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252 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
National Institutes of Health Consensus Conference
The National Institutes of Health (NIH) Consensus Panel concluded that several monthsof polychemotherapy 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
patientsfor chemotherapy, this consensusgroup
acknowledged the difficulty in identifying specific patient groups that might not require adjuvant chemotherapy. They agreed on the need
to individualize recommendations for nodenegative cancers smaller than 1 cm and state
that the retrospective data indicate that the use
of chemotherapy, in the absence of other worrisome 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 ofthese patients to trials because
there is limited evidence regarding adjuvant chemotherapy 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 oncology, which are available to all practitioners in
both published form and on the Internet. Treatment algorithms are presented in flowchart formats 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
recommend adjuvantchemotherapy for patients
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 disease 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 hormone 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 Conference gathers a worldwide group of breast
cancer experts on a regular basis to discuss
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.
the latest research in breast cancer and provide
updates on adjuvant therapy recommendations 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 primarytumor,nodal status, estrogen 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 recommend adjuvant chemotherapy for patients with
hormone receptor positive, high-risk disease,
or hormone receptor negative, intermediate- or
high-risk disease. They also recommend consideration 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 overexpressed. Low-risk is considered age greater than
35, tumor size less than or equal to 2 cm, grade
1, no angiolymphatic invasion, and Her2negative.
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 approximate 15% 10-year risk of recurrence without
systemic therapy. The NCCN guidelines would
recommend considering adjuvant chemotherapy 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.
25316—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER
SYSTEMIC ADJUVANT TREATMENT – HORMONE RECEPTOR POSITIVE – HER-2 NEGATIVE DISEASE
pT1, pT2,
or pT3; and
pN0 or pN1mi
(≤2 mm axillary
node metastasis)
Histology:
• Ductal
• Lobular
• Mixed
• Metaplastic
metastases >2 mm
• Tumor ≤0.5 cm or
• Microinvasive or
• Tumor 0.6–1.0 cm,
well differentiated,
no unfavorable
features
• Tumor 0.6–1.0 cm,
moderate/poorly
differentiated or
unfavorable
features
• Tumor >1 cm
Node positive
(one or more
to one or more
ipsilateral axillary
lymph nodes
pN0
pN1mi
Consider
21-gene
RT-PCR assay
(category 2B)
Adjuvant
endocrine therapy
+ adjuvant chemotherapy
(category 1)
No adjuvant
therapy
Consider adjuvant
endocrine therapy
Not
done
Low
recurrence
score (<18)
Intermediate
recurrence
score (18–30)
High
recurrence
score (≥31)
Adjuvant
endocrine therapy
± adjuvant
chemotherapy
(category 1)
Adjuvant
endocrine therapy
(category 2B)
Adjuvant
endocrine therapy
± adjuvant
chemotherapy
(category 2B)
Adjuvant
endocrine therapy
+ adjuvant
chemotherapy
(category 2B)
b
Figure 16–1. A sample page from the National Comprehensive Cancer Network Guidelines for Adjuvant
Therapy in Breast Cancer. Available at www.nccn.org/professionals/physician_gls.
TABLE 16–2St. Gallen Systemic Adjuvant Therapy Recommendations
Risk Category Associated Features Adjuvant Therapy Options
Low risk
Intermediate
risk
High risk
CTX, chemotherapy; ER, estrogen receptor; LVI, lymphovascular invasion; PR, progesterone receptor; T, tumor size.
Node-negative, ER/PR positive,
T 1 cm, grade 1, no LVI,
Her-2/neu negative, age 35
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
Node positive (one to three nodes) and
Her-2/neu positive
Node positive ( four nodes)
Adjuvant Online
To make it easier for physicians to apply
guidelines to individual patients and help
patients understand the deci sion they are
making, there are several computer programs
1. None
2. Endocrine only
3. Consider Oncotype DX
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-)
1. CTX followed by endocrine (ER/PRþ)
2. CTX
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
254 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
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)
patients. The most popular program is Adjuvant! Online (Adjuvant! Inc.), which is easily
accessible to all practitioners via the Internet
at www.adjuvantonline.com. Taking survival
information derived main ly from surveillance, epidemiology, and end results (SEER)
data combined with the benefits of adjuvant
therapy based on the Oxford overview, t his
program uses a Bayesian method to make
estimates for individual pa tients based on
their demographic and staging information.
After entering the patient age, comorbidities,
menopausal status, tumor size, nodal involvement, grade, and ER status, baseline prognostic estimates are shown. In addition,
estimates for the efficacy of endocrine the rapy, systemic chemotherapy, and the combination (for both relapse and death) are
shown i n both numerical and graphical
forms (Figure 16–2). The user can examine
several chemotherapy reg imens 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.
