database Syst Rev 2002;1:CD000487.
6. Effects of adjuvant tamoxifen and of cytotoxic ther-
apy on mortality in early breast cancer. An over-
view
of
61
randomized
trials
among
28,896
women. Early Breast Cancer Trialists’ Collaborative
Group. N Engl J Med 1988;319(26):1681–1692.
7. Goldhirsch A, Glick JH, Gelber RD, et al. Meeting
highlights: international expert consensus on the
primary therapy of early breast cancer 2005. Ann
Oncol 2005;16(10):1569–1583.
8. Hudis CA. Trastuzumab—mechanism of action
and use in clinical practice. N Engl J Med 2007;
357:39–51.
9. Mamounas EP, Bryant J, Lembersky B, et al. Pacli-
taxel after doxorubicin plus cyclophosphamide as
adjuvant chemotherapy for node-positive breast
cancer: results from NSABP B-28. J Clin Orthod
2005;23(16):3686–3696.
10. Martin M, Pienkowski T, Mackey J, et al. Adjuvant
docetaxel for node-positive breast cancer. N Engl
J Med 2004;352(22):2302–2313.
11. Newman LA, Singletary SE. Overview of adjuvant
systemic therapy in early stage breast cancer. Surg
Clin North Am 2007;87(2):499–509.
12. Paik S, Shak S, Tang G, et al. A multigene assay
to predict recurrence of tamoxifen-treated, node-
negative
breast
cancer.
N
Engl
J
Med
2004;
351(27):2817–2826.
13. Piccart-Gebhart MJ, Proctor M, Leyland-Jones B,
et al. Trastuzumab after adjuvant chemotherapy
in HER2-positive breast cancer. N Engl J Med
2005;353(16):1659–1672.
14. Polychemotherapy for early breast cancer: an over-
view of the randomized trials. Early Breast Cancer
Trialists’ Collaborative Group. Lancet 1998;352
(9132):930–42.
15. Ravdin PM, Siminoff LA, Davis GJ, et al. Computer
program to assist in making decisions about adju-
vant therapy for women with early breast cancer.
J Clin Orthod 2001;19(4):980–991.
16. Romond EH, Perez EA, Bryant J, et al. Trastuzumab
plus adjuvant chemotherapy for operable HER2-
positive breast cancer. N Engl J Med 2005;353(16):
1673–1684.
17. Slamon DJ, Clark GM, Wong SG, et al. Human
breast cancer: correlation of relapse and survival
with amplification of the Her-2/neu oncogene.
Science 1987;235:177–182.
266
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

17
Principles of Adjuvant
Hormonal Therapy
THE ESTROGEN RECEPTOR
Estrogen Receptor-Alpha versus
Estrogen Receptor-Beta
Expression
Progesterone Receptor
Expression
ESTROGEN AND BREAST
CANCER
SELECTIVE ESTROGEN
RECEPTOR MODULATORS
Tamoxifen
Raloxifene
AROMATASE INHIBITORS
Anastrozole
Exemestane
Letrozole
Toxicity of Aromatase
Inhibitors
Adjuvant Therapy with
Aromatase Inhibitors
OVARIAN SUPPRESSION/
ABLATION
Principles of Adjuvant Hormonal Therapy: Key Points
Understand the expression of estrogen receptors and the impact of
estrogen on the growth of normal and cancerous breast cells.
Describe the mechanism of action of selective estrogen receptor
modulators.
Describe the benefits of adjuvant hormonal therapy after surgery and the
data from the Early Breast Cancer Trialists Collaborative Group.
Know the prospective data regarding the use of aromatase inhibitors instead
of or after a selective estrogen receptor modulator.
Describe the side effects of tamoxifen and aromatase inhibitors.
Understand the potential of ovarian suppression or ablation as hormonal
therapy.
267

In the treatment of most solid tumors, adju-
vant systemic therapy typically refers to the
use of cytotoxic chemotherapy after surgery
to prevent clinically occult micrometastases
from
becoming
distant
treatment
failures.
However, because breast cancer is often stimu-
lated by endogenous estrogen, another form of
adjuvant therapy is endocrine or hormonal.
The effects of hormonal therapy on breast can-
cer were first noted over 100 years ago when
Beatson described the regression of advanced
breast cancer after oophorectomy. Subsequently,
ovarian ablation (typically through irradiation)
became a therapy for metastatic breast cancer,
and eventually made its way to the adjuvant
setting. In the 1960s, hormonal therapy shifted
from surgery and radiation for ovarian ablation
to pharmacologic methods. This included both
suppressing estrogen synthesis (using luteiniz-
ing hormone releasing hormone [LHRH] ago-
nists) and blocking the binding of estrogen to
the estrogen receptor (ER; using tamoxifen).
Sincethe 1970s, multiple randomized controlled
trials have demonstrated its efficacy in reducing
relapse rates and death.
The Estrogen Receptor
The steroid hormones estrogen and progester-
one are involved in both the development of
the normal breast and the changes in the breast
seen with the menstrual cycle and pregnancy
(see Chapter 1). They influence the molecular
processes involved in proliferation, differentia-
tion, and function. They do not act alone, but
rather in concert with other steroid hormones
(glucocorticoids), peptide hormones (insulin,
prolactin, oxytocin, and growth hormones)
and peptide growth factors (epidermal growth
factor, fibroblast growth factor, insulin like
growth factor, and transforming growth factors).
The ER behaves differently than most recep-
tors of the steroid family. The typical steroid
receptoris a “translocatingreceptor.”Thismeans
that the receptor is distributed in the cytoplasm
in the absence of the hormone, moving to the
nucleus when the cell is hormone stimulated.
The ER works as a “ligand-dependent transcrip-
tion factor,” and is primarily located in the
nucleus in the absence or presence of estrogen.
Estrogen diffuses through the cell and binds to
the ER’s ligand-binding domain. This causes
a dramatic change in the conformation of
the receptor, resulting in the dissociation of
the receptor from the heat shock protein 90
(HSP-90) and heterodimerization. These com-
plexes can then bind to DNA sequences, caus-
ing the activation or repression of target genes
(Fig. 17–1). This can be either the result of direct
binding to estrogen response elements (ERE)
in the promoter of target genes or to inter-
actions with coactivators at their respective
promoter sites.
Dimerization
Gene
Promoter
Estrogen
receptor
Estrogen
Hsp-90
ER
ER
ER
ER
ER
ER
ER
Co-activators
A
B
mRNA
Co-activators
Gene
Promoter
Figure 17–1. Estrogen receptor binding. When estrogen binds to the estrogen receptor, heat shock protein 90 is
dissociated, resulting in a change in conformation. This allows the receptors to dimerize. The dimerized hormone
receptor molecules then bind to DNA and interact with coactivators to modulate expression of the target gene.
268
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

There are two isoforms of the estrogen
receptor; ER-alpha (ERa) and ER-beta. (ERb)
Both have the same basic structure and are
made up of six components or “domains,”
A to F. Estradiol binds to the ligand-binding
site in the E domain. This mediates ER dimer-
ization, which is required for DNA binding.
Domain D contains a nuclear localization
signal. Both isoforms bind estrogens with
a similar affinity and activate the expres-
sion of genes containing estrogen response
elements in an estrogen-dependent manner.
They differ in the N terminal A/B (transacti-
vation) domain. These are the regions that
promote transcription activation functions,
and thus the transcriptional properties of
ERa and ERb are dissimilar. In addition, their
distribution is different. ERa is expressed in
breast, ovary, uterus, vagina, bone, and hypo-
thalamus. ERb is found primarily on the ovar-
ies, hypothalamus, cerebral cortex, and in
male organs such as the testis and prostate
(Box 17–1).
Expression of the ER, and to a lesser degree
the progesterone receptor (PR), on breast can-
cer is crucial for predicting a response to
adjuvant hormonal therapy. Estrogen and
progesterone receptors can be measured by
means of a ligand-binding assay (LBA), which
involves the competitive binding of radiola-
beled steroid ligand, or by the use of antibodies
specific for the receptors through either immu-
nohistochemical staining (IHC) or enzyme
immunoassay (EIA).
Estrogen Receptor-Alpha versus
Estrogen Receptor-Beta Expression
Although ERa expression is a moderate prog-
nostic sign (meaning that patients who are
ER positive will do better than patients who
are ER negative in the absence of any treat-
ment; estimated to be about 5% to 10% lower
chance of recurrence), it is an extremely strong
predictive tool (meaning that patients who are
ER positive will respond significantly better to
endocrine therapy than those who are ER neg-
ative). Whereas 5 years of tamoxifen is asso-
ciated with a 50% to 60% reduction in the
relative risk of relapse and a 25% reduction in
the relative risk of death for women with ER-
positive breast cancer, there is no significant
benefit for women with ER-negative breast
cancer. Part of this depends on how one
defines ER-negative. The response rates are
also related to the quantitative analysis of the
receptor. Response rates to endocrine therapy
increase with the amount of ER present in
the tumors rather than simply the absence or
presence of the receptor.
What of ERb? Although ERb is present in
human breast cancer, its role in the develop-
ment of breast cancer remains unknown. Some
groups have reported that there is a beneficial
effect of ERb, suggesting it may protect against
the mitogenic action of estrogen, and may be
associated with node-negative and low-grade
breast cancers. ERb-positive tumors may be
more likely to respond to hormonal therapy.
Other groups have suggested a poor prognostic
value of ERb, and think it may be associated
with endocrine resistance. Further research is
ongoing, and studies of both ER subtypes
may further select subgroups that may benefit
from variations in endocrine therapy. Today,
however, the routine measurement of ERb
has yet to been shown to be of benefit in the
management of breast cancer.
Progesterone Receptor Expression
Although progesterone is necessary for the
development of the breast, most research has
focused on estrogen and the ER. It is unclear
whether the PR has prognostic significance.
However, we routinely measure both the ER
and PR. How does the PR help with clinical
decision making? The presence of PR suggests
that the ER is not only present but also func-
tioning, which is crucial for response to hor-
monal therapy. Therefore the expression of
both receptors suggests a better response to
BOX 17–1 EXPRESSION OF a OR b
ESTROGEN RECEPTORS BY TISSUE
TYPE
Breast
a and b (" a in breast
cancer)
Uterus
mostly a, some b
Ovary
a and b
Blood vessels
b
Heart
a and b
Bone
a (cortical), b
(cancellous)
Brain
a (hypothalamus), b
(whole brain)
Gut
b
Immune cells
b
Liver
mostly a, some b
Modified from Fabian CJ, Kimler BF. J Clin Orthod
2005;23:1644-1655.
269
17—PRINCIPLES OF ADJUVANT HORMONAL THERAPY

