Metastatic Breast CA PDF

Metastatic Breast Cancer
Kellie L. Jones, Pharm.D., BCOP

Reviewed by J. Aubrey Waddell, Pharm.D., FAPhA, BCOP; Judy W.M. Cheng, Pharm.D., MPH, FCCP, BCPS
(AQ Cardiology); and Benita E. Busch, Pharm.D., BCPS
Learning Objectives
Goals of Therapy in the

Metastatic Setting
1. Given an individuals medical history, distinguish

whether chemotherapy or hormonal therapy should be
used to treat the patients metastatic breast cancer.
2. Develop a treatment approach using hormonal therapy
for recurrent, hormone-positive metastatic breast
cancer.
3. For a given patient with metastatic breast cancer, design
an optimal chemotherapeutic regimen to manage the
disease.
4. Assess the role of biologic therapies (single and
combined therapy) in the treatment of metastatic breast
cancer.
5. Analyze bisphosphonate use in the treatment of bone
metastases in patients with metastatic breast cancer.
When a patient is given a diagnosis of MBC, the treatment

goal shifts from one end of the spectrum (cure, as in earlystage disease) to the other (palliation). In the metastatic
setting, treatment modalities are given to improve quality
of life, alleviate symptoms or complications of therapy,
and prolong survival. The risks and benefits of therapy are
weighed to determine the best option for the patient. Only
a few patients remain disease free for prolonged periods,
even if treated with doxorubicin, one of the most efficacious
agents in breast cancer. This was demonstrated in a trial
that spanned 20 years and compared use of fluorouracil,
doxorubicin, and cyclophosphamide.
The mean survival time for patients with MBC is about
24 years from diagnosis; however, this range may vary
greatly depending on the site (e.g., bone metastases) and
pathology (e.g., estrogen receptor/progesterone receptor
[ER/PR] positivity) of the metastatic disease. Patients with
bone-only disease, ER/PR-positive disease, or both tend to
have cancer that is more indolent and that responds better to
hormonal therapy.
Overview of Metastatic
Breast Cancer
Patients who receive a diagnosis of early-stage breast
cancer are treated with the intent to cure. Yet even with
the best therapies available today, about 30% of patients
will have recurrent breast cancer. A small proportion of
patients (10%) will present with metastatic disease at their
initial diagnostic examination. No standardized tools or
techniques are available to determine which patients will
have recurrent disease; therefore, clinicians treat all patients
with a similar approach involving several modalities such
as surgery, radiation, chemotherapy, and hormonal therapy.
Unfortunately, the median survival time for a patient
receiving a diagnosis of metastatic disease is only about 3
years. Some patients experience rapidly progressive disease,
whereas others may live for many years. Despite a decline
in overall mortality with breast cancer, metastatic breast
cancer (MBC) is still incurable with the treatment options
currently available.
Pharmacotherapy Self-Assessment Program, 6th Edition
Sites of Metastatic Disease

Lung, liver, and bone are the most common metastatic sites
for breast cancer. However, breast cancer can metastasize
anywhere in the body. Invasive ductal carcinomas commonly
spread to the lung, liver, bone, and brain, whereas invasive
lobular carcinomas can also spread to serosal surfaces,
meninges, and other unusual sites.
Therapy Selection
Selecting the best form of therapy includes evaluating
the prognostic and predictive features of the patients
tumor to determine whether local treatment (radiation or
surgery) or systemic treatment (hormonal or chemotherapy)
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in MBC is palliation, all of these factors are weighed before

making a treatment decision.
Abbreviations in
This Chapter
AI
CT
EGFR
ER
HER2
LHRH
MBC
MRI
PR
Monitoring Response to Therapy

Once a therapy is chosen, the patient should be assessed
periodically to evaluate disease response. According to the
American Society of Clinical Oncology, routine monitoring
of tumor markers (specifically CA15.3 [normal concentration
less than 30 U/mL] and CA27.29 [normal concentration less
than 40 U/mL]), in conjunction with diagnostic imaging,
is valuable in assessing disease status. Tumor markers
CA15.3 and CA27.29 measure similar mucinous proteins
and commonly are elevated in patients with MBC. An
elevated tumor marker by itself does not warrant a change
in therapy; therefore, the concentration should be evaluated
in conjunction with radiologic findings to determine further
therapy. Radiologic tests such as computed tomography
(CT) of the abdomen or lungs or magnetic resonance
imaging (MRI) of the brain can document stabilization
or progression. By combining the clinical examination,
radiologic findings, and tumor marker levels, the clinician
can optimally prescribe the next line of therapy. Throughout
the patients treatment, the pharmacist plays a valuable role
in monitoring hematologic, kidney, and liver function for
dosage adjustments of chemotherapy regimens. In addition,
it is important to monitor common toxicities associated
with treatment, such as nausea/vomiting, palmar-plantar
erythrodysesthesia, mucositis, constipation/diarrhea, and
pain. Knowledge of supportive care therapies is an invaluable
asset in the treatment of oncology patients.
Aromatase inhibitor
Computed tomography
Epidermal growth factor receptor
Estrogen receptor
Human epidermal growth
factor receptor 2
Luteinizing hormonereleasing hormone
Metastatic breast cancer
Magnetic resonance imaging
Progesterone receptor
will provide the best outcome. Factors such as time to

recurrence, extent of disease, location of metastatic sites,
symptoms, ER/PR positivity, human epidermal growth
factor receptor 2 (HER2) positivity, and performance status
must be assessed.
Local vs. Systemic Therapy
If the patient has a single metastatic lesion, a focal
symptom, or a local crisis (e.g., impending fracture, spinal
cord compression, brain metastasis), local therapy such as
radiation or surgery may be initiated for immediate symptom
relief. If the patient has several sites of metastasis and is
experiencing symptoms from visceral disease, systemic
therapy with hormonal therapy or chemotherapy should
be used. Chemotherapy is chosen over hormonal therapy
if an immediate response is desired because chemotherapy
exhibits a quicker onset of action compared with hormonal
therapy.
Disease recurrence more than 5 years after the patients
initial diagnosis and treatment is considered a favorable
prognostic indicator. This reflects an indolent tumor instead
of rapidly progressing disease. Other favorable features
are ER and PR positivity. An ER- or PR-positive tumor is
predictive of longer progression-free survival and can be
treated with hormonal agents. The site of metastatic disease
is also important. Patients with several sites of disease or
disease that has spread to visceral organs (e.g., lung and
liver) have a poorer prognosis and might benefit from
chemotherapy.
Hormonal Therapy Options

Hormonal therapy plays a large role in the treatment of
MBC. More than 60% of women with breast cancer have
ER/PR-positive disease. Response rates to hormonal therapy
for ER/PR-positive disease are 50% to 75%, but with ER/
PR-negative disease, they are less than 10%.
Aromatase Inhibitors
Aromatase inhibitors (AIs) work by inhibiting
the aromatase enzyme responsible for converting
androstenedione to estrone and testosterone to estradiol
in postmenopausal women. Aminoglutethimide, a firstgeneration AI, was a nonspecific inhibitor of aromatase
with numerous toxicities and adverse effects such as rash
and drowsiness. Mineralocorticoids and glucocorticoids are
depleted with this agent, and supplemental steroids (e.g.,
hydrocortisone) must be administered. Second-generation
agents such as formestane and fadrozole are only available
as injectable formulations and are not currently available
in the United States. This leads to the third-generation
AIs: anastrozole, letrozole, and exemestane. Anastrozole
and letrozole are nonsteroidal AIs that bind reversibly to
aromatase. Exemestane is a steroidal AI that exhibits weak
androgenic properties because of its steroidal structure.
These agents have superseded the use of first- and secondgeneration AIs.
When AIs first came on the market, tamoxifen was
considered the first-line treatment option for ER/PR-positive,
postmenopausal MBC, followed by megestrol acetate
Hormonal vs. Chemotherapy

The decision to initiate hormonal therapy is supported if
the patient has ER- and/or PR-positive breast cancer, a long
disease-free interval, and/or a prior response to hormonal
therapy. In patients with ER/PR-negative disease, a short
disease-free interval, rapidly progressing visceral disease,
and disease refractory to prior hormonal therapy, initiation
of chemotherapy is appropriate. Any patient with HER2positive disease should be considered for trastuzumab
therapy, and patients with bone metastasis should be
considered for bisphosphonate therapy. Two final decision
points are treatment effects on the patients quality of life
and the patients ability to tolerate therapy. Because the goal
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Table 2-1. Comparison of Aromatase Inhibitors with Tamoxifen and Megestrol Acetate
Anastrozole vs. megestrol acetate
Study 1
(n=256)
Study 2
(n=260)
Letrozole vs. megestrol acetate
Study 1
(n=363)
Study 2
(n=400)
Exemestane vs. megestrol acetate
(n=769)
Anastrozole vs. tamoxifen
Study 1
(n=353)
Study 2
(n=668)
Letrozole vs. tamoxifen
(n=907)
Objective Response (%)
Clinical Benefit Ratea (%)
TTP (months)
10.2 vs. 5.5
36.7 vs. 35.2
5.6 vs. 5.0
10.4 vs. 10.4
34.1 vs. 32.8
4.3 vs. 3.9
23.6 vs. 16.4
34.5 vs. 31.7
5.6 vs. 5.5
16.1 vs. 14.9
26.7 vs. 23.4
3 vs. 3
15.0 vs. 12.4
37.4 vs. 34.6
4.7 vs. 3.8
21.1 vs. 17.0
59.1 vs. 45.6
11.1 vs. 5.6
32.9 vs. 32.6
56.2 vs. 55.5
8.2 vs. 8.3
32.0 vs. 21.0
50.0 vs. 38.0
9.4 vs. 6.0
40.9 vs. 13.6
55.7 vs. 42.4
8.9 vs. 5.2
Exemestane vs. tamoxifen