25516—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER
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 ata population of patients withbreast cancer, 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 predict the likelihood of cancer recurring regardless 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 immunohistochemical staining to identify individual tumor
markers expressed on breast cancer cells that
may provide additional prognostic information. 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 microarray analysis. Microarray analysis allows for
the measurement of thousands of genes in a
single RNA sample. Although there are a variety of microarray platforms that have been
developed to accomplish this, the basic idea
is the same. Microarray analysis involves spotting up to 25,000 genes in an ordered “array”
on a glass slide. These genes are then hybridized 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 regulates 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 regulated and up regulated in the tumor sample.
Figure 16–3. Microarray analysis 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 expresses levels of a particular
RNA that are higher than those
of the reference sample (overexpressed), the spot will fluoresce red. If the reference
sample expresses more RNA
than the tumor (underexpressed), the spot will fluoresce
green. If the tumor and reference sample are equal, the
spot will be yellow.
Tumor
Tumor sample
Labeled tumor RNA or DNA
Labeled control RNA or DNA
256 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
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 outcome and create molecular “signatures.” Several reports now demonstrate how gene
expression profiling can be used to predict
clinical outcome in patients with breast cancer, above and beyond standard clinical and
pathologic prognostic features. For example,
tissues from almost 300 patients in the Netherlands (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 overall survival of 95%, whereas the women with a
“bad” signature had a 55% survival. In multivariate analysis, the molecular signature of
the tumor was a more powerful predictor than
any clinical or histologic criteria. Unfortunately, efforts to validate these findings
have not been as impressive. Prospective studies are presently under way. Other drawbacks
to microarray analysis are the cost, and the
fact that fresh tissue is required, so the decision 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 chemotherapy 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 predicting outcome. The advantage of using RT-PCR
is that the test can be performed on paraffinembedded 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 nodenegative, 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 reference 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 population. Oncotype DX cannot be used to make chemotherapy 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 addition to tamoxifen. Using data from both NSABP
B14 and NSABP B20, the benefit of chemotherapy 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 addition to tamoxifen. Womenin the low-risk group
would see little added benefit to chemotherapy,
and hormonal therapy alone should be sufficient. On the other hand, women in the highrisk group should receive chemotherapy in
addition to hormonal therapy. The recommendation 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 oncologists 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 candidates (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 chemotherapy regardless of her risk, the test is also
not indicated.
Other gene assays are moving toward clinical use. The MammaPrint assay was recently
cleared for marketing by the U.S. Food and
25716—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER
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. Although this assay can provide additional prognostic information, there is less data regarding
the ability of the MammaPrint assay to improve
patient outcome. This assay is presently being
studiedin a randomized trial. Anothermolecular
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 cancer 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 cyclophosphamide, alone or in combination, in
reducing breast cancer recurrence rates. Cyclophosphamide 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 (-CH
Agents with a single alkyl group damage DNA
bases or cause single-stranded DNA breaks.
Agents with two alkyl groups form DNA crosslinks, which lead to interference with DNA synthesis and transcription and double stranded
DNA breaks. Side effects include myelosuppression, nausea and vomiting, alopecia, infertility,
hemorrhagic cystitis, and syndrome of inappropriate antidiuretic hormone (SIADH).
Ultimately, two combination regimens
involving cyclophosphamide gained acceptance, both delivered in 3-week cycles. One
was CMF. Both methotrexate and fluorouracil
fall into the category of antimetabolites. Antimetabolites are structural analogues to a variety 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
C) which covalently binds DNA.
2
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 thymidylate, purines, serine, and methionine.
The other popular regimen was cyclophosphamide, 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 formation of free radicals. Although doxorubicin
is the most commonly used anthracycline in
the United States and Canada, epirubicin
0
(4
-epidoxorubicin) is commonly used elsewhere. This is the semisynthetic L-arabino
derivative of doxorubicin in which the amino
sugar daunosamine is replaced with acosamine. It appears to have a better safety profile than doxorubicin on a milligram per
milligram basis, with less nausea and cardiotoxicity when given at roughly equal myelosuppressive 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 anthracyclines is myelosuppression. Neutrophil nadirs
typically occur 10 to 14 days after treatment.