endocrine therapy than in ER-positive and PR-
negative tumors. Absence or loss of PR over
time may be associated with a more aggressive
tumor type and decreased responsiveness to
hormonal therapy. Although this has been
demonstrated for advanced breast cancer, it
has not been shown to be true for predicting
response to tamoxifen in the adjuvant setting.
However, there is that small subset of patients
(5%) who will be ER negative but PR positive.
These patients will frequently respond to hor-
monal therapy (possibly because low but criti-
cal levels of ER are present, or the ERbreceptor
is
present
and
not
being
measured).
So
although it may not help predict benefit from
adjuvant hormonal therapy in patients who
are ER positive, measuring PR is clinically use-
ful for women with both early-stage breast
cancer and metastatic disease.
Estrogen and Breast Cancer
Since Beaston’s original observation, there has
been a preponderance of evidence that indi-
cates exposure to estrogen is an important
determinant of the risk of breast cancer. Sev-
eral studies have shown that women with per-
sistently elevated serum levels of estrogen
have an increased risk of breast cancer. Several
factors related to estrogen are associated with
an increased risk of breast cancer, including
an early age of menarche, a late onset of men-
opause,
and
obesity
(likely
related
to
an
increased production of estrogen by aromatase
activity in adipose tissue). This evidence sug-
gests that cumulative exposure to estrogen
across a woman’s life span contributes to the
development of breast cancer.
Another piece of evidence comes from the
use of hormone replacement therapy. In the
United States, hormone replacement therapy
typically consists of estrogen alone (conjugated
estrone plus various conjugated equine estro-
gens) or estrogen plus progesterone (medroxy-
progesterone acetate). A meta-analysis of data
involving more than 160,000 women found
that users of hormone replacement therapy
for 5 years or longer had a relative risk of
1.35 for the development of breast cancer. An
observational study from France showed a sim-
ilar risk (1.4), although this was limited to
women receiving estrogen and progesterone.
Another observational study from the United
Kingdom showed an even higher risk asso-
ciated with hormone replacement. The results
from these studies suggest that ongoing or
recent hormonal replacement therapy is asso-
ciated with an increased risk of breast cancer.
Fortunately, in both the meta-analysis and the
United Kingdom study, women who stopped
using hormone replacement therapy reduced
their risk of cancer, suggesting that this effect
may be reversible.
These observational studies prompted a pro-
spective trial—the Women’s Health Initiative.
Postmenopausalwomen were randomlyassigned
to receive placebo or hormone replacement ther-
apy. Women with a uterus received estrogen and
progesterone, whereas women who had under-
gone a hysterectomy receivedestrogenonly.After
5 years, the study was terminated because of the
increased incidence of cardiopulmonary events
(for which hormone replacement was thought
to be protective). Women who received estrogen
and progesterone had an increased risk of stroke,
coronary heart disease, and pulmonary embo-
lism (PE). These women also had an increased
risk of breast cancer. Women receiving estrogen
alone had an increased incidence of stroke and
PE, but not breast cancer. Why there is a differ-
ence between estrogen versus estrogen plus pro-
gesterone is unclear, and the contribution to
breast cancer of progestin requires additional
investigation.
How does estrogen contribute to breast
cancer? There are two mechanismsby whichthis
may occur. Metabolism of estrogen involves
several cytochrome P-450 enzymes that cata-
lyze the conversion of estrone and estradiol to
hydroxycatechols. Several in vitro and animal
studies support the hypothesis that oxidative
metabolites of estrogen have genotoxic, muta-
genic, transforming, and carcinogenic potential
(Box 17–2). This has yet to be demonstrated in
human breast cancer, however. Another mech-
anism by which estrogen can contribute to
breast cancer is the increased proliferation and
inhibition of apoptosis associated with the est-
rogen receptor signal-transduction pathways
(Fig. 17–2).
BOX 17–2 EFFECTS OF ESTROGEN
METABOLITES SEEN IN IN VITRO
AND ANIMAL STUDIES

Estrogen 3,4-quinone DNA adducts
and depurination

Oxidative DNA damage

Gene mutation

Neoplastic transformation

Tumor development
270
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

Selective Estrogen Receptor
Modulators
Selective estrogen receptor modulators (SERMs)
are competitive inhibitors of estrogen binding
to estrogen receptors. SERMs include tamoxi-
fen, raloxifene, and related drugs. In the past,
these were referred to as “antiestrogens” how-
ever this label is misleading because this class
of compounds can act as an antagonist in one
tissue and an agonist in another. It is this com-
bination of antagonistic and agonistic proper-
ties that are responsible for both the effects
and the side effects of these drugs. The antago-
nistic activity can be both beneficial (inhibition
of breast cancer cell growth) and detrimental
(menopausal symptoms). Likewise, the agonis-
tic effects can be both beneficial (preventing
bone demineralization) and detrimental (risk
of uterine cancer and thromboembolism).
The process behind how a drug can act posi-
tively on one tissue type and negatively on
another is just beginning to be understood
(Box 17–3). One possibility is that the change
in the receptor conformation that follows bind-
ing of the ER by a SERM results in variable inter-
actions with cofactors that determine their
gene regulation. These nuclear coactivators and
corepressors are sensitive to differences between
binding of ER to estrogen or a SERM. When
estrogen is bound to ER, coactivators promote
an interaction between the receptor and the
transcriptional
apparatus
that
provides
the
machinery for gene activation. Corepressors
restrain this activity. When ER is bound to a
SERM, the ligand-binding domain is distorted,
which may result in corepressor binding rather
than coactivator binding.
Another variable in the tissue-specific ago-
nist or antagonist activity of SERMs is the rela-
tive concentration of ERb. Tamoxifen, which
Proteins involved in
Inhibition of apoptosis
Altered cell-cycle control
Cell proliferation
mRNA
ER-mediated gene
expression
Estrogen
receptor
SRC
RAS
RAF
RAS
RAF
Estrogen
receptor
G-protein
activation
EGFR
IGF-1R
MAPK family
P13K
Estrogen
Figure 17–2. Upon binding estrogen, the estrogen receptor interacts with transcription factors to modulate
gene transcription for proteins involved in both proliferation and inhibition of apoptosis.
BOX 17–3 FACTORS DETERMINING
WHETHER A SELECTIVE ESTROGEN
RECEPTOR MODULATOR DISPLAYS
AGONIST OR ANTAGONIST EFFECTS
Structure of the selective estrogen
receptor modulator
Tissue factors
Relative levels of ERa and ERb
Levels of other growth factors
(epidermal growth factor receptor
[EGRF]; HER-2, IGFR)
Presence of coactivators or corepressors
Target genes
Promoter site activated by estrogen
response element or AP-1
271
17—PRINCIPLES OF ADJUVANT HORMONAL THERAPY

shows agonist activity in some tissues on bind-
ing to ERa, has no agonistic activity when it
interacts with ERb. In addition, the partial ago-
nist activity of tamoxifen that is manifest
through ERa can be completely abolished on
coexpression of ERb. When coexpressed in
tumor cells, ERb functions as a transdominant
inhibitor of ERa transcriptional activity at sub-
saturating hormone levels and decreases over-
all cellular sensitivity to estradiol.
Tamoxifen
Tamoxifen is the most studied hormonal therapy
for breast cancer and the most widely prescribed
anticancer drug in the world (Box 17–4). Tamoxi-
fen is given at a dose of 20 mg/day for 5 years.
Trials of higher doses (30 or 40 mg/day) have
not demonstrated any increased benefit. Sev-
eral trials have looked at varying durations. At
least four trials have demonstrated a significant
improvement in outcome with 5 years as com-
pared to 2 years of tamoxifen therapy. However,
taking tamoxifen for longer than 5 years is
controversial. Two of three trials, a National Surgi-
cal and Adjuvant Breast Project (NSABP) trial and
a Scottish trial, suggest that taking tamoxifen for
longer than 5 years may be associated with a
worse outcome. The incidence of endometrial
cancer appeared to double in women who took
tamoxifen for longer than 5 years (2.1% versus
1.1%). One of the three trials, an Eastern Cooper-
ative Oncology Group (ECOG) trial, suggests that
prolonged
treatment
with
tamoxifen
may
improve relapse-free survival and possibly overall
survival (OS). Longer-term follow-up is pending;
however, recent studies have suggested that the
sequential administrationof aromatase inhibitors
after 5 years of tamoxifen may be optimal
therapy.
Benefits of Tamoxifen in the Adjuvant
Setting
Relapse and Mortality
As with chemotherapy, it is worth bypassing a
lengthy discussion of the individual trials and
moving straight to the data from the EBCTCG.
The 1998 overview demonstrated a 47% pro-
portional reduction in recurrence and a 27%
improvement in mortality rates over a 10-year
period (Table 17–1). The 2000 update of the
BOX 17–4 ANTIHORMONAL THERAPIES IN BREAST CANCER
Drug
Mechanism
Setting
Side Effects
Risks
Tamoxifen
(Nolvadex)
Selective estrogen
receptor modulator
Adjuvant or
metastatic
Fatigue, hot flashes,
vaginal discharge, mood
swings, headache, skin
rash, nausea, and fluid
retention/weight gain
Thromboembolic
events, uterine
cancer, and
cataracts
Toremifene
(Fareston)
Selective estrogen
receptor modulator
Metastatic
Fulvestrant
(Faslodex)
Eliminates estrogen
receptor
Metastatic
Hot flashes, nausea, or
fatigue
Letrozole
(Femara)
Inhibit aromatase
and block
nonovarian
production of
estrogen
Adjuvant or
metastatic
Joint stiffness, bone, and
joint pain, nausea,
headache, and fluid
retention/weight gain
Osteoporosis
Anastrozole
(Arimidex)
Exemestane
(Aromasin)
Aromatase
inactivator
Goserelin
(Zoladex)
Blocks ovarian
production of
estrogen.
Adjuvant or
metastatic
Hot flashes and
menopause symptoms.
Osteoporosis
Leuprolide
(Lupron)
Megestrol
acetate
(Megace)
Progesterone
analog
Metastatic
Headache, nausea,
dizziness, SOB, hot
flashes, insomnia, and
weight gain
Thromboembolic
events and allergic
reactions
272
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