(n=120)
Clinical benefit rate = complete response plus stable disease plus stabilization of disease for 24 weeks or longer.
TTP = time to treatment progression.
a
Despite differences in response rates among studies

(because of the lack of standard testing for ER/PR status
in Europe), the U.S. Food and Drug Administration (FDA)
approved anastrozole for labeling as a first-line treatment
of patients with ER/PR-positive MBC. When letrozole was
compared with tamoxifen, it received the same approval by
the FDA. Exemestane is the newest agent to be marketed. In a
recent Phase III trial, exemestane was superior to tamoxifen
in response rate and progression-free survival in patients
with MBC. Exemestane is also approved for use in MBC
after tamoxifen failure. If a patient receives a nonsteroidal
AI (anastrozole or letrozole) and achieves stable disease,
the patient may be offered the steroidal agent exemestane if
his or her disease progresses. Cross-resistance has not been
reported between steroidal and non-steroidal AIs. The use of
AIs in patients with ER/PR-positive MBC has substantially
changed during the past 10 years, with tamoxifen use
dramatically falling because AIs offer similar efficacy with
fewer toxicities.
as second-line therapy. The clinical importance of AIs

started to become clear when initial studies were conducted
comparing their efficacy with megestrol acetate. Although
only marginal benefits were demonstrated with the thirdgeneration AIs compared with megestrol acetate, all of the
agents were associated with a lower incidence of adverse
effects (Table 2-1). These data catapulted AIs to the first-line
treatment position, and studies were initiated comparing
AIs head to head with tamoxifen. Aromatase inhibitors are
now standard first-line therapy in postmenopausal patients.
A combined analysis of two studies evaluating anastrozole
and tamoxifen has been published. One trial took place in
the United States and the other, in Europe; 1021 patients
were included in the analysis. With a median follow-up of
18.2 months, anastrozole was considered at least equivalent
to tamoxifen; the median time to progression was 8.5 versus
7 months, respectively. Clinical benefit rates (complete
response plus stable disease plus stabilization of disease
for 24 weeks or more) were also higher for anastrozole
compared with tamoxifen (57.1% vs. 52%, respectively), but
the difference was not statistically significant. Individual
trial results are listed in Table 2-1. Data demonstrated that
anastrozole was as effective as tamoxifen; however, patients
receiving anastrozole exhibited significantly fewer venous
thromboembolic events than those receiving tamoxifen.
Pure Antiestrogens
Pure antiestrogens offer a specific mechanism for
inhibiting the growth of ER/PR-positive MBC. Fulvestrant
is the only agent in this class; it works by binding and
blocking the ER and increasing the degradation of the ER
protein. This activity ultimately leads to the inhibition of
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mechanism is to add an agent that exhibits a different

pathway of inhibiting estrogen (e.g., AIs). Fulvestrant
is also being studied in combination with trastuzumab.
Previous data demonstrated cross-communication between
the human epidermal growth factor receptor (EGFR) and
ER signal transduction pathways. As these data mature,
new combinations and dosages may be warranted in the
treatment of ER/PR-positive MBC. Table 2-2 describes
fulvestrant combinations in ongoing trials.
estrogen signaling to the ER. Unlike tamoxifen, fulvestrant

does not exhibit any estrogen agonistic activity. This
agent must be administered by intramuscular injection.
Fulvestrant is currently approved at a dosage of 250 mg
once monthly. The current formulation is available in a 50mg/mL concentration as 2.5- and 5.0-mL prefilled syringes.
Administering 5 mL of the drug by intramuscular injection
can be painful; however, doses can be given in one injection
or in two smaller injections of 125 mg each.
Like the AIs, fulvestrant was tested as a second-line agent
for MBC. In trials conducted concurrently in North America
and in other countries, fulvestrant 250 mg/month was tested
against anastrozole 1 mg/day in patients whose previous
antiestrogen therapy had failed. Fulvestrant demonstrated
efficacy similar to anastrozole regarding time to progression
and objective response rates. In subsequent survival
analysis of the combined trials, no significant difference
was identified between agents, and both drugs were well
tolerated. Based on data from these trials, fulvestrant was
approved by the FDA for use in patients whose antiestrogen
therapy had failed in the metastatic setting. In the first-line
setting, fulvestrant did not exhibit a statistically significant
decrease in time to progression and did not meet criteria for
noninferiority compared with tamoxifen. In a preplanned
subgroup analysis of patients with ER/PR-positive disease,
the median time to progression was similar to tamoxifen.
As with many drugs, clinicians try to find better ways
of administering a drug to optimize efficacy and decrease
toxicity. Because hormonal therapy is slower in onset
compared with chemotherapy, fulvestrant has been tested
using a loading dose to allow quicker steady-state values
and earlier patient benefit. Studies under way are using 500
mg on day 1 and 250 mg on days 14 and 28, followed by 250
mg once monthly; or another dosing schedule of 500 mg on
days 1, 14, and 28, followed by 500 mg monthly.
In addition, clinicians are evaluating the use of other
agents in combination with fulvestrant. One proposed
Luteinizing HormoneReleasing Hormone

Agonists
The idea of ovarian ablation has been used for more than
100 years in the treatment of early and advanced stages of
breast cancer. Knowing that estrogen plays a large role in
breast cancer, using an agent that induces chemical ovarian
ablation is well founded. Meta-analysis data are available
evaluating luteinizing hormone-releasing hormone (LHRH)
agonists for MBC. With an LHRH agonist alone (e.g.,
goserelin), response rates were comparable with historic
outcomes from oophorectomy or irradiation. Tamoxifen
in combination with an LHRH agonist demonstrated
significant improvements in objective response rates and
survival compared with tamoxifen alone. These data reveal
that combination therapy using tamoxifen and an LHRH
agonist is the preferred method of hormonal manipulation
in treating patients with premenopausal, hormone receptor
positive MBC. Studies are under way to evaluate the use
of AIs in combination with LHRH agonists for use in
premenopausal women. The logic is to induce menopause
with the LHRH agonist and then give the patient an AI
after the patient has achieved chemical menopause. Recent
studies demonstrated improved complete and partial
response, clinical benefit, and stabilization of disease with
such sequential treatment.
Table 2-2. Current Trials Evaluating the Sequence of Fulvestrant and Other Hormonal Therapies
Trial Name
Phase
Randomization
Fulvestrant Dosing Schedule
Comments
EFECT
(n=660)
III
Fulvestrant
vs.
exemestane
250 mg on days 0, 14, and 28, then

monthly
For patients with recurrent disease

after an NSAI
SOFEA
(n=750)
III
Fulvestrant
vs.
Anastrozole + fulvestrant
vs.
Exemestane
250 mg monthly
For patients with recurrent disease

after an NSAI
FACT
(n=512)
III
vs.
Anastrozole
500 mg on day 0, then 250 mg on

days 14 and 28, then 250 mg
monthly
FIRST
(n=200)
II
500 mg on day 1 (then monthly)
First-line treatment
EFECT = Evaluation of Faslodex versus Exemestane Clinical Trial; FACT = Fulvestrant and Anastrozole in Combination Trial; FIRST = Study to
Compare the Efficacy and Tolerability of Fulvestrant with Anastrozole as First Line Hormonal Treatment for Postmenopausal Women with Hormone
Positive Metastatic Breast Cancer; n = number of people included in the study; NSAI = nonsteroidal aromatase inhibitor; SOFEA = Study of Faslodex
with or Without Concomitant Arimidex vs. Exemestane After Progression on Nonsteroidal Aromatase Inhibitors.
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Table 2-3. Treatment Options for Patients with Hormone-Positive Metastatic Breast Cancer Disease
Premenopausal
Tamoxifen
Oophorectomy
LHRH agonist
Radiation-induced oophorectomy
Megestrol acetate
Androgens
High-dose estrogens
If patient becomes postmenopausal, treatment options for
postmenopausal women can be considered.
Postmenopausal
Previous Tamoxifen
NSAI
Exemestane
Fulvestrant
Megestrol acetate
Androgens
Ethinyl estradiol
Previous NSAI
Exemestane
Fulvestrant
Tamoxifen
Megestrol acetate
Androgens
High-dose estrogens
LHRH = luteinizing hormone releasing-hormone; NSAI = nonsteroidal aromatase inhibitor.
of response or stable disease or if they experience numerous

toxicities.
If a patient has exhausted the treatment options (both
hormonal and chemotherapy), then best supportive care is
a reasonable choice. The National Comprehensive Cancer
Network recommends that clinicians consider no further
cytotoxic therapy when the patient has had no response
to three sequential regimens or has a performance status
greater than 3 (i.e., the person is capable of only limited
self-care and confined to a bed or chair for more than 50%
of waking hours). This classification is based on the Eastern
Cooperative Oncology Group performance status grading
scale.
Drug Selection
If the patient had a long disease-free survival with
prior hormonal therapy, the likelihood of having a
positive response to another hormonal agent is high. The
next issue to evaluate is the patients menopausal status.
Aromatase inhibitors cannot be used in premenopausal
patients because they are still producing robust amounts of
estrogen in their ovaries. If the patient is premenopausal,
has had prior endocrine therapy (tamoxifen), and is within
1 year of antiestrogen exposure, the preferred secondline therapy choices are oophorectomy, radiation-induced
ovarian ablation, or LHRH agonists and endocrine therapy.
In a premenopausal patient who has not been exposed to
antiestrogen therapy, treatment with an antiestrogen with or
without ovarian ablation is preferred.
For patients who are postmenopausal and antiestrogen
nave, or even those who received previous antiestrogen
therapy but had recurrent tumors within 1 year of therapy,
an AI is considered the first-line treatment. There are no
data to stipulate which AI should be used first because no
head-to-head trials have been conducted. If the patient was
initially prescribed a nonsteroidal AI and had progression
of disease, the patient may be switched to a steroidal AI. If
the cancer continues to progress after these treatments, the
next treatment option could include tamoxifen, fulvestrant,
progestins, androgens, and even estrogens. Table 2-3
describes different treatment options. After a patient
has received second-line hormonal therapy, choices for
sequential therapy are not based on high levels of evidence.
Sequential vs. Combination Therapy