Other common toxicities include alopecia, nausea 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 cumulative dose of less than or equal to 450 mg/m
2
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 doxorubicin (such as FAC or AC) or epirubicin (such as
FEC), was that there was an improvement with
the doxorubicin- or epirubicin-based regimens
is
258 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
TABLE 16–3Chemotherapeutic 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
Thiotepa Alkylating agent Myelosuppression
Nausea/vomiting
Mucositis
Hypersensitivity
Rash
Hemorrhagic cystitis
Second-degree malignancies
Paclitaxel Antimicrotubule Myelosuppression
Hypersensitivity
Neurotoxicity
Alopecia
Mucositis
Diarrhea
Cardiac arrhythmia
Hepatotoxicity
Docetaxel Antimicrotubule Myelosuppression
Hypersensitivity
Fluid retention
Neurotoxicity
Alopecia
Arthralgias
Myalgias
Mucositis
Diarrhea
Rash
5-Fluorouracil Antimetabolite Myelosuppression
Blepharitis
Cardiac ischemia
Capecitabine Antimetabolite Mucositis
Hand-foot syndrome
Diarrhea
Nausea/vomiting
Hepatotoxicity
Blepharitis
Cardiac ischemia
Methotrexate Antimetabolite Myelosuppression
Mucositis
Hepatotoxicity
Renal failure
Pneumonitis
Arachnoiditis (when given
intrathecally)
Gemcitabine Antimetabolite Myelosuppression
Nausea/vomiting
Flulike syndrome
Hepatotoxicity
Dyspnea
Rash
Hemolytic-uremic syndrome
-Encourage oral fluids (2–3 L/day)
to prevent hemorrhagic cystitis
-May increase the effects of
anticoagulation
-Have resuscitation supplies nearby
during administration for
hypersensitivity reactions
-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
-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
-Severe toxicity in patients with
DPD deficiency
-May increase toxicity of
antiepileptic medications
-Severe toxicity in patients with
DPD deficiency
-May increase the effects of
Coumadin
-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
(Continued)
TABLE 16–3 Chemotherapeutic Agents Used in Breast Cancer
Agent Type of Agent Side Effects Precautions
Doxorubicin Antitumor
antibiotics
Mitomycin-C Antitumor
antibiotic
ARDS, adult respiratory distress syndrome; DPD, dihydropyrimidine dehydrogenase.
Myelosuppression
Nausea/vomiting
Cardiotoxicity
Alopecia
Mucositis
Diarrhea
Rash (radiation recall)
Myelosuppression
Nausea/vomiting
Mucositis
Pulmonary toxicity/ARDS
Renal failure
Hemolytic-uremic syndrome
Cystitis (intravesicular
treatment)
-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
-Avoid FiO2 > 50% that may
worsen pulmonary toxicity
25916—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER
(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 anthracycline-based regimens are now the most recommended 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 regimens 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
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
was the emergence of the taxanes as a highly
effective agent against breast cancer. The second was the development of tolerable bone
marrow supportive therapy in the form of
granulocyte colony-stimulating factors, allowing dose-dense regimens (higher doses within
shorter time frames) without the risks of severe
neutropenia. Finally, the development of trastuzumab, a monoclonal antibody that targets
the Her-2/neu marker, and proven to be effective in the metastatic setting, was recently
shown to be extremely effective in the adjuvant 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 stable microtubule bundles to accumulate in the
cell. These cellsare incapable of forming normal
mitotic spindles and become blocked in the
G2 and M phases of the cell cycle. The dysfunctional 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 pharmacologic characteristics. Paclitaxel was first identified as the active component of a bark extract
from the Pacific yew Taxus brevifolia. Docetaxel
260 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
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 radiosensitizing effects, can induce apoptosis, and have
antiangiogenic properties.
The major dose-limiting toxicity of taxanes
is profound myelosuppression. Another significant side effect is the hypersensitivity
reaction (HSR). Within a few mi nutes 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 antihistamines, steroids, and sometimes vasopressors are administered. With pretreatment
dexamethasone, diphenhydramine and
cimetidine, the incidence of HSR is only 1%
to 3%. Another difficult side effect of the taxanes is a peripheral neuropathy characterized
by numbness and paresthesias in a stockingand-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 pati ents with nodepositive 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 approximately 4% OS advantage (OS 80% versus
77%) with the addition of taxanes. A retrospective subset analysis of CALGB 9344 suggests t he benefit to DFS and OS are primarily
among the patients who were E R negative,
with little benefit seen in patients who were
ER positive. NSABP B-28 also evaluated adjuvant taxanes in patients who were node positive. 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, subset analysis suggested a trend toward benefit
for patients who were ER negative. However,
the data was updated in 2003 and the addition of paclitaxel to AC resulted in a significant 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 paclitaxel 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 cyclophosphamide (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 proliferation, survival, adhesion, migration, and differentiation 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 extracellular 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 several types of human cancer. In contrast to the
26116—PRINCIPLES OF ADJUVANT CHEMOTHERAPY FOR BREAST CANCER
other receptors, Her-2 can adopt a fixed conformation 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 specifically 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 signaling (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 theextracellular domainof the Her-2 receptor.
This prevents the activation of its intracellular
tyrosinekinase. This mayoccur through prevention of dimerization, endocytic destruction of
the receptor, or inhibition of shedding of the
extracellular domain. The IgG does have a conserved Fc portion, so it can trigger immune recognition. Although most investigators consider
trastuzumab a “targeted therapy,” it may also
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.***
be a form of “immunotherapy” because it is possible that immune activation plays a role in the
mechanism of action of trastuzumab. There is
some evidence for antibody-dependent cytotoxicity, 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 efficacy and safety of trastuzumab in the management of stage IV disease, studies in the
adjuvant setting were initiated. Four large,
multicenter, randomized trials (and some
smaller studies) reported a significant benefit
Figure 16–4. Herceptin
binding.
EGF
ligand
Trastuzumab
(Herceptin)
HER2
MAPK
Nucleus