Targeted Therapies in Breast Cancer: Implications for Advanced Oncology Practice.

TLDR: The clinical development and utilization of targeted therapies currently in use or in clinical trials are described, with a focus on considerations for the oncology advanced practitioner.

Abstract: The systemic therapeutic management of breast cancer has undergone significant transformation in the past decade. Without targeted therapies, conventional treatment with cytotoxic agents has reached the limit of its potential in terms of patient survival for most types of cancer. Enhanced understanding of the pathogenesis of tumor cell growth and metastasis has led to the identification of signaling growth pathways as targets for these directed therapies. Novel therapies targeted to HER2/neu, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), poly(ADP ribose) polymerase (PARP), mammalian target of rapamycin (mTOR), histone deacetylase (HDAC), the heat shock protein, and cyclin-dependent kinase (CDK) inhibitors have been developed and have demonstrated some efficacy in breast cancer. Recognition and management of the toxicities associated with targeted therapies is imperative. This review will describe the clinical development and utilization of targeted therapies currently in use or in clinical trials, with a focus on considerations for the oncology advanced practitioner.

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246
REVIEW
Targeted Therapies in Breast
Cancer: Implications for
Advanced Oncology Practice
LAURA BOURDEANU, PhD, and THEHAN LUU, MD
From The Sage Colleges, Troy, New York, and
City of Hope National Medical Center, Duarte,
California
Authors' disclosures of potential conflicts of
interest are found at the end of this article.
Correspondence to: Laura Bourdeanu, PhD,
The Sage Colleges, Department of Nursing, 65
1st Street, Troy, NY 12180. E-mail: lbourdeanu@
yahoo.com
© 2014 Harborside Press®
Abstract
The systemic therapeutic management of breast cancer has undergone
significant transformation in the past decade. Without targeted thera-
pies, conventional treatment with cytotoxic agents has reached the limit
of its potential in terms of patient survival for most types of cancer. En-
hanced understanding of the pathogenesis of tumor cell growth and me-
tastasis has led to the identification of signaling growth pathways as tar-
gets for these directed therapies. Novel therapies targeted to HER2/neu,
epidermal growth factor receptor (EGFR), vascular endothelial growth
factor (VEGF), poly(ADP ribose) polymerase (PARP), mammalian target
of rapamycin (mTOR), histone deacetylase (HDAC), the heat shock pro-
tein, and cyclin-dependent kinase (CDK) inhibitors have been developed
and have demonstrated some ecacy in breast cancer. Recognition and
management of the toxicities associated with targeted therapies is im-
perative. This review will describe the clinical development and utiliza-
tion of targeted therapies currently in use or in clinical trials, with a focus
on considerations for the oncology advanced practitioner.
J Adv Pract Oncol 2014;5:246–260
D
uring the past decade,
the systemic thera-
peutic management of
breast cancer has un-
dergone a significant transforma-
tion. Without targeted therapies,
conventional treatment with cyto-
toxic agents has maximized its po-
tential in terms of patient survival
for most types of cancer. Enhanced
understanding of the pathogenesis
of tumor cell growth and metasta-
sis has led to the identification of
signaling growth pathways as tar-
gets for these directed therapies.
ANTI-HER2/neu THERAPY
Trastuzumab
The HER2/neu oncogene, a
transmembrane tyrosine kinase re-
ceptor belonging to the epidermal
growth factor receptor (EGFR) fam-
ily, has been shown to be amplified
in up to 30% of human breast can-

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TARGETED THERAPIES IN BREAST CANCER
REVIEW
cer cell lines (Slamon et al., 1987). Identification
of HER2/neu led to the development of trastu-
zumab (Herceptin), a humanized monoclonal an-
tibody of the IgG1 type directed against the extra-
cellular portion of human EGFR HER2/neu, and
revolutionized the management of both early and
advanced breast cancer. Pivotal phase II and III
clinical trials of trastuzumab given in combination
with chemotherapy to women with early-stage
and metastatic breast cancer (MBC) have dem-
onstrated that trastuzumab is associated with sig-
nificantly longer overall survival (OS), longer time
to tumor progression (TTP), and longer duration
of response (Slamon et al., 2004; Romond et al.,
2005; Piccart-Gebhart et al, 2005; Joensuu et al.,
2006; Robert et al., 2006; Pierga et al., 2010; Marty
et al., 2005; Inoue et al., 2010).