EBCTCG database now shows that these bene-
fits extend to 15 years.
The studies included trials of 1, 2, and 5 years
of tamoxifen and showed a highly significant
trend toward greater effect with longer duration
of therapy. The EBCTCG was not able to exam-
ine duration longer than 5 years, but the data
from the aforementioned studies address this
issue. The data also included about 8000 patients
who were included in these studies but were ER
negative or low risk. These patients clearly derive
no benefit from adjuvant tamoxifen.
Is there one group that benefits from tamoxi-
fen more than others? No. The relative benefit
of tamoxifen was similar for patients who were
both node positive and node negative (although
the absolute benefit is obviously greater for
patients who are node positive) and is irrespec-
tive of age, menopausal status, and whether or
not tamoxifen is used alone or in conjunction
with chemotherapy. The data is clear that hor-
monal therapy is not indicated in patients who
are ER and PR negative; however, one less clear
population are those patients who are ER nega-
tive but PR positive. The overview suggests a
benefit of tamoxifen in these patients, but the
numbers are too small to be conclusive.
Beyond the reduction in relapse and death,
there are other benefits to adjuvant tamoxifen.
Tamoxifen is associated with an increase in bone
mineral density in postmenopausal women and
may reduce fractures. It is also associated with a
reduction in low-density lipoprotein cholesterol.
Although it was hypothesized that tamoxifen
may reduce the risk for coronary heart disease,
and this was suggested by some individual
studies, this has not been validated. However,
one of the strongest side benefits of tamoxifen
is the prevention of new breast cancers. In the
1995 EBCTCG review, tamoxifen reduced the
incidence of new contralateral breast cancer by
46%. This is similar to what was seen in the
NSABP P-01 prevention trial (see Chapter 8).
Risks of Tamoxifen
Although the risk-to-benefit ratio for tamoxifen
is greatly in its favor, the drug is not without risks
and side effects. Tamoxifen is associated with an
increased incidence of hot flashes, vaginal dis-
charge, and night sweats. Sexual dysfunction is
not a common complaint, although it may cor-
relate with vaginal dryness. In addition to meno-
pause symptoms, there is an increased risk of
tamoxifen inducing menopause in premeno-
pausal women, although this is restricted to
women 45 years or older and is in part related
to the normal aging process. Several studies have
shown that despite these symptoms, quality of
life in women undergoing therapy with tamo-
xifen is not significantly worse than women
receiving placebo. Tamoxifen has also been
associated with ocular toxicities, specifically cor-
neal changes and retinopathy. For this reason,
it has been recommended that women con-
sider a baseline ophthalmic evaluation during
the first year of initiating tamoxifen and have
appropriate follow-up.
Thromboembolic disease is a worrisome risk
of tamoxifen because these can lead to fatal
consequences. This appears to affect less than
1% of patients and is more common in women
over the age of 50.
The most significant risk of tamoxifen appears
to be that of uterine cancer. Most of these cases
consist of adenocarcinoma of the endometrium,
although a small percentage of reported cases of
uterine cancers consist of uterine sarcoma, a rare
and aggressive form of uterine cancer. Half of
these cases are mixed mullerian tumors, which
have been linked to estrogen use and carry
a worse prognosis. In the prevention trial of
tamoxifen, the incidence of endometrial adeno-
carcinoma was 2.2 per 1000 woman-years for
women on tamoxifen (and with an intact uterus)
compared with 0.71 per 100 woman-years for
placebo. For sarcomas, the incidence was 0.17
compared with 0. Routine screening with trans-
vaginal ultrasound or endometrial biopsy is not
useful and thus not recommended. Instead,
women should be counseled about the need to
alert their physician for abnormal vaginal bleed-
ing and undergo regular gynecologic evaluations.
TABLE 17–1  Annual Percentage Risk
Reduction with 5 Years of Tamoxifen
from the Early Breast Cancer Trialists
Collaborative Group Overview
Relapse Death
Overall
42  3
22  4
Hormonal
status
ER positive
ER unknown
ER negative
50  4
37  8
6  11
28  5
21  9
3  11
Lymph nodes
Positive
Negative
43  4
49  4
28  6
25  5
Chemotherapy
52  8
47  9
Age
<50
50 to 59
60 to 69
>70
45  8
37  6
54  5
54  13
32  10
11  8
33  6
34  13
273
17—PRINCIPLES OF ADJUVANT HORMONAL THERAPY

Raloxifene
Raloxifene (Evista) resulted from efforts to
design SERMs that have estrogen activity in
bone and cardiovascular tissue but not in the
reproductive tissues, for the purpose of lower-
ing the risk of osteoporotic fractures. They
have been found to have similar effect to
tamoxifen on the chemoprevention of breast
cancer. This was incidentally discovered in a
trial of raloxifene or placebo in over 7700 post-
menopausal women with osteoporosis. With
4 years of follow-up, there was an 84% relative
reduction
in
the
incidence
of
ER-positive
breast cancer. This data prompted the Study
of Tamoxifen and Raloxifene (STAR) trial,
which randomized postmenopausal women
who are high risk for the development of
breast cancer to receive either tamoxifen or ral-
oxifene. The initial results of STAR show that
the drug raloxifene is as effective as tamoxifen
in reducing the breast cancer risk of the
women on the trial. In STAR, both drugs
reduced the risk of developing invasive breast
cancer by about 50% (see Chapter 8). How-
ever, raloxifene has never been studied in the
adjuvant setting, and its effect on known
breast cancer remains unknown. Thus it is
not recommended for the adjuvant therapy
of breast cancer in postmenopausal women.
Aromatase Inhibitors
Althoughtamoxifen has had tremendoussuccess
in the treatment of hormone-receptor-positive
breast cancer, it is not without problems. As a
partial estrogen agonist it has several potentially
serious side effects and tamoxifen resistance
poses a significant problem for clinicians. The
introduction of aromatase inhibitors (AIs) has
changed the scope of adjuvant hormonal ther-
apy for postmenopausal women.
AIs act by inhibiting the cytochrome P450
enzyme aromatase, which is responsible for
the peripheral aromatization of androgens,
converting them to estrogens. In postmeno-
pausal women, aromatase is primarily located
in the skeletal muscle and fat and represents
the predominant source of estrogen in the
body. AIs can either be steroidal inhibitors,
(formestane or exemestane) which are irrevers-
ible, or nonsteroidal inhibitors (anastrazole,
letrozole), which bind to a site distant to the
hormone-binding site and are reversible. AIs
do not impact the ovaries, and thus they are
only effective in postmenopausal women.
Several trials have examined AIs in the adju-
vant setting (Table 17–2). Most of these trials
compared an AI to tamoxifen or placebo. Little
data
has
emerged
comparing
one
AI
to
another. One has to be careful in interpreting
data interchangeably for anastrozole, letrozole,
and exemestane. Likewise, findings from AI
trials in early breast cancer can only be applied
to the select group of patients in which the
trial was conducted. Further trials meant to
better define the use of AIs in the adjuvant
setting are ongoing, and the recommendations
for AI use in the adjuvant setting are likely
to continue to change over the next several
years.
Anastrozole
The Arimidex, Tamoxifen, Alone or in Combi-
nation (ATAC) trial randomized 9366 post-
menopausal women to either tamoxifen or
anastrozole or the combination of the two.
The goal of this study was not only to see
TABLE 17–2  Aromatase Inhibitors in the Adjuvant Setting
Trial
Groups
N
Median
Follow-
Up
Disease-
Free
Survival
Contralateral
Tumors
Arimidex, Tamoxifen,
Alone or in
Combination
T versus A versus
combination
9366
68
DFS: A > T
42% reduction
with A
Italian
T versus A after 2–3
years of tamoxifen
426
30
DFS: A > T
Study too small
MA-17
L versus placebo after
5 years of tamoxifen
5187
29
DFS: L >
placebo
46% reduction
with L
Intergroup Exemestane
Study
T versus E after 2–3
years of tamoxifen
4742
31
DFS: E > T
56% reduction
with E
A, Arimidex; DFS, disease-free survial; E, exemestane; L, Letrozole; T, tamoxifen.
274
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