In MBC, response rates can vary with single or
combination chemotherapy in nave or previously treated
patients. A meta-analysis demonstrated that combination
chemotherapy is associated with higher response rates and
a longer time to progression, but, understandably, it has
greater toxicity. Few studies, however, have demonstrated
an improvement in survival with combination therapy.
The only combination regimens that have demonstrated
survival benefits are docetaxel and capecitabine, paclitaxel
and gemcitabine, and doxorubicin and paclitaxel. There is
little compelling evidence that combination therapy should
be given rather than sequential therapy. If a patient requires
a rapid response to shrink the disease as fast as possible,
combination therapy can be used even if it produces greater
toxicity. Table 2-4 lists single and combination treatment
options.
Chemotherapy Options
Anthracyclines
Before the introduction of taxanes, anthracyclines were
considered the most active class of chemotherapeutic agents
for the treatment of breast cancer. For patients who had not
received treatment in the metastatic setting, single-agent
therapy with an anthracycline resulted in response rates of
35% to 50%. Today, most patients with metastatic disease
have previously been treated with an anthracycline in the
adjuvant setting. This limits the use of these agents for
metastatic disease. However, if there is a long disease-free
interval between uses, anthracyclines can be reintroduced.
Several clinical factors should be considered to help

predict the likelihood of response to chemotherapy.
Patients with a better performance status, less extensive
prior treatment, a prolonged disease-free interval, and less
extensive metastatic disease are more likely to respond
to this treatment. Chemotherapy is typically continued as
long as the patient responds to the regimen and tolerates the
adverse effects. Patients may be granted a chemo holiday
(i.e., a break with no chemotherapy) if they have long periods
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Table 2-4. Single and Combination Chemotherapy Regimens for Patients with Metastatic Breast Cancer
Single Agent
Doxorubicin
Epirubicin
Liposomal doxorubicin
Paclitaxel
Docetaxel
Capecitabine
Vinorelbine
Gemcitabine
Albumin-bound paclitaxel
Combination
Fluorouracil-doxorubicin-cyclophosphamide/cyclophosphamidedoxorubicin-fluorouracil
Fluorouracil-epirubicin-cyclophosphamide
Doxorubicin-cyclophosphamide
Epirubicin-cyclophosphamide
Doxorubicin-docetaxel
Cyclophosphamide-methotrexate-fluorouracil
Docetaxel and capecitabine
Gemcitabine-paclitaxel
Paclitaxel-carboplatin-trastuzumab
Docetaxel-trastuzumab
Vinorelbine-trastuzumab
Lapatinib-capecitabine
Nanoparticle albuminbound paclitaxel has been

compared with both paclitaxel and docetaxel. Compared
with every-3-week paclitaxel administration, nanoparticle
albuminbound paclitaxel (260 mg/m 2 infused for 30
minutes every 3 weeks) resulted in significantly higher
response rates and longer time to progression. More grade
3 neuropathies were identified with nanoparticle albumin
bound paclitaxel compared with paclitaxel; however, the
neuropathy experienced was for a shorter duration than with
paclitaxel. Data comparing nanoparticle albuminbound
paclitaxel with docetaxel, although presented, have not been
published in full. Nanoparticle albuminbound paclitaxel
(given either weekly or every 3 weeks) demonstrated better
progression-free survival and a better safety profile than
docetaxel given every 3 weeks. This has led investigators to
evaluate weekly dosing with nanoparticle albuminbound
paclitaxel versus every-3-week administration of docetaxel
in a large Phase III trial.
The epothilones, which have a mechanism of action
similar to taxanes, are a novel class of agents being used
and studied in MBC. Ixabepilone is a semisynthetic analog
of epothilone B that binds to a specific site on tubulin;
this differs from the taxanes and results in microtubule
stabilization. Ixabepilone at a dose of 40 mg/m 2 is approved
in combination with capecitabine for patients with MBC
whose anthracycline and taxane therapy has failed or as a
single agent for patients whose disease has progressed after
treatment with anthracyclines, taxanes, and capecitabine.
Progression-free survival (25% reduction in risk of disease)
was significantly better with combined ixabepilone and
capecitabine therapy compared with capecitabine alone.
This benefit was similar to that observed with upfront
taxane therapy in chemotherapy-nave patients. Greater
toxicity was identified in the combination arm (i.e., sensory
neuropathy, fatigue, and neutropenia). These study results
are the first to be published regarding epothilone therapy in
the treatment of MBC, but additional studies are planned
(see Table 2-4).
The anthracyclines most commonly used are doxorubicin,

liposomal doxorubicin, and epirubicin. Numerous
combination regimens with or without anthracyclines have
been shown to be effective and are included in Table 2-4.
Taxanes
Up to 50% of patients with MBC respond to single-agent
treatment with paclitaxel or docetaxel. There has been
considerable research on different dosing and scheduling
regimens. The Cancer and Leukemia Group B compared a
weekly regimen with an every-3-week regimen of paclitaxel
in women with metastatic, HER2-positive breast disease.
Weekly paclitaxel administration (80 mg/m 2 for 1 hour)
was superior to every-3-week administration (175 mg/
m2 for 3 hours), producing statistically significant better
response rates, time to progression, and survival. The
toxicities identified were slightly different depending on
the schedule, with every 3-week therapy having more grade
3 granulocytopenia, myalgias, and arthralgias and weekly
administration resulting in more grade 3 sensory and motor
neuropathies.
A head-to-head trial comparing paclitaxel (175 mg/m 2)
with docetaxel (100 mg/m 2) given every 3 weeks for MBC
found docetaxel to be superior in overall survival and time
to progression. More hematologic and nonhematologic
toxicities were noted with docetaxel. It is difficult to interpret
this information and the data for weekly paclitaxel versus
paclitaxel given every 3 weeks. It is not known whether
docetaxel given every 3 weeks would provide results similar
to weekly paclitaxel.
Nanoparticle albuminbound paclitaxel, a novel
formulation created through nanotechnology, has an
improved toxicity profile. Regular paclitaxel requires
polyethoxylated castor oil for solubility; however,
nanoparticle albuminbound paclitaxel does not. Therefore,
there is little risk of hypersensitivity reactions. Albumin is a
natural carrier of lipophilic molecules in humans; it allows
nanoparticle albuminbound paclitaxel to be administered
at higher doses and for a shorter infusion time (i.e., 30
minutes) than paclitaxel.
Other Active Agents

Cisplatin
Carboplatin
Etoposide (oral)
Vinblastine
Fluorouracil (continuous infusion)
Ixabepilone
Ixabepilone and capecitabine
26
3 weeks and gemcitabine 1250 mg/m 2 was given on days