Ado-Trastuzumab Emtansine
Ado-trastuzumab emtansine (Kadcyla) is an
antibody-drug conjugate designed to combine the
biological activity of trastuzumab with targeted
delivery of a potent microtubule-disrupting agent,
DM1 (a maytansine derivative), to HER2/neu-
expressing cancer cells (Lewis Phillips et al.,
2008). In a phase I study, ado-trastuzumab emtan-
sine showed clinical activity in heavily pretreated
patients with HER2/neu-overexpressing meta-
static breast cancer (Krop et al., 2010).
The recommended dose for phase II trials was
determined to be 3.6 mg/kg every 3 weeks. The
phase II studies confirmed this strong activity in
patients with HER2/neu-positive MBC whose
disease progressed while receiving HER2/neu-
directed therapy or who were previously treated
with an anthracycline, a taxane, capecitabine,
lapatinib (Tykerb), and trastuzumab, with overall
response (OR) rates in the range of 23.9% to 39.5%
(Burris 3rd et al., 2011).
The open-label phase III trial (EMILIA)
comparing ado-trastuzumab emtansine vs.
capecitabine and lapatinib in HER2/neu-positive
locally advanced or metastatic breast cancer previ-
ously treated with trastuzumab and a taxane con-
firmed that ado-trastuzumab emtansine signifi-
cantly improved progression-free survival (PFS,
p < .001) and OS was not reached vs. 23.3 months
(p = .005) compared with capecitabine and lapa-
tinib (Blackwell et al., 2012).
The primary results from a phase III trial,
called the TH3RESA trial, showed that ado-
trastuzumab emtansine increased PFS in patients
whose cancer was inoperable or had recurred or
metastasized after several treatments including
trastuzumab and lapatinib and were treated with
ado-trastuzumab emtansine vs. physician’s choice
of treatment (6.2 vs. 3.3 months, respectively,
p < .0001). The interim analysis of OS showed a
trend in favor of ado-trastuzumab emtansine, but
it did not reach a level of statistically significant
benefit (Wildiers et al., 2013).
Pertuzumab
Pertuzumab (Perjeta) is a monoclonal anti-
body that binds to the dimerization domain of
HER2/neu and prevents receptor dimerization,
thus preventing HER2/neu-mediated intracel-
lular signaling (Franklin et al., 2004). Data from
a phase I trial demonstrated the dosage of pertu-
zumab to be > 5 mg/kg given every 3 weeks (Agus
et al., 2005).
A phase II trial in patients with HER2/neu-
negative disease suggested that pertuzumab had
some activity as a single agent; however, the ben-
efit was so limited that further investigation of
single-agent pertuzumab in unselected patients
with HER2/neu-negative disease was unwarrant-
ed (Gianni et al., 2010).
Another phase II trial assessed the ecacy and
safety profile of pertuzumab in combination with
trastuzumab in patients with HER2/neu-positive
breast cancer whose disease had progressed during
prior trastuzumab-based therapy. Patients received
trastuzumab weekly (4 mg/kg loading dose, then
2 mg/kg every week) or every 3 weeks (8 mg/kg
loading dose, then 6 mg/kg every 3 weeks) and per-
tuzumab every 3 weeks (840 mg loading dose, then
420 mg every 3 weeks). Treatment continued until
disease progression or excessive toxicity. Overall,
the combination of pertuzumab and trastuzumab
was well tolerated, and adverse events were mild to
moderate (Baselga et al., 2010).
A subsequent phase III trial (CLEOPATRA)
assessed the activity of pertuzumab in patients
with HER2/neu-positive adenocarcinoma of the
breast with locally recurrent or metastatic disease.