whether Arimidex was superior to tamoxifen,
but also if the combination might be synergis-
tic. In the most recently published results,
after a median follow-up of 68 months, ana-
strazole significantly prolonged disease-free
survival (DFS; hazard ratio 0.87, p ¼ 0.01).
Time to recurrence and number of distant
metastases were also significantly improved.
It will take considerably more time before
any conclusions regarding OS can be made.
Anastrozole was also superior to the combina-
tion of anastrazole and tamoxifen, and this
approach has been abandoned.
Three trials have examined the benefits of
switching to Arimidex after 2 or 3 years of
tamoxifen, including the Austrian Breast and
Colorectal Cancer Study Group (ABCSG) 8 trial,
the Arimidex-Nolvadex (ARNO) 95 trial, and
the Italian Tamoxifen Anastrazole (ITA) trial.
All three showed a benefit to switching to
anastrazole.
Finally, the PreOperative Arimidex Compared
with Tamoxifen (PROACT) and Immediate Pre-
operative Arimidex, Tamoxifen or Combined
with Tamoxifen (IMPACT) trials compared preop-
erative treatment with anastrazole with the
preoperative treatment of tamoxifen in postmen-
opausal women with large hormone-receptor-
positive breast cancer. In both studies, 3 months
of anastrazole appears to increase the likelihood
of breast-conserving surgery compared with
tamoxifen (43% versus 31%, combined data,
p ¼ 0.019).
Exemestane
The Intergroup Exemestane Study (IES) rando-
mized 4742 postmenopausal women who had
completed 2 or 3 years of tamoxifen to either
continue with tamoxifen to a total of 5 years
or to switch to exemestane. At 3 years follow-
up, switching to exemestane was associated
with a significantly improved DFS but no dif-
ference in OS. Fewer toxic effects were seen
with exemestane.
Letrozole
The MA.17 study performed by the National
Cancer Institute of Canada looked at the role
of letrozole in women who have completed 5
years of tamoxifen. Over 5000 women were ran-
domized to placebo or letrozole after 5 years of
tamoxifen. The 4-year DFS was 93% for patients
receiving letrozole and 87% for patients receiv-
ing placebo (p < 0.001). Unfortunately, without
longer follow-up, it is unclear whether OS or
distant DFS is improved or if long-term adverse
effects may preclude the benefit.
The BIG 1-98 trial is a four-arm trial compar-
ing 5 years of letrozole, 5 years of tamoxifen,
2 years of letrozole followed by 3 years of
tamoxifen, and 2 years of tamoxifen followed
by 3 years of letrozole. Mature data are not yet
available, although preliminary data suggest
that 5 years of letrozole may be better than 5
years of tamoxifen, with an improvement in
DFS (0.81, p < 0.001). As with the ATAC trial,
an improvement in OS has not yet been seen
and will require much longer follow-up.
Toxicity of Aromatase Inhibitors
The AIs have a considerably different side
effect profile than SERMs. Because anastrazole,
letrozole, and exemestane have different struc-
tures and pharmacokinetic profiles, it cannot
be assumed they will all have the same safety
profiles. However, long-term data (beyond 5
years) is available only for anastrazole and
head-to-head
comparisons
have
not
been
performed.
Gynecological events, a problem for tamoxi-
fen, do not appear to be as much of a problem
for AIs. In the ATAC trial, anastrazole was asso-
ciated with significantly fewer effects on the
endometrium, less endometrial cancer, and
reductions in hot flashes, vaginal bleeding,
and discharge compared with tamoxifen. Sim-
ilar findings were reported with exemestane
and letrozole from those studies, although
not all were significant.
Another major concern of tamoxifen is the
risk of thromboembolic disease. Again, AIs
seem to have a lower risk compared to tamoxi-
fen, as evidenced from both the ATAC trial and
BIG 1-98 trial. In the ATAC trial, there was a sig-
nificant reduction of ischemic cerebrovascular
and thromboembolic events with anastrazole.
In contrast, patients on AIs will not receive
the estrogen agonist benefits of tamoxifen. This
is particularly true for the tamoxifen-induced
promotion of bone mass and protective effects
on bone. Thus AIs have a higher rate of fracture
and joint disorders. These may be minimized
by monitoring bone densities and the use of
bisphosphonates, where appropriate. Another
presumed advantage to tamoxifen is the protec-
tion against heart disease by estrogen-induced
changes in plasma lipids. However, the data is
mixed, and in some cases contradictory, as to
whether AIs confer a higher cardiac risk than
tamoxifen.
275
17—PRINCIPLES OF ADJUVANT HORMONAL THERAPY

Adjuvant Therapy with Aromatase
Inhibitors
With all this recent data about the potential of
AIs, how does one incorporate this into clini-
cal practice when treating postmenopausal
women? Should postmenopausal women go
directly to an AI or should they start with
tamoxifen and then switch after 2 or 3 years?
Should women already on tamoxifen switch
now or finish 5 years and then continue therapy
with an AI? Should AIs even be considered in the
absence of OS data and long-term safety studies?
Several groups, including ASCO, the National
Comprehensive Cancer Network (NCCN), and
the St. Gallen Expert Consensus Group have
concluded that an AI should be included in the
adjuvant treatment of postmenopausal women
with hormone-receptor-positive breast cancer.
The decision should obviously be based partly
on the patient’s history, including thromboem-
bolic risk, prior hysterectomy, cardiovascular risk
factors, osteopenia, and osteoporosis. In the
absence of these factors leading one way or the
other, only the NCCN has made specific recom-
mendations. They have recommended that ana-
strazole should be used as initial therapy for
women newly diagnosed with breast cancer
and beginning adjuvant hormonal therapy;
switching treatment from tamoxifen to either
anastrazole or exemestane in postmenopausal
women 2 to 3 years into tamoxifen therapy,
and extending hormonal therapy for an addi-
tional 5 years with letrozole in women who have
completed 5 years of tamoxifen.
Ovarian Suppression/Ablation
The original hormonal therapy consisted of
ovarian ablation, either by surgery, irradia-
tion, or pharmacologic methods. This still
remains an option for premenopausal women
with hormone-receptor-positive breast cancer
(Table 17–3). Ovarian ablation can be achieved
through several mechanisms. The first is surgi-
cal oophorectomy. The safety of this approach
has increased with the introduction of laparo-
scopic surgery, and there may be additional
benefits in regard to prophylaxis against ovar-
ian cancer in high-risk patients, such as those
with breast cancer gene 1 and 2 (BRCA 1 and
2) mutations or those with a family history of
ovarian cancer. Ovarian irradiation can also be
effective at ablating ovarian function. However,
there are morbidities associated with both of
these approaches, and they are irreversible,
which may be a problem for young patients
with breast cancer. An alternative approach is
the use of LHRH agonists, a medical form of
ovarian ablation. Goserelin acetate is an ana-
logue of LHRH, which suppresses ovarian func-
tion,
allowing
patients
to
maintain
their
function after completion of therapy.
The benefits of ovarian ablation/suppression
are seen in the meta-analysis conducted by the
EBCTCG. A 2000 EBCTCG overview analyzed
4900 women who underwent ovarian suppres-
sion with or without chemotherapy. Ovarian
suppression was associated with an improve-
ment in OS in women who did not receive che-
motherapy,
but
there
was
no
impact
on
survival in patients who did receive chemother-
apy. The survival benefit of ovarian ablation
alone was similar to the survival benefit of
chemotherapy alone.
Several individual trials highlight the poten-
tial of goserelin as an alternative to chemother-
apy in premenopausal women with ER-positive
tumors.
The
Zoladex
Early
Breast
Cancer
Research Association (ZEBRA) trial randomized
women to either 2 years of goserelin or cyclo-
phosphamide, methotrexate, and fluorouracil
(CMF) chemotherapy. Among patients who
were ER positive, survival was equal, whereas
CMF was significantly better among patients
who were ER negative. Importantly, menses
returned in the majority of women randomized
to goserelin, whereas 77% of women on CMF
had ovarian ablation with permanent amenor-
rhea. Another trial, the ABCSG 05 trial, com-
pared CMF to goserelin plus tamoxifen. Again,
no difference in survival was seen, and the
authors concluded that goserelin plus tamoxi-
fen is more effective and better tolerated.
The EBCTCG overview found no benefit to
ovarian suppression in women receiving adju-
vant chemotherapy; however, many women
receiving adjuvant chemotherapy will have
chemotherapy-induced ovarian ablation. So is
there a benefit to ovarian ablation/suppression
among women receiving chemotherapy who
maintain ovarian function? This has been
addressed in several trials without definitive
results. The Zoladex in Premenopausal Patients
(ZIPP) analysis combined data from four rando-
mized trials initiated by international collabora-
tive groups. Initial results (median follow-up of
4.3 years) suggest that the addition of goserelin
to standard chemotherapy will decrease the risk
of recurrence, although OS was not improved.
Intergroup trial INT-0101 randomized patients
276
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

to chemotherapy, chemotherapy plus goserelin,
or chemotherapy plus goserelin plus tamoxifen.
The triple therapy arm had an improvement
in 5-year DFS, with no improvement in OS.
The effect was greatest in women less than 40,
which may be as a result of the higher fraction
of women who maintained ovarian function.
However, there was no chemotherapy plus
tamoxifen arm, which is the standard of care,
so it is difficult to know how to use this data
clinically. Finally, the International Breast Can-
cer Study Group (IBCSG) trial randomized
women to chemotherapy, goserelin, or both
(a no adjuvant treatment group was dropped
during the course of the trial). No difference in
DFS or OS was seen between the three groups.
Further data is necessary to answer whether
ovarian suppression added to chemotherapy
and tamoxifen is beneficial in patients who are
premenopausal and ER positive, particularly if
ovarian function is maintained after chemother-
apy. An ongoing study of ovarian ablation/sup-
pression will hopefully answer this question. For
now, the only conclusion one can make is that
ovarian ablation/suppression is a potential alter-
native to chemotherapy in this subset of patients.
TABLE 17–3  Adjuvant Therapy with Ovarian Ablation/Suppression
Trial
N
Patients
Arms
Results
ZEBRA
1640
Node positive
G  2 years
CMF
No difference in DFS
IBCSG
1063
Node negative
Chemo
G  2 years
Chemo þ G
No difference in DFS
Scottish Trial
332
Node positive
CMF
OA
OS better for OA for ER 
20 but worse for ER < 20
Scandinavian Trial
732
Node positive
ER positive
CMF
OA
No difference in DFS or OS
TABLE
600
Node positive
ER positive
CMF
Leuprorelin  2 years
No difference in DFS or OS
ABCSG
1034
ER positive
CMF
G þ T
G þ T improved DFS
GROCTA
244
ER positive
OA þ T
CMF
No difference in DFS or OS
France
162
Node positive
ER positive
FAC
OA þ T
No difference in DFS or OS
FACS 06
333
Node positive
ER positive
Triptorelin þ T
FEC
No difference in DFS or OS
ZIPP
2631
G
T
G þ T
No further treatment
G improved DFS
INT-0101
1504
Node positive
ER positive
CAF
CAF þ G
CAF þ G þ T
T improved DFS
Vietnam
709
OA þ T
No further treatment
" DFS and OS with OA þ T
France
926
Chemo
Chemo þ OA
No difference in DFS or OS
Mam-1 GOSCI
466
Node positive
Chemo
Chemo þ G þ T
DFS " with G þ T
IBCSG
174
Node positive
ER positive
Chemo þ OA þ T
OA þ T
No difference in DFS or OS
CAF, cyclophosphamide, doxorubicin, fluorouracil; CMF, cyclophosphamide, methotrexate, and fluorouracil; DFS,
disease-free survival; ER, estrogen receptor; FAC, fluorouracil, doxorubicin, cyclophosphamide; FEC, fluorouracil,
epirubicin, cyclophosphamide; G, Goserelin; Mam-1 OA, ovarian ablation; OS, overall survival; T, tamoxifen;
ZEBRA, Zoladex Early Breast Cancer Research Association; ZIPP, Zoladex in Premenopausal Patients.
277
17—PRINCIPLES OF ADJUVANT HORMONAL THERAPY