1 and 8 in patients who did not respond to anthracycline
adjuvant therapy unless an anthracycline was clinically
contraindicated. The combination significantly improved
overall survival compared with paclitaxel alone; however,
greater toxicity was experienced in the combination arm of
the trial. Gemcitabine can be considered first-line treatment
in combination with paclitaxel or second- or third-line
treatment as a single agent.
Platinum analogs (cisplatin and carboplatin) originally
were not commonly used in the treatment of breast cancer.
However, after data demonstrated synergy when cisplatin
was used in combination with trastuzumab, research
interest in this area grew. The desire to develop a non
anthracycline-containing regimen also helped boost interest
in these agents. Both drugs form platinum adducts that
intercalate DNA, leading to the inhibition of DNA synthesis.
Common toxicities associated with these agents include
myelosuppression, nausea, nephrotoxicity, neurotoxicity,
and electrolyte (potassium and magnesium) wasting. Both
agents have been studied in weekly and every-3-week
regimens in both the adjuvant and metastatic setting and in
combination with trastuzumab, paclitaxel, and docetaxel.
Cisplatin plus paclitaxel in previously treated patients
and as a first-line treatment of MBC demonstrated response
rates of 38% to 45% and 48% to 90%, respectively. Positive
results were also identified with the combination of
docetaxel and cisplatin. Data for several different doses and
administration schedules are available, and cisplatin is now
used more readily for MBC in clinical practice.
Carboplatin has also demonstrated benefit in this patient
population. With paclitaxel plus carboplatin as a firstline treatment of MBC, response rates of about 50% were
reported. Responses of up to 60% were identified with
the use of carboplatin plus docetaxel. These data include
various doses and administration schedules. Carboplatin
causes more thrombocytopenia and less nephrotoxicity than
cisplatin. Both agents are being incorporated into adjuvant
treatment of breast cancer. As a class, they can be offered as
a first-line treatment of MBC, as well as later treatment (see
Table 2-4).
Capecitabine
Capecitabine is an oral fluorouracil prodrug that
undergoes enzymatic activation by thymidine phosphorylase
to fluorouracil in tumor tissue. This agent was approved in
1998 as a single-agent therapy in patients whose disease has
progressed on anthracycline and taxane therapy. Response
rates range from 20% to 37% in patients with MBC.
Toxicities commonly associated with capecitabine use
include diarrhea, palmar-plantar erythrodysesthesia (handfoot syndrome), nausea, and fatigue. Approved dosing is
1250 mg/m 2 twice daily on days 114 of a 21-day cycle;
however, because of toxicities, many patients are initiated
on a lower starting dose of 1000 mg/m 2. Because of the ease
of oral administration, many combination chemotherapy
studies use capecitabine.
In a trial of docetaxel plus capecitabine versus docetaxel
alone, patients receiving the combined therapy exhibited
a superior time to progression and overall survival. More
overall toxicity was identified in the combination arm,
including gastrointestinal toxicities and hand-foot syndrome,
whereas those receiving single-agent docetaxel experienced
more myalgias, arthralgias, and neutropenia. This trial is
the first combination study to exhibit increases in overall
survival in this patient population compared with singleagent therapy. Study participants receiving only docetaxel
were allowed to switch to capecitabine if their disease
progressed (27% of patients), so a true understanding of
the effect of capecitabine on overall survival cannot be
determined.
Vinorelbine, Gemcitabine, and Platinum Analogs
Other commonly used chemotherapeutic agents in MBC
include vinorelbine, gemcitabine, and platinum analogs.
Vinorelbine is a vinca alkaloid that blocks polymerization of
microtubules and impairs mitotic spindle formation, leading
to cell death. Common toxicities associated with this agent
include neutropenia, neuropathy, constipation, anemia,
and thrombocytopenia. As a single agent, vinorelbine has
demonstrated response rates from 40% to 50% as a first-line
treatment of MBC and between 25% and 40% as secondline therapy. Doses range from 25 mg/m 2 to 35 mg/m2 with
weekly intravenous administration. The overall efficacy of
this agent has led to many combination regimens including
those with gemcitabine and trastuzumab (discussed in
the section on biologic therapy). No increase in survival
was identified with the combination of gemcitabine and
vinorelbine. In summary, vinorelbine is considered a
second- or third-line option for MBC.
Gemcitabine is a pyrimidine nucleoside antimetabolite
that inhibits DNA polymerization activity, ultimately
interrupting DNA replication. By itself, gemcitabine as
a first-line treatment demonstrates responses in 14% to
37% of patients and up to 30% as a second-line treatment.
Doses range from 800 mg/m2 to 1250 mg/m2 with weekly
intravenous administration. Schedules include days 1 and
8 of a 21-day cycle, and days 1, 8, and 15 of a 28-day cycle.
Common toxicities include myelosuppression, fatigue,
and flu-like symptoms. Single-agent therapy is commonly
administered, and gemcitabine is included in combination
therapy with trastuzumab. Paclitaxel plus gemcitabine is an
approved regimen for MBC; this is based on a 2004 study
in which paclitaxel 175 mg/m 2 was administered every
Drug Selection
Identifying which chemotherapy to use for MBC largely
depends on the chemotherapy and hormonal therapy used
in the adjuvant setting. Most individuals treated today will
have received an anthracycline and a taxane as part of their
adjuvant therapy. If the disease recurs quickly after this
treatment, the disease can be considered resistant to these
agents. There are data to support a lack of cross-resistance
among taxanes. If a woman receives paclitaxel in the
adjuvant setting, she may still benefit from docetaxel in the
metastatic setting. In addition, the more agents a patient
is exposed to, the less likely her disease is to respond to
additional agents. If, at any time, the patient is eligible for a
clinical trial and has a good performance status, this should
also be an option for the patient.
In conclusion, current therapeutic options for MBC
include capecitabine, paclitaxel/docetaxel/nanoparticle
albuminbound paclitaxel (depending on which agent the
patient has used previously), vinorelbine, gemcitabine,
cisplatin, carboplatin, and an anthracycline such as liposomal
27
Trastuzumab alone has demonstrated response rates of

up to 20% as salvage therapy and 25% to 28% as first-line
therapy. Depending on the patients performance status,
single-agent therapy with trastuzumab may be an option
because of its relatively few adverse effects. Common
toxicities include fever, chills, infusion-related reactions,
and diarrhea, together with the well-known cardiac toxicity.
If cardiac toxicity is identified, trastuzumab therapy should
be discontinued until the patients cardiac function improves.
Therapy can be reinitiated if the patient is maintained on
appropriate cardiac therapy.
It is unknown if a patient whose disease progresses on
a regimen of trastuzumab and chemotherapy should be
continued on trastuzumab when the chemotherapy agent
is changed. Current practice is to continue trastuzumab
regardless of the switch in chemotherapy. There is also a
question of whether the patient might develop resistance
to trastuzumab and whether drugs such as lapatinib would
play a role in these circumstances in the future. Combination
therapies including trastuzumab and other biologic therapies
are currently being studied.
doxorubicin (depending on the disease-free interval from the

anthracycline used in the adjuvant setting). Rarely, etoposide
or vinblastine may also be used as last-line options. There is
no standardized approach when deciding which agent to use
first. As discussed previously, a full review of the patients
previous therapy, toxicity, and performance status is crucial
in the decision-making. If the patient is HER2 positive,
incorporating trastuzumab is an important consideration.
If the patient has bone metastases, bisphosphonate therapy
should be considered. Eligible patients should also be offered
participation in clinical trials.
Biologic Therapy
Biologic therapy revolutionized the treatment of breast
cancer with the advent of trastuzumab and newer agents
such as bevacizumab and lapatinib, each with its own
specific mechanisms and toxicities.
Trastuzumab
Trastuzumab is a humanized monoclonal antibody
with numerous proposed mechanisms of action, including
binding to the extracellular domain of the HER2 receptor
and exerting antigen-dependent cellular cytotoxicity. To
determine if a patient is a candidate for trastuzumab therapy,
testing with immunohistochemistry (which detects protein
expression of HER2 on the cell surface) or fluorescence in
situ hybridization (which detects gene amplification [number
of gene copies] of HER2) is needed to establish if the patient
is positive for HER2.
Interpretation of immunohistochemistry relies on a
qualitative scoring system. On a scale of 0 to 3+, a patient
may score a 0 (negative), 1+ (negative), 2+ (borderline), or
3+ (positive) based on the pathologists interpretation of
staining intensity. With fluorescence in situ hybridization,
the results are quantitative instead of qualitative. Results
are interpreted as negative or positive by calculating the
HER2 gene copy number. These results are determined by
the ratio of the number of HER2 signals to the number of
chromosome signals. A normal specimen results in a ratio
of less than 2.0, whereas a specimen with an amplification
of HER2 has a ratio of 2.0 or greater, which is considered
HER2 positive.
In the previously discussed cisplatin and trastuzumab
trial, improved response rates were identified with this
combination compared with treatment using each agent
alone. In 2001, a pivotal trial was published with trastuzumab
and chemotherapy as a first-line treatment of MBC. Overall
survival was better with the trastuzumab arm, which led
to the approval of trastuzumab for the treatment of MBC.
The study was also the first to identify cardiotoxicity
as a consequence of trastuzumab, which led to cardiac
monitoring in all trastuzumab trials. Numerous agents
have been combined with trastuzumab, including cisplatin,
vinorelbine, capecitabine, gemcitabine, carboplatin plus
paclitaxel or docetaxel, cisplatin plus docetaxel, and
anastrozole. Any of these combinations are good choices for
the patient with HER2-positive metastatic disease who does
not have cardiac dysfunction (which prohibits the patient
from receiving trastuzumab).
Bevacizumab
Bevacizumab is a recombinant, humanized, monoclonal
antibody that inhibits vascular endothelial growth factor
and ultimately inhibits angiogenesis. The dosing regimen
approved was 10 mg/kg intravenously every 14 days. Toxicities
associated with this agent include hypertension, proteinuria,
venous and arterial thromboembolism, hemorrhage, wound
healing complications, and gastrointestinal perforation.
Single-agent trials produced modest benefit in previously
treated patients. Preclinical data supported the theory of
synergy with chemotherapy, and numerous clinical trials of
combination therapies are under way. In one trial comparing
capecitabine alone or in combination with bevacizumab in
patients who were anthracycline and taxane resistant, the
addition of bevacizumab did not prolong progression-free
survival and did not improve overall survival. Researchers
believed that the lack of response was because of the extent
of prior therapies the patients had received.
This theory was put to the test in another trial that
evaluated the combination of paclitaxel and bevacizumab
versus paclitaxel alone as first-line treatment of MBC.
The investigators randomized patients to receive weekly
treatments with paclitaxel 90 mg/m 2 and bevacizumab 10
mg/kg on days 1 and 15 of a 28-day cycle. The primary
end point of the study was progression-free survival, which
was significantly improved with combination (11.8 months)
versus single-agent (5.9 months) therapy. Overall survival,
a secondary end point, did not show statistically significant
improvement. Greater toxicity (including hypertension,
neuropathy, and infection) was identified in the combination
arm. Although overall survival was not significantly
improved, bevacizumab labeling was granted accelerated
approval by the FDA for MBC in February 2008. Many
proponents question the use of this combination because
of the lack of improvement in overall survival; however,
this combination therapy has been added to the National
Comprehensive Cancer Network guidelines as an option for
first-line treatment of MBC.
28
Table 2-5. Emerging Targeted Therapies for Breast