Patients were randomized (1:1) to receive docetax-
el, trastuzumab, and pertuzumab or docetaxel,

248
BOURDEANU and LUU
REVIEW
trastuzumab, and placebo. The median PFS in-
creased significantly by 6.1 months in the pertu-
zumab group (hazard ratio [HR] for disease pro-
gression or death, 0.62; 95% confidence interval
[CI] = 0.51–0.75; p < .001). The interim analysis of
OS data showed a strong trend toward a survival
benefit with pertuzumab/trastuzumab/docetax-
el therapy, although it did not reach significance
(Baselga & Swain, 2010).
Side Eects
Although there are similarities in the side-
eect profiles of all three of these drugs, there
are some adverse events that are unique to each
agent. The most common adverse reactions as-
sociated with trastuzumab include headache, di-
arrhea, nausea, chills, infection, congestive heart
failure, insomnia, cough, and rash (Robert et al.,
2006; Pierga et al., 2010; Marty et al., 2005; Inoue
et al., 2010). The most common side eects associ-
ated with pertuzumab are diarrhea, alopecia, neu-
tropenia, nausea, rash, and peripheral neuropathy.
Finally, the most common side eects associated
with ado-trastuzumab emtansine are thrombo-
cytopenia, epistaxis, eye-tearing/conjunctivitis
disorder, and elevated liver enzymes (Baselga et
al., 2010; Baselga & Swain, 2010; Agus et al., 2005;
Blackwell et al., 2012; Burris 3rd et al., 2011; Gianni
et al., 2010; Krop et al., 2010).
One of the most concerning side eects of
HER2/neu therapy is cardiac dysfunction or
failure. Cardiac toxicity occurs in 7% to 28%
of patients treated with trastuzumab alone or
in combination with anthracycline-based che-
motherapy, and in 1.2% of patients treated with
pertuzumab in combination with chemotherapy
(Agus et al., 2005; Baselga et al., 2010; Baselga &
Swain 2010; Gianni et al., 2010; Inoue et al., 2010;
Marty et al., 2005; Pierga et al., 2010; Robert
et al., 2006; Slamon et al., 2001; Wardley et al.,
2010). Anti-HER2/neu therapy–induced cardiac
failure may be severe, and in some cases associ-
ated with death.
Other concerning grade 3 side eects of anti-
HER2/neu therapy include neutropenia, leuko-
penia, thrombocytopenia, diarrhea, elevated liver
enzymes, and palmar-plantar erythrodysesthesia
(Agus et al., 2005; Baselga et al., 2010; Baselga &
Swain, 2010; Gianni et al., 2010; Inoue et al., 2010;
Marty et al., 2005; Pierga et al., 2010; Robert et al.,
2006; Slamon et al., 2001; Wardley et al., 2010).
These side eects have generally been observed
when the therapy is used in combination with oth-
er antineoplastic agents. Other less common and
grade < 3 side eects are listed in Table 1.
HER2 AND EGFR PATHWAY
INHIBITORS
Lapatinib
Lapatinib is a reversible dual EGFR/HER1 and
HER2 tyrosine kinase inhibitor (TKI) that acts in-
tracellularly, directly targeting the TK domains
of HER1 and HER2 and inhibiting the receptor
phosphorylation, leading to inhibition of down-
stream pathways that control cell proliferation
and survival (Tevaarwerk & Kolesar, 2009). The
combination of lapatinib and capecitabine showed
clinical activity in a phase I study of patients with
advanced solid tumors at a dose of 1,500 mg/day
(Chu et al., 2007).
Several phase II trials examined the ecacy
of lapatinib in HER2/neu-positive MBC patients
who failed to respond to trastuzumab therapy. The
OR rate was 4% to 8%, whereas 15% to 46% of pa-
tients had stable disease and 13% to 22% remained
progression-free at 16 weeks after treatment with
lapatinib (Burstein et al., 2008; Gajria et al., 2012;
Johnston et al., 2009; Jagiello-Gruszfeld et al.,
2010; Rugo et al., 2012).
The ecacy of lapatinib was evaluated in
phase III trials, which led to its US Food and Drug
Administration (FDA) approval in combination
with capecitabine and in combination with letro-
zole for HER2/neu-positive MBC (Blackwell et al.,
2010; Cameron et al., 2008; Di Leo et al., 2008).