Suggested Readings
1. Arimidex, Tamoxifen, Alone or in Combination
(ATAC) Trialists’ Group, Forbes JF, Cuzick J, et al. Effect
of anastrozole and tamoxifen as adjuvant treatment
for early-stage breast cancer: 100-month analysis of
the ATAC trial. Lancet Oncology 2008;9(1):45–53.
2. Baum M, Budzar AU, Cuzik J, et al. Anastrozole
alone or in combination with tamoxifen versus
tamoxifen alone for adjuvant treatment of post-
menopausal women with early breast cancer: first
results
of
the
ATAC
randomized
trial.
Lancet
2002;359(9324):2131–2139.
3. Buzdar AU. Aromatase inhibitors: Changing the
face of endocrine therapy for breast cancer. Breast
Disease 2006;24:107–117.
4. Coombes RC, Hall E, Gibson LJ, et al. A randomized
trial of exemestane after two to three years of tamoxi-
fen therapy in postmenopausal women with primary
breast cancer. N Engl J Med 2004;350(11):1081–1092.
5. Fisher B, Costantino J, Redmond C, et al. A rando-
mized clinical trial evaluating tamoxifen in the
treatment of patients with node-negative breast
cancer who have estrogen-receptor positive tumors.
N Engl J Med 1989;320(8):479–484.
6. Fisher B, Dignam J, Bryant J, , et al. Five versus more
than five years of tamoxifen therapy for breast
cancer patients with negative lymph nodes and
estrogen receptor positive tumors. J Natl Cancer
Inst 1996;88(21):1529–1542.
7. Goss PE, Ingle JN, Martino S, et al. A randomized trial
of letrozole in postmenopausal womenafter five years
of tamoxifen therapy for early stage breast cancer.
N Engl J Med 2003;349(19):1793–1802.
8. Ovarian ablation for early breast cancer. Cochrane
Database Syst Rev 2000;3:CD000485.
9. Ovarian ablation for early breast cancer: overview
of the randomized trials. Early Breast Cancer Tri-
alists’ Collaborative Group. Lancet 1996;348(9036):
1189–1196.
10. Tamoxifen for early breast cancer. Cochrane Data-
base Syst Rev 2001;(1):CD000486.
11. Tamoxifen for early breast cancer: an overview of
the randomised trials. Early Breast Cancer Trialists’
Collaborative Group. Lancet 1998;351:1451.
12. Winer EP, Hudis C, Burstein HJ, et al. American
Society of Clinical Oncology technology assess-
ment working group update: use of aromatase inhi-
bitors in the adjuvant setting. J Clin Oncol 2003;
21(13):2597–2599.
13. Yager JD, Davidson NE. Estrogen carcinogenesis in
breast cancer. N Engl J Med 2006;354:270–282.
278
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18
Neoadjuvant Therapy
NEOADJUVANT THERAPY
REGIMENS
PATIENT SELECTION FOR
NEOADJUVANT THERAPY
NEOADJUVANT
CHEMOTHERAPY AND SURGERY
Breast Conservation Rates
Local Recurrence Rates after
Neoadjuvant Chemotherapy
Primary Surgery after Neoadju-
vant Chemotherapy
Sentinel Lymph Node Biopsy
after Neoadjuvant
Chemotherapy
NEOADJUVANT
CHEMOTHERAPY AND
OUTCOME
Does Earlier Delivery of Che-
motherapy Improve Survival?
Can Neoadjuvant Chemother-
apy Be Used as a Chemosen-
sitivity Test?
Neoadjuvant Therapy: Key Points
Describe the potential benefits of delivering chemotherapy
before surgery.
Know the indications and contraindications to neoadjuvant chemotherapy.
Be familiar with the implications of neoadjuvant chemotherapy on breast
surgery.
Develop an algorithm for interrogating the sentinel lymph node in patients
undergoing neoadjuvant chemotherapy.
Understand the potential of neoadjuvant hormonal therapy.
Neoadjuvant therapy refers to the delivery of
systemic therapy before surgical intervention
in an attempt to not only control distant dis-
ease, but also to decrease the size of the primary
tumor. This allows for the potential resection
of an inoperable cancer or the use of breast-
conservation therapy (BCT) in a case in which
amastectomywouldhave beenindicated.Neoad-
juvant therapy can include preoperative chemo-
therapy or preoperative hormonal therapy.
Using systemic therapy upfront is consid-
ered the standard treatment for patients who
present with inoperable breast cancer. This
includes patients with locally advanced tumors
279

(T4 tumors), inflammatory breast cancer, and
patients with involvement of the supra or infra-
clavicular lymph nodes (N3). This was not
always the case because there was concern that
the effect of chemotherapy would increase the
surgical complication rate or negatively affect
overall survival (OS) by delaying the surgery.
However, surgery first was associated with dis-
mal results in treating locally advanced breast
cancer (LABC), and trials of primary chemo-
therapy quickly demonstrated the benefits of
preoperative downstaging of disease to improve
respectability. This will be discussed in more
detail in Chapter 19.
The success of primary systemic therapy in
inoperable breast cancer led to the suspicion that
it may be preferable in operable breast cancer.
Today, the phrase neoadjuvant therapy typically
refers to the use of preoperative chemotherapy
as an alternative to postoperative chemotherapy.
Based on the experience with LABC, it was
thought that giving the chemotherapy before
surgery to treat the occult micrometastases at an
earlier time may increase survival. However, all
the large randomized trials of preoperative che-
motherapy demonstrated equivalent disease-free
survival (DFS) and OS. What did become appar-
ent was that the rate of breast conservation was
significantly increased afterneoadjuvant therapy
(Table 18–1). The primary indication today for
neoadjuvant chemotherapy is the patient with
operable breast cancer (good candidates for mas-
tectomy) who desires breast conservation. It may
also be considered for patients who could techni-
cally undergo a lumpectomy but will receive a
better cosmetic outcome if the tumor decreases
in size (Box 18–1).
It must be remembered that delivering the
chemotherapy preoperatively is an alternative
to adjuvant chemotherapy. The determinant
for the use of chemotherapy is the risk of dis-
tant recurrence. Therefore, neoadjuvant che-
motherapy should only be offered to patients
who, based on clinical staging (tumor size,
grade, estrogen receptor/progesterone recep-
tor [ER/PR] status, clinically involved lymph
nodes, and possibly genetic profiling), would
be candidates for chemotherapy. It should
not be used to shrink a primary tumor in a
patient who would not otherwise require sys-
temic therapy. For example, a small-breasted
woman with a 1.5-cm, intermediate-grade,
ER/PR-positive primary tumor, clinically node
negative, may benefit from shrinking the
tumor, but she might not require adjuvant
chemotherapy based on her low risk of distant
recurrence. This would be particularly true if
her genomic profiling suggested a low risk of
recurrence (see Chapter 16). An improved
TABLE 18–1
Breast Conservation
Rates After Neoadjuvant
Chemotherapy
Breast-Conservation
Therapy Rate
Study
Patients Preopera-
tively (%)
Postopera-
tively (%)
Institut
Bergonie
272
63.1
0
Institut Curie
414
82
77
Royal
Mardson
309
89
78
NSAPB B18
1523
68
60
EORTC
698
37
21
ECTO
892
71
35
ABCSG
423
67
60
ABCSG, Austrian Breast and Colorectal Cancer Study
Group; ECTO, European Cooperative Trial; EORTC,
European Organization for Research and Treatment
of Cancer; NSAPB, National Surgical and Adjuvant
Breast Project.
BOX 18–1 POTENTIAL
ADVANTAGES TO NEOADJUVANT
CHEMOTHERAPY


May allow for breast-conservation
therapy in a woman who would
otherwise require a mastectomy.


May improve the aesthetic outcome of a
lumpectomy by decreasing the volume of
tissue needing to be resected.


Allows for an assessment of the response
of the tumor to chemotherapy. This may
allow for modifications of therapy based
on response. In addition, a demonstrable
response may also have a positive effect
on the patient’s compliance with further
treatment and on the patient’s willingness
to accept some adverse events.


Allows patients to delay surgery so they
have more time to accept the need for
mastectomy, consider reconstructive
options, or undergo genetic counseling
and testing if prophylactic mastectomies
are considered.


Allows women in their second or third
trimester of pregnancy to delay the
surgery and radiotherapy until after
delivery.


