1. health and fitness
2. disease
3. cancer

Medicinal Research Reviews 2012, 32(1), 166–215
ErbB family receptor inhibitors as
therapeutic agents in breast cancer: Current
status and future clinical perspective
Ruchi Saxena and Anila Dwivedi*
Division of Endocrinology Central Drug Research Institute, CSIR, Lucknow-26001, (U.P.), India
*Corresponding author: A. Dwivedi, e-mail: [email protected];
Phone: 091- 0522- 2612411-18, Extn 4438 Fax: +91-091-(522)-2623405 / 2623938 / 2629504
ABSTRACT
Breast cancer is the most common cancer diagnosed in women and the second most common cause of
female cancer related deaths with more than one million new cases diagnosed per year throughout the
world. With the recent advances in the knowledge of cellular processes and signaling pathways involved
in the pathogenesis of breast cancer, the current focus of researchers and clinicians is to develop novel
treatment strategies that can be included in the armamentarium against breast cancer. With the failure of
endocrine- targeted therapy and the development of resistance to existing chemotherapy, the most
explored pathway as next generation target for breast cancer therapy has been the EGFR (ErbB-1)/HER-2
(ErbB-2) pathway. The present review focuses on the rationale for targeting members of ErbB receptor
family and numerous agents that are in use for inhibiting the pathway. The mechanism of action, preclinical and clinical trial data of the agents that are in use for targeting the EGFR/HER-2 pathway and the
current status thereof have been discussed in detail. In addition, the future clinical promises these agents
hold either as monotherapy or as combination therapy with conventional agents or with other antisignaling agents have been pondered, so as to provide better and more efficacious treatment strategies for
breast cancer patients.
KEYWORDS: ErbB; EGFR; HER-2; breast cancer; tyrosine kinase
1. INTRODUCTION
Breast cancer is the most common female cancer and the second most common cause of female cancer
related deaths with more than one million new cases diagnosed per year throughout the world.1 Despite
advances in the early detection of breast cancer and the advent of novel targeted therapies, breast cancer
still remains a significant public health problem due to the involvement of multiple aberrant and redundant
signaling pathways in the tumorigenesis and the development of resistance to the existing therapeutic
agents. Initially, various cytotoxic agents were employed for the treatment of breast cancer. These agents
were non-selective and included alkylating agents, anthracyclines, anti-metabolites and tumor antibiotics
that kill neoplastic cells by causing DNA damage, interference with DNA repair mechanisms and
disturbance of metabolic pathways.2 Soon after combination strategy was formulated as the simultaneous
3-4
combination of two or more agents provided better results. In 1980s clinical trials in breast
cancer patients gave many new agents including the taxanes – paclitaxel and docetaxel.5 Though
these agents caused tumor regression but cellular toxicity caused by these agents was a serious
problem. Subsequently, the endocrine therapy was introduced for early stage breast cancer as
large number of tumors were found to be estrogen dependent 6. With the increasing understanding of
cellular processes involved in breast cancer at molecular level and the signaling pathways involved, focus
Medicinal Research Reviews 2012, 32(1), 166–215
was later, directed towards the development of targeted therapies for more efficacious treatment of breast
cancer. Besides, for the formulation of correct therapy for an individual, it became essential to identify the
class of the tumor based on the phenotypic markers 7 and a newer classification, was proposed:
(i) Estrogen receptor (ER) - positive or luminal type: These low grade tumors are characterized by gene
expression patterns similar to normal cells that line the breast ducts and glands and show positive
immunohistochemical staining for luminal cytokeratins 8/18.These are further categorized into two
types –(a) Luminal A type that express higher levels of estrogen receptor and have better prognosis,
(b) Luminal B type that more often express EGFR or HER-2 and have poor prognosis.8,9 The arrival
of estrogen antagonist tamoxifen and more recently aromatase inhibitors have significantly prolonged
the survival of patients with ER positive luminal A type disease.6, 10-11
(ii) HER-2 type: These are characterized by extra copies of the HER-2 (ErbB-2) gene and are usually of
high grade. These cancers grow faster and show poor patient outcome. However, targeted therapies
such as trastuzumab and lapatinib are proving to be useful in the treatment of such cancers.12-13
(iii) Basal type: The gene expression pattern of such cancers is similar to those of basal cells that line the
outer basal layer of mammary duct, including expression of keratin 5, keratin 6, keratin 17 and four
kallikrein genes (klk5-klk8). There tumors show normal expression of HER-2 (ErbB-2) and lower
expression of ER.13-14 The “triple negative subgroup” of the basal type lacks expression of estrogen
receptor and progesterone receptors, have normal expression of HER-2 and are p53 mutated.15-16
These are high grade cancers, grow faster and have a lower ‘recurrence –free’ and overall survival,
regardless of disease stage at diagnosis. This type of cancer is more common among women with
BRCA1 mutations.17-18 These cancers do not respond to hormonal therapy and anti-HER-2 targeted
therapy. The poly (ADP-ribose) polymerase (PARP) inhibitors appear to be among the most
promising treatments under investigation for BRCA-associated cancers and sporadic triple-negative
disease.19-22 However, recent findings report that most (>60 %) basal like tumors are EGFR-positive
and EGFR-inhibitors are being evaluated in clinical trials in pre-selected patients with basal like
tumors.23-24
This modern classification of breast cancer based on molecular features, has directed the efforts of
scientists towards the identification and development of agents that would target specific cellular
processes/ receptor type with a view to benefit a particular group of patients. In this review, the targeted
therapies for breast cancer patients currently undergoing clinical trials have been discussed with special
focus on ErbB family receptor inhibitors.
2. TARGETED THERAPIES FOR BREAST CANCER
The first selective and targeted therapy came when it was found that majority of cases of breast cancer
express higher levels of estrogen receptor-α (ERα).25-28 With the evolving understanding of the biology of
ERα pathway, selective estrogen receptor modulators (SERMs) were developed that represented the first
targeted endocrine therapy.29-30 Tamoxifen is currently the first line endocrine agent for the treatment of
ERα-positive primary and advanced breast cancers.28,30-33 As an adjuvant therapy in early breast cancer,
tamoxifen improves overall survival (OS) and its widespread use has led to a reduction of about 26% in
breast cancer mortality for both pre- and post-menopausal patients.6,32-34 In previously untreated metastatic
breast cancer, more than 50% of ERα- positive tumors achieve an objective response or tumor
stabilization on tamoxifen treatment.35-39 Further, tamoxifen shows clinical application as a
preventive agent for hormone dependent breast cancer and it also appears to maintain bone
density.40-42 Despite the obvious advantages and benefits associated with the use of tamoxifen,
there are some negative side-effects that include increased incidences of endometrial cancer in
post menopausal women,43-44 increased occurrences of hot flashes and other menopausal
symptoms,43 increased blood clots and increased cataracts.45 Another problem with the use of
tamoxifen is that all patients with metastatic disease and about 40% patients on adjuvant
Medicinal Research Reviews 2012, 32(1), 166–215
tamoxifen therapy eventually relapse and ultimately die from this disease and many ERα-positive
patients do not respond to tamoxifen therapy at all.46-47 Several mechanisms of resistance to
tamoxifen therapy have been proposed.48-52 These include: (1) decrease in or loss of expression of
ERα;49 (2) increased expression of coactivator proteins like Amplified in breast and ovarian
cancer-1 (AIB-1) gene amplification51 (AIB-1 associates with other coactivators and the ER
transcription machinery to form large complexes capable of synergistically activating ER
mediated transcription); (3) decreased expression of corepressors like Nuclear receptor
Corepressor (NCoR)52 (NCoR associates with the transcription assembly and influence transcription by
recruiting the histone deacetylase complex which leads to chromatin-condensation and decreased rates of
transcription); (4) activated growth factor pathways that lead to phosphorylation of ER-α and ligand
independent growth signals and cross-talk between ER-α and EGFR/HER-2 pathways which is discussed
in detail in Section 3.2.53-55
Fig 1: Potential sites for therapeutic intervention in growth factor mediated pathway. Therapeutic agents specifically
targeted at the inhibition of growth factor receptors and events within the signal transduction pathway include antireceptor antibodies, receptor tyrosine kinase inhibitor, farnesyl transferase inhibitor, bcl-2 antisense nucleotide,
topoisomerase II inhibitors, and inhibitors of several other signaling intermediates like PKC inhibitor, Ras/Raf/MEK
pathway and mTOR/PI3K/Akt pathway inhibitors.
In many clinical cases, the lack of response to endocrine therapy together with increased
metastasis was found to be associated with overexpression of EGFR/HER-2 and increased crosstalk of this
pathway with ERα.56-58 Thus, targeting the growth factor - mediated signaling has become an important
therapeutic option for breast cancer treatment. Modes of blocking growth factor signaling include (i)
ligand antagonists, (ii) anti-receptor antibodies, (iii) small molecule tyrosine kinase inhibitors, (iv)
farnesyl transferase inhibitors and (v) antisense oligonucleotides. These inhibitors can be employed at
various steps to ultimately effect gene transcription via growth factor signaling (Fig.1). Therapeutic agents
specifically targeted at the inhibition of growth factor receptors and several downstream targets including
PKC, MAPK pathway, mTOR/PI3K/Akt pathway, inhibitors of bcl-2, topoisomerase II and ubiquitin
proteasome pathway are being developed.59-65 These inhibitors have met various degrees of success and
Medicinal Research Reviews 2012, 32(1), 166–215
are under different phases of clinical trials. A summary and overview of the targeted therapies for breast
cancer is given in Table - I.
Table-Ι: A bird’s eye view of targeted therapies for breast cancer
S.No.
Pathway targeted /type of therapy
Agent
Phase of clinical trial for breast cancer
1.
Endocrine Therapy
1. Selective Estrogen Receptor
Modulators (SERMs)
Tamoxifen
Raloxifene
FDA approved
FDA approved for BC risk reduction
2. Aromatase Inhibitors
Anastrazole
FDA approved for adjuvant therapy of
ER+ve BC
FDA approved for adjuvant therapy of
ER+ve BC
FDA approved for adjuvant therapy of
ER+ve BC
FDA approved for refractory ER+ve
MBC
Letrozole
Exemestane
3. Pure antiestrogen
2.
3.
4.
5.
6.
7.
ICI 182,780
Epidermal growth factor receptor
1. Monoclonal antibody
Trastuzumab
Pertuzumab
Cetuximab
Approved for HER2 overexpressing BC
Phase II
Phase II
2. Small molecule inhibitors
Gefitinib
Erlotinib
Lapatinib
Canertinib
HKI-272
Phase II
Phase II
FDA approved for MBC
Phase II
Phase II
1. Monoclonal antibody
Bevacizumab
FDA approved for ER-ve BC
2. Small molecule inhibitors
Pazopanib
Sunitinib
Axitinib
Sorafenib
Phase II
Phase II
Phase II
Phase II
1. Farnesyl Transferase Inhibitor
2. Raf inhibitor
Antisense oligonucleotide
Small molecule inhibitor
3. MEK inhibitor
Mammalian Target of Rapamycin
and the PI3K/Akt pathway
Topoisomerase II
R115777
Phase II
ISIS 5132
Bay 43-9006
CI-1040
CCI-779
RAD001
C1311
Phase II
Phase I
Phase II
Phase II
Phase II
Phase II
Hsp90 (ubiquitin proteasome
pathway)
Tanespimycin
Phase II
Vascular endothelial Growth factor
receptor
Ras/Raf/MEK/ERK pathway
The following sections will briefly review the current status of ErbB receptor inhibitors
particularly the EGFR/HER-2 receptor inhibitors developed / being developed so far, for breast cancer
therapy and their future clinical implications will be discussed.
Medicinal Research Reviews 2012, 32(1), 166–215
3. ErbB RECEPTORS AS A TARGET FOR BREAST CANCER THERAPY
The epidermal growth factor receptor family i.e. ErbB family serves as an excellent candidate for
therapeutic intervention based on studies of tumor formation, which is defined by aberrant cell
proliferation.66-67 To date, four members of ErbB receptor family have been identified: (i) EGFR (HER1/ErbB-1), (ii) HER-2 (ErbB-2/neu), (iii) HER-3 (ErbB-3) and (iv) HER-4 (ErbB-4). These ErbB receptor
family members promote tumor cell proliferation as well as survival in a variety of malignancies including
breast, lung, prostate, head and neck, stomach, kidney, brain and pancreas.68-75 EGFR is overexpressed in
16-48% of the human breast cancers and an association has been reported between EGFR expression and
poor prognosis.76-77 EGFR is also found to be overexpressed in ‘triple-negative’ breast cancers which are
characterized by their unique molecular profile, aggressive behavior and distinct patterns of metastasis.1315
Hence EGFR could also serve as a target for therapeutic intervention in subgroup of triple negative
breast cancer patients that overexpress EGFR. HER-2 is overexpressed in 25-30% of all human
breast carcinomas and a significant correlation between overexpression and reduced survival of
breast cancer patients has been found.73-78 Further, overexpression of these ErbB receptor family
members may mediate endocrine resistance, due to crosstalk with the ER signal transduction
pathways, 56-58,68 as already mentioned in the previous section
.
Fig 2: Structure of a typical ErbB family receptor showing (1) The extracellular domain containing cysteine rich
ligand binding domains I, II, III and IV (2) Transmembrane domain and (3) The intracellular domains i.e.
juxtamembrane domain; tyrosine kinase domain and regulatory region domain, including autophosphorylated
tyrosine.
3.1. ErbB RECEPTOR SIGNALING
ErbB family receptors are transmembrane receptor tyrosine kinases, composed of an extracellular ligandbinding domain;79-81 a trans-membrane domain that anchors the receptor to the membrane; a
juxtamembrane domain which is believed to regulate various functional aspects of ErbB receptor
including control of the tyrosine kinase activity (Fig. 2), receptor downregulation, ligand internalization,
Medicinal Research Reviews 2012, 32(1), 166–215
and receptor sorting. The domain also has binding motifs that mediate its interaction with second
messengers like calmodulin82-83; and an intracellular tyrosine kinase domain with enzymatic activity.84
The cytoplasmic domain also consists of a carboxy-terminal tail containing tyrosine autophosphorylation
sites which link these receptors to proteins containing Src homology 2 (SH2) and phosphotyrosine-binding
(PTB) domain motifs. In the absence of a ligand, the receptors exist as inactive monomers. When the
ligands like epidermal growth factor (EGF) and transforming growth factor-α (TGF- α) bind to receptors
causing some conformational changes, it results in homo- or hetero- dimerization of the receptors.85
Dimerization of receptor brings the intracellular C-terminal tyrosine kinase domains in close proximity to
each other, leading to autophosphorylation. This in turn allows for docking of second messenger proteins
like Src homology domain consensus protein (Shc) and growth factor receptor-bound protein (Grb-2)
containing SH2 or PTB domains on these phosphorylated tyrosine residues on the receptor,86 activating
multiple downstream pathways involved in tumor progression and metastatic disease. Major pathways
associated with ErbB signaling include the Ras/mitogen activated protein kinase (MAPK) pathway, the
phosphatidyl inositol 3-kinase (PI3K)/Akt pathway, the Janus kinase(JAK)/signal transducers and
activators of transcription (STAT) pathway, and the phospholipase Cγ (PLCγ) pathway (Fig. 3). These
signaling pathways ultimately affect cell proliferation, survival, motility, and adhesion.87-92
Fig 3: The ErbB signaling pathway. The ErbB family receptors are activated by binding to ligands, including EGF,
TGF-heparin-binding EGF-like growth factor, amphiregulin, betacellulin, and epiregulin.Ligand binding induces
formation of functionally active dimers (details given in Fig. 4). Dimerization induces the activation of the
intracellular tyrosine kinase domain, which leads to autophosphorylation of the receptor on multiple tyrosine
residues. This in turn leads to recruitment of adaptor proteins like Shc, Grb-2 and activates a series of intracellular
signaling cascades to effect gene transcription resulting in cancer cell proliferation, invasion, metastasis and also
stimulates tumor induced angiogenesis.