Lapatinib, as a single agent or in combination
with capecitabine, was also assessed for the treat-
ment of brain metastases in patients with HER2/
neu-positive MBC. Lapatinib alone resulted in
objective CNS responses of 3% to 6%, while the
addition of capecitabine resulted in an objective
CNS response of 20% in patients who received
prior whole-brain radiation (Lin et al., 2008). Sev-
eral other studies of lapatinib plus capecitabine
reported response rates of 31.8% to 38.5% (Lin et
al., 2011; Sutherland et al., 2010). The combina-
tion of lapatinib plus capecitabine in patients with
HER2/neu-positive MBC who have not received

249
TARGETED THERAPIES IN BREAST CANCER
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Table 1. Anti-HER2/neu Therapy
Agent Status Most common adverse events
Box warning or rare but
serious adverse events
Trastuzumab
a
FDA approved for the
treatment of HER2/neu-
overexpressing breast cancer
Fever, nausea, vomiting, infusion
reactions, diarrhea, infections,
increased cough, headache,
fatigue, dyspnea, rash, neutropenia,
anemia, and myalgia
CHF, significant decline
in left ventricular cardiac
function, severe infusion
reactions, pulmonary
toxicity
Ado-trastuzumab
emtansine
b
FDA approved for the
treatment of patients with
HER2/neu-positive MBC
who previously received
trastuzumab and a taxane,
separately or in combination
Fatigue, nausea, musculoskeletal
pain, thrombocytopenia, headache,
increased transaminases, and
constipation
Hepatotoxicity, left
ventricular dysfunction,
pulmonary toxicity,
infusion-related reactions,
hypersensitivity
reactions,
thrombocytopenia,
neurotoxicity
Pertuzumab
c
FDA approved in combination
with trastuzumab and
docetaxel for the treatment
of patients with HER2/neu-
positive MBC who have not
received prior anti-HER2/neu
therapy or chemotherapy for
metastatic disease
Diarrhea, alopecia, neutropenia,
nausea, fatigue, rash, PN
Left ventricular
dysfunction, infusion-
associated reactions,
hypersensitivity
reactions/anaphylaxis
Note. FDA = US Food and Drug Administration; CHF = congestive heart failure; MBC = metastatic breast cancer;
PN = peripheral neuropathy.
a
Information from Inoue et al. (2010), Marty et al. (2005), Pierga et al. (2010), Robert et al. (2006), Slamon et al. (2001),
Wardley et al. (2010).
b
Information from Blackwell et al. (2012), Burris 3rd et al. (2011), Krop et al. (2010).
c
Information from Agus et al. (2005), Baselga & Swain (2010), Baselga et al. (2010), Gianni et al. (2010).
whole-brain radiation resulted in an objective re-
sponse of 57% (Bachelot et al., 2013).
Neratinib
Neratinib, a highly selective irreversible inhib-
itor of the kinase activity of HER2/neu and EGFR,
showed antitumor activity as a single agent in pa-
tients with trastuzumab-pretreated MBC (Burst-
ein et al., 2010; Tsou et al., 2005). Phase I/II trials
evaluating the safety and ecacy of neratinib plus
vinorelbine or paclitaxel in HER2/neu-positive
MBC patients previously treated with anti-HER2/
neu therapy reported the maximum tolerated dose
(MTD) of neratinib to be 240 mg with promising
antitumor activity, with an OR rate of 57% and
71%, respectively, and no unexpected toxicities
(Chow et al., 2010; Awada et al., 2013).
Currently, neratinib is being studied in combina-
tion with temsirolimus (Torisel) in HER2/neu-posi-
tive or triple-negative MBC, as monotherapy vs. lapa-
tinib plus capecitabine in trastuzumab pretreated
HER2/neu-positive MBC, and in combination with
paclitaxel vs. paclitaxel plus trastuzumab in the first-
line treatment of HER2/neu-positive MBC (Clinical-
Trials.gov identifiers NCT01111825, NCT00777101,
and NCT00915018, respectively). Neratinib is also
being investigated in the adjuvant setting upon com-
pletion of trastuzumab-based therapy, as well as for
neoadjuvant treatment in locally advanced HER2/
neu-positive breast cancer (NCT01008150).