Cancer
Other Targeted Therapies

Another targeted therapy approved for use in patients with
MBC is lapatinib. Lapatinib is a small molecule that inhibits
the tyrosine kinase activity of the oncogenes HER2 and
epidermal growth factor receptor (also known as EGFR). In
prior studies, this agent did not show cross-resistance with
trastuzumab; in fact, it exhibited benefits when combined
with capecitabine and trastuzumab. In a combination trial
evaluating lapatinib and capecitabine in patients who
received anthracyclines, taxanes, and trastuzumab, patients
were randomized to receive one of two regimens. One group
received capecitabine alone at 2500 mg/m 2 orally in two
divided doses on days 114 of a 21-day cycle. The second
group receive lapatinib 1250 mg/day orally plus capecitabine
2000 mg/m2 in two divided doses on days 114 of a 21-day
cycle. A 51% reduction in the risk of disease progression
was identified with the combination therapy, resulting in
early reporting of the data.
Because lapatinib is an inhibitor of human EGFR
similar to trastuzumab, cardiac toxicity was a concern.
Left ventricular ejection fraction was monitored by
echocardiography or multigated acquisition scan at the same
time as efficacy assessments. At the time of data reporting,
only four patients in the combination arm experienced
asymptomatic cardiac events compared with one patient
in the single-agent arm. No symptomatic cardiac events
occurred and no patient discontinued lapatinib therapy
because of a decrease in left ventricular ejection fraction.
The most common toxicities of lapatinib included diarrhea,
hand-foot syndrome, rash, nausea/vomiting, and fatigue.
Questions must still be answered to fully understand the
place of lapatinib in the treatment of MBC. Should lapatinib
be compared with trastuzumab? Should these agents be
combined? Answers to these and other questions will
help clinicians better understand the usefulness of small
molecules such as lapatinib in the treatment of MBC. Drug
combinations currently being studied include taxanes,
liposomal doxorubicin, trastuzumab, and lapatinib, as well
as other classes of agents (Table 2-5).
Another concern with lapatinib and other oral
antineoplastic drugs currently available is drug-drug
interactions. Lapatinib is a cytochrome P450 3A4 and 2C8
inhibitor. Drug-drug interactions can be expected with
several agents including verapamil, rifampin, phenytoin,
and St. Johns wort. Pharmacists should conduct a thorough
review of all the patients drugs and over-the-counter
supplements to ensure that the patient will not experience
any adverse events or require drug dosage alteration.
Class
Epidermal growth factor receptor inhibitors
Dual epidermal growth factor receptor/HER2
tyrosine kinase inhibitors
Multitargeted kinase inhibitors
Farnesyltransferase inhibitors
Rapamycin inhibitors
Heat shock proteins
Sunitinib
Tipifarnib
Lonafarnib
Sirolimus
Temsirolimus
17-AAG
KOS-953
HER2 = human epidermal growth factor receptor 2.
monthly. In head-to-head evaluations, both were effective

in treating bone metastases and were beneficial in treating
or preventing skeletal events; however, there was a longer
time to the first event with zoledronic acid (310 days)
compared with pamidronate (174 days). Overall, zoledronic
acid helped reduce skeletal morbidity more effectively than
pamidronate.
The first reports of osteonecrosis of the jaw were
published in 2003. For a patient to be classified as having
bisphosphonate-induced osteonecrosis, the American
Association of Oral and Maxillofacial Surgeons set forth
the following criteria: the patient must have received
bisphosphonates in the past, have exposed and necrotic bone
in the maxillofacial region for longer than 8 weeks, and
have no history of radiation therapy to the jaw. Although
not defined, risk factors associated with the development
of osteonecrosis of the jaw include bisphosphonate therapy,
dental surgery (extractions), radiation therapy, concomitant
oral disease (periodontal and dental abscesses), poor oral
hygiene, corticosteroid use, and dental trauma.
The mechanism by which bisphosphonates induce
osteonecrosis of the jaw is not understood. The best
prevention modality is for patients to undergo a thorough
dental examination and, if needed, consultation with an oral
maxillofacial surgeon before bisphosphonate therapy. The
best course of action is to do dental extractions or other oral
surgery before initiating biphosphonate therapy. If possible,
extractions should be avoided after bisphosphonates are
started. When numerous tooth extractions are needed, the
American Dental Association Council on Scientific Affairs
recommends treating one tooth at a time with a 2-month
window between extractions to ensure appropriate healing.
These recommendations also include patients who require
oral bisphosphonate therapy. If the patient taking intravenous
bisphosphonates develops osteonecrosis of the jaw, treatment
guidelines have been formulated to help the clinician make
appropriate recommendations. First, however, the patient
should be referred to an oral/maxillofacial surgeon so that
further care can be coordinated by the surgeon and the
patients medical oncologist.
Bisphosphonates
Bisphosphonates are used in the treatment and prevention
of skeletal events (e.g., pathologic fractures, spinal cord
compression, surgery to bone, radiation therapy to bone)
associated with bone metastases in breast, lung, and
prostate cancer and in lytic lesions associated with multiple
myeloma. Bisphosphonates reduce hypercalcemia, stabilize
bony involvement, and help prevent fractures. Agents on
the market used for this purpose include zoledronic acid
(4 mg infused for 15 minutes) and pamidronate (90 mg
infused for 2 hours). Both agents are administered once
Agent
Gefitinib
Erlotinib
Lapatinib
29
Brain Metastases
Annotated Bibliography
About 15% to 20% of patients with MBC eventually

receive a diagnosis of brain metastasis. Patients typically
present with symptoms such as headache, mental status
changes, diplopia, gait disturbances, seizures, and speech
problems. If brain metastasis is suspected, an MRI should
be ordered to evaluate for possible lesions. Treatment with
corticosteroids helps decrease inflammation around the
tumors and can lead to symptomatic improvement. Survival
is poor and can range from 3 months to 6 months, with up
to 20% of patients alive at 1 year. Different modalities are
available for treatment, including radiation, surgery, and
systemic therapy. Choice of therapy varies based on the
number and size of the lesions as well as their location.
The number of patients receiving a diagnosis of brain
metastasis has increased as the number of patients living
longer with MBC increases. Traditionally, clinicians believed
that chemotherapy could not cross the blood-brain barrier;
however, there is evidence that demonstrates disruption of
the barrier by the brain metastases themselves. This theory
could lend itself to successful treatment of brain metastases
with smaller, lipid-soluble molecules or small molecules
with targeted activity (i.e., inhibitors of EGFR). In a trial
evaluating capecitabine versus capecitabine and lapatinib,
fewer patients with central nervous system progression
were observed in the combination arm. Studies should be
conducted to evaluate the incorporation of these types of
agents to see if survival is improved.
1.
2. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer.

N Engl J Med 2003;348:243142.
This paper is a review of AIs in the treatment of breast
cancer. The authors review the development and classification
of each AI, including the clinical development of this class
and how each AI compares with the others. The authors then
describe the clinical role of AIs as first- and second-line
treatment of breast cancer in the neoadjuvant, adjuvant, and
metastatic setting. A thorough review of the toxicities is also
included.
3.
Bonneterre J, Buzdar A, Nabholtz JM, Robertson JF,

Thurlimann B, von Euler M, et al. Anastrozole is superior to
tamoxifen as first line therapy in hormone receptor positive
advanced breast carcinoma. Cancer 2001;92:224758.
This article reveals the results of two randomized trials
designed for combined analysis. One of the studies was
conducted in the United States and Canada, and the other was
conducted in Europe, Australia, New Zealand, South America,
and South Africa. These two trials were run concurrently.
Initial results identified anastrozole as at least equivalent
to tamoxifen in median time to progression. However, with
a subgroup analysis, anastrozole was superior to tamoxifen
when evaluating only patients with ER- or PR-positive breast
cancer. On further review, it was identified that patients
outside North America were allowed to enter the study even
if their ER/PR status was unknown. In the North American
trial, 90% of patients were known to be ER/PR positive; in
the other trial, only 45% of patients were known to be ER/PR
positive. These findings highlighted the disparity in clinical
practice around the world in 2001. This trial concluded that
patients with ER/PR-positive disease fared better in time
to progression and clinical benefit (complete response plus
partial response plus stabilization of 24 weeks or more). In
addition, anastrozole resulted in significantly fewer venous
thromboembolic events and less vaginal bleeding than
tamoxifen, and anastrozole was well tolerated. With the
results of these two trials, anastrozole was approved as a
first-line treatment option for women with MBC.
4.
Howell A, Pippen J, Elledge RM, Mauriac L, Vergote I, Jones

SE, et al. Fulvestrant versus anastrozole for the treatment of
advanced breast carcinoma: a prospectively planned combined
analysis of two multicenter trials. Cancer 2005;104:2369.
Conclusion
The treatment of MBC has slowly evolved; however,
overall survival has only slightly improved. When selecting
a treatment plan, the goal of palliation should be kept in
mind. The patients site of disease and performance status
must be considered when planning care. If a patient has ER/
PR-positive breast cancer, hormonal therapy is an option. If
the patient has extensive disease or numerous symptoms,
chemotherapy is appropriate. Chemotherapy can be used
regardless of the patients ER/PR status, and a decision about
which agent or regimen to use is dependent on the treatment
administered previously in the adjuvant setting. Singleagent therapy is preferred to combination therapy because
combination therapy has demonstrated little additional
survival benefit. There are no clear guidelines for a stepwise
approach when choosing an agent.
If a patient is HER2 positive, treatment with
trastuzumab is warranted as long as the patient does
not have underlying cardiac dysfunction. Together with
trastuzumab, bevacizumab and lapatinib are being explored
for the treatment of HER2-positive MBC. Newer agents
and combination therapies are also being evaluated. As we
learn more about tumor biology and the signaling pathways
involved in breast cancer progression, we may someday be
able to better target therapy and improve overall survival in
this patient population.
Greenberg PA, Hortobagyi GN, Smith TL, Ziegler LD,