The extracellular portion i.e. the N-terminus of ErbB receptors is the ligand binding domain and
binds a variety of ligands.93 The ligands of ErbB family receptors can be divided into three groups based
on their affinities for various receptors: (i) epidermal growth factor (EGF), transforming growth factor α
(TGF- α), and amphiregulin bind to EGFR (HER-1 i.e. ErbB-1);94-96 (ii) betacellulin, heparin-binding
growth factors, and epiregulin can interact with both EGFR (HER-1/ ErbB-1) and HER-4 (ErbB-4);97-100
and (iii) tomoregulins and heregulins/neuregulins (NRG-1, NRG-2, NRG-3, NRG-4) bind to HER-4
(ErbB-4). NRG-1 and NRG-2 also bind to HER-3 (ErbB-4).101-102 There is no known ligand for HER-2
Medicinal Research Reviews 2012, 32(1), 166–215
(ErbB-2), but it is the preferred hetero-dimerization partner for other members of the ErbB receptor
family (Fig. 4).93 A List of ErbB family receptors and their cognate ligands is given in Table - II.
Fig 4: ErbB family receptor dimerization and downstream signaling. Ligand binding to the receptor induces
formation of homo- or hetero-dimers. Upon dimerization the intracellular tyrosine kinase domains of the receptors
get phosphorylated and thus get activated. The active dimers subsequently initiate downstream signaling. (details
given in Fig. 3). 1, EGFR (HER-1); 2,- HER-2; 3, HER-3; 4, HER-4.
Table-ІІ: ErbB family receptors and their ligands
Receptor
Ligands
EGFR
(ErbB-1/HER-1)
Epidermal growth factor (EGF)
Transforming growth factor-α (TGFα)
Epiregulin (EP)
Amphiregulin (AR)
Betacellulin (BTC)
Heparin-binding EGF-like growth factor
(HB-EGF)
HER-2
(ErbB-2)
Unknown
HER-3
(ErbB-3)
Neuregulin(NRG-1)/heregulin(HRG)
isoforms NRG-2α and β
HER-4
(ErbB-4)
NRG-1/HRG isoforms
NRG-2α and β
NRG-3
NRG-4
Tomoregulin
HB-EGF
BTC
EP
The ErbB receptor family regulates cell proliferation, differentiation, apoptosis, invasion, and
angiogenesis and thus plays an important role in normal organogenesis by mediating morphogenesis and
Medicinal Research Reviews 2012, 32(1), 166–215
differentiation in normal conditions.103-105 In normal cells, the EGFR/HER-2 signaling pathway is under
tight regulation by different regulatory mechanisms but this tight control is often lost in case of tumor cells
due to which they gain the advantage to proliferate under adverse conditions, metastasize to surrounding
tissues, and increase angiogenesis.66-67 Under normal conditions, when a ligand binds to ErbB family
receptor, the receptor gets activated which triggers the downstream signaling but in tumor cells, ligand
independent activation of the receptor can occur.85-90 Several mechanisms have been proposed for this
ligand -independent activation :
(i) Overexpression of the wild type EGFR/HER-2 in some cases like cancers of breast, lung,
glioblastoma, head and neck cancer, bladder carcinoma, ovarian carcinoma, and prostate cancer, may lead
to ligand independent receptor dimerization and subsequent up regulation of EGFR/HER-2
signalling.95,106-107
(ii) Gene amplification is not a commonly reported phenomenon in tumors, with the exception of
glioblastoma108 and 20-25% of ER-positive breast cancers that overexpess HER-2.78
(iii) Presence of mutant EGFR causing it to be inappropriately activated. These mutations include point
mutations or deletions in the tyrosine kinase activation domain,109-110 seen in about 81% non-small cell
lung cancer (NSCLC), and deletion in the extracellular domain (EGFRviii variant), seen in about 2%
NSCLC,109-111 25-50% cases of glioblastomas112-113 and in 42% of head and neck cancers.110 However,
there are no known tyrosine kinase domain mutations in breast cancer.
(iv) Dysregulation of the EGFR pathway in some cancers could be a result of overexpression of TGF-α,
an EGFR ligand, leading to the development of an autocrine loop.114
3.2. ROLE OF EGFR/HER-2 IN ENDOCRINE RESISTANCE : CROSS TALK
MECHANISM
The ER-induced signaling mechanism coupled with the fact that over two thirds of breast cancers exhibit
high expression of ER, have provided the rationale for preventing and treating breast cancer by estrogen
antagonism, highlighted by the discovery of tamoxifen. However, a serious problem emerging with the
use of tamoxifen is intrinsic or acquired resistance to endocrine agents.46-47 Cumulative clinical data
suggest that patients with HER-2 and EGFR overexpressing tumors have a poorer outcome when treated
with tamoxifen.115-117 Many patients present with primary (de novo) resistance to endocrine therapy,
despite high tumor levels of ER, and all patients with advanced disease eventually acquire resistance.48-50
Although as mentioned in earlier Section 2, a number of probable explanations for the
development of resistance to endocrine therapy have been given, the activation of ER and the cross-talk
between ER-α and EGFR/HER-2 pathways appears to be one of the major players. For example, the
membrane bound ERs play key role in the mechanism of cross-talk between ERs and growth factor
receptors.118-120 In addition to the activation of gene transcription via the genomic pathway, ER regulates
its nongenomic functions via the membrane estrogen receptor mediated signaling.121-123 The membrane
estrogen receptors functionally mimic the growth factor ligands and increase the levels of second
messengers such as cyclic-adenosine monophosphate (c-AMP) within minutes124-126 which in turn activate
various tyrosine kinase receptors such as Insulin-like growth factor-1 receptor (IGF-1R) , EGFR, and
HER-2.127-128 ER can also interact with the growth factor receptors either by associating with adaptor
molecules or by direct phosphorylation of EGFR/HER-2. Finally, ER-induced signaling pathway also
induce EGFR ligands such as TGF-and cause downregulation of EGFR and HER-2.129-131
The crosstalk between the ER and the growth factor signaling pathway is bidirectional. The ER
can be phosphorylated at serine-118 within its activation function-1 (AF-1) domain by the MAPKs
(Erk1/2) and Akt which are downstream components of EGFR/HER-2 pathway, leading to ligandindependent ER activation.132-133Also, serine-167 in AF-1 is phosphorylated by the ribosomal S6 kinase
(RSK) which is itself activated by Erk1 and Erk2.134-136 In addition, phosphorylation of ER coregulatory
137-138
proteins by growth factor kinases modulate the ER signaling pathway.
For example,
phosphorylation of ER coactivator AIB1 by MAPK increases ER-dependent transcription,139-140
and overexpression of AIB1 converts tamoxifen-bound ER into an estrogen agonist rather than an
Medicinal Research Reviews 2012, 32(1), 166–215
antagonist.124 These finding suggests that the crosstalk between the ER and EGFR/HER-2
signaling pathways has an important role in tamoxifen resistance. Delineation of the interplay
between the estrogens, ER, and ER cross-talk with receptors like EGFR and HER-2 should be an
important diagnostic and prognostic objective in anti-EGFR/ HER-2 therapy.
4. EGFR/HER-2 INHIBITORS IN BREAST CANCER THERAPY
Overexpression of at least two of the members (EGFR and HER-2) of the ErbB receptor family has been
associated with a more aggressive clinical behavior. Thus, ErbB receptor family was identified early as an
important target for drug development. Till date, a number of therapeutic strategies have been developed
which specifically target either intracellular or extracellular domains of the EGFR and its family
members.74-76,129-130 The extracellular portion of the receptor can be targeted either by the use of ligand
antagonists or by monoclonal antibodies against the receptor. Attempts to make small molecules that
could compete with EGFR/HER-2 ligands for the ligand binding domain of the receptor have not met
success and this strategy is discontinued.141 Monoclonal antibodies bind to the extracellular domain of the
receptor preventing its activation by the ligand. A summary of monoclonal antibodies is given in TableIII. The intracellular portion of the receptor can be targeted by using the small molecule tyrosine kinase
inhibitors that block the adenosine triphosphate (ATP) binding site of the tyrosine kinase domain as
summarized in Table- IV.
Table-ΙΙI: Summary of the anti-EGFR/HER-2 monoclonal antibodies for breast cancer treatment
Agent
Class of
EGFR/HER-2
inhibitor
Phase of
clinical
developm
-ent
FDA
approved
Adverse
effects
Clinical activity in Source
breast cancer
Refer
ences
Trastuzumab
Anti HER-2
antibody
Cardiac
dysfunction,
cardiotoxicity
As monotherapy
in HER2
overexpressing
breast cancer, c/w
TKIs and Tam
Roche
155160
Pertuzumab
Anti HER-2
antibody
Phase II
Diarrhea, pain, c/w Trastuzumab
nausea,
Vomiting,
mucositis
Roche
216221
Cetuximab
Anti-EGFR
antibody
Phase II
Rash, diarrhea, c/w carboplatin
nausea,
triple negative BC
vomiting
c/w Ironotecan
234237
Agent
Gefitinib
Erlotinib
Lapatinib
Canertinib
Neratinib
S.No.
1.
2.
3.
4.
5.
Structure
Irreversible
pan-HER
inhibitor
Irreversible
pan-HER
inhibitor
Irreversible
Dual TKI
for
EGFR/
HER2
Reversible
EGFR
inhibitor
Reversible
EGFR
inhibitor
Class of
EGFR
inhibitor
Phase I/II
Phase II
FDA
approved
for MBC
Phase II
Phase II
Phase of
clinical
trial
c/w
trastuzumab;
c/w paclitaxel
monotherpy
monotherapy in
inflammatory
BC;
c/w
trastuzumab;
c/w
bevacizumab
c/w
pertuzumab
c/w anastrazole
Clinical
activity in
breast cancer
Pfizer
Glaxo
Smith
Kline
Genentech
/Roche
Astra
Zeneca
Source
Covalently binds to a
conserved cysteine
residue located in the
kinase domains of
these proteins.
covalently binds to
the ATP binding site
of the intracellular
kinase domain
inhibitor of the
intracellular tyrosine
kinase domains of
both EGFR andHER2 receptors
inhibits EGFR
tyrosine kinase by
binding to the ATPbinding site of the
enzyme.
inhibits EGFR
tyrosine kinase by
binding to the ATPbinding site of the
enzyme.
Mechanism of action
Diarrhea, nausea
Rash, nausea,
vomiting, asthenia,
diarrhea,
mucosutis,
hypersensitivity,
thrombocytopenia
Rash, diarrhea,
nausea, vomiting
Rash, diarrhea,
nausea, fatigue,
headache
Rash, diarrhea,
nausea, vomiting
Adverse effects
302306
296297
269270,
288
264267
246247
Refer
ences
Medicinal Research Reviews 2012, 32(1), 166–215
Medicinal Research Reviews 2012, 32(1), 166–215
4.1. ANTI-EGFR/HER-2 MONOCLONAL ANTIBODIES
4.1.1. TRASTUZUMAB
HER-2 overexpression is seen in 15-30% of breast cancers and is usually caused by gene amplification.142143
It is linked to higher grade and extensive forms of ductal carcinoma in situ144-145 and is also associated
with adverse outcome in invasive lobular carcinoma.78,146 In order to select the patients that are likely to
benefit from HER-2 targeted therapy, it is important to determine the status of HER-2 in breast cancer.
Currently, two types of tests i.e. immunohistochemistry (IHC) that detects receptor overexpression and
fluorescence in situ hybridization (FISH) that identifies HER-2 gene amplification, are used for the
purpose.147-149 Though detection of HER-2 by FISH is more accurate but it requires special equipments
that makes it more expensive. Recent reports indicate a considerable degree of concordance between the
two methods of detection on same tumor specimens. While 100% concordance was observed in IHC 3+
readings when compared with FISH, cases with 2+ IHC score were not very reproducible.150 Thus, such
patients must have a confirmatory FISH test before administration of trastuzumab therapy. When
compared to IHC, FISH test is also found to be a better predictor of response to trastuzumab therapy and
overall prognosis. Another test known as chromogenic in situ hybridization (CISH) uses small DNA
probes to count the number of HER-2 genes in breast cancer cells.151-152 This has advantage over FISH of
being less expensive as it measures color changes and doesn’t require a special microscope. Newer tests
are being developed that could measure the amount of HER-2 protein in cancer cells more precisely and
thus help in identification of patients who could respond to HER-2 targeted therapies such as trastuzumab.
Trastuzumab is a humanized anti-HER-2 monoclonal antibody that has been approved for
treatment of patients with breast cancers that overexpress HER-2 protein or that exhibit HER-2 gene
amplification.153 It binds to the extracellular domain IV of HER-2, important in facilitating the overall
conformational change induced by binding of the ligand to the receptor.154-155 In this way, trastuzumab
exhibits its antitumor activity either by antibody-dependent cell mediated cytotoxicity, downregulation of
signaling following antibody mediated receptor internalization, or inhibition of signaling through other
156-57
members of the ErbB receptor family by preventing the formation of heterodimer.
This in turn
will result in decreased angiogenesis, increased apoptosis and decreased proliferation. This
antibody therapy was initially targeted specifically for patients with advanced relapsed breast
cancer that overexpressed the HER-2 protein.158-159 Since its launch in 1998, trastuzumab has
become an important therapeutic option for patients with HER-2/neu-positive breast cancer. It is
widely used for its approved indication as a second line of treatment for advanced metastatic
disease, and is also being studied in adjuvant treatment for earlier-stage disease and in neoadjuvant treatment protocols.160-163
4.1.1.1. TRASTUZUMAB AS FIRST/ SECOND LINE MONOTHERAPY IN MBC
The efficacy and safety of trastuzumab as monotherapy has been assessed in various phase II trials. In one
such trial, 164 trastuzumab was administered weekly to 46 patients with pretreated metastatic breast cancer
whose tumors overexpressed HER-2. A loading dose of 250 mg trastuzumab was administered
intravenously, followed by 10 weekly doses of 100 mg each. After 10 weeks, patients with no disease
progression were given weekly maintenance dose of 100 mg. Toxicity was minimal, with no
antibodies formed against trastuzumab. Objective responses were observed in 5 of the 43
evaluable patients, including 1 complete response (CR) and 4 partial responses (PR), for an
overall response rate (ORR) of 11.6%. Responses were seen in mediastinum, lymph nodes, liver,
and chest wall lesions. Minor responses (seen in 2 patients) and stable disease (14 patients) lasted
for a median of 5.1 months. These results demonstrated that trastuzumab is well tolerated and
Medicinal Research Reviews 2012, 32(1), 166–215
clinically active in patients with HER-2 overexpressing metastatic breast cancers (MBC) with
extensive prior therapy.
The efficacy of trastuzumab as a single agent was also assessed in a pivotal phase II study by
Cobleigh et al. (1999), 165 on heavily pretreated patients whose tumor overexpressed HER-2 at the 2+ and
3+ levels by IHC. The ORR in this group was 15% with a median survival (MS) of 9.1 months in this
population refractory to anthracyclines and taxoids treatment. Retrospective analysis of response rate (RR)
and median survival (MS) restricted to the patients whose tumors overexpressed HER-2 at the highest
levels (IHC 3+) showed a RR of 18% and MS of 16.4 months.
Another Phase II study166 investigated the clinical efficacy and safety of trastuzumab monotherapy
as first-line treatment given once every 3 weeks in woman with HER-2 positive MBC. In 105 patients
receiving five cycles of therapy, the ORR was 19% and the clinical benefit rate (CBR) was 33%. Median
time-to-progression (TTP) was 3.4 months. The monotherapy was well tolerated and no significant
adverse events were reported. The most common treatment-related adverse events were only mild-tomoderate rigors, pyrexia, headaches, nausea, and fatigue.