May reduce distant metastases compared
with classic adjuvant systemic therapy.
280
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

cosmetic result does not justify the toxicity
and sequelae of chemotherapy. In addition,
as the primary goal of neoadjuvant chemo-
therapy is to allow BCT, patients who will still
require mastectomy after chemotherapy (Box
18–2), are not ideal candidates, although there
are other reasons why neoadjuvant chemo-
therapy might be considered.
There are other potential and real advantages
to neoadjuvant therapy. In addition to allowing
more women to proceed with breast conserva-
tion, it also allows women who will require mas-
tectomy to come to terms with their diagnosis,
think about whether to have reconstruction
and what type of reconstruction to have, and
possibly undergo genetic counseling and testing
and decide whether to undergo bilateral mastec-
tomies. In addition, the patient’s response to the
chemotherapy provides prognostic information.
Patients who have a complete pathological
response (pCR) have a better long-term outcome
than those who do not. Whether this informa-
tion can be used to adjust pre- or postsurgical
chemotherapy is still an area of investigation.
However, clinical trials using neoadjuvant che-
motherapy do allow for a more rapid and less
expensive means for evaluating the efficacy of
new agents and regimens. Adjuvant therapy
trials require many patients over many years,
whereas neoadjuvant therapy trials can be com-
pleted over the course of just a few years. This
chapter will address several of these issues.
Neoadjuvant Therapy
Regimens
Most of the attention in neoadjuvant therapy
has been focused on chemotherapy. However,
hormonal therapy plays a crucial role in the
management
of
breast
cancer,
particularly
among women who are post-menopausal and
hormone-receptor positive. This patient popula-
tion often does not require systemic chemother-
apy. It should then seem reasonable to believe
that these patients could receive the benefits of
preoperative therapy without the need for che-
motherapy.
Neoadjuvant
hormonal
therapy
has been less extensively studied than chemo-
therapy protocols, but it is a viable option for
postmenopausal women who have hormone-
receptor-positive disease. Several trials examined
the effect of preoperative hormonal therapy.
In a direct comparison of hormonal therapy to
chemotherapy, the St. Petersburg trial showed
that comparable, though not equivalent, rates
of both response (75.8% versus 89.8%) and
breast conservation (21% versus 37.2%). Other
studies demonstrated that neoadjuvant aroma-
tase inhibitors were superior to tamoxifen in the
neoadjuvant setting (Table 18–2). The data sug-
gest that primary endocrine therapy is a valid
option for postmenopausal patients with hor-
mone-receptor-positive breast cancer who desire
breast conservation but for whom cytotoxic
chemotherapy is not indicated.
At least 3 to 4 months of neoadjuvant endo-
crine therapy is generally needed to achieve a
significant clinical response, and this may need
to be continued for 6 months to see a benefit.
As opposed to chemotherapy, the response takes
a longer time to become clinically apparent.
Often a response is not visible until 2 months
into therapy, a point important for surgeons
and patients alike, so they do not discontinue
therapy and proceed with surgery too quickly.
Current data suggests that aromatase inhibitors
may offer better clinical responses than tamoxi-
fen and increased rates of breast-conserving
BOX 18–2 SITUATIONS IN WHICH
NEOADJUVANT CHEMOTHERAPY
IS NOT NECESSARILY APPROPRIATE


Women for whom the use of
chemotherapy is not indicated based on
clinical staging or not clear


Women with diffuse microcalcifications
throughout the breast


Women with multicentric breast cancer


Women who can not undergo
radiotherapy and so are not candidates
for breast conservation
TABLE 18–2
Hormonal Therapy
in the Neoadjuvant Setting
Study
Therapy
Breast-
Conservation
Therapy Rate (%)
IMPACT
anastrazole
46
tamoxifen
22
anastrazole þ
tamoxifen
26
Letrozole
024 Trial
letrozole
45
tamoxifen
35
St. Petersburg
anastrazole
21
doxorubicin
and
paclitaxel X4
37
IMPACT, Immediate Preoperative Arimidex, Tamoxifen
or Combined with Tamoxifen.
281
18—NEOADJUVANT THERAPY

surgery. Ongoing prospective clinical trials will
better define which aromatase inhibitor (if any)
might be best and provide valuable clinical infor-
mation regarding the clinical use of neoadjuvant
hormonal therapy on downstaging tumors.
Future trials directly comparing neoadjuvant
hormonal therapy to neoadjuvant chemother-
apy are planned.
Most neoadjuvant therapy consists of cyto-
toxic chemotherapy. Anthracycline-based regi-
mens are the most extensively studied, and the
typical neoadjuvant approach consists of four to
six cycles of Adriamycin and cyclophosphamide.
More recent data demonstrate a higher clinical
and pathologic response rate with the addition
of a taxane, and four cycles of Adriamycin/cyclo-
phosphamide followed by four cycles of taxol
have become a common neoadjuvant regimen
(Table 18–3). For patients who are human epider-
mal growth factor receptor 2 (Her-2/neu) posi-
tive,
even
higher
response
rates
may
be
achieved
with
the
addition
of
Herceptin.
Although a wide variety of timing schedules have
been studied, there is no consensus on whether
sequential, concurrent, or dose-dense approaches
should be considered the standard of care.
Patient Selection for
Neoadjuvant Therapy
As stated, the primary indication for delivering
chemotherapy in the neoadjuvant setting is to
downstage the primary tumor to increase the
likelihood of successful breast conservation.
Patients who will require mastectomy regard-
less of response, such as those with multi-
centric disease, widespread calcifications, or
those who cannot undergo radiation therapy,
do not directly benefit from the chemotherapy
being delivered before surgery as compared to
after surgery, although giving neoadjuvant
therapy may give the patient time to consider
reconstructive options or contralateral mastec-
tomy, and the tumor response may yield prog-
nostic
information.
Likewise,
patients
who
would
not
require
adjuvant
chemotherapy
(based on their risk of distant disease) should
not be given neoadjuvant chemotherapy simply
to downstage their primary tumor. The indica-
tions for chemotherapy should be clear. For
example, some patients with large-volume, pal-
pable ductal carcinoma in situ (DCIS) may
require a mastectomy based on the size of the
tumor, but clearly do not merit chemotherapy,
and thus neoadjuvant chemotherapy is contrain-
dicated. It is important, however, to confirm that
they have only DCIS or DCIS with microinvasion
and not a large invasive component. If this can-
not be done with multiple core-needle biopsies,
an open, incisional biopsy may be necessary.
Recommendations for neoadjuvant chemo-
therapy may also be based on the likelihood of
downstaging occurring. Hormone receptor sta-
tus, Her-2/neu status, tumor grade, primary
tumor histology, and patient age are factors that
may influence this. ER/PR-positive, low-grade
tumors are less likely to decrease in size than
ER/PR-negative or high-grade tumors. Com-
pared with ductal carcinoma, lobular carcinoma
tends to present at a more advanced stage and is
less likely to respond to neoadjuvant therapy.
These women have lower rates of breast conser-
vation after neoadjuvant therapy than women
with ductal carcinoma, and although this should
be discussed with the patient with lobular carci-
noma, it is not an absolute contraindication to
neoadjuvant chemotherapy.
Neoadjuvant Chemotherapy
and Surgery
Breast Conservation Rates
The National Surgical Adjuvant Breast and Bowel
Project (NSABP) B-18 trial was the first and larg-
est study to compare delivery of chemotherapy
before surgery, with postoperative chemother-
apy. This trial found that although doxorubicin
and cyclophosphamide (four cycles) given pre-
operatively did not improve survival, there
was a 7% higher rate of breast conserving sur-
gery (p < 0.01). Other trials confirmed these
results, although they varied in the eligibility cri-
teria and the regimen of chemotherapy. Using
TABLE 18–3
Taxanes in the
Neoadjuvant Setting
Study
Regimen
Breast-
Conservation
Therapy rate (%)
Geparduo
APx4 q2W
66
ACx4 ! Tx4
75
Geparduo
TACx6
81
AGO
ETx4
55
Ex3 ! Tx3, q2W
66
NSABP B-27
ACx4
62
ACx4 ! Tx4
64
A, doxorubicin; C, cyclophosphamide; E, epirubicin;
P, paclitaxel; T, docetaxel.
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SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

four cycles of fluorouracil, epirubicin and cyclo-
phosphamide (FEC), both the Institute Curie
and the European Organization for Research
and Treatment of Cancer (EORTC) reported
increased rates of breast conservation with pre-
operative chemotherapy (5% and 16% increases,
respectively).
Using improved combinations or sequences
of drugs, the breast conservation rate can
be further increased. The European Coopera-
tive Trial (ECTO) compared preoperative or
postoperative doxorubicin and paclitaxel in
combination,
followed
by
four
cycles
of
cyclophosphamide, methotrexate, and fluoro-
uracil (CMF). In this study, the breast-con-
serving surgery rate increased from 34% to
65%. Subsequent studies confirmed that the
response rates and breast-conserving surgery
rates could be further improved by adding
taxanes
to
the
combination.
The
NSABP
B-18 trial had a pathologic complete response
rate of 9.8%. This is substantially higher in
studies
using
taxanes
(GEPARDUO-22%;
AGO-18%; NSABP B27-26%).
Local Recurrence Rates after
Neoadjuvant Chemotherapy
The primary indication for neoadjuvant chemo-
therapy, outside of a clinical trial, is to down-
size the primary breast tumor, facilitating a
margin-negative lumpectomy with a smaller
volume. However, there are two ways the
tumor may shrink (Fig. 18–1), often compared
to either a lollipop or a dandelion. As with a lol-
lipop being licked, the tumor may shrink down
concentrically, toward a smaller central mass
but
leaving
no
disease
at
the
periphery.
This would lend itself quite well to a reduced-
volume lumpectomy. However, if the tumor
shrinks in a way that leaves microscopic satellite
lesions, then breast conservation may be com-
promised. This honeycombed response has
been compared to blowing on a dandelion to
completely rid it of its seeds. The tumor disap-
pears in a more scattered pattern, leaving micro-
satellite lesions anywhere within the original
tumor volume. After lumpectomy, this would
result in a high rate of margin failure and local
recurrence rates.
Of the major randomized studies of neoad-
juvant chemotherapy, local recurrence rates
have been either equivalent or higher in the
preoperative chemotherapy arms, but within
acceptable limits (Table 18–4). Local recur-
rence rates varied between 3% and 27% and
depend on the duration of follow-up, the type
of surgery, and the margins obtained. The
largest study, NSABP B-18, randomized over
1500 women with stages I through IIIA breast
cancer to preoperative or postoperative che-
motherapy. There was a statistically significant
increase in breast conservation (68% versus
60%), but with a median follow-up of 72
months, there was no statistically significant
difference in local recurrence following BCT
Concentric
Allows for decreased
volume of resection.
Honeycombed
Requires the same
volume of resection as
before chemotherapy
Figure 18-1. As with a lollipop
beinglicked,chemotherapymay
shrink the tumor concentrically,
toward a smaller central mass
but leaving no disease at the
periphery. A smaller area of re-
sectionis appropriate. However,
if the tumor shrinks in a way
that leaves microscopic satel-
lite lesions, the same area of
resection as before chemother-
apy may be needed.
283
18—NEOADJUVANT THERAPY