Frye DK, Buzdar AU. Long-term follow-up of patients with
complete remission after combination chemotherapy for
metastatic breast cancer. J Clin Oncol 1996;14:2197205.
This article is included as a historic reference. The authors
conducted a retrospective review of 1581 patients who
received front-line chemotherapy regimens of doxorubicin
and an alkylating agent for MBC from 1973 to 1982. Of the
patients able to achieve a complete response with their initial
chemotherapy regimen, 18% were still disease free at 5 years,
and more than 10% remained disease free for 10 years. Many
factors helped identify patients likely to achieve a complete
response. They included younger patients (median age of
50), lower number of different metastatic sites, and better
performance status. It is understood that most patients with
metastatic disease are not curable. However, a few patients,
as demonstrated in this review, maintain long-term remission
with standard chemotherapy that includes an anthracycline.
30
process of when to initiate therapy, how long to treat, and

when to discontinue therapy, and also reviews common
chemotherapies used in MBC. In addition, the author
addresses indications for single-agent versus combination
therapy. Summary data are available regarding the different
classes of drugs, the particular chemotherapeutic agents
used, and the toxicities associated with those drugs. The
author concludes with future directions for chemotherapy use
in treatment of MBC.
This study is a combined survival analysis of two

multicenter trials that were conducted concurrently, with one
study in North America and the other in Europe, Australia,
and South Africa. In overall survival, fulvestrant was
considered at least as effective as anastrozole (27.4 months
vs. 27.7 months, respectively) when used as second-line
treatment of postmenopausal women with advanced breast
cancer. Based on these trials, fulvestrant was approved for
the treatment of hormone-positive MBC in postmenopausal
women with disease progression after antiestrogen therapy.
9.
5. Robertson JF. Fulvestrant (Faslodex): how to make a good

drug better. Oncologist 2007;12:77484.
This article reviews the data available for fulvestrant in the
treatment of MBC. The author discusses the role of fulvestrant
in the treatment of tamoxifen-resistant breast cancer and
as first-line treatment of advanced cancer. The author also
reviews the data available on different dosing regimens (i.e.,
standard dose, loading dose, or high dose). As discussed
in this chapter, a question posed by clinicians is, How can
steady-state concentrations of fulvestrant be achieved more
quickly, allowing the patient to have an earlier response? In
addition, the author discusses upcoming combination trials
using other therapies such as AIs and trastuzumab.
6.
Michaud LB. Aromatase inhibitors in early and advanced

disease. Agrawal A, Roberts JF, Cheung KL. Fulvestrant in
metastatic disease. Espirito JL. Progestins and androgens.
All in Buzdar AU, ed. Endocrine Therapies in Breast Cancer.
New York: Oxford University Press, 2007.
These three chapters discuss AIs in early and advanced
breast cancer, fulvestrant in metastatic disease, and progestins
and estrogens in advanced disease. Together they form a
concise summary of hormonal treatments for breast cancer,
containing information on both early- and advanced-stage
disease and offering guidance in selecting hormonal therapy
for patients. Because this book is a pocket guide, concise
summaries of the data are presented throughout. This guide
offers a brief, helpful review of currently published data and
of trials in progress.
7.
Ingle JN. Sequencing of endocrine therapy in postmenopausal

women with advanced breast cancer. Clin Cancer Res
2004;10:362S7S.
This article reviews the trials conducted in patients who
have progressed while on hormonal therapy. The author
groups patients into four categories: (1) hormonal therapy
nave (patients who have not received hormonal therapy
previously); (2) prior exposure to tamoxifen for more than 1
year; (3) prior exposure to tamoxifen within 1 year; and (4)
prior anastrozole exposure. This patient classification helps
the clinician decide how to proceed with therapy. The article
also highlights how a patient may respond after completing
previous hormonal therapy. If a patient responds to previous
hormonal therapy with a long progression-free survival, the
patient is more likely to respond to subsequent hormonal
therapy. The author subsequently states that patients who
are hormonal therapy nave are becoming increasingly
rare whereas patients with prior anastrozole exposure are
becoming more prevalent because of the use of anastrozole
in the adjuvant setting.
8.
Mayer EL, Burstein HJ. Chemotherapy for metastatic breast

cancer. Hematol Oncol Clin North Am 2007;21:25772.
This article reviews chemotherapy in the treatment of
MBC. The author walks the reader through the thought
Briest S, Stearns V. Chemotherapeutic strategies for advanced

breast cancer. Oncology (Williston) 2007;21:132535.
This article reviews all aspects and treatment of MBC.
The author discusses the roles of treatment and explains
how treatment decisions should be based on a review of the
prognostic and predictive factors and the appropriateness
of hormonal therapy versus chemotherapy. An extensive
review of data is presented, with information encompassing
both single-agent treatment and combination therapy. Newer
strategies for targeted therapies are discussed, as are future
directions in MBC management.
10. Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L,

Lower E, et al. Randomized Phase III study of docetaxel
compared with paclitaxel in metastatic breast cancer. J Clin
Oncol 2005;23:554251.
This article discusses the first trial to directly compare
docetaxel with paclitaxel as single-agent therapy for MBC.
The overall response duration (32% vs. 25%; p=0.10), time to
progression (5.7 vs. 3.6 months; p<0.0001), and overall survival
(15.4 vs. 12.7 months; p=0.03) were better with docetaxel
chemotherapy. More hematologic and non-hematologic
toxicities were identified with docetaxel compared with
paclitaxel. However, the quality of life score between the
groups did not differ. Although these data were clinically
significant, it is difficult to interpret this information and
the information regarding weekly versus every-3-week
paclitaxel. The results of the previously conducted studies
of weekly paclitaxel cannot be compared with every-3-week
docetaxel.
11. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai
N, Bhar P, et al. Phase III trial of nanoparticle albuminbound paclitaxel compared with polyethylated castor oilbased paclitaxel in women with breast cancer. J Clin Oncol
2005;23:7794803.
This article describes the first trial to evaluate nanoparticle
albuminbound paclitaxel, a nonpolyethoxylated castor
oil-based taxane agent, in patients with MBC. The albumin
formulation allows higher doses of paclitaxel to be given
and results in fewer hypersensitivity reactions because
of the absence of polyethoxylated castor oil. In this trial,
nanoparticle albuminbound paclitaxel was demonstrated to
be significantly better (response rate and time to progression)
than standard every-3-week paclitaxel. Grade 3 sensory
neuropathies were higher with the nanoparticle albumin
bound paclitaxel compared to traditional paclitaxel (10%
vs. 2%, respectively; p<0.001); however, the duration of this
toxicity was reduced compared with every-3-week paclitaxel.
This formulation offers a new opportunity for patients
unable to use the traditional formulation of paclitaxel or for
patients unable to tolerate the high doses of steroids required
to prevent diluent-related hypersensitivity reactions. This
agent is currently being studied in the adjuvant setting. When
these data become available, nanoparticle albuminbound
31
paclitaxel may become part of the treatment regimen for

adjuvant breast cancer.
15. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez

EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone
for metastatic breast cancer. N Engl J Med 2007;357:2666
76.
This article one of the newest publications on the
treatment of MBC evaluates the combination of paclitaxel
and bevacizumab as first-line treatment in MBC versus
single-agent treatment with paclitaxel. The primary end point
of this trial was progression-free survival. Response rates
were significantly better with the combination arm compared
to the single agent arm (36.9% vs. 21.2%, respectively;
p<0.001). Overall survival (a secondary end point) was
similar in both arms of the study. This combination was
approved on the fast track as a first-line treatment of MBC.
However, many clinicians questioned the approval because of
the lack of survival benefit. Patients receiving bevacizumab
therapy should be evaluated for appropriate use because this
agent can cause or exacerbate hypertension, proteinuria, and
thromboembolism.
12. Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan
VF, et al. Ixabepilone plus capecitabine for metastatic breast
cancer progressing after anthracycline and taxane treatment.
J Clin Oncol 2007;25:52107.
Ixabepilone is the first agent in the class of epothilones
approved for the treatment of MBC. Epothilones work by
stabilizing the microtubule complex leading to apoptosis.
In this trial, progression-free survival was the primary end
point, and ixabepilone exhibited a 25% reduction in risk of
disease progression. Overall survival was a secondary end
point; however, at the time of the studys publication, the
planned number of events for analysis had not been reached.
Of interest, patients had a 25% reduction in risk of progressive
disease even after their anthracycline and taxane therapy
had failed. This agent poses promise in MBC as well as the
likelihood of being studied in the adjuvant setting.
16. Arnedos M, Seidman AD. Emerging targeted therapies for

breast cancer. Hematol Oncol Clin North Am 2007;21:321
40.
This article reviews emerging targets for the treatment
of MBC. Classes of agents discussed include tyrosine
kinase inhibitors, EGFR inhibitors, dual EGFR and HER2
tyrosine kinase inhibitors, multitargeted kinase inhibitors,
farnesyltransferase inhibitors, and heat shock proteins.
Studies evaluating the combination of a targeted therapy with
chemotherapy are also discussed. Targeted therapy represents
the future of breast cancer treatment. Many of these agents
are administered orally, which increases convenience for
patients. One of the main problems with these agents is how
they are metabolized. Many of them are metabolized by
means of the CYP 450 3A4 pathway. Pharmacists can play
a significant role in monitoring drug-drug interactions in
patients receiving these agents.
13. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG,

Pienkowski T, et al. Lapatinib plus capecitabine for HER2positive advanced breast cancer. N Engl J Med 2006;355:2733
43.
Clinicians understand the role of HER2 in breast
cancer, but they also understand the possibility of patients
developing resistance to trastuzumab; therefore, alternatives
are under evaluation. Lapatinib is a small-molecule tyrosine
kinase inhibitor that targets HER2 and EGFR. This article
discusses the combination of capecitabine and lapatinib
versus capecitabine alone in patients who have already
received anthracyclines, taxanes, and trastuzumab. In this
trial, a 51% reduction in risk of progression was identified
with the combination of lapatinib and capecitabine; as a
result, lapatinib was approved for use in combination with
capecitabine to treat patients with MBC who have progressed
despite anthracyclines, taxanes, and trastuzumab. This is
only one of numerous trials to evaluate the combination of
a targeted therapy with traditional chemotherapy for the
treatment of MBC.
17. Ruggiero S, Gralow J, Marx RE, Hoff AO, Schubert MM,