In a recently published study, 167 where trastuzumab was used as a single agent, the RR in 111
assessable patients with 3+ IHC staining was 35% and the RR for 2+ cases was 0%; the response rates in
patients with and without HER-2 gene amplification detected by FISH were 34 and 7%, respectively. 103 It
is now clear that 3+ expression by IHC method or gene amplification demonstrated by FISH is required
for likely benefit from trastuzumab. The most common adverse effects of trastuzumab were mild to
moderate infusion-related reactions, which are usually noted with the first infusion and decrease in
frequency thereafter. The most clinically significant adverse event included symptomatic cardiac
dysfunction, which occurred in 2% to 4.7% of patients on trastuzumab monotherapy.
Thus trastuzumab was accepted to be effective and tolerable in first or second line treatment of
HER-2 positive metastatic breast cancer as single agent.
4.1.1.2. TRASTUZUMAB IN COMBINATION THERAPY
Many landmark phase II and phase III trials reported additive and synergistic activity of trastuzumab when
used in combination with standard chemotherapy (either paclitaxel or anthracycline based). In the pivotal
randomized phase III study by Slamon et al. 2001,168 patients were randomized to receive chemotherapy
with or without trastuzumab. Patients were grouped according to whether or not adjuvant chemotherapy
contained an anthracycline, such that the majority of patients who did not have adjuvant chemotherapy or
adjuvant therapy not containing an anthracycline were randomized to doxorubicin and cyclophosphamide
with or without trastuzumab. In the group, with adjuvant anthracycline, patients were randomized to
paclitaxel with or without trastuzumab. TTP was significantly longer in each of the combination
subgroups (cyclophosphamide vs. trastuzumab + cyclophosphamide, 6.1 months vs. 7.8 months; paclitaxel
vs. trastuzumab + paclitaxel, 2.7 months vs.6.9 months). When both chemotherapy subsets were
considered, a survival benefit attributable to trastuzumab with chemotherapy vs. chemotherapy alone was
noted (MS, 25 months vs. 20 months). This observed survival difference was despite the fact that
nearly three-quarters of patients treated initially with chemotherapy alone crossed over to
trastuzumab as a single agent on progression of disease. The retrospective analysis showed that
the difference was much greater in all the parameters in case of patients with HER-2 expression
level of 3+ as determined by IHC. These two studies by Cobleigh et al.165 and Slamon et al.168 led
to the licensing of trastuzumab as treatment for metastatic breast cancer.
In the pivotal phase III trastuzumab combination trial, 169 trastuzumab was associated with class
III or IV cardiac dysfunction in 27% of the anthracycline and cyclophosphamide plus trastuzumab-treated
group compared with 8% of the group given an anthracycline and cyclophosphamide alone. Cardiac
toxicity has remained a significant limiting factor for the use of trastuzumab since its FDA approval in late
1998. Trastuzumab trials since then have included cardiac eligibility criteria and prospective cardiac
Medicinal Research Reviews 2012, 32(1), 166–215
monitoring. The incidence of congestive heart failure in a pooled analysis of six recent trials was 2.7%.
Cardiotoxicity is usually reversible and manageable even with continued trastuzumab therapy.
A randomized, multicenter trial, 170 compared first-line trastuzumab plus docetaxel vs. docetaxel
alone in patients with HER-2 positive MBC. Trastuzumab plus docetaxel was significantly superior to
docetaxel alone in terms of ORR (61% vs. 34%), Overall survival (OS) (median, 31.2 v 22.7 months; P <
.0325), TTP (median, 11.7 vs. 6.1 months), time to treatment failure (median, 9.8 vs. 5.3 months), and
duration of response (median, 11.7 v 5.7 months). There was little difference in the number and severity of
adverse events between the arms.
Another randomized Phase II study,171 evaluated the activity of weekly paclitaxel vs. its
combination with trastuzumab for treatment of patients with advanced breast cancer overexpressing HER2. The combination group exhibited superior ORR (75% vs. 56.9%), particularly in the subset of IHC 3+
patients (84.5% vs. 47.5%). A statistically significant better median TTP was also seen in the subgroup
with IHC 3+ (369 vs. 272 days) and visceral disease (301 vs. 183 days). Thus weekly paclitaxel plus
trastuzumab was found to be highly active and safe and it is superior to paclitaxel alone in patients with
IHC score of 3+.
The combination of trastuzumab and navelbine has been tested in the phase II setting. 172 The ORR
to the combination in patients with metastatic disease was 75%, and in patients whose tumors
overexpressed HER-2 at the IHC 3+ level, it was 80%. The combination was well tolerated.
Trastuzumab was also tested in combination with vinorelbine, 173 because vinorelbine therapy is
not associated with cardiotoxicity, alopecia, or significant gastrointestinal side effects. In a phase II trial,
174
trastuzumab was administered weekly with vinorelbine on the same day. The ORR was 68%. Median
time to treatment failure was 5.6 months; 38% of patients were progression free after one year. The data
support the use of trastuzumab and vinorelbine as a safe, well-tolerated, and effective first-line treatment
for women with HER-2 positive MBC. In a similar trial by Papaldo et al. (2006),175 that compared
vinorelbine alone with vinorelbine plus weekly trastuzumab as combination therapy, the combination
group showed higher ORR (51.4% vs.27.3%). The median duration of response was 8 months for women
treated with vinorelbine and 10 months for those who received the combination. Patients in the
combination arm also had a longer TTP (9 months vs. 6 months) and OS (27 months vs. 22 months)
Toxicity was mild in both groups. Concerning cardiotoxicity in combination group, 20% patients had left
ventricular systolic dysfunction. A study by De Maio et al. (2007), 176 tested the activity of the same
combination, with trastuzumab given every 3 weeks. Activity of 3-weekly trastuzumab plus vinorelbine
fell within the range of results reported with weekly schedules. Toxicity was prevalently manageable. This
combination was found to be safe and active for metastatic breast cancer patients who received adjuvant
taxanes with anthracyclines.
Trastuzumab was also tested in combination with polychemotherpy. Burris et al. (2004),177 tested
efficacy and toxicity of weekly paclitaxel/carboplatin with or without trastuzumab following initial
treatment with trastuzumab. Patients were given trastuzumab (8 mg/kg followed by 4 mg/kg/wk) for 8
weeks. Out of 61 patients in the trial, 52 patients were assessable for response and all 61 patients were
assessable for survival. Out of the 52 patients, 33% experienced a PR to trastuzumab monotherapy and
given 8 additional weeks of trastuzumab, 29% had stable disease and proceeded to receive
paclitaxel/carboplatin/trastuzumab. 31 patients with measurable disease were assessable for response after
initial single-agent trastuzumab followed by paclitaxel/carboplatin/trastuzumab. An ORR of 84%, median
TTP of 14.2 months, and median OS of 32.2 months was reported with the triplet combination. In the
patients treated with paclitaxel/carboplatin alone after disease progression on initial trastuzumab, an ORR
of 69%, median TTP of 8.3 months, and median OS of 22.2 months was reported. Median TTP for all 61
patients is 10 months and the median OS is 26.7 months. This trial confirmed the activity and tolerability
of weekly paclitaxel/carboplatin alone or in combination with trastuzumab in women with HER-2
overexpressing MBC. Robert et al. (2006), 178 conducted a phase III multicenter trial to evaluate the safety
and efficacy of trastuzumab and paclitaxel with or without carboplatin in HER-2 overexpresing MBC.
Patients were randomized to recieve six cycles of either trastuzumab 4 mg/kg loading dose plus 2 mg/kg
weekly thereafter with paclitaxel 175 mg/m2 every 3 weeks , or trastuzumab 4 mg/kg loading dose plus 2
Medicinal Research Reviews 2012, 32(1), 166–215
mg/kg weekly thereafter with paclitaxel 175 mg/m2 and carboplatin area under the time-concentration
curve = 6 every 3 weeks followed by weekly trastuzumab alone. The ORR was 52% for the triplet
combination versus 36% for combination of trastuzumab and paclitaxel, median progression free survival
(PFS) was 10.7 months and 7.1 months respectively. The improved clinical response with triple
combination was more evident in HER-2 3+ patients. Both regimens were well tolerated, and
febrile neutropenia and neurotoxicity occurred infrequently; Grade 4 neutropenia occurred more
frequently with triple combination.
4.1.1.3. TRASTUZUMAB AFTER DISEASE PROGRESSION
Trastuzumab has clearly revolutionized treatment for HER-2 positive patients; however in majority of the
cases disease progression occurs within 1 year of treatment. It is also uncertain whether further
trastuzumab either as monotherapy or in combination with chemotherapy is of any benefit. It is also
unknown if retreatment on relapse is useful for patients on adjuvant trastuzumab. Preclinical studies by
Fujimoto-Ouchi et al. (2005)179 suggested that trastuzumab in combination with chemotherapy can slow
down tumor growth in the presence of disease progression on trastuzumab monotherapy. Clinical
evidences for the use of trasuzumab after disease progression are largely derived from the retrospective
studies.180-183 The retrospective analyses suggest that continuation of trastuzumab beyond disease
progression in patients with HER-2 overexpressing metastatic breast cancer appears to be of value,
producing responses and clinical benefit, and is well tolerated without significant cardiac toxicity. The
feasibility of this approach warranted examination in prospective trials. However a similar analysis by
Montemurru et al.184 gave contrasting results.
A phase II trial by Bartsch et al. 185 evaluated the efficacy and safety of gemcitabine and
trastuzumab after earlier exposure to anthracyclines, docetaxel and/or vinorelbine, and trastuzumab.
Patients received gemcitabine at a dose of 1,250 mg/m² on day one and eight, every 21 days. Trastuzumab
was administered in three-week cycles. Earlier therapies consisted of trastuzumab (100%), anthracyclines
(100%), vinorelbine (96.6%), docetaxel (72.4%), and capecitabine (72.4%). Nineteen point two percent
patients experienced PR, and stable disease ≥ 6 months was observed in a further 26.9%, resulting in a
clinical benefit rate of 46.2%. TTP was median 3 months, and OS 17 months. Neutropenia (20.7%),
thrombocytopenia (13.8%), and nausea (3.4%) were the only treatment-related adverse effects that
occurred with grade 3 or 4 intensity. Four patients (13.8%) developed brain metstasis (BM) while on
therapy. Together with the favourable toxicity profile, this regimen appeared to be a safe and potentially
effective salvage therapy option in a heavily pre-treated population.
A phase III trial By O’Shaughnessy et al. 186 comparing trastuzumab and lapatinib with lapatinib
alone did not give significant evidence in favor of using trastuzumab after disease progression. Another
phase III randomized trial, 187 GBG26/TBP, investigated the efficacy of continuing trastuzumab plus
capecitabine compared to capecitabine alone in patients progressing on any prior trastuzumab treatment.
The study required 482 patients, with the first interim analysis to be done after 150 events. However, it
was closed early on after recruiting 156 patients. The final analysis reported statistically significant
advantage for the combination arm with increase in RR (48% vs. 27%) and mean TPP (8.2 vs. 5.6 months)
with no significant increase in OS.
In a recent trial, the effect of Ttrastuzumab on survival after BM was analyzed in 78 HER-2
positive breast cancer patients.188 Patients were grouped according to trastuzumab therapy; no treatment
and treatment before and after BM were diagnosed. The OS after the diagnosis of BM as well as TTP of
intracranial tumors was prolonged in patients who received trastuzumab after BM was diagnosed.
Conversely, BM occurred much later in patients who received trastuzumab before BM. In the multivariate
Cox regression model, age at BM <50 years, disease-free interval of about 24 months, TTP of intracranial
tumor of about 4.8 months, and trastuzumab treatment after BM were significantly associated with longer
survival after the onset of BM. Thus trastuzumab therapy after the onset of BM in HER-2 positive breast
Early-stage invasive
BC, node positive or
high-risk node negative
Early-stage invasive
BC, node positive or
high-risk node
negative
Early stage, node
positive, invasive BC
Node positive or high
risk node negative
Early stage, node
positive or node
negative BC
NCCTG N9831
NSABP B-31
BCIRG 006
FINHER
Tumor
characteristics
HERA
Study
232
3222
3969
3401
Patient
no.
3
A: doxorubicin+cyclophosphamide→ docetaxel
B: doxorubicin+cyclophosphamide→docetaxel+
trastuzumab
A: docetaxel or vinorelbine→cyclophosphamide+
fluorouracil+epirubicin
B: docetaxel or vinorelbine +trastuzumab→
cyclophosphamide +fluorouracil+epirubicin
3
3
A: doxorubicin+cyclophosphamide→paclitaxel
B: doxorubicin+cyclophosphamide →paclitaxel+
trastuzumab
C: docetaxel+carbopltin+trastuzumab
3
2
Median
follow up
A: doxorubicin+cyclophosphamide→paclitaxel
B: doxorubicin+cyclophosphamide →paclitaxel+
trastuzumab
C: doxorubicin+cyclophosphamide →paclitaxel
→trastuzumab
A: chemotherpy→observation
B: chemotherapy→trastuzumab for 1 yr
C: chemotherapy→trastuzumab for 2 yrs
Arms
Table V: Summary of the randomized phase III trials of Trastuzumab in adjuvant therapy
88% at 3 yrs
95% at 3 yrs
0.41(0.16-1.08)
89% at 3 yrs
0.42(0.21-0.83)
90% at 4 yrs
0.66(0.47-0.93)
86% at 4 yrs
92% at 4 yrs
0.59(0.40-0.85)
89% at yrs
93% at 4 yrs
0.63(0.49-0.81)
92% at 3 yrs
90% at 3 yrs
0.66 (0.47-0.91)
OS
HR(95%CI)
78% at 3 yrs
82% at 4 yrs
0.67(0.54-0.83)
77% at 4 yrs
83% at 4 yrs
0.61(0.37-0.65)
73% at 4 yrs
86% at 4 yrs
0.49(0.41-0.58)
4 % at 3 yrs
83% at 3 yrs
0.64(0.54-0.76)
DFS
HR(95%CI)
Medicinal Research Reviews 2012, 32(1), 166–215
Medicinal Research Reviews 2012, 32(1), 166–215
cancer patients is associated with a significant survival benefit after BM diagnosis compared with patients
who never received or completed trastuzumab before the BM diagnosis.
Thus, trastuzumab appears be useful in preventing BM, but there are no definitive evidences to
support the continuation of trastuzumab after disease progression. Also, because trastuzumab does not
appear to cross the blood brain barrier efficiently, it seems to be of limited use in preventing metastasis.
4.1.1.4. TRASTUZUMAB IN ADJUVANT SETTING
Some large international randomized clinical trial have been conducted to test the efficacy of trastuzumab
in the adjuvant settings and have given encouraging outcomes except for the PACS04 trial.189, 277
Characteristics of the included trials for trastuzumab are summarized in Table-V. HER-2 positivity was
assessed by IHC and FISH in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31,
North Central Cancer Treatment Group (NCCTG) 9831, and Herceptin Adjuvant (HERA) trials, by IHC
and CISH in the Finland Herceptin2 (FinHer) trial, and by FISH only in the Breast Cancer International
Group (BCIRG) 006 trial. Patients at high risk for recurrence were enrolled in all studies, as demonstrated
by the high prevalence of hormone receptor negative disease and node-positive disease in the populations
accrued. Three trials (the NASBP B-31, NCCTG N9831, and BCIRG 006 trials) evaluated the
combination of doxorubicin and cyclophosphamide followed by an anthracycline, with or without
trastuzumab. The HERA, BCIRG 006, and NCCTG N9831 trials were three-arm studies, while the FinHer
trial was a 2 x 2 study (randomizing all patients to vinorelbine or docetaxel and then randomizing the
HER-2 positive subgroup to trastuzumab or observation).190-191
Similar sudy design of the (NSABP) B-31 and (NCCTG) 9831 led to the joint analysis of these
trials192. Both these trials included treatment with the standard adjuvant chemotherapy regimen of
doxorubicin plus cyclophosphamide followed by paclitaxel and 1 year with or without concurrent
trastuzumab therapy in women with operable HER-2 positive breast cancer. The combined analysis of
data from these two treatment arms was approved by the National Cancer Institute (NCI). A third arm
included in the N9831 study, in which patients received sequential trastuzumab after administration of
doxorubicin plus cyclophosphamide and paclitaxel, was not included in the combined analysis, but the
interim analysis by Perez et al. (2006),193 compared this sequential arm with the control and concurrent
trastuzumab–paclitaxel arms. The absolute difference in disease-free survival (DFS) between the
trastuzumab group and the control group was 12% at three years. Trastuzumab therapy was associated
with a 33% reduction in the risk of death. The three-year cumulative incidence of class III or IV
congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1% in trial B-31 and
2.9% in trial N9831. Both the studies suggest that trastuzumab combined with paclitaxel after doxorubicin
and cyclophosphamide improves outcomes among women with surgically removed HER-2 positive breast
cancer.