(7.9% versus 5.8%). However, this includes
those patients who were candidates for lump-
ectomy before they received their chemo-
therapy. If you look at just those patients
who would have required mastectomy, but
were downstaged to become eligible for BCT,
there was a higher local recurrence rate. The
rate of local recurrence in patients who had
BCT after neoadjuvant chemotherapy instead
of mastectomy was 16% compared to the
10% of patients who were considered candi-
dates for BCT before chemotherapy. It is hard
to say how significant this increase in local
recurrence this was, because most of these
were T3 tumors and would have had an
increased rate of chest wall recurrence if mas-
tectomy would have been performed.
Primary Surgery after Neoadjuvant
Chemotherapy
When neoadjuvant chemotherapy was first
proposed, there was some concern that this
might increase the rate of surgical complica-
tions or radiation side effects. After 30 years
of experience, this has not been seen and
should not be a concern. Surgery should not
be performed until leukocyte counts and
hemoglobin and hematocrit levels are back
to normal, which typically takes 3 to 4
weeks after the last cycle of chemotherapy
(although it may take up to 6 weeks in some
patients).
The goal of the chemotherapy is to shrink the
primary tumor to allow for breast conservation.
Hopefully, the tumor will completely disappear
because a complete pathologic response is asso-
ciated with an improved OS. The surgeon there-
fore needs to plan on the possibility that at the
time of surgery, there will be no way of identify-
ing where the primary tumor was. Therefore,
before the initiation of chemotherapy, the
surgeon should assure that precise localization
will still be possible when the chemotherapy is
completed. Several methods have been pro-
posed for this. One option is to mark on the
skin of the patient the exact location and size
of the tumor and the proposed surgical skin
incision and then photograph this. The bound-
aries of the tumor can also be marked on the
skin with small tattoos, similar to the tattooing
done for radiation therapy. The most common
method is to place a metal clip or coil in the
center of the lesion. In the patient who had a
core biopsy of a palpable mass performed in
the office, this may require an additional proce-
dure. However, this will be well worth it if there
is complete clinical resolution of the mass. With
improving chemotherapeutic regimens, a com-
plete
clinical
response
is
becoming
more
frequent.
When the decision is made to use preoperative
chemotherapy, it is accepted that surgery is an
obligatorypart of the multidisciplinary approach
to the tumor. However, after a complete clinical
response, patients often question why they still
need to undergo surgery. It is important to
inform patients that even when there is a com-
plete disappearance of the tumor on physical
examination, mammography, or ultrasound,
there remains uncertainty whether there is
microscopic disease still in the region. Therefore,
lumpectomy is still required to assess the patho-
logic response. Although some studies have sug-
gested magnetic resonance imaging (MRI) may
be more accurate for assessment of residual dis-
ease, it is still not reliable enough to avoid lump-
ectomy. Likewise, the presence of a residual mass
does not always mean that a complete patho-
logic response has not been achieved because it
may not be possible to differentiate chemother-
apy-induced fibrosis from tumor.
A careful physical examination should be
performed to document the extent of disease
TABLE 18–4
Local Recurrence Rates After Neoadjuvant Chemotherapy
Overall Survival
Local Recurrence
Study
Patients
Median Follow-Up
(Months)
Preopera-
tively (%)
Postopera-
tively (%)
Preopera-
tively (%)
Postopera-
tively (%)
Institut
Bergonie
272
124
55
55
23
NA
Institut Curie
414
66
86
78
24
18
Royal
Mardson
309
48
80
80
3
4
NSAPB B18
1523
108
69
70
10.7
7.6
NSAPB, National Surgical and Adjuvant Breast Project.
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SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

in both the breast and regional lymph nodes.
This should be accompanied by repeat imag-
ing
studies
including
mammography
and
ultrasound. MRI should only be used if it was
also used preoperatively. The surgeon must
decide whether the residual mass may be
excised with a satisfactory cosmetic result and
negative margins. The geography of the resi-
dual mass, the shape and size of the breast,
and the presence of microcalcifications will
influence this decision. Malignant-appearing
calcifications
do
not
always
resolve
with
chemotherapy, and if there remain large areas
of calcifications on the postchemotherapy
mammogram, these must be incorporated in
the lumpectomy. Patients who began with
locally advanced cancer should have regres-
sion of any skin or chest wall involvement.
Patients who began with inflammatory carci-
noma should undergo mastectomy regardless
of their clinical response.
When the surgeon takes the patient to the
operating room, they are faced with a question
of how much tissue to remove. Obviously, if
the tumor was large enough to warrant a mas-
tectomy, then using the original tumor size to
guide the excision would preclude breast con-
servation and obviate the need for having
delivered the chemotherapy upfront. How-
ever, there may be no macroscopic evidence
of disease to guide the surgeon in how much
tissue to remove. What about the patient
who was a candidate for a lumpectomy before
neoadjuvant chemotherapy? Should the lump-
ectomy be guided by the size of the present
tumor,
or
should
the
extent
of
excision
be based on the original size of the tumor?
Within the limits of aesthetics, the wider mar-
gins the better (with an optimum margin of
1 cm). Reducing the volume of tissue will
increase the likelihood of reexcision; however,
this can often still successfully clear the mar-
gins satisfactorily. The balance between the
oncologic resection and the cosmetic outcome
is a decision for the surgeon and patient, but
should tilt toward the former.
Sentinel Lymph Node Biopsy after
Neoadjuvant Chemotherapy
Before the introduction of sentinel lymph node
(SLN) biopsy as a method of staging the axilla,
there was little impact surgically on whether
patients received neoadjuvant chemotherapy
or not because either way they would be receiv-
ing an axillary lymph node dissection (ALND).
The most significant impact of preoperative
therapy was that there were some patients
who may have been node positive initially but
were node negative after chemotherapy and
so their true nodal status remained unknown.
This did not alter their surgery, and at the time
there was less impact of nodal status in guiding
radiation therapy.
This
changed
dramatically
as
lymphatic
mapping and SLN biopsy became standard in
the surgical therapy of breast cancer. Now
patients who opted for neoadjuvant chemo-
therapy to shrink their primary tumor were
obligated to undergo ALND as part of their sur-
gery, whereas if they had surgery first, they
could opt for an SLN biopsy and avoid ALND
if they were node negative. In addition, the
nodal status plays a larger role in therapy deci-
sions. Some medical oncologists would reserve
the use of taxanes or dose-dense regimens
for patients they know to be node positive.
The
use
of
postmastectomy
radiation
for
patients who are node positive has become
more prevalent. These practices made it more
important to know whether the patient was
node positive. Thus the question arose of how
to best integrate SLN biopsy with neoadju-
vant chemotherapy for clinically node-negative
breast cancer.
SLN biopsy is only necessary in patients
who are clinically node negative. Patients with
palpable disease in the lymph nodes can have
this
confirmed
by
fine-needle
aspiration
(FNA) and proceed with neoadjuvant chemo-
therapy with a planned ALND at the comple-
tion of systemic therapy. Patients who are
clinically node negative should have an ultra-
sound of the axilla looking for abnormal
lymph
nodes.
Ultrasound-guided
FNA
can
then document these patients to be node pos-
itive before neoadjuvant chemotherapy. For
patients who are clinically and ultrasonogra-
phically node negative, there are two options
for the use of SLN biopsy if they are candidates
for neoadjuvant chemotherapy.
The first option is to perform the SLN biopsy
before beginning chemotherapy. There are sev-
eral advantages to this approach. The first is
that the true nodal status is known before initi-
ating chemotherapy, which may be important
if this will help decide what regimen and sched-
ule to use. Likewise, this will help the radiation
oncologist decide whether they would recom-
mend postmastectomy radiation should the
patient not be a candidate for BCT. However,
there are several factors that go into this deci-
sion, including the size of the primary tumor.
285
18—NEOADJUVANT THERAPY

If the nodal status would not change either the
medical oncologists’ or radiation oncologists’
recommendations, then knowing the preche-
motherapy nodal status becomes less important.
This emphasizes the importance of presenting
these patients at a tumor board and formu-
lating a treatment plan in a multidisciplinary
setting.
Another advantage to performing SLN biopsy
before chemotherapy is the confidence in the
feasibility and accuracy of the procedure. There
has been some concern that the chemotherapy
may affect the lymphatic drainage and make
identification of the SLN more difficult. In addi-
tion, performing SLN biopsy after chemother-
apy supposes that if there was disease in the
lymph nodes it will either completely disappear
from all the nodes, or if not, it will remain in
the sentinel node. However, if it is eradicated
from the sentinel node, but not the nonsenti-
nel nodes, this will lead to a false-negative
finding. Unfortunately, performing SLN biopsy
before the onset of chemotherapy means an
extra procedure and a delay in the initiation
of therapy (Box 18–3).
The second option is to perform the SLN
biopsy after completing chemotherapy. This
presumes that it is accurate to do so. Several
studies of SLN biopsy after neoadjuvant che-
motherapy have been performed, and although
some have suggested an unacceptably high
false-negative rate, overall this seems to be rea-
sonable (Table 18–5). Although a clear disad-
vantage of this approach is not knowing the
true nodal status, if this would not impact
the chemotherapy decisions, this is less of a
factor. In regard to postmastectomy radiation,
some might argue that the nodal status after
chemotherapy might serve as a better indi-
cator of whether to offer radiation to the
chest wall. Delaying the SLN biopsy to after
chemotherapy also allows the chemotherapy
to start immediately and may preclude the
need for an additional surgery. The most
important advantage to SLN biopsy after che-
motherapy is that patients who may have
been
node
positive
before
chemotherapy,
but are now node negative, will be spared
from ALND. Approximately 20% of patients
may be converted from node positive to node
negative, and the use of SLN biopsy before
chemotherapy would obligate those patients
to undergo ALND. Future clinical trials will
BOX 18–3 ADVANTAGES AND DISADVANTAGES OF SENTINEL LYMPH
NODE BIOPSY BEFORE OR AFTER NEOADJUVANT CHEMOTHERAPY
Advantages
Disadvantages
Before
chemotherapy

Higher identification rate

Likely lower false-negative rate

Accurate pretherapy nodal staging

Requires an additional surgery

Delays the beginning of chemotherapy

May subject patients converted to node
negative to an unnecessary axillary
lymph node dissection
After
chemotherapy