Afatinib
Afatinib is an irreversible dual inhibitor of
EGFR/HER1 and HER2 TKI (Minkovsky & Ber-
ezov, 2008). This first phase I study evaluated the
feasibility of oral dosing of afatinib in patients with
solid tumors for 14 days on followed by 14 days o
treatment and determined the MTD to be 70 mg
once daily (Eskens et al., 2008). Another phase I
trial assessing continuous administration of afatinib
in patients with solid tumors recommended a phase
II study dose of 50 mg once daily (Yap et al., 2010).
A phase II trial assessing the ecacy and
safety of afatinib in extensively pretreated pa-

250
BOURDEANU and LUU
REVIEW
tients with HER2/neu-negative MBC found that
afatinib had limited activity in HER2/neu-nega-
tive breast cancer (Schuler et al., 2012). Another
phase II trial evaluated afatinib monotherapy in
patients with HER2/neu-positive MBC after fail-
ure of trastuzumab treatment. Data demonstrated
11% of evaluable patients had a partial response,
37% had stable disease as best response, and 46%
achieved clinical benefit. Median PFS was 15.1
weeks and median OS was 61.0 weeks. The data
revealed that afatinib monotherapy has promising
clinical activity in extensively pretreated HER2/
neu-positive breast cancer patients whose disease
had progressed following trastuzumab treatment
(Lin et al., 2012).
Other ongoing phase II studies are currently
assessing the activity of afatinib in HER2/neu-pos-
itive MBC alone or in combination with a variety
of agents, such as vinorelbine, trastuzumab, lapa-
tinib, and letrozole (ClinicalTrials.gov Identifiers
NCT01325428 and NCT01531764, NCT01325428,
NCT00826267, NCT00708214, respectively),
in dierent settings, including brain metastases
and as neoadjuvant therapy (NCT01441596 and
NCT01594177, respectively). An ongoing phase
III study is comparing the addition of afatinib or
trastuzumab to vinorelbine in HER2/neu-pos-
itive MBC patients who progressed on or after
one prior trastuzumab-based treatment regimen
(NCT01125566).
Side Eects
The most commonly observed side eects
with all HER2/neu and EGFR inhibitors are acne-
like rash or folliculitis, diarrhea, and fatigue. Pal-
mar-plantar erythrodysesthesia, nausea, vomiting,
and fatigue were frequently seen with lapatinib.
Although not common, decreased left ventricular
ejection fraction, prolonged QT interval, and hep-
atotoxicity have been reported. Patients receiving
Table 2. HER2 and EGFR Pathway Inhibitors
Agent Status Adverse events
Box warning or
rare but serious
adverse events
Lapatinib
a
FDA-approved combination with (1)
capecitabine, for the treatment of patients
with advanced cancer or MBC whose
tumors overexpress HER2/neu and who
have received prior therapy including an
anthracycline, a taxane, and trastuzumab,
(2) letrozole for the treatment of
postmenopausal women with hormone
receptor–positive MBC that overexpresses
the HER2/neu receptor for whom hormonal
therapy is indicated
Diarrhea, PPE, nausea, rash,
vomiting, fatigue
Hepatotoxicity
Neratinib
b
Investigational Diarrhea, nausea, vomiting,
fatigue
Cardiotoxicity
Afatinib
c
Investigational Diarrhea, rash, fatigue Dehydration,
hyponatremia,
leukocytoclastic
vasculitis,
reduction in
cardiac LVEF,
acute renal
failure, reduced
general state
Note. FDA = US Food and Drug Administration; MBC = metastatic breast cancer; PPE = palmar-plantar
erythrodysesthesia; LVEF = left ventricular ejection fraction.
a
Information from Blackwell et al. (2010), Burstein et al. (2008), Cameron et al. (2008), Chu et al. (2007), Di Leo et al.
(2008), Gajria et al. (2012), Jagiello-Gruszfeld et al. (2010), Johnston et al. (2009), Rugo et al. (2012).
b
Information from Awada et al. (2013), Chow et al. (2010).
c
Information from Lin et al. (2012), Schuler et al. (2012), Yap et al. (2010).