Huryn JM, et al. Practical guidelines for the prevention,
diagnosis, and treatment of osteonecrosis of the jaw in
patients with cancer. J Oncol Pract 2006;2:714.
With the increased use of bisphosphonates to treat patients
with MBC, osteonecrosis of the jaw has become more
commonly reported. The specific mechanism by which this
occurs is unknown, but risk factors for occurrence include
malignancy, use of chemotherapy, corticosteroids, head
and neck radiotherapy, periodontal disease, and dental
procedures involving bone surgery. Practical guidelines have
been developed to help physicians determine the appropriate
prevention, diagnosis, and treatment of osteonecrosis of the
jaw. These guidelines were based on expert opinion alone
and were not evaluated fully in controlled, clinical trials. If
a patient develops osteonecrosis of the jaw, consultation with
an oral maxillofacial surgeon or dental oncologist is strongly
recommended. A nonsurgical approach, if at all possible,
should be chosen for treatment. Intermittent or continuous
antibiotics may be given depending on the circumstance.
Disrupting or discontinuing bisphosphonate therapy may be
necessary in severe cases of jaw osteonecrosis or if surgery
is required. All patients should have an extensive dental
examination before starting bisphosphonate therapy.
14. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V,

Bajamonde A, et al. Use of chemotherapy plus monoclonal
antibody against HER2 for metastatic breast cancer that
overexpresses HER2. N Engl J Med 2001;344:78392.
This article, included for historic purposes, is the trial that
led to the approval of trastuzumab for MBC. It dramatically
changed the way patients with breast cancer were treated
around the world. Patients were randomized to receive
chemotherapy alone or in combination with trastuzumab.
The trial arms included the following: doxorubicin and
cyclophosphamide, either with or without trastuzumab, or
paclitaxel either alone or in combination with trastuzumab.
Cardiac toxicity was identified with the anthracycline and
trastuzumab combination in 27% of patients, whereas only
8% of patients receiving doxorubicin plus cyclophosphamide
experienced cardiac toxicity. In the paclitaxel combination
group, compared with the single-agent therapy group, the risk
of cardiac toxicity was 13% versus 1%, respectively. When
this article was published, very few studies had demonstrated
survival advantages in the metastatic setting. This is the
first trial in which a monoclonal antibody exhibited survival
advantages when added to traditional chemotherapy in the
treatment of patients with MBC.
18. Pegram MD, Slamon DJ. Combination therapy with

trastuzumab (Herceptin) and cisplatin for chemoresistant
32
metastatic breast cancer: evidence for receptor-enhanced

chemosensitivity. Semin Oncol 1999;26(Suppl 12):8995.
In this Phase II trial, patients with MBC who were
previously exposed to chemotherapy had a 24% response rate
when treated with the combination of cisplatin and
trastuzumab. This trial was the first to demonstrate an
improved response to the combination of chemotherapy with
trastuzumab. Based on these results, the authors suggested
the idea of enhancing chemosensitivity with trastuzumab.
This has led to numerous clinical trials incorporating
combination chemotherapy with trastuzumab, which shows
increased effectiveness compared with trastuzumab alone.
This trial is also the basis for many of the ongoing trials
incorporating trastuzumab for enhanced activity.
33
34
Self-Assessment Questions
23. In addition to bisphosphonate therapy, which one of the
following is the best regimen at this time for G.T.?
A. Anastrozole daily.
B. Paclitaxel weekly.
C. Tamoxifen daily.
D. Capecitabine twice daily.
Questions 21 and 22 pertain to the following case.

J.J., a 65-year-old African American woman, presented to
the outpatient clinic after her first-ever mammogram and
subsequent breast biopsy. Before her examination, the patient
admitted to having had pain in her right breast for about
1 year but had not gone for an evaluation. In addition, J.J.
complains of right abdominal pain for about 2 months, not
relieved with around-the-clock hydrocodone therapy. This
pain keeps her awake at night, and she is unable to complete
activities of daily living. Breast biopsy revealed invasive
ductal carcinoma that is estrogen receptor (ER) negative,
progesterone receptor (PR) 2%, and human epidermal
growth factor receptor 2 (HER2) negative. Her computed
tomography (CT) scan of the abdomen revealed two liver
lesions (0.7 cm and 1.1 cm) consistent with metastatic
disease. J.J.s medical history is significant for obesity,
hyperlipidemia, hypertension, and diabetes mellitus.
24. G.T. did well during the next year and presented to the
clinic for a yearly follow-up examination. Follow-up
bone and CT scans revealed new metastases in her left
femur and another metastatic site in her ribs. In addition
to bisphosphonate therapy, which one of the following
is the best regimen for G.T. at this time?
A. Fulvestrant.
B. Exemestane.
C. Tamoxifen.
D. Letrozole.
21. Which one of the following is the best treatment for J.J.
at this time?
A. Hormonal therapy.
B. Single-agent chemotherapy.
C. Combined chemotherapy and biologic therapy.
D. Combination chemotherapy.
Questions 2527 pertain to the following case.

M.D., a 64-year-old woman, received a diagnosis of left
breast cancer in 2000. Her cancer history includes a left
modified radical mastectomy that revealed an invasive
lobular carcinoma (1.5 cm, ER 63%, PR 59%, and HER2
negative) by fluorescence in situ hybridization with 2 of 15
positive axillary lymph nodes. After surgery, she received
four courses of doxorubicin and cyclophosphamide,
followed by four courses of every-3-week paclitaxel. Her
adjuvant hormonal therapy consisted of anastrozole for
5 years. In 2007, M.D. developed metastatic disease in
her right humerus and was placed on exemestane and a
bisphosphonate. She continues this regimen today.
M.D. returns to the clinic for a follow-up examination
and is noted to have tenderness in her abdomen and a
lingering pain in her right hip. A CT scan demonstrates a
small 1-cm liver lesion, and a bone scan reveals a lesion in
her right sacrum as well as disease in her right humerus.
Her laboratory values are all within normal limits except
for a CA27.29 (a tumor marker for breast cancer), which is
elevated at 65 U/mL.
22. J.J. responds well to treatment and is able to perform

activities of daily living. In the past 2 weeks, however,
she has noticed increased pain in her left arm that
never goes away; she does not remember falling or
experiencing any trauma to the area. A radiograph
reveals a suspicious lesion in her left arm. A bone scan
demonstrates increased uptake in the left humerus and
right femur consistent with metastatic disease. Which
one of the following is the best therapeutic option for
J.J. at this time?
A. Zoledronic acid 4 mg intravenously monthly.
B. Pamidronate 90 mg intravenously monthly.
C. Alendronate 70 mg orally once daily.
D. Risedronate 35 mg orally once weekly.
G.T., a 62-year-old white woman, was given a diagnosis of
left breast cancer 15 years ago. At her initial diagnosis, her
tumor characteristics included ER 70%; PR 65%; and HER2
negative. On physical examination, the tumor measured
2.1 cm, and the axillary lymph nodes were negative. G.T.
was taken to the operating room, and a modified radical
mastectomy was completed with a sentinel lymph node
biopsy. Pathology revealed a 2.2-cm invasive ductal
carcinoma with negative lymph nodes. In the adjuvant setting,
G.T. received four courses of fluorouracil, doxorubicin, and
cyclophosphamide and completed 5 years of tamoxifen
therapy. G.T. has presented to the clinic with persistent bone
pain during the past month. She does not recall any injuries
to this area. A bone scan reveals metastatic breast cancer
(MBC) in her left sixth rib.
25. In addition to a bisphosphonate, which one of the

following is the best therapy for M.D.?
A. Fluoxymesterone 10 mg orally twice daily.
B. Ethinyl estradiol 3 mg/day orally.
C. Fulvestrant 250 mg intramuscularly once monthly.
D. Megestrol acetate 160 mg orally in divided doses
daily.
26. Which one of the following should be prescribed to help
prevent toxicity associated with M.D.s bisphosphonate
therapy?
A. Monitoring of serum calcium and creatinine.
B. Tooth extractions after thorough discussion with
her dentist and medical oncologist.
35
C. Avoidance of endodontic and restorative dental

procedures.
D. Prophylactic antibiotics.
as follows: CA27.29 = 75 U/mL and blood urea nitrogen and

serum creatinine slightly elevated at 24 mg/dL and 1.2 mg/
dL, respectively.
27. As part of M.D.s follow-up, in addition to CT and bone

scan, which of the following tests and laboratory values
are best to monitor during her treatment course?
A. CA27.29 and CA15.3.
B. CA15.3 and circulating tumor cells.
C. CA27.29 and brain magnetic resonance imaging
(MRI).
D. CA15.3 and position emission tomography scan.
30. Based on the new information from this biopsy, which

one of the following is the best first-line treatment for
N.W.s MBC?
A. Capecitabine plus lapatinib.
B. Trastuzumab plus paclitaxel.
C. Trastuzumab plus liposomal doxorubicin.
D. Trastuzumab.
31. For 15 months, N.W. responded with stable disease. She
returns to the clinic today with repeat staging consisting
of CT and bone scans together with laboratory data. Her
bone scan is negative; however, her CT scan shows new
liver lesions. Which one of the following regimens is
best for N.W. at this time?
A. Capecitabine plus lapatinib.
B. Trastuzumab.
C. Liposomal doxorubicin.
D. Gemcitabine plus paclitaxel.

C.F., a 42-year-old premenopausal woman, recently received
a diagnosis of breast cancer that had metastasized to the
lungs. Two years ago, C.F. received a diagnosis of stage II
invasive lobular, right breast cancer. Her tumor was ER/PR
negative and HER2 negative. She completed neoadjuvant
chemotherapy consisting of flurouracil, doxorubicin, and
cyclophosphamide for four cycles, followed by weekly
paclitaxel for 12 doses. C.F. was doing well until the past
month when she started experiencing shortness of breath.
This kept her from walking up and down the stairs in
her home and from performing normal activities of daily
living. A CT scan demonstrates new nodules in both lungs,
consistent with metastatic disease.
32. B.A. is a 59-year-old woman who received a diagnosis

of stage II breast cancer in 2003. She underwent
a right modified radical mastectomy, followed by
chemotherapy consisting of fluorouracil, doxorubicin,
and cyclophosphamide for four cycles. She has remained
disease free to this point. She returns today with results
of restaging bone and CT scans and a liver biopsy. The
bone scan was negative, as is the CT scan of the chest.
However, the CT scan of her abdomen was positive for
two metastatic lesions measuring 0.7 cm and 0.9 cm. A
biopsy of the liver metastases reveals a disease status
of ER/PR negative, HER2 negative. Which one of the
following is the best therapy for B.A. at this time?
A. Paclitaxel weekly.
B. Paclitaxel every 3 weeks.
C. Nanoparticle albuminbound paclitaxel every 3
weeks.
D. Paclitaxel and bevacizumab.
28. Which one of the following is the best therapy for C.F.
at this time?
A. Docetaxel plus capecitabine.
B. Goserelin plus anastrozole.
C. Liposomal doxorubicin plus vinorelbine.
D. Goserelin plus tamoxifen.
29. C.F. continued treatment for 8 months and tolerated
therapy well. She has been monitored in the clinic
monthly; today, she brings the results of repeat scans
that show progression of her lung metastases. C.F. has
been able to walk up and down the stairs at home with
no problems. Which one of the following is the best
therapy for C.F. at this time?
A. Gemcitabine plus paclitaxel.
B. Vinorelbine.
C. Capecitabine plus lapatinib.
D. Carboplatin.
33. S.S. is a 45-year-old premenopausal woman seen in the

clinic for recently diagnosed left breast cancer. A biopsy
reveals ER/PR-positive and HER2-negative disease.
On a routine staging work-up, a CT scan reveals three
metastatic lesions in her liver, but her bone scan is
negative. Her medical history is noncontributory. S.S.
says she has not experienced any problems with pain or
jaundice, maintaining that she is able to perform normal
activities of daily living. Based on this information,
which one of the following is the best drug regimen for
S.S. at this time?
A. Goserelin plus anastrozole.
B. Goserelin plus tamoxifen.
C. Paclitaxel plus bevacizumab.
D. Doxorubicin plus cyclophosphamide.

N.W., a 64-year-old woman, received a diagnosis of breast
cancer last year and underwent surgery and chemotherapy.
She does not remember what chemotherapy she received but
recalls that it was red. She moved recently and has been
unable to obtain her records from her doctors office. She
recently completed restaging because of increased abdominal
pain. A CT scan of N.W.s chest and abdomen revealed a 1.5cm liver lesion. A liver biopsy was performed. The tumor is
ER/PR negative and HER2 positive by fluorescence in situ
hybridization. Her medical history includes hypertension,
hypothyroidism, and gout. Her laboratory values today are
36
B. Discontinue trastuzumab therapy and do not

reinitiate therapy.
C. Discontinue trastuzumab therapy and initiate
medical management.
D. Continue trastuzumab and initiate monthly
echocardiography.
Questions 3436 pertain to the following case.

C.L. is a 68-year-old woman with MBC. Her stage II right
breast cancer was diagnosed in 1997, and she received
neoadjuvant chemotherapy consisting of four doses of
doxorubicin and cyclophosphamide, followed by a right
lumpectomy and radiation therapy. The pathology report
at that time showed ER/PR positive, HER2 negative, and
a 2.1-cm invasive ductal carcinoma; none of the 15 lymph
nodes excised was positive. After therapy, C.L. received
adjuvant tamoxifen for 5 years. In 2004, C.L. complained
of left hip pain, and a bone scan detected metastatic disease.
She has received several hormonal agents: anastrozole for
1 year; exemestane for 8 months; fulvestrant for 8 months;
megestrol acetate for 6 months; and, finally, fluoxymesterone
for 4 months. She also received a bisphosphonate. Her
medical history is significant for hypertension, deep vein
thrombosis, and coronary artery disease. A recent bone scan
reveals new metastases in the rib cage and left sacrum; her
CT scan reveals probable metastases in the lung. She is still
able to perform activities of daily living.
38. M.J. is a 55-year-old woman with MBC confined to the

lungs. She is being seen in the clinic for a second opinion
regarding her treatment options. Her previous physician
recommended paclitaxel and bevacizumab. Her
medical history is significant for hypercholesterolemia,
hypertension, hypothyroidism, arthritis, and diabetes
mellitus. Her vital signs today are as follows: blood
pressure 175/100 mm Hg; pulse rate 65 beats/minute;
respiratory rate 16 breaths/minute; height 164 cm;
and weight 73 kg. She currently takes levothyroxine,
simvastatin, metoprolol extended release, amlodipine,
metformin, glyburide, and naproxen sodium. Which one
of the following conditions would most likely eliminate
M.J. as a candidate for bevacizumab therapy?
A. Uncontrolled hypertension.
B. Lack of approval for use in MBC.
C. History of diabetes.
D. Pulmonary metastases.
34. Based on C.L.s past treatment of her MBC, which one

of the following is the best treatment at this time for
C.L.?
A. Ethinyl estradiol.
B. Paclitaxel.
C. Letrozole.
D. Vinorelbine.
39. W.S. is a 53-year-old woman diagnosed with stage II,

ER/PR-positive, HER2-positive breast cancer. In 2003
she underwent a left mastectomy (2.3-cm tumor with
2 of 12 lymph nodes positive), followed by adjuvant
doxorubicin and cyclophosphamide every 3 weeks.
This was followed by sequential weekly paclitaxel in
addition to trastuzumab. A recent CT scan of her lungs
revealed metastatic disease. Her current drugs include
metoprolol, gabapentin, carbamazepine, Multivitamin
Plus (purchased at a health food store; W.C. is not sure
what is in it) and acetaminophen. Which one of the
following drugs should be discussed with the physician
regarding drug-drug interactions before dispensing
lapatinib and capecitabine to the patient?
A. Metoprolol.
B. Gabapentin.
C. Carbamazepine.
D. Multivitamin Plus.
35. C.L. tolerates her therapy well and returns to the clinic
with new CT and bone scans. The CT scan shows
progression of her disease in the lung and new bone
metastases. Which one of the following is the next best
option for C.L. at this time?
A. Clinical trial.
B. Best supportive care.
C. Chemotherapy holiday.
D. Hormonal therapy.
36. During the next 6 months, C.L. develops brain
metastases. An MRI identifies three metastatic
lesions of various sizes. She has completed wholebrain radiation therapy and comes to the clinic today
to discuss systemic treatment of her brain metastases.
Which one of the following treatments is best for C.L.
at this time?
A. Liposomal doxorubicin.
B. Trastuzumab.
C. Lapatinib.
D. Sunitinib.
40. A patient in your outpatient clinic is receiving therapy

today for treatment of her MBC. The attending
physician has ordered nanoparticle albuminbound
paclitaxel 260 mg/m 2 = 510 mg intravenously for 30
minutes. The patient is to be premedicated with one
dose each of dexamethasone 20 mg intravenously,
diphenhydramine 50 mg intravenously, and ranitidine
150 mg intravenously, to be given 30 minutes before
her chemotherapy is begun. Which one of the following
statements is the best regarding the orders you
received?
A. An in-line filter should be used for administration.
B. No premedication is required.
C. Prepare in a DHEP-free solution container.
D. The infusion rate should be 3 hours.
37. As part of a baseline work-up before starting

chemotherapy, a patient had echocardiography that
revealed an ejection fraction of 64%. After 3 months of
trastuzumab therapy, repeat echocardiography reveals
an ejection fraction of 49%. Which one of the following
is the best course of action for this patient at this time?
A. Continue trastuzumab and tell the patient to inform
the clinic of any symptoms of congestive heart
failure.
37
38

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Metastatic Breast Cancer

Kellie L. Jones, Pharm.D., BCOP

Goals of Therapy in the

1. Given an individuals medical history, distinguish

When a patient is given a diagnosis of MBC, the treatment

Sites of Metastatic Disease

Metastatic Breast Cancer

in MBC is palliation, all of these factors are weighed before

Monitoring Response to Therapy

will provide the best outcome. Factors such as time to

Hormonal Therapy Options

Hormonal vs. Chemotherapy

Pharmacotherapy Self-Assessment Program, 6th Edition

Objective Response (%)

Clinical Benefit Ratea (%)

10.2 vs. 5.5

36.7 vs. 35.2

5.6 vs. 5.0

10.4 vs. 10.4

34.1 vs. 32.8

4.3 vs. 3.9

23.6 vs. 16.4

34.5 vs. 31.7

5.6 vs. 5.5

16.1 vs. 14.9

26.7 vs. 23.4

15.0 vs. 12.4

37.4 vs. 34.6

4.7 vs. 3.8

21.1 vs. 17.0

59.1 vs. 45.6

11.1 vs. 5.6

32.9 vs. 32.6

56.2 vs. 55.5

8.2 vs. 8.3

32.0 vs. 21.0

50.0 vs. 38.0

9.4 vs. 6.0

40.9 vs. 13.6

55.7 vs. 42.4

8.9 vs. 5.2

Exemestane vs. tamoxifen

Despite differences in response rates among studies

as second-line therapy. The clinical importance of AIs

Metastatic Breast Cancer

mechanism is to add an agent that exhibits a different

estrogen signaling to the ER. Unlike tamoxifen, fulvestrant

Luteinizing HormoneReleasing Hormone

Fulvestrant Dosing Schedule

250 mg on days 0, 14, and 28, then

For patients with recurrent disease

For patients with recurrent disease

500 mg on day 0, then 250 mg on

500 mg on day 1 (then monthly)

Metastatic Breast Cancer

Pharmacotherapy Self-Assessment Program, 6th Edition

LHRH = luteinizing hormone releasing-hormone; NSAI = nonsteroidal aromatase inhibitor.

of response or stable disease or if they experience numerous

Sequential vs. Combination Therapy

Several clinical factors should be considered to help

Metastatic Breast Cancer

Nanoparticle albuminbound paclitaxel has been