No need for surgery before
chemotherapy

No axillary lymph node dissection
performed on patients who become
node negative

Slightly lower identification rate

Higher false-negative rate

Will mislabel some patients who were
initially node positive as node negative
TABLE 18–5
Success Rates and False-
Negative Rates of Sentinel Lymph Node
Biopsy After Neoadjvuant
Chemotherapy
Author
Patients Sentinel
Lymph Node
Identification
Rate (%)ate
False-
Negative
Rate (%)
Breslin
81
85
12
Nason
15
87
33
Haid
33
88
0
Fernandez
40
90
20
Tafra
29
93
0
Stearns
26
88
6
Julian
34
91
0
Miller
35
86
0
Brady
14
93
0
Piato
42
98
17
Balch
32
97
5
Schwartz
21
100
9
Reitsamer
30
87
7
Mamounas
428
85
11
TOTAL
87
9
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SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

better define the timing of SLN biopsy with
neoadjuvant chemotherapy.
Neoadjuvant Chemotherapy
and Outcome
Does Earlier Delivery of
Chemotherapy Improve Survival?
The ultimate danger of breast cancer is not
the primary tumor, but rather the ability of
breast cancer metastases to cause vital organ
dysfunction. Therefore, the persistence of dis-
tant micrometastases through systemic ther-
apy is ultimately what will determine survival
after treatment. The original hypothesis of
neoadjuvant chemotherapy was that instead
of delaying systemic therapy until after sur-
gery, the earlier initiation might do a better
job of eradicating these micrometastases. There
are animal studies to suggest that after resec-
tion of the primary tumor, an increase in the
growth rate of micrometastases is seen. The
explanation for this is unclear, possibly related
to inhibitory factors released by the primary
tumor or an immunosuppressive effect of sur-
gery. However, these studies show that preop-
erative chemotherapy can prevent this growth
spurt. This survival advantage to neoadjuvant
chemotherapy for operable breast cancer, how-
ever, has not been borne out by any of the ran-
domized trials, all of which had equivalent
survivals between preoperative and postopera-
tive chemotherapy.
Can Neoadjuvant Chemotherapy Be
Used as a Chemosensitivity Test?
A pCR is defined as the complete absence of
residual invasive and in situ disease follow-
ing neoadjuvant chemotherapy and surgery,
although
some
have
defined
a
complete
absence of invasive disease, even in the pres-
ence of in situ disease, as a pCR. Although
the studies failed to show any difference in
OS or DFS between preoperative and postoper-
ative chemotherapy, they did demonstrate a
correlation between the response of the tumor
to chemotherapy and the outcome. For exam-
ple, in the NSABP B-18 trial, patients who had
a complete clinical response had an overall
survival of 78%. This dropped to 67% for
patients with a partial clinical response and
65% for patients with no clinical response.
The correlation between response and out-
come is independent of tumor size, nodal
status, or age. A better predictor of outcome
than clinical response is pathologic response.
At 9 years of follow-up, the OS of patients
who achieved a pCR was 85%, compared to
73% for patients with residual cancer.
In addition to downstaging the primary
tumor, the status of the regional lymph nodes
is also downstaged. Patients who have a pCR
in the breast are more likely to have a pCR in
the axillary lymph nodes as well, although
not always. Kuerer and others, from the MD
Anderson Cancer Center, found that of the
16% of patients who had a pCR in the primary
tumor, 75% also had a pCR in the axillary nodes.
Rouzier and others reported that of patients with
documented disease in the regional nodes before
chemotherapy, a pCR in the axillary nodes was
associated with a significantly better 5-year
DFS. The effect in the nodes may be a better
marker of outcome than the effect on the pri-
mary tumor. In the NSABP B-27 trial, patients
who received a pCR in the breast, but still had
residual disease in the nodes, had a similar out-
come with those patients who did not receive a
pCR in the breast. This suggested that the
response in the nodes may be the strongest prog-
nostic factor. This makes biologic sense because
distant micrometastases (whose ablation ulti-
mately defines overall survival) are probably
more similar to nodal metastases than the pri-
mary tumor.
Knowing that a pCR in the primary tumor
and axillary nodes is associated with a signifi-
cantly improved outcome, how can this infor-
mation be used? The potential for research is
evident. Without neoadjuvant chemotherapy,
the only way to assess a new systemic therapy
is to perform a prospective randomized trial
comparing the new agent to standard chemo-
therapy and looking at DFS or OS. This takes
many patients and will take several years to
provide an answer. In the neoadjuvant setting,
new systemic therapies can be delivered before
surgery, with pathologic response as the end-
point. This takes considerably less patients
and can be concluded in a matter of months.
In addition, the use of neoadjuvant therapy,
with the ability to obtain tumor specimens
before and after chemotherapy, allows for the
investigation of molecular markers for predic-
tion of tumor response.
Does this benefit individual patients? In
other words, is there a benefit to the patient
to assess in vivo their individual response to
the chemotherapy? Patients showing a poor
response
to
therapy
can
have
ineffective
chemotherapies stopped, avoiding unnecessary
287
18—NEOADJUVANT THERAPY

toxicity. They can then opt to proceed with
surgery or try a different agent.
What about the patient who completes their
chemotherapy and undergoes surgery but is
found to have only a partial response? As
patients with residual disease in either the
breast or axillary lymph nodes are known to
have a poorer outcome compared with those
who have a pCR, does this mean that these
patients should receive additional chemother-
apy with a new agent after surgery?
Achieving a pCR is clearly associated with
better outcome but does the response rate
translate into better DFS and OS? In other
words, if you can increase the pCR rate (per-
haps by changing drugs or treating for more
cycles) will this translate into improved out-
come? The NSABP B-27 trial hoped to answer
this.
Patients
were
randomized
into
three
groups. The first group received preoperative
doxorubicin/cyclophosphamide (AC). The sec-
ond group received preoperative AC, had sur-
gery,
and
then
received
postoperative
docetaxel. The third group received AC and
docetaxel before surgery. As expected, the addi-
tion of taxanes increased the pCR rate. Arms 1
and 2, which had AC before surgery, had pCR
rates of 12.8% and 14.3%, respectively. Arm 3,
which had preoperative AC and docetaxol,
had a pCR rate of 26%. In all three groups, a
pCR
was
associated
with
a
significantly
improved outcome compared to patients who
did not achieve a pCR. However, all three
groups had the same OS. Perhaps the increase
in pCR rate was not sufficient enough to trans-
late to a statistically significant improvement
for the entire group. Unfortunately, without a
difference in survival, the trial could not answer
whether patients who did not achieve a pCR
with AC received any survival benefit to the
addition of docetaxel. To date, therefore, no
data exist in the literature to guide clinicians,
and so decisions about further systemic therapy
must be made on an individual patient basis.
If it were demonstrated that patients who
do not receive a pCR benefit from additional
systemic
therapy,
then
the
indication
for
neoadjuvant chemotherapy as a “chemosensi-
tivity test” would argue for the expanded use
of chemotherapy before surgical intervention,
even in patients for whom breast conservation
is feasible. However, there may be additional
markers that can be used besides pCR. The
search continues for new molecular markers
of response through the use of proteomics,
microarray analysis, and immunohistochemi-
cal staining. It may be feasible in the future
to analyze the tumor during or after chemo-
therapy to determine whether the regimen
should be altered or if additional therapy is
needed after surgery.
Suggested Readings
1. Bear HD, Anderson S, Brown A, et al. The effect on
tumor response of adding sequential preoperative
docetaxel to preoperative doxorubicin and cyclo-
phosphamide: preliminary results from National Sur-
gical Adjuvant Breast and Bowel Project Protocol
B-27. J Clin Oncol 2003;21:4165–4174.
2. Beresford M, Padhani AR, Goh V, et al. Imaging
breast cancer response during neoadjuvant systemic
therapy.
Expert
Review
of
Anticancer
Therapy
2005;5(5):893–905.
3. Kaufmann M, von Minckwitz G, Smith R, et al.
International expert panel on the use of primary
(preoperative) systemic treatment of operable breast
cancer: review and recommendations. J Clin Oncol
2003;21:2600–2608.
4. Khan A, Sabel MS, Nees A, et al. Comprehensive axil-
lary
evaluation
in
neoadjuvant
chemotherapy
patients with ultrasonography and sentinel lymph
node biopsy. Ann Surg Oncol 2005;12(9):697–704.
5. Kuerer HM, Sahin AA, Hunt KK, et al. Incidence and
impact of documented eradication of breast cancer
axillary lymph node metastases before surgery in
patients treated with neoadjuvant chemotherapy.
Ann Surg 1999;230:72–78.
6. von Minckwitz G, Costa SD, Raab G, et al. Dose-dense
doxorubicin,
docetaxel,
and
granulocyte
colony-
stimulating factor support with or without tamoxifen
as preoperative therapy in patients with operable car-
cinoma of the breast: a randomized, controlled, open
phase IIb Study. J Clin Oncol 2001;19:3506–3515.
7. Wolmark N, Wang J, Mamounas E, et al. Preopera-
tive chemotherapy in patients with operable breast
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cer Inst Monogr 2001;30:96–102.
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SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

19
Locally Advanced and
Inflammatory Breast Cancer
LOCALLY ADVANCED BREAST
CANCER
Diagnosis and Workup of
Locally Advanced Breast
Cancer
Treatment of Locally Advanced
Breast Cancer
INDUCTION CHEMOTHERAPY
Local Surgery after Induction
Chemotherapy
Regional Surgery after Induc-
tion Chemotherapy
INFLAMMATORY BREAST
CANCER
Diagnosis and Workup
Treatment of Inflammatory
Breast Cancer
Locally Advanced and Inflammatory Breast
Cancer: Key Points
Define locally advanced breast cancer.
Describe the workup and staging of the patient presenting with
locally advanced breast cancer.
Know the benefits of induction chemotherapy in the management of locally
advanced breast cancer.
Understand the clinical presentation and diagnosis of inflammatory breast
cancer.
Describe the treatment algorithm for inflammatory breast cancer, including
the surgical management.
With the promotion of breast self-examination
(BSE) and screening mammograms, the aver-
age size at which breast cancer is detected have
been steadily decreasing. Some women, unfor-
tunately, will either not be diagnosed or will
not seek treatment until the breast cancer is
more advanced. This is generally referred to as
locally advanced breast cancer (LABC) and
continues to represent a significant burden.
This is especially true in areas where access to
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