The HERA trial,190,194 was a multicenter, randomized, three-arm trial in patients with HER-2
positive early stage invasive BC who have completed at least four cycles of (neo)adjuvant chemotherapy,
with or without radiotherapy. Patients were randomized to observation only, 1 year of trastuzumab, or 2
years of trastuzumab, given on a 3-weekly schedule. Efficacy results for the standard approach and the 1year trastuzumab therapy treatment arms have been reported. At a 1-year median follow-up, patients
treated with trastuzumab in the HERA trial experienced a 46% lower risk of a first event than patients
under observation. This corresponded to an absolute benefit of 8.4% in DFS favoring trastuzumab at 2
years. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs.
37 with observation). Severe cardiotoxicity developed in 0.5% of the women who were treated with
trastuzumab. The HERA trial thus concluded that one year of treatment with trastuzumab after adjuvant
chemotherapy significantly improves DFS among women with HER-2 positive breast cancer.
The Breast Cancer International Research Group (BCIRG) 006 trial, 195 was designed to assess the
role of trastuzumab in a docetaxel-containing chemotherapy regimen with or without doxorubicin. Patients
were randomized to one of three regimens: doxorubicin plus cyclophosphamide followed by docetaxel,
doxorubicin plus cyclophosphamide followed by docetaxel with concurrent trastuzumab, or combined
Medicinal Research Reviews 2012, 32(1), 166–215
docetaxel, carboplatin, and trastuzumab that did not contain an anthracycline. In an interim analysis
presented at the 2006 San Antonio Breast Cancer Symposium (SABCS), investigators confirmed that, at a
median follow-up of 3 years, the addition of trastuzumab to chemotherapy resulted in a significantly
longer survival time than with standard adjuvant chemotherapy alone for patients with HER-2 positive
breast cancer. A 39% longer DFS duration for patients in the doxorubicin plus cyclophosphamide
followed by docetaxel with concurrent trastuzumab arm and a 41% longer OS time were found compared
with the doxorubicin plus cyclophosphamide followed by docetaxel control arm. Similarly, a 33% longer
DFS time for combined docetaxel, carboplatin, and trastuzumab and a 34% longer OS time were found,
compared with the the doxorubicin plus cyclophosphamide followed by docetaxel control arm. The
difference in DFS between the two investigational arms was not considered to be statistically significant.
The FinHer trial, 196 compared docetaxel with vinorelbine for the adjuvant treatment of early
breast cancer. The patients were randomized to three cycles of docetaxel or vinorelbine followed by three
cycles of fluorouracil, epirubicin, and cyclophosphamide. The patients of HER-2 positive subgroup were
further randomized to either receive or not receive trastuzumab for 9 weeks along with the first three
cycles of docetaxel or vinorelbine. DFS at three years with docetaxel was 91% vs. 86% with vinorelbine
but OS did not differ between the groups. Within the subgroup of patients who had HER-2 positive
cancer, those who received trastuzumab had a DFS of 89 % vs. 78 % for the subgroup without
trastuzumab. The trial led to the conclusion that docetaxel was associated with more adverse events than
vinorelbine. Trastuzumab was not associated with decreased left ventricular ejection fraction or cardiac
failure. Adjuvant treatment with docetaxel, as compared with vinorelbine, improves DFS in women with
early breast cancer. A short course of trastuzumab administered concomitantly with docetaxel or
vinorelbine is effective in women with breast cancer who have an amplified HER-2 gene.
Though trastuzumab seems to be promising in the adjuvant settings, the question that remains
unanswered is the treatment duration and regimen and if it should be given simultaneously or sequentially
after chemotherapy. Comparison of trials B-31 and N9831 and the HERA trial suggests that cardiotoxicity
is lower after sequential administration. However, we cannot rule out the possibility that simultaneous
administration of chemotherapy and trastuzumab is more effective than sequential administration.
Simutaneous administration gives cytotoxic effects while sequential administration is cytostatic. Another
problem associated with the combination of chemotherapy with adjuvant trastuzumab is cardiotoxicity
which limits the benefits of the therapy. Further follow-up of the adjuvant trials will add to the knowledge
of the nature and reversibility of cardiac events associated with trastuzumab use and will help in
formulating an optimal combination for an individual patient.
Presently, trastuzumab appears to be the best treatment available for HER-2 positive breast cancer
patients, but there are some issues associated with its use. Firstly, selection of patients who could benefit
from trastuzumab therapy should be more accurate. The cardiotoxicity associated with trastuzumab is
another serious problem which could be combated with the formulation of optimum treatment strategy in
relation to dose, duration and combination with other agents. The emerging problem with trastuzumab
therapy is development of resistance to the agent. The majority of HER-2 overexpressing tumors
demonstrated primary (de novo or intrinsic) resistance to single-agent trastuzumab. In fact, the rate of
primary resistance to single-agent trastuzumab for HER-2 overexpressing MBC is 66% to 88%.165-168 The
majority of patients who achieve an initial response to trastuzumab in combination with chemotherapy
develop resistance within one year.169-171 In the adjuvant setting, administration of trastuzumab in
combination with or following chemotherapy improves the DFS and OS rates in patients with early stage
breast cancer.192-195 However, approximately 15% of these women still develop metastatic disease despite
trastuzumab-based adjuvant chemotherapy.
4.1.1.5. MECHANISM OF DEVELOPMENT OF TRASTUZUMAB RESISTANCE
The majority of HER-2 overexpressing breast cancers either develops resistance or do not respond
to trastuzumab therapy alone. This could be due to the one of the following reasons:
Medicinal Research Reviews 2012, 32(1), 166–215
(1) Overexpression of MUC4 sterically hinders trastuzumab from binding HER-2 surface receptor and
may mediate cross-talk to activate HER-2 leading to disrupted interaction between HER-2 and
trastuzumab.197-198
(2) Expression of redundant survival signaling pathways like the insulin-like growth factor (IGF) receptor;
growth factor ligands of EGFR, HER-3, or HER-4 (EGF, betacellulin, heregulin) reduce growth inhibitory
effect of trastuzumab by 57, 84, and 90 percent, respectively.199-200,202
(3) Deficient expression of the PTEN tumor suppressor gene and enhanced PI3K signaling.203
(4) Expression of p95 truncated form of HER-2 that lacks the extracellular domain, which is the
recognition site for trastuzumab.204 In HER-2 overexpressing cancer cells, the extracellular domain (ECD)
of HER-2 is cleaved by the sheddases like ADAM (a disintegrin and metalloproteinase) family of zincdependent, membrane-associated metalloprotease.204-205 The ectodomain shed of HER-2 renders its
remaining transmembrane portion, p95, a constitutively active, phosphorylated tyrosine kinase. 206-208 In
vitro studies indicate that the p95 fragment of HER-2 is 10–100 times more oncogenic than the full length
receptor.195 In the clinic, the presence of the ECD in the serum of cancer patients has been linked to a
poor prognosis,208-211 with decreases in serum ECD levels during treatment being a predictor of response
to trastuzumab therapy.212-214 Accordingly, inhibition of the sheddases responsible for ECD shedding and
p95 production may have potential therapeutic benefit in HER-2 positive patients.
(5) Downregulation of the cyclin-dependent kinase inhibitor p27kip1.215-217
However, these mechanisms of trastuzumab resistance do not appear to preclude the antitumor activity of
small molecule inhibitors of ErbB family receptors.
4.1.2. PERTUZUMAB / 2C4
Pertuzumab is a recombinant humanized monoclonal antibody (2C4) that binds to the extracellular domain
II of the HER-2 receptor.218-219 Through its binding, it blocks the ability of dimerization between HER-2
receptor with other ErbB family receptors. Pertuzumab is referred to as a HER dimerization inhibitor, or
HDI. Pertuzumab binds at different positions on the receptor from trastuzumab, blocking the pathway
through different mechanisms and inhibiting cellular proliferation.201,220 Phase I clinical trial221-222 with
pertuzumab as monotherapy has given promising results. Initial phase II studies223 of pertuzumab in MBC
patients showed that pertuzumab was safe and well tolerated but had limited efficacy in this group of
patients. Phase I and II trials have both demonstrated synergy between pertuzumab and trastuzumab, with
the addition of pertuzumab to trastuzumab providing responses among women refractory to trastuzumab
therapy. The first Phase II study224 evaluating pertuzumab plus trastuzumab included 66 patients with
HER-2 positive, metastatic breast cancer who had progressed on trastuzumab therapy. Overall responses
were achieved in 24% of patients with 7.6% CR and 16.7% partial response PR. Disease stabilization for
at least six months was achieved in nearly 26% of patients. The adverse effects of this combination
included diarrhea, pain, nausea, vomiting and mucositis.
There is a hope that the combination of trastuzumab and pertuzumab used with chemotherapy will
be even more effective if used to treat women newly diagnosed with advanced cancer. The combination is
being evaluated in first-line MBC patients in another study; CLEOPATRA (CLinical Evaluation Of
Pertuzumab and TRAstuzumab) conducted by Roche.225 This phase III study began recruiting patients in
January 2008 and is underway in 18 countries worldwide. If this study is successful, this combination of
trastuzumab plus pertuzumab and chemotherapy has the potential to become a new standard of care in
HER-2 positive MBC patients.
4.1.3. CETUXIMAB / C225
Cetuximab is a human-mouse chimeric monoclonal antibody derived from the murine anti-EGFR
monoclonal antibody M225.226-227 It has shown growth inhibitory effects in EGFR overexpressing cell
lines and tumor xenografts 226,228 and so was considered for the treatment of EGFR overexpressing breast
cancer patients including the triple negative cases that overexpress EGFR.15,22-23 It competitively binds to
the accessible extracellular domain III of EGFR with high affinity preventing EGFR ligand binding and
Medicinal Research Reviews 2012, 32(1), 166–215
inhibiting receptor dimerization.229-230 Irreversible binding of EGFR by Cetuximab facilitates receptor
internalization and subsequent degradation. Receptor downmodulation induces cell-cycle arrest,
upregulation of p27Kip1 and subsequently inhibits tumor growth and metastasis.228, 231 Cetuximab may also
work by mediating complement fixation and ADCC (antibody dependent- cell mediated cytotoxicity).
More importantly, this antibody is able to block the activation of the tyrosine kinase domain of the EGFR
following stimulation with a specific ligand.232-233 In addition, blockade of the EGFR with monoclonal
antibodies results in a significant inhibition of neoangiogenesis. This phenomenon seems to be related to
the reduction in the synthesis of angiogenic factors such as interleukin-8 (IL-8), vascular endothelial
growth factor (VEGF) and basic fibroblast growth factor (bFGF) in tumor cells following treatment with
anti-EGFR monoclonal antibodies.234-235 Although cell lines treated with cetuximab show only a 20–40%
antitumor response in vitro, tumors in athymic mice are growth inhibited by more than 75% on cetuximab
treatment. Improved antitumor responses in vivo could be due to downmodulation of angiogenic
factors.236-237 A supra-additive antitumor effect was observed in preclinical studies when cetuximab was
combined with paclitaxel in breast cancer models. However, this combination was not found to be
promising in a phase I trial due to disappointing preliminary efficacy.238
A phase II study on 163 MBC patients was done to evaluate the combination of cetuximab with
irinotecan and carboplatin, the standard chemotherapeutic agents used for breast cancer therapy.239 The
patients were randomized to receive either irinotecan (90 mg/m2) followed by carboplatin on days 1 and 8
of each 21-day cycle or the same treatment except with cetuximab at a dose of 400 mg/m2 i.v. for dose 1
then 250 mg/m2 weekly thereafter. The ORR was significantly improved with the addition of cetuximab
than with irinotecan and carboplatin alone (39% vs. 19%) but it is associated with greater toxicity. In
another phase II multi-center randomized clinical trial240 on 102 patients with metastatic triple negative
(basal like) breast cancer, patients were randomly given either carboplatin in combination with weekly
2
cetuximab (250 mg/m ) or carboplatin alone. In the carboplatin monotherapy cohort 6% achieved
a PR, 4% achieved stable disease, and the CBR was 10%. In the combination arm, the ORR was
18%, 9% of patients had stable disease and the CBR was 27%. Although, due to the progressive
nature of the disease, most patients progressed rapidly, the combination of carboplatin and
cetuximab show significantly improved anti-tumor activity in comparison to carboplatin alone. In
another phase II trial cetuximab was combined with Irinotecan in patients with MBC pre-treated
with an anthracycline or a taxane-based therapy but the results were not very promising in
pretreated patients.241 In this study, 19 patients were treated with cetuximab 250 mg/m2 weekly
and Irinotecan 80 mg/m2, the ORR was 11% with one patient achieving a PR and 1 patient
achieving a CR. One patient had stable disease for 11 cycles. The combination was well tolerated
with dermatologic toxicities in some cases.
Thus cetuximab seems to a promising agent and requires further clinical trials to be used for the
treatment of breast cancer. As it targets specifically EGFR, it also holds promise for the subgroup of
patients with aggressive triple negative phenotype that overexpress EGFR. But for this patient selection is
an important criterion. The majority of the studies with anti- EGFR agents merely required EGFR to be
present in the tumor or have not preselected at all for patient selection. Currently, there are no accurate
diagnostic methods of determining the level of EGFR expression of a tumor and hence, the clinical
benefits from anti EGFR therapies are limited. More work is required to be done for the precise indication
of EGFR status and predictive value of currently used preclinical models should a lso be reassessed so as
to improve the clinical outcome of EGFR targeting agents.
4.2. SMALL MOLECULE TYROSINE KINASE INHIBITORS
Numerous ErbB family receptor inhibitors are in clinical development but only lapatinib has received US
Food and Drug Administration (FDA) approval for the treatment of breast cancer for MBC.280 These small
molecules compete with ATP for binding to the kinase domain of the receptor.242 Tyrosine kinase
inhibitors have several potential advantages over monoclonal antibodies. First, they are orally bioavailable
Medicinal Research Reviews 2012, 32(1), 166–215
and generally well tolerated. Second, they appear active against truncated forms of HER2 receptors (p95)
in vitro.243-244 Third, their small size may allow them to penetrate sanctuary sites, such as the central
nervous system. Finally, by taking advantage of the homology between kinase domains of ErbB family
receptors, tyrosine kinase inhibitors can be developed to target more than one member of the receptor
family simultaneously.112
4.2.1. GEFITINIB
Gefitinib a synthetic anilinoquinazoline is an oral, selective and reversible inhibitor of EGFR tyrosine
kinase. It competes with ATP for EGFR ATP binding site within the tyrosine kinase domain of the
receptor that ultimately blocks signal transduction pathway implicated in proliferation and survival of
cancer cells.245 In vitro, gefitinib can bind to the related ErbB receptor family member , however, its
affinity for HER-2 is 200-fold lower than that for EGFR.246 The efficacy of treatment with gefitinib
improves with increasing levels of EGFR in the tumor.247 HER-2 overexpressing tumors are also
susceptible to gefitinib treatment, theoretically by virtue of their heterodimerization with EGFR.248-250
While at low doses gefitinib is cytostatic in vitro, at higher doses it inhibits cellular proliferation, induces
apoptosis and decreases in vitro colony formation. Several studies have demonstrated that gefitinib
treatment results in a dose and time-dependent growth inhibition in solid tumors.249-251 Gefitinib treatment
downmodulates levels of angiogenic factors including vascular endothelial growth factor (VEGF) and
basic fibroblast growth factor (bFGF) secreted by tumors in vivo, thereby lowering the degree of
neoangiogenesis and microvessel production.252-253 In order to improve the antitumor efficacy of gefitinib
it has been combined with chemotherapy or radiotherapy. Gefitinib administered with chemotherapeutic
agents is reported to demonstrate supra additive tumor inhibition compared to either treatment alone. 253-254
Its use as monotherapy in advanced and refractory MBC has proven to be disappointing. A phase
II multicenter trial was done to evaluate the antitumor activity and pharmacodynamic/biologic effect of
gefitinib 500 mg/day monotherapy in patients with pre-treated, advanced breast cancer.255 The study
showed clinically significant activity of gefitinib when used as monotherapy. However, a phase II trial by
Von Minckwitz et al. (2005) evaluating gefitinib as monotherpy on patients with taxane and anthracycline
256
pretreated metastatic breast cancer did not gave encouraging results.
Gefitinb monotherapy was
found to be well tolerated and the side-effect profile was as expected from current knowledge of
the drug. There was no correlation between EGFR expression and response in this study.
However, its activity in combination therapy has shown more potential.
Gefitinib has also been evaluated in combination therapy in two phase II studies for which it was
combined with docetaxel as first line therapy. In one of these studies,257 41 patients were given oral
gefitinib 250 mg per day along with docetaxel ( 75 mg/m2 or 100 mg/m2). The ORR was 54% with a CR
and PR in 22 out of 41 patients. Toxicities included neutropenia, diarrhea, rash and anemia. The second
study was a phase II multi-institutional trial258 to determine the efficacy and tolerability of gefitinib and
docetaxel as first-line treatment in 33 patients with MBC.115 Patients received gefitinib 250 mg once daily
and docetaxel 75 mg/m2 every 3 weeks, until tumor progression, toxicity or other reasons for
discontinuation. The clinical benefit rate was 51.5% and the overall objective response rate was 39.4%. .
The median duration of clinical benefit was 10.9 months. The most common reason for study
discontinuation was disease progression (16 patients), followed by toxicity (10 patients). Toxicities were
mainly attributable to docetaxel, including ≥ grade 3 neutropenia in 43% of patients rather than gefitinib.
It was concluded that the combination of docetaxel and gefitinib was an active regimen in MBC, and the
toxicities and efficacy were similar to those of docetaxel alone. Unfortunately, gefitinib's activity in MBC
could not be elucidated in these two phase II studies as the trials did not include a docetaxel alone group
for comparison.
Gefitinib was also tested in combination with hormonal therapy that included anastrazole, an
aromatase inhibitor approved for adjuvant therapy in the treatment of ER-positive breast cancer.259-260 In a
double-blind, placebo-controlled randomized trial261 of 56 postmenopausal patients with ER-positive and
EGFR-positive primary breast cancer, patients were randomly assigned to gefitinib (250 mg given orally
Medicinal Research Reviews 2012, 32(1), 166–215
once a day) and the aromatase inhibitor, anastrazole (1 mg given orally once a day), and to gefitinib (250
mg given orally once a day) and placebo of identical appearance to anastrazole given orally once a day,
all given for 4–6 weeks before surgery. The combination arm showed a significantly greater reduction
of proliferation. Tumor size reduction of ≥30% was achieved in 14 out of 28 patients with the combination
treatment and in 12 of 22 patients receiving gefitinib alone.Gefitinib was also evaluated in combination
with anastrazole in a phase II multicenter, double blind, randomized trial to investigate its efficacy on
reversing resistance to hormonal therapy in women with newly diagnosed hormone receptor positive
MBC.262 The patients were randomized to receive anastrazole in combination with either gefitinib or
placebo. The gefitinib group showed a superior PFS (14.5 months vs. 8.2 months) and CBR (49% vs.
34%) when compared with placebo. The treatment was well tolerated but adverse events were seen twice
as often in the gefitinib arm when compared with the placebo arm. The results suggested that the
combination of anastrazole plus gefitinib is well tolerated and shows increased anti-tumor activity when
compared to anastrazole alone in MBC patients and further studies are required to evaluate its efficacy.
4.2.2. ERLOTINIB/ OSI-774
Erlotinib selectively, potently and reversibly inhibits EGFR tyrosine kinase activity of wild-type EGFR
and also of the constitutively active mutant EGFRvIII.241, 263 Studies in human cancer cells found that it
inhibits epidermal growth factor-dependent cell proliferation at nanomolar concentrations. It binds in a
reversible fashion to the ATP binding site of the receptor, blocking the downstream pathway that leads to
cellular proliferation. 132 Like gefitinib, erlotinib does not decrease the level of EGFR protein.264 Erlotinib
shows activity against multiple breast cancer cell lines in vitro and in xenograft models.265
In a phase II dose escalation study of erlotinib in combination with the standard dose of
trastuzumab, evidences of antineoplastic activity were observed with the recommended dose of 150
mg/day.265 In a phase II clinical trial erlotinib was given in combination with bevacizumab (a monoclonal
antibody that inhibits VEGF pathway) to 13 pre-treated breast cancer patients, the response to therapy was
observed in 1 out of 9 evaluable patients.266 The most commonly reported adverse events with erlotinib
treatment are grade 1 or 2 rash, diarrhea, asthenia, nausea and vomiting. Erlotinib was also tried in
combination with weekly docetaxel treatment as first line therapy; a RR of 55% was obtained in this
trial.267
Both gefitinib and erlotinib did not show success in the treatment of breast cancer. One probable
reason seems be the lack of tyrosine kinase domain mutations in cases of breast cancer. Another reason for
the failure of these agents as breast cancer therapy could be inaccurate selection of patients. So there is
need to develop techniques to assess the level of EGFR in tumors before the formulation of
therapy for a patient.
4.2.3. LAPATINIB
Lapatinib (lapatinib ditosylate), is an orally active dual inhibitor of the tyrosine kinase domain of both
EGFR and HER-2. It binds to the ATP binding pocket of the tyrosine kinase domain of the receptor
preventing autophosphorylation and thus inhibiting the growth signals.268 Lapatinib has shown activity in a
number of different metastatic and advanced tumor cell lines including breast cancer cell lines
overexpressing either EGFR or HER-2,269-270 and has recently shown positive results in clinical testing as
well. Lapatinib also binds with p95 (the truncated form of HER-2) and thus might be effective in
trastuzumab resistant cases.271 This novel investigational agent has given enthusiastic results in patients
with metastatic, treatment-refractory disease. It is the most clinically advanced of kinase inhibitors in
breast cancer and has been approved in March 2007 for use in combination with capecitabine in patients
with advanced, refractory MBC.285
Medicinal Research Reviews 2012, 32(1), 166–215
4.2.3.1. LAPATINIB AS MONOTHERAPY
The efficacy of lapatinib as single agent second-line therapy in advanced/metastatic breast cancer has been
studied in a number of trials. Initial suggestions of the clinical activity of lapatinib came from several
phase I trials testing its safety, tolerability and pharmacokinetics. A phase I trial273 on 39 enrolled patients
with solid tumors was conducted with dose-escalation from 175 to 1800 mg/day. Adverse events reported
include grade 3 diarrhea (2 of 6 patients administered 900 mg lapatinib twice a day) and grade 1–2 skin
rash, diarrhea, vomiting, constipation, fatigue and anorexia. Evidences of antitumor activity were observed
in patients treated with 1200 mg/day of lapatinib. In another phase Ib dose ranging study by Dees et al
(2004),274 in which 30 heavily pretreated breast cancer patients received lapatinib as monotherapy, 4
patients showed confirmed PR and 10 others had prolonged stable disease. All 10 had EGFR expression
by IHC, and 8 of these 10 overexpressed HER-2.274
An open-label multicenter phase II study275 was done on 80 HER-2 positive MBC patients
refractory to trastuzumab therapy, with an oral dose of 1500 mg daily of lapatinib. The ORR was 8%, 14%
of patients achieved stable disease and 22% of patients achieved PFS. Adverse events with lapatinib were
tolerable with anorexia, nausea, rash, vomiting, diarrhea, and weight loss being the most common.
Cardiotoxicity was not significantly observed. Another phase II study by Gomez et al. (2005),276 assessed
the efficacy of lapatinib as first line therapy in HER-2 positive MBC. The patients were randomized to
receive either 1500 mg daily or 500 mg daily of lapatinib. The ORR achieved was about 24% with no
significant difference between the two groups. These two phase II studies led the way for lapatinib to be
investigated in further clinical trials.
A phase II study (EGF20008) by Burstein et al. (2008),272 examined the safety and efficacy of
lapatinib monotherapy in chemotherapy-refractory tumors. This study included 2 cohorts of patients,
cohort A with HER-2 positive and cohort B with HER-2 negative patients. More than 95% of patients had
stage IV disease, and nearly all patients had received 3 or more lines of anti-cancer therapy previously.
97% of HER-2 positive patients had received at least 12 weeks of prior trastuzumab therapy. Lapatinib
1500 mg daily was administered, with dose reduction to 1250 mg in the event of grade 3/4 toxicity. HER2 positive cohort showed an ORR of 1.4% versus 0.0% in the HER-2 negative cohort. The independent
review reported that 5.7% of HER-2 positive patients received a clinical benefit, but there was no clinical
benefit in the HER-2 negative group. Median OS was 29.4 weeks (cohort A) vs. 18.6 weeks (cohort B).
These responses were modest, but this was a heavily pretreated cohort.
Patients with HER-2 overexpressing breast cancer have been found to have a significantly higher
risk of developing BM. Lapatinib is capable of penetrating the blood brain barrier and have been used in
clinical trials for the treatment of BM. A phase II study (EGF20009)278 assessed the clinical activity and
safety of lapatinib as a first line treatment in locally advanced or metastatic HER-2 positive breast cancer
without prior targeted therapy. The ORR was 24% and did not differ significantly between the two dosage
groups (1500 mg daily or 500 mg twice daily). The median duration of response was 28.4 weeks, and PFS
was 63% at 4 months, and 43% at 6 months. This trial suggested a role for first-line lapatinib therapy in
locally advanced or metastatic HER-2 positive breast cancer. Another phase II study (EGF105084) was
done by Lin et al. 279 on 39 HER-2 positive patients with progressive BM. The primary end point was
objective response in the CNS by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary
end points included objective response in non-CNS sites, time to progression, overall survival, and
toxicity. One patient achieved a PR in the brain by RECIST (ORR 2.6%). 7 patients (18%) were
progression free in both CNS and non-CNS sites at 16 weeks. Exploratory analyses identified additional
patients with some degree of volumetric reduction in brain tumor burden. The most common AEs were
grade 3 diarrheas and fatigue.
Medicinal Research Reviews 2012, 32(1), 166–215
Table VI: Summary of phase II trials of lapatinib as monotherapy
Study
(reference)
Blackwell et al.
275
Johnston et al.
280
Burstein et al.
272
Gomez et al.
276
Lin et al.
279
Kaufman et al.
281
Tumor
characteristics
Patient
no.
Lapatinib dose
Response rate
HER-2+,
T- refractory MBC
80
1500 mg od
8%
Relapsed/refractory
IBC;HER-2+(n=24),
EGFR+/HER2-(n=12)
36
1500 mg od
62%(PR) HER2+
8.3%(PR) EGFR-/ HER2+
Chemo-refractory
ABC/MBC
229
1500 mg od
1.4% HER2+
0.0% HER2-
First-line HER-2+
LABC/MBC
138
Arm A:1500 mg od
Arm B: 500 mg bid
24%
750 mg bid
2.6%
1500 mg bid
40%-HER2+
1PR-EGFR+/ HER-2- ve
T-refractory/relapsed
HER-2+ with BM
Chemo-/T-refractory/
relapsed IBC,
HER-2+(n=126),
EGFR+/HER2-(n=15)
39
141
Lapatinib monotherapy was evaluated in patients with HER-2 positive relapsed/refractory
inflammatory breast cancer. In a phase II trial (EGF103009) by Spector et al. (2006), 280 of the 24 patients
with HER-2 positive tumors, 62% achieved a PR, with additional 21% experiencing stabilization of the
disease. In contrast, in EGFR positive/ HER-2 negative subgroup only 8.3% of the 12 patients achieved a
PR. In another study, HER-2 positive patients with inflammatory breast cancer refractory to
anthracyclines, taxanes, and trastuzumab were treated with continuous lapatinib monotherapy at 1500 mg
daily.281 Preliminary data demonstrated an estimated ORR of 40%. The most frequent toxicities were
diarrhea and skin rash. It was concluded that lapatinib monotherapy is active in the treatment of
relapsed/refractory HER-2 positive inflammatory breast cancer where currently only a few effective
therapies are available. 1 A summary of phase II trials of lapatinib monotherapy is given in Table-VI.
4.2.3.2. LAPATINIB IN COMBINATION WITH OTHER TARGETED THERAPIES
Lapatinib is also giving promising results in combination with other targeted agents like inhibitors of the
VEGFR signaling pathway that is involved in angigiogenesis and is believed to play an important role in
metastsis of breast cancer. Lapatinib in combination with pazopanib, an investigational tyrosine kinase
inhibitor and angiogenesis inhibitor,282 is in phase II trial (VEG20007) in patients who have not been
treated for their progressive disease. Preliminary reports show a 44% versus 30% RR for the combination
arm, with a 73% versus 43% reduction in target lesions at 12 weeks.283
Another phase II trial investigated the effects of combining lapatinib with the angiogenesis
inhibitor bevacizumab.284 Bevacizumab is a monoclonal antibody that specifically inhibits VEGFR
mediated signaling and has been approved by FDA for the treatment of ER-negative breast cancer.285-286
The combination therapy gave promising results in heavily pretreated patients conferring a 34.4% clinical
benefit at Week 24 (CR/PR/ stable disease), while 62.5% of patients had PFS at Week 12 and the
combination was well tolerated.
A phase III trial (EGF104900) was conducted to assess the advantage of combining lapatinib with
trastuzumab in heavily pretreated HER-2 positive MBC patients refractory to trastuzumab therapy.287 In
the study, 296 patients heavily pretreated with trastuzumab, were randomized to either lapatinib 1000 mg
Medicinal Research Reviews 2012, 32(1), 166–215
daily plus trastuzumab 2 mg/kg weekly or lapatinib 1500 mg daily alone. The combination group
demonstrated significantly improved PFS (3 months vs. 2.1 months), and CBR (25.2% vs. 13.2%).
However the differences in OS and ORR were not statistically significant. Both treatments were well
tolerated with similar side-effect profile and an asymptomatic decline in left ventricular ejection fraction
occurring in 5% of the patients in the combination arm and in 2% of the patients in the lapatinib only arm.
The data showed that combined targeting gave better clinical outcomes in comparison with
lapatinib alone in the pretreated metastatic setting. Ongoing trials involving lapatinib and
trastuzumab include a phase III trial comparing paclitaxel and trastuzumab with lapatinib or
placebo in HER-2 positive metastatic breast cancer (EGF104383), and a phase I study combining
lapatinib, trastuzumab, carboplatin and paclitaxel (EGF103892).
4.2.3.3. LAPATINIB IN COMBINATION WITH CHEMOTHERAPY
Lapatinib has also been successfully combined with chemotherapy in breast cancer patients.The standard
chemotherapeutic agents with which lapatinib was tested include capecitabine and taxanes and the
combination groups exhibited better prognosis in comparison to chemotherapy alone. A randomized phase
III trial (EGF100151) was conducted to compare lapatinib plus capecitabine with capecitabine alone in
women with advanced, progressive HER-2 positive breast cancer who experienced disease
progression after treatment with regimens that included an anthracycline, a taxane, and
trastuzumab.288-289 The patients were randomly allocated to receive either combination of
lapatinib 1250 mg daily plus capecitabine 2000 mg daily or capecitabine 2500 mg daily alone.
The interim analysis showed that the addition of lapatinib to capecitabine was associated with a
51% reduction in the risk of disease progression. The median TTP was 8.4 months in the
combination group as compared with 4.4 months in the capecitabine monotherapy group. The
ORR was 22% vs. 14% in favor of combination group. This improvement was achieved without an
increase in serious grade 3/4 events. Again, cardiotoxicity was not a significant event. This trial led to its
first approval for use in MBC patients.
Lapatinib was further tested in combination therapy when it was evaluated in conjunction with
taxanes. A phase III randomized double-blind study (EGF3001),290 was carried out on 579 MBC patients
which were either HER-2 negative or have never been tested, The patients were randomized to receive
either lapatinib 1500 mg daily combined with paclitaxel 175 mg/m2 or with paclitaxel 175 mg/m2 alone as
first-line treatment. The ORR was 35% vs. 25% in favor of the combination group. However, TTP and
OS were not significantly different between the two arms except in a subgroup of patients with HER-2
positive advanced breast cancer. As expected, there was a significantly greater toxicity profile in the
combination group over the paclitaxel monotherapy group with alopecia, nausea, vomiting, rash and
diarrhea being the most common adverse events.
4.2.3.4. LAPATINIB IN COMBINATION WITH HORMONAL THERAPY
The evidences of molecular crosstalk between ER- and EGFR/HER-2 pathway, and its association with
the development of resistance to hormonal therapy provides the rationale for combining treatments
targeting both the pathways. Lapatinib has been tested in preclinical and clinical studies in combination
with anti-estrogens like letrozole (an aromatase inhibitor) and tamoxifen (a selective estrogen receptor
modulator) that are already approved for the treatment of breast cancer. Preclinical studies by Xia et al.
(2006),291 provided evidence that the combining lapatinib with antiestrogen might delay or prevent the
development of resistance to lapatinib in HER-2 overexpressing, ER-positive cells. There is also evidence
that lapatinib can overcome hormone resistance, caused by cross-talk between HER-2 and ER, in
preclinical models.292 A phase III study by Chowdhary et al. (2007),293 to compare lapatinib in
combination with letrozole versus letrozole alone in post-menopausal women with ER positive MBC is
currently ongoing. Patients are randomized to letrozole with or without lapatinib regardless of HER-2
status to test if lapatinib treatment prevents the conversion of ER positive/ HER-2 negative to ER positive/
Medicinal Research Reviews 2012, 32(1), 166–215
HER-2 positive breast cancer, thus blocking the development of resistance to endocrine therapy. Two
phase II trials in hormone resistant, ER positive MBC are currently examining lapatinib as single agent
(NCT00225758) or in combination with tamoxifen (NCT00118157).
20
5.3
25
22.8
6.7
35
A: paclitaxel
+laptinib
B: paclitaxel
+placebo
579
HER2-ve or untested
MBC
Di Leo et al.
2007
response not
reached
8.4
4.4
22
14
A: Capecitabine
B: Capecitabine
+lapatinib
Chemo-/Trastuzumab
-refractory HER2+ MBC
Geyer et al.
2006
324
12.9
9.7
3(PFS)
2.1(PFS)
10.3
6.9
A: lapatinib
B: lapatinib
+trastuzumab
296
T-refractory, HER2+
MBC
O’Shoughnessy et al.
2008
TTP
(months)
RR
(%)
Arms
Patient
no.
Tumor
characteristics
Study
(reference)
Table VII: Summary of the phase III trials of Lapatinib in combination therapy
OS
(months)
Major phase III clinical trials of lapatinib have been summarized in table -VII.
Based on the available data, lapatinib was found to be an active and well-tolerated oral dual
tyrosine kinase inhibitor for the treatment of HER-2 overexpressing breast cancer. Lapatinib is also active
in trastuzumab refractory MBC patients. Due to its small size it can efficiently cross blood brain barrier
and hence has potential benefits in patients with BM. Lapatinib is also found to be useful in inflammatory
Medicinal Research Reviews 2012, 32(1), 166–215
breast cancer patients. Lapatinib is associated with either a very low incidence of or no cardiotoxicity and
also does not increase toxicity when combined with trastuzumab.
Recently, lapatinib treatment in
a neo-adjuvant setting has shown to decrease the number of breast cancer stem cells and in tumor biopsies
as opposed to chemotherapy which led to an increase.294-295 Therefore, the agents like lapatinib which are
less toxic and more efficacious could be of significant importance in the treatment of breast cancer.
Hence, lapatinib holds the potential to become the mainstay of HER-2 positive breast cancer therapy in
future.
4.2.4. CANERTINIB / CI-1033
Canertinib/CI-1033 is an irreversible pan-erbB inhibitor. It covalently binds to the ATP binding site of the
intracellular kinase domain of the receptor thus blocking the downstream signaling pathway.1, 296-297
Canertinib is a non-selective inhibitor of the members of ErbB receptor family, and thus it has a broader
range of antitumor activity. As it is irreversible it has prolonged clinical effect and needs less frequent
dosing. It inhibits EGFR kinase activity at low nanomolar range and has antitumor activity in EGFR and
HER-2 dependent preclinical models.299 It is also active against HER-3 and HER-4 but has no effect on
other tyrosine kinases. Canertinib has been shown to be active in both in vitro and in vivo tumor xenograft
models of breast cancer.296 In a phase I trials of 10 heavily pretreated patients, one patient achieved stable
disease for more than 25 weeks, but objective responses have not yet been reported.299-301 The adverse
events associated with canertinib include grade 1–2 diarrhea, rash, nausea, and vomiting.201 At higher
doses hypersensitivity reactions have also been observed. In addition to the typical EGFR-related toxicity,
there is a 28% incidence of thrombocytopenia associated with canertinib, which might complicate its
combination with myelosuppressive cytotoxic agents. It is presently being evaluated in phase II clinical
trials.
Canertinib could be a potential therapeutic agent in breast cancer patients as it is a non-specific
inhibitor of ErbB receptor family but does not inhibit other receptor tyrosine kinases. Hence it has broader
range of action and needs further clinical evaluation before it can be used as a therapy for breast cancer.
4.2.5. NERATINIB/HKI-272
HKI-272 is an irreversible orally active pan-HER receptor tyrosine kinase inhibitor with potential
antineoplastic activity. It is a dual EGFR and HER-2 inhibitor that is in phase II clinical trial for breast
cancer.1 It forms a covalent bond with the conserved cysteine residue of the ATP-binding pocket within
the kinase domain of the receptor which thus prevents autophosphorylation of the receptor. HKI-272
treatment of cells results in inhibition of downstream signal transduction events and cell cycle regulatory
pathways that ultimately decreases tumor cell proliferation. 302-303 It is highly active against HER-2
overexpressing human breast cancer cell lines, inhibits the EGFR kinase and proliferation of EGFRdependent cells in culture and also in xenograft models. HKI-272 also inhibits the growth of cultured cells
that contain sensitizing and resistance-associated EGFR mutations.304 HKI-272 has the particular
advantage of having inhibitory activity in tumors that have mutated and become resistant to reversible
inhibitors like erlotinib and gefitinib.285
In a preliminary phase I trial on 51 patients, 23 with advanced stage breast cancer, resulted in two
confirmed and two unconfirmed PR in breast cancer.305 The encouraging response rate in this phase I trial,
led to the initiation of a phase II clinical trial of HKI-272 in patients with advanced stage breast cancer. A
phase II study was carried out involving 49 advanced HER-2 positive breast cancer patients who were
divided into two treatment arms. The first arm included HER-2 positive breast cancer patients pre-treated
with trastuzumab and the second arm included HER-2 patients with no prior trastuzumab treatment.
Tumor response and PFS data continues to be gathered, but out of 32 evaluable patients, 6 patients
achieved a confirmed PR with additional patients achieving an unconfirmed PR. Diarrhea and nausea were
the major adverse effects noted in the study. In another Phase II open label study306 on 102 patients with
stage IIIB, IIIC, or IV breast cancer, daily oral doses of 240 mg HKI-272 were generally well tolerated
Medicinal Research Reviews 2012, 32(1), 166–215
with diarrhea as the predominant adverse event.1 The primary end point was the rate of PFS defined at 16
weeks. Patients not pretreated with trastuzumab had a PFS rate of 75% while patients with prior
trastuzumab treatment had a 16-week PFS of 51%. These data show HKI-272 to be useful in HER-2
positive advanced breast cancer. It is also being evaluated in combination therapy with paclitaxel and with
vinorelbine in patients with advanced breast cancer.1
These clinical investigations appear promising and may lead to further treatment options for
patients with advanced HER-2 positive breast cancers and also for patients refractory to agents like
erlotinib and gefitinib.
5. SUMMARY AND FUTURE IMPLICATIONS
In recent years, there has been significant advancement in the treatment of breast cancer, and the number
of mortalities due to the disease has substantially reduced for the past few years. These accomplishments
have been led by the emergence of targeted therapies that include hormonal inhibitors, growth factor
receptor tyrosine kinase inhibitors,59 the farnesyl transferase inhibitors,60 the bcl-2 antisense
oligonucleotides61-62 and several other signaling intermediates like mTOR/PI3K/Akt pathway inhibitors63
and inhibitors of ubiquitin proteasome pathway.64-65 Many of these agents are now integrated in the first
line therapy for several groups of MBC patients and continue to be the basis of successful treatment. With
increasing incidence of tumor resistance to chemotherapy in breast cancer, it is of crucial importance to
apply novel therapeutic agents alongwith current treatment standards and to explore newer agents that are
under investigation in clinic.
The epidermal growth factor receptor family i.e. ErbB family serves as an excellent example for
therapeutic intervention based on studies of tumor formation, which is defined by aberrant cell
proliferation. The ErbB receptor family consists of four members viz. EGFR, HER-2, HER-3 and HER-4
and promotes tumor cell proliferation in a variety of malignancies including breast cancer Two members
of the family EGFR and HER-2 are frequently overexpressed in breast cancer. EGFR is overexpressed in
16-48% of the human breast cancers and an association has been reported between EGFR expression and
poor prognosis. HER-2 is over expressed in 25-30% of all human breast carcinomas and a significant
correlation between overexpression and reduced survival of breast cancer patients has been found.
Trastuzumab has revolutionized the HER-2 overexpressing breast cancer treatment by improving survival
in metastatic breast cancers when endocrine therapy failed. However, the majority of HER-2
overexpressing breast cancers do not respond to trastuzumab therapy alone. Several reasons have been
proposed for this resistance including expression of redundant survival signaling pathways like IGFR,
deficient expression of tumor suppressor gene PTEN, expression of p95HER2, a truncated form of HER-2
lacking extracellular domain recognized by trastuzumab; and downregulation of cyclin dependent kinase
inhibitor p27kip. Cetuximab is another monoclonal antibody that is being evaluated in clinical trials and
giving promising results. Since it targets EGFR, it also holds promise for subgroup of breast cancer
patients with triple negative phenotype that overexpress EGFR.
Small molecule tyrosine kinase inhibitors (TKIs) have shown promise in cases that are resistant to
trastuzumab therapy as these compounds compete with ATP for binding to the EGFR/HER-2 catalytic
kinase domain of the receptor to block the signaling pathway. These agents are also associated with lower
risk of cardio-toxicity. Though research in this field has been going on for a long time and numerous
EGFR inhibitors are under development, but to date only lapatinib has been approved by FDA for MBC.
Lapatinib when combined with capecitabine has shown clinical efficacy in heavily pre-treated HER-2
overexpressing breast cancer patients. A number of other small molecule inhibitors like canertinib and
HKI-272 are under development and numerous clinical trials are being conducted to assess the efficiency
of these agents but unfortunately only limited gains have been achieved when these agents are used as
monotherapy. Among the available therapies, TKIs appear to be better as compared to antibodies targeting
EGFRs, in terms of side effects, cost-effectiveness and efficient delivery to tumor sites. However, a big
challenge still lies ahead for medicinal chemists and pharmacologists for want of improved strategies,
synthesis and identification of novel chemical entities targeting EGFR/HER-2.
Medicinal Research Reviews 2012, 32(1), 166–215
The major obstacles in development of successful ErbB targeted therapy include the redundancy
of cellular pathways, the concomitant aberrations and involvement of multiple cross talk mechanisms in
cancer cells which eventually lead to the development of resistance. Therefore, it is likely that multiple
targets need to be addressed for maximal clinical effects and to minimize development of resistance.
There are evidences to show that EGFR/HER-2 inhibitors hold greater promise when used in combination
with radiation or chemotherapy compared to either treatment alone. So the combination therapy may
involve use of EGFR inhibitors with HER-2 inhibitors like trastuzumab with lapatinib that has shown
promising results in clinic. The crosstalk between estrogen receptor α and EGFR/HER-2 provides a
rationale for combining antiestrogens with HER-2 targeting therapies. Till date only tamoxifen and
fulvestrant have been used for ER positive tumors.307 There is also a need for introducing newer
antiestrogens with improved profile e.g. toremefine, raloxifene, into combination therapy. Similarly,
IGFR1 inhibitors can also be used in combination with EGFR/HER-2 inhibitors.308 Crosstalk between
VEGFR and EGFR/HER-2 pathways provides rationale for combining anti-VEGF antibodies or VEGFR
tyrosine kinase inhibitors with ErbB inhibitors. Clinical trials are underway to investigate the efficacy of
these combination therapies in breast cancer. EGFR/HER-2 inhibitors can also be used with hsp90
antagonists that leads to proteolysis of EGFR/HER-2 or with the inhibitors of PI3K/Akt/mTOR
pathway.64-65 Future strategies may also be designed towards the combination of ErbB inhibitors with
integrin antagonists to be utilized for enhanced outcome in MBC patients.309 In case of triple negative
cancers having EGFR positive status, the PARP inhibitors combined with EGFR inhibitors, may be
another ray of hope. Currently, the challenge remains ahead to formulate an appropriate combination
strategy to maximize the treatment outcome. On the other hand, it is highly desirable to explore various
resistance mechanisms as well.
Another recent approach to combat development of resistance involves targeting the breast cancer
stem cells.310 This subset of breast cancer cells has the unique property to proliferate and develop new
tumors that might be resistant to the ongoing therapy. So it would be advantageous to target these stem
cells in contrast to merely treating the symptoms of the disease. Lapatinib treatment in a neo-adjuvant
setting has shown to decrease the number of breast cancer stem cells and in tumor biopsies as opposed to
chemotherapy which led to an increase.294-295 Therefore, the agents like lapatinib which are less toxic and
more efficacious could be of significant importance in the treatment of breast cancer. It is also important
to identify the genes that trigger molecular pathways involved in chemoresistance, tumor formation and
malignant cell self - renewal associated with the cancer stem cells. New therapies to inhibit breast cancer
stem cells would be of vital importance and if these are not targeted, any targeted therapy would be of
limited efficacy.
Important work also needs to be done to identify patients who will benefit from targeting the ErbB
family receptors. This requires the molecular characterization of the tumor of every individual patient and
also the identification of biological markers predictive of response or development of resistance to the
targeted agents. Development of more precise and accurate methods for the evaluation of expression
levels of EGFR/HER-2 is highly mandatory. The selection of appropriate dose and schedule with new
agents entering the clinic and implementation of the appropriate combination therapy with conventional
therapies as well as with other anti-signaling agents, will aid to the success of upcoming candidate drugs.
With the advancement of techniques in genomics and proteomics analysis, it is hoped that future research
will also be directed towards the identification of signature genes associated with activation of specific
signaling pathway.295 This would help in the identification of the major pathway involved in the
tumorigenesis in any case which would lead to the formulation of more specific and appropriate
individualized targeted therapy.
ACKNOWLODGEMENT
CDRI Communication No. 7932
Medicinal Research Reviews 2012, 32(1), 166–215
ABBREVIATIONS
AIB1
amplified in breast and ovarian cancer-1
BM
brain metastasis
CISH
chromogenic in situ hybridisation
CR
complete response
c/w
combination with
DFS
disease-free survival
EGF
epidermal growth factor
EGFR epidermal growth factor receptor
ERα
estrogen receptor α
FasL
fas ligand
FISH
fluorescent in situ hybridization
FKHR
forkhead in rhabdomyosarcoma
Grb
growth factor receptor-bound protein
GSK
glycogen synthase kinase
HER-2
herceptin-2
IGFR
insulin –like growth factor receptor
IHC
immunohistochemistry
JAK
janus kinase
LBD
ligand binding domain
MAPK mitogen activated protein kinase
MBC
metastatic breast cancer
MS
median survival
mTOR
mammalian target of rapamycin
NRG
neuregulin
NFκB
nuclear factor kappa B
ORR
overall response rate
OS
overall survival
PFS
progression free survival
PI3K
phosphotidyl inositol 3 kinase
PKC
Protein Kinase C
PLCγ
phospho lipase C γ
PR
partial response
PTEN
phosphatase and tensin homolog deleted on chromosome 10
RR
response rate
SOS
sf sevenless guanine nucleotide exchange factor
STAT
signal transducers and activators of transcription
TTP
time to progression
VEGFR
vascular endothelial growth factor receptor
REFERENCES
1.
2.
3.
Chu D, Lu J. Novel Therapies in Breast Cancer: What is New from ASCO 2008. J Hematol Oncol
2008; 1:16.
Bange J, Zwick E, Ullrich A. Molecular targets for breast cancer therapy and prevention. Nat Med
2001; 7(5):548-552.
Carter SK. Single and combination nonhormonal chemotherapy in breast cancer. Cancer 1972;
30(6):1543–1555.
Medicinal Research Reviews 2012, 32(1), 166–215
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Fossati R, Confalonieri C, Torri V, Ghislandi E, Penna A, Pistotti V, Tinazzi A, Liberati A.
Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published
randomized trials involving 31,510 women. J Clin Oncol 1998; 16(10):3439–3460.
Lanni JS, Lowe SW, Licitra EJ, Liu JO, Jacks T. p53-independent apoptosis induced by paclitaxel
through an indirect mechanism. Proc Natl Acad Sci U S A 1997; 94(18):9679–9683.
Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer
Trialists' Collaborative Group. Lancet 1998; 351(9114):1451-1467.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen
H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL,
Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature 2000;406(6797):747752.
Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu
ET. Breast cancer classification and prognosis based on gene expression profiles from a populationbased study. Proc Natl Acad Sci U S A 2003;100(18):10393-10398.
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler
S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D. Repeated
observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U
S A 2003;100(14):8418-8423.
Santen RJ. Inhibition of aromatase: insights from recent studies. Steroids 2003;68: 559–567.
Johnston SR, Dowsett M. Aromatase inhibitors for breast cancer: lessons from the laboratory. Nat
Rev Cancer 2003;3(11):821-831.
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M,
Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, BorresenDale AL. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical
implications. Proc Natl Acad Sci U S A 2001;98(19):10869-10874.
Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C,
Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM.
Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast
carcinoma. Clin Cancer Res 2004;10(16):5367-5374.
Diaz LK, Cryns VL, Symmans F, Sneige N. Triple negative breast carcinoma and the basal
phenotype: from expression profiling to clinical practice. Adv Anat Pathol 2007; 14: 419–430.
Anders C, Carey LA. Understanding and treating triple-negative breast cancer. Oncology (Williston
Park) 2008; 22(11):1233-1239; discussion 1239-1240, 1243.
Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review. Histopathology 2008;52(1):108118.
Breur A, Kandel M, Fisseler-Eckhoff A, Sutter C, Schawaab E, Luck HJ, duBois A. BRCA1
germline mutation in a woman with metaplastic squamous cell breast cancer. Onkologie
2007;30:316-318.
Young SR, Pilarski RT, Donenberg T, Shapiro C, Hammond LS, Miller J, Brooks KA, Cohen S,
Tenenholz B, Desai D, Zandvakili I, Royer R, Li S, Narod SA. The prevalence of BRCA1 mutations
among young women with triple-negative breast cancer. BMC Cancer 2009;9:86.
Drew Y, Plummer R. The emerging potential of poly(ADP-ribose) polymerase inhibitors in the
treatment of breast cancer. Curr Opin Obstet Gynecol 2010;22(1):66-71.
Pal SK, Mortimer J. Triple-negative breast cancer: novel therapies and new directions. Maturitas
2009;63(4):269-274.
Drew Y, Calvert H. The potential of PARP inhibitors in genetic breast and ovarian cancers. Ann N Y
Acad Sci 2008;1138:136-145.
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A,
O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS. Inhibition of
Medicinal Research Reviews 2012, 32(1), 166–215
23.
24.
25.
26.
27.
28.
29.
30.
31.
poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med
2009;361(2):123-134.
Siziopikou KP, Cobleigh M. The basal subtype of breast carcinomas may represent the group of
breast tumors that could benefit from EGFR-targeted therapies. Breast 2007;16(1):104-107.
Siziopikou KP, Ariga R, Proussaloglou KE, Gattuso P, Cobleigh M. The challenging estrogen
receptor-negative/ progesterone receptor-negative/HER-2-negative patient: a promising candidate for
epidermal growth factor receptor-targeted therapy? Breast J 2006;12(4):360-362.
McGuire W, Clark G. Prognostic factors and treatment decisions in axillary-node-negative breast
cancer. N. Engl. J. Med.1992; 326:1756–1762.
Miyoshi Y, Akazawa K, Kamigaki S, Ueda S, Yanagisawa S, Inoue T, Yamamura J, Taguchi T,
Tamaki Y, Noguchi S. Prognostic significance of intra-tumoral estradiol level in breast cancer
patients. Cancer Lett 2004; 216:115–121.
Fuqua SA, Cui Y. Estrogen and progesterone receptor isoforms:clinical significance in breast cancer.
Breast Cancer Res. Treat. 2004; 87:3–S10.
Clarke R, Skaar TC, Bouker KB, Davis N, Lee YR, Welch JN, Leonessa F. Molecular and
pharmacological aspects of antiestrogen resistance. J. Steroid Biochem. Mol. Biol. 2001; 76:71–84.
Riggs BL, Hartmann LC. Selective Estrogen-Receptor Modulators — Mechanisms of Action and
Application to Clinical Practice. N Engl J Med 2003; 348(7):618-629.
Lee WL, Cheng MH, Chao HT, Wang PH. The role of selective estrogen receptor modulators on
breast cancer: from tamoxifen to raloxifene. Taiwan J Obstet Gynecol 2008;47(1):24-31.
Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late breast cancer. An early clinical
appraisal of ICI46474. Br J Cancer 1971; 25:270–275.
32. Peto R, Boreham J, Clarke M, Davies C, Beral V. UK and USA breast cancer deaths down 25% in
year 2000 at ages 20–69 years. Lancet 2000; 355(1822):592-593.
33. Gradishar WJ. Tamoxifen- what next? Oncologist 2004; 9:378-384.
34. Tamoxifen for early breast cancer. Early Breast Cancer Trialists’ Collaborative Group. Cochrane
Database Syst. 2004; Rev1: CD000486.
35. Paridaens R, Sylvester RJ, Ferrazzi E, Legros N, Leclercq G, Heuson JC. Clinical significance of the
36.
37.
38.
39.
40.
41.
quantitative assessment of estrogen receptors in advanced breast cancer. Cancer 1980; 46(12
Suppl):2889–2895.
Lippman ME, Allegra JC. Quantitative estrogen receptor analyses: the response to endocrine and
cytotoxic chemotherapy in human breast cancer and the disease-free interval. Cancer 1980; 46(12
Suppl):2829–2834.
Campbell FC, Blamey RW, Elston CW, Morris AH, Nicholson RI, Griffiths K, Haybittle
JL.Quantitative oestradiol receptor values in primary breast cancer and response of metastases to
endocrine therapy. Lancet 1981; 2(8259):1317–1319.
Stewart J, King R, Hayward J, Rubens R. Estrogen and progesterone receptors: correlation of
response rates, site and timing of receptor analysis. Breast Cancer Res Treat 1982; 2(3):243–250.
Ingle JN, Twito DI, Schaid DJ, Cullinan SA, Krook JE, Mailliard JA, Marschke RF, Long HJ,
Gerstner JG, Windschitl HE. Randomized clinical trial of tamoxifen alone or combined with
fluoxymesterone in postmenopausal women with metastatic breast cancer. J Clin Oncol 1988;
6(5):825-831.
Veronesi U, Maisonneuve P, Costa A, Saccini V, Maltoni C, Robertson C. Prevention of breast
cancer with Tamoxifen: preliminary findings from Italian randomized trial among hysterectomised
women. Lancet 1998; 352:, 93–97.
Fisher B, Constantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V,
Robidoux A, Dimitrov J, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Woolmark H. Tamoxifen
for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1
study. J. Natl. Cancer Inst. 1998; 90:1371–1388.
Medicinal Research Reviews 2012, 32(1), 166–215
42. Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S, Boyle P. Overview of the main
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
outcomes in breast cancer prevention trials. Lancet 2003;3 61(9354):296–300.
Fisher B, Constantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V,
Robidoux A, Dimitrov J, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Woolmark H. Tamoxifen
for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1
study. J Natl Cancer Inst 1998; 90:1371–1388.
MacGregor JI, Jordan VC. Basic guide to the mechanism of antiestrogen action. Pharmacol Rev
1998; 50:151–196.
Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN,Bevers TB,
Fehrenbacher L, Pajon ER, Jr., Wade JL, 3rd, Robidoux A, Margolese RG, James J, Lippman SM,
Runowicz CD, Ganz PA, Reis SE, McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark N. Effects
of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease
outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. Jama 2006;
295(23):2727-2741.
Howell A, Defriend D, Anderson E. Mechanism of response and resistance to endocrine therapy for
breast cancer and the development of new treatments. Rev Endocr-Related Cancer 1993; 43:5-21.
Ring A, Dowsett M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer 2004; 11(4):643-658.
Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BS. Profiling of estrogenup- and down-regulated gene expression in human breast cancer cells: Insights into gene networks
and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology
2003; 144:4562–4574.
Nicholson RI, Staka C, Boyns F, Hutcheson IR, Gee JMW. Growth factor-driven mechanisms
associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy.
Endocr Relat Cancer 2004; 11(4):623–641.
McClelland RA, Barrow D, Madden TA, Dutkowski CM, Pamment J, Knowlden JM, Gee JM,
Nicholson RI. Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells
after long-term culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex).
Endocrinology 2001; 142(7):2776-2788.
Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP,
Trent JM, Meltzer PS. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer.
Science 1997; 277(5328):965-968.
Lavinsky RM, Jepsen K, Heinzel T, Torchia J, Mullen TM, Schiff R, Del-Rio AL, Ricote M, Ngo S,
Gemsch J, Hilsenbeck SG, Osborne CK, Glass CK, Rosenfeld MG, Rose DW. Diverse signaling
pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad
Sci U S A 1998; 95(6):2920-2925.
Dickson RB, Lippman ME. Growth factors in breast cancer. Endocr Rev 1995; 16(5):559-589.
Paik S, Hartmann DP, Dickson RB, Lippman ME. Antiestrogen resistance in ER positive breast
cancer cells. Breast Cancer Res Treat 1994; 31(2-3):301-307.
Osborne CK, Shou J, Massarweh S, Schiff R. Crosstalk between estrogen receptor and growth factor
receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res
2005; 11(2 Pt 2):865s-870s.
Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, Barrow D, Wakeling AE,
Nicholson RI. Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an
autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology
2003;144(3):1032-1044.
Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R. Mechanisms of
tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast
cancer. J Natl Cancer Inst 2004; 96(12):926-935.
Medicinal Research Reviews 2012, 32(1), 166–215
58. Britton DJ, Hutcheson IR, Knowlden JM, Barrow D, Giles M, McClelland RA, Gee JM, Nicholson
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
RI. Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifenresistant growth. Breast Cancer Res Treat 2006; 96(2):131-146.
Gswind A, Fischer OM, Ullrich A. The discovery of receptors tyrosine kinases: targets for cancer
therapy. Nat Rev Cancer 2004; 4:361-370.
Prendergast GC. Farnesyl transferase inhibitors: antineoplastic mechanism and clinical prospects.
Curr Opin Cell Biol 2000; 12:166-173.
Faria M, Spiller DG, Dubertret C, Nelson JS, White MR, Scherman D, Helene C, Giovannangeli C.
Phosphoramidate oligonucleotides as potent antisense molecules in cells and in vivo. Nat Biotechnol
2001; 19(1):40-44.
Lavelle F. [New anticancer molecules: drugs for tomorrow?]. Bull Cancer 1999; 86(1):91-95.
Carraway H, Hidalgo M. New Targets for therapy of breast cancer: mammalian target of rapamycin
(mTOR) antagonists. Breast Cancer Res 2004; 6(5):219-224.
Adams J. Proteasome Inhibitors as anticancer drugs. Curr Opin Oncol 2002; 14(6):628-634.
Brown J, Von Roenn J, O’Regan R, Bergan R, Badve S, Rademaker A, Feehan S, Petersen J, Patton
M, Gradishar W. A phase II study of the proteasome inhibitor PS-341 in patients(pts) with metastatic
breast cancer (MBC). J Clin Oncol (ASCO Meeting abstract) 2004; 22 Suppl 14;546.
Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene
2000;19(56):6550-6565.
Jezdic S, Popov I. EGF receptor as a therapeutic target in oncology Archive of Oncology 2005; 13
Suppl 1:53-55.
Lewis S, Locker A, Todd JH, Bell JA, Nicholson R, Elston CW, Blamey RW, Ellis IO. Expression of
epidermal growth factor receptor in breast carcinoma. J Clin Pathol 1990; 43(5):385-389.
Chrysogelos SA, Yarden RI, Lauber AH, Murphy JM. Mechanisms of EGF receptor regulation in
breast cancer cells. Breast Cancer Res Treat 1994;31(2-3):227-236.
Gershtein ES, Ermilova VD, Kuz'mina ZV, Kuzlinskii NE, Letiagin VP. [Expression of epidermal
growth factor receptors and their ligands in malignant tumors of the breast]. Vestn Ross Akad Med
Nauk 1996(3):15-19.
Biswas DK, Cruz AP, Gansberger E, Pardee AB. Epidermal growth factor-induced nuclear factor
kappa B activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast
cancer cells. Proc Natl Acad Sci U S A 2000; 97(15):8542-8547.
Bolufer P, Lluch A, Molina R, Alberola V, Vazquez C, Padilla J, Garcia-Conde J, Llopis F, Guillem
V. Epidermal growth factor in human breast cancer, endometrial carcinoma and lung cancer. Its
relationship to epidermal growth factor receptor, estradiol receptor and tumor TNM. Clin Chim Acta
1993;215(1):51-61.
Harari D, Yarden Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer.
Oncogene 2000; 19(53):6102-6114.
Jardines L, Weiss M, Fowble B, Greene M. neu(c-erbB-2/HER2) and the epidermal growth factor
receptor (EGFR) in breast cancer. Pathobiology 1993;61(5-6):268-282.
Bates SE, Fojo T. Epidermal Growth Factor Receptor Inhibitors: A Moving Target? Clin Cancer Res
2005; 11(20):7203-7205.
Klijn JG, Berns PM, Schmitz PI, Foekens JA. The clinical significance of epidermal growth factor
receptor (EGF-R) in human breast cancer: a review on 5232 patients. Endocr Rev 1992; 13:3-17.
Tsutsui S, Ohno S, Murakami S, Hachitanda Y, Oda S: Prognostic value of epidermal growth factor
receptor (EGFR) and its relationship to the estrogen receptor status in 1029 patients with breast
cancer. Breast Cancer Res Treat 2002; 71:67-75.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer:
correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;
235:177-182.
Medicinal Research Reviews 2012, 32(1), 166–215
79. Garrett TP, McKern NM, Lou M, Frenkel MJ, Bentley JD, Lovrecz GO, Elleman TC, Cosgrove LJ,
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
Ward CW. Crystal structure of the first three domains of the type-1 insulin-like growth factor
receptor. Nature 1998; 394(6691):395-399.
Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Zhu HJ, Walker F, Frenkel
MJ, Hoyne PA, Jorissen RN, Nice EC, Burgess AW, Ward CW. Crystal structure of a truncated
epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha.
Cell 2002;110(6):763-773.
Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M,
Shirouzu M, Yokoyama S. Crystal structure of the complex of human epidermal growth factor and
receptor extracellular domains. Cell 2002;110(6):775-787.
Aifa S, Aydin J, Nordvall G, Lundstrom I, Svensson SP, Hermanson O. A basic peptide within the
juxtamembrane region is required for EGF receptor dimerization. Exp Cell Res 2005; 302(1):108114.
Mineo C, Gill GN, Anderson RG. Regulated migration of epidermal growth factor receptor from
caveolae. J Biol Chem 1999; 274(43):30636-30643.
Gotoh N, Tojo A, Hino M, Yazaki Y, Shibuya M. A highly conserved tyrosine residue at codon 845
within the kinase domain is not required for the transforming activity of human epidermal growth
factor receptor. Biochem Biophys Res Commun 1992;186(2):768-774.
Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and
their receptors in human malignancies. Crit Rev Oncol/Hematol 1995; 19:183–232.
Pawson T. Protein modules and signalling networks. Nature 1995; 373:573–580.
Carpenter G. The EGF receptor: A nexus for trafficking and signaling. Bioassays 2000; 22:697–707.
Maruta H, Burgess AW. Regulation of the Ras signalling network. Bioessays 1994; 16:489–496.
Luo J, Manning B, Cantley L. Targeting the PI3K-Akt pathway in human cancer: Rationale and
promise. Cancer Cell 2003; 4:257–262.
Vivanco I, Sawyers CL. The phosphatidyl inositol 3-kinase Akt pathway in human cancer. Nat Rev
Cancer 2002; 2:489–501.
Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by
restraining the phosphoinositide 3-kinase/akt pathway. Proc Natl Acad Sci U S A 1999; 96:4240–
4245.
Falasca M, Logan SK, Lehto VP, Baccante G, Lemmon MA, Schlessinger J. Activation of
phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting. Embo J
1998; 17(2):414–422.
Normanno N, Bianco C, De Luca A, Salomon DS. The role of EGF-related peptides in tumor growth.
Front Biosci 2001; 6:D685–707.
Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signalling network: receptor dimerisation
in development and cancer. EMBO Journal 2000;19: 3159–3167.Shoyab M, Plowman GD,
McDonald VL, Bradley JG , Todaro GJ. Structure and function of human amphiregulin: a member of
the epidermal growth factor family. Science 1989; 243:1074–1076.
Shoyab M, Plowman GD, McDonald VL, Bradley JG, Todaro GJ. Structure and function of human
amphiregulin: a member of the epidermal growth factor family. Science 1989; 243:1074–1076.
Carpenter G & Cohen S 1990 Epidermal growth factor. J Biol Chem 1990; 265:7709–7712.
Riese DJ, Kim ED, Elenius K, Buckley S, Klagsbrun M, Plowman GD, Stem DF. The epidermal
growth factor receptor couples transforming growth factor-alpha, heparin-binding epidermal growth
factor like factor, and amphiregulin to neu, ErbB-3, and ErbB-4. J Biol Chem 1996; 271(33):20047–
20052.
Elenius K, Paul S, Allison G, Sun J, Klagsbrun M. Activation of HER4 by heparin-binding EGF-like
growth factor stimulates chemotaxis but not proliferation. EMBO Journal 1997; 16:1268–1278.
Medicinal Research Reviews 2012, 32(1), 166–215
99. Shelly M, Pinkas-Kramarski R, Guarino BC, Waterman H, Wang LM, Lyass L, Alimandi M, Kuo A,
Bacus SS, Pierce JH, Andrews GC, Yarden Y. Epiregulin is a potent pan-ErbB ligand that
preferentially activates heterodimeric receptor complexes. J Biol Chem 1998; 273:10496–10505.
100. Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Bush J,
Godowski PJ. Neuregulin 3 (NRG3): a novel neural tissue-enriched protein that binds and activated
ErbB4. Proc Natl Acad Sci U S A 1997; 94: 9562–9567.
101. Harari D, Tzahar E, Romano J, Shelly M, Pierce JH, Andrews GC, Yarden Y. Neuregulin-4: a novel
growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene 1999; 18:2681–2689.
102. Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G,
Caponigro F, Salomon DS. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene
2006; 366(1):2-16.
103. Sato JD, Kawamoto T, Le AD. Biological effect in vitro of monoclonal antibodies to human EGF
receptors. Mol Biol Med 1983; 1:511-529.
104. Masui H, Kawamoto T, Sato JD. Growth inhibition of human tumor cells in athymic mice by antiepidermal growth factor receptor monoclonal antibodies. Cancer Res 1984; 44:1002-1007.
105. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol
2002;20(18 Suppl):1s-13s.
106. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL,
Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating
mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung
cancer to Gefitinib. N Engl J Med 2004; 350(21):2129-2139.
107. Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, Huang HJ. A mutant epidermal
growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad
Sci U S A 1994; 91(16):7727–7731.
108. Kuan CT, Wikstrand CJ, Bigner DD: EGF mutant receptor vIII as a molecular target in cancer
therapy. Endocr Relat Cancer 2001; 8:83-96.
109. Moscatello DK. Frequent expression of a mutant epidermal growth factor receptor in multiple human
tumors. Cancer Res 1995; 55:5536-5539.
110. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N,
Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR
mutations in lung cancer: correlation with clinical response to Gefitinib therapy. Science 2004;
304(5676):1497-1500.
111. Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B.
Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad
Sci 1992; 89(7):2965–2969.
112. Ekstrand AJ, Longo N, Hamid ML, Olson JJ, Liu L, Collins VP, James CD. Functional
characterization of an EGF receptor with a truncated extracellular domain expressed in glioblastomas
with EGFR gene amplification. Oncogene 1994; 9(8):2313–2320
113. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth
factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer
Res 1993; 53(15):3579–3584.
114. De Laurentiis M, Arpino G, Massarelli E, Ruggiero A, Carlomagno C, Ciardiello F, Tortora G,
D’Agostino D, Caputo F, Cancello G, Montagna E, Malorni L, Zinno L, Lauria R, Bianco AR, De
Placido S. A meta-analysis on the interaction between expression and response to endocrine
treatment in advanced breast cancer. Clin Cancer Res 2005; 11:4741–4748.
115. Arpino G, Green SJ, Allred DC, Lew D, Martino S, Osborne CK, Elledge RM.
HER-2
amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic
breast cancer: a southwest oncology group study. Clin Cancer Res 2004; 10:5670–5676.
116. Ellis M. Overcoming endocrine therapy resistance by signal transduction inhibition. Oncologist
2004; 9(Suppl 3):20–26.
Medicinal Research Reviews 2012, 32(1), 166–215
117. Levin ER, Pietras RJ. Estrogen receptors outside the nucleus in breast cancer. Breast Cancer Res
Treat 2008;108(3):351-361.
118. Lin NU, Winer EP. New targets for therapy in breast cancer Small molecule tyrosine kinase
inhibitors Breast Cancer Res 2004; 6(5):204-210.
119. Osborne CK, Schiff R. Estrogen-receptor biology: continuing progress and therapeutic implications.
J Clin Oncol 2005; 23(8):1616–1622.
120. Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, Wong J, Allred DC,
Clark GM, Schiff R. Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in
tamoxifen resistance in breast cancer. J Natl Cancer Inst 2003;95(5):353-361.
121. Razandi M, Oh P, Pedram A, Schnitzer J, Levin ER. ERs associate with and regulate the production
of caveolin: implications for signaling and cellular actions. Mol Endocrinol 2002; 16:100–115.
122. Pedram A, Razandi M, Sainson RC, Kim JK, Hughes CC, Levin ER. A conserved mechanism for
steroid receptor translocation to the plasma membrane. J Biol Chem 2007;282:22278–22288.
123. Marquez DC, Chen HW, Curran EM, Welshons WV, Pietras RJ. Estrogen receptors in membrane
lipid rafts and signal transduction in breast cancer. Mol Cell Endocrinol 2006; 246:91–100.
124. Aronica SM, Kraus WL, Katzenellenbogen BS. Estrogen action via the cAMP signaling pathway:
stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci U S A
1994;91(18):8517-8521.
125. Kahlert S, Nuedling S, van Eickels M, Vetter H, Meyer R, Grohe C. Estrogen receptor alpha rapidly
activates the IGF-1 receptor pathway. J Biol Chem 2000;275(24):18447-18453.
126. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen
receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature
2000;407(6803):538-541.
127. Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R, Santen RJ. Linkage of rapid
estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation. Mol
Endocrinol 2002;16(1):116-127.
128. MacGregor Schafer J, Liu H, Levenson AS, Horiguchi J, Chen Z, Jordan VC. Estrogen receptor
alpha mediated induction of the transforming growth factor alpha gene by estradiol and 4hydroxytamoxifen in MDA-MB-231 breast cancer cells. J Steroid Biochem Mol Biol 2001;78(1):4150.
129. Wilson MA, Chrysogelos SA. Identification and characterization of a negative regulatory element
within the epidermal growth factor receptor gene first intron in hormone-dependent breast cancer
cells. J Cell Biochem 2002;85(3):601-614.
130. Russell KS, Hung MC. Transcriptional repression of the neu protooncogene by estrogen stimulated
estrogen receptor. Cancer Res 1992;52(23):6624-6629.
131. Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida
E, Kawashima H. Activation of the estrogen receptor through phosphorylation by mitogen-activated
protein kinase. Science 1995; 270:1491–1494.
132. Bunone G, Briand PA, Miksicek RJ, Picard D. Activation of the unliganded estrogen receptor by
EGF involves the MAP kinase pathway and direct phosphorylation. Embo J 1996; 15:2174–2183.
133. Joel PB, Smith J, Sturgill TW, Fisher TL, Blenis J, Lannigan DA. pp90rsk1 regulates estrogen
receptor-mediated transcription through phosphorylation of Ser-167. Mol Cell Biol 1998; 18:1978–
1984.
134. Coutts AS, Murphy LC. Elevated mitogen-activated protein kinase activity in estrogennonresponsive human breast cancer cells. Cancer Res 1998; 58(18): 4071–4074.
135. Shim WS, Conaway M, Masamura S, Yue W, Wang JP, Kmar R, Santen RJ. Estradiol
hypersensitivity and mitogen activated protein kinase expression in long-term estrogen deprived
human breast cancer cells in vivo. Endocrinology 2000; 141: 396–405.
Medicinal Research Reviews 2012, 32(1), 166–215
136. Lavinsky RM, Jepsen K, Heinzel T, Torchia J, Mullen TM, Schiff R, Del-Rio AL, Ricote M, Ngo S,
Gemsch J, Hilsenbeck SG, Osborne CK, Glass CK, Rosenfeld MG, Rose DW. Diverse signaling
pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad
Sci U S A 1998; 95(6): 2920–2925.
137. Font de Mora J, Brown M. AIB1 is a conduit for kinase mediated growth factor signaling to the
estrogen receptor. Mol Cell Biol 2000; 20:5041–5047.
138. Hong SH, Privalsky ML. The SMRT corepressor is regulated by a MEK-1 kinase pathway:
inhibition of corepressor function is associated with SMRT phosphorylation and nuclear export. Mol
Cell Biol 2000; 20:6612–6625.
139. Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, Tsai MJ, O’Malley BW. Regulation of SRC-3
(pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase. Mol Cell Biol 2002;
22:3549–3561.
140. Ross JS, Fletcher JA, Bloom KJ, Linette GP, Stec J, Symmans WF, Pusztai L, Hortobagyi GN.
Targeted Therapy in Breast Cancer :the HER-2/neu gene and protein. Mol Cell Proteomics 2004;
3(4):379-398.
141. Levitzki A. EGF receptor as a therapeutic target. Lung Cancer 2003; 41:S9-S14.
142. Pauletti G, Godolphin W, Press MF, Slamon DJ. Detection and quantifation of HER-2/neu gene
amplification in human breast cancer archival material using fluorescence in situ hybridization.
Oncogene 1996; 13(1):63–72.
143. Hynes NE, Gerber HA, Saurer S, Groner B. Overexpression of the c-erbB-2 protein in human breast
tumor cell lines. J Cell Biochem 1989;39(2):167–73.
144. Bose S, Lesser ML, Norton L, Rosen PP. Immunophenotype of intraductal carcinoma. Arch Pathol
Lab Med 1996;120(1):81-85.
145. Moreno A, Lloveras B, Figueras A, Escobedo A, Ramon JM, Sierra A, Fabra A. Ductal carcinoma in
situ of the breast: correlation between histologic classifications and biologic markers. Mod Pathol
1997; 10(11):1088-1092.
146. Slamon DJ, Godolphin W, Jones LA. Studies of the HER2/neu proto-oncogene in human breast and
ovarian cancer.Science 1989; 244(4905):707–712.
147. Mack L, Kerkvliet N, Doig G, O'Malley FP. Relationship of a new histological categorization of
ductal carcinoma in situ of the breast with size and the immunohistochemical expression of p53, cerb B2, bcl-2, and ki-67. Hum Pathol 1997; 28(8):974-979.
148. Rosenthal SI, Depowski PL, Sheehan CE, Ross JS. Comparison of HER-2/neu oncogene
amplification detected by fluorescence in situ hybridization in lobular and ductal breast cancer. Appl
Immunohistochem Mol Morphol 2002; 10:40–46.
149. Barron JJ, Cziraky MJ, Weisman T, Hicks DG. HER-2 testing and subsequent trastuzumab treatment
for breast cancer in a managed care environment. Oncologist 2009; 14(8):760-768.
150. Cuadros M, Villegas R. Systematic review of HER-2 breast cancer testing. Appl Immunohistochem
Mol Morphol 2009;17(1):1-7.
151. Gong Y, Sweet W, Duh YJ, Greenfield L, Fang Y, Zhao J, Tarco E, Symmans WF, Isola J, Sneige N.
Chromogenic in situ hybridization is a reliable method for detecting HER2 gene status in breast
cancer: a multicenter study using conventional scoring criteria and the new ASCO/CAP
recommendations. Am J Clin Pathol 2009;131(4):490-497.
152. Gong Y, Sweet W, Duh YJ, Greenfield L, Tarco E, Trivedi S, Symmans WF, Isola J, Sneige N.
Performance of chromogenic in situ hybridization on testing HER2 Status in breast carcinomas with
chromosome 17 polysomy and equivocal (2+) herceptest results: a study of two institutions using the
conventional and new ASCO/CAP scoring criteria. Am J Clin Pathol 2009; 132(2):228-236.
153. Huston JS, George AJ. Engineered antibodies take center stage. Hum Antibodies 2001;10:127–142.
154. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulates in vivo
cytotoxicity against tumor targets. Nat Med 2000, 6:443-446.
Medicinal Research Reviews 2012, 32(1), 166–215
155. Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A: p185HER2 monoclonal
antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor
necrosis factor. Mol Cell Biol 1989;9:1165-1172.
156. Nahta R, Esteva FJ: Herceptin: mechanisms of action and resistance. Cancer Lett 2006;232(2):123138.
157. Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG. Trastuzumab--mechanism of action and
use. N Engl J Med 2007;357(16):1664; author reply 1665-1666.
158. Barok M, Isola J, Palyi-Krekk Z, Nagy P, Juhasz I, Vereb G, Kauraniemi P, Kapanen A, Tanner M,
Vereb G, Szollosi J. Trastuzumab causes antibody-dependent cellular cytotoxicity-mediated growth
inhibition of submacroscopic JIMT-1 breast cancer xenografts despite intrinsic drug resistance. Mol
Cancer Ther 2007;6(7):2065-2072.
159. Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA. Nonclinical studies
addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol 1999;26(4) Suppl
12:60-70.
160. Emens LA, Davidson NE. Trastuzumab in breast cancer. Oncology (Williston Park) 2004;
18(9):1117-1128; discussion 1131-1112, 1137-1118.
161. Bartsch R, Wenzel C, Steger GG. Trastuzumab in the management of early and advanced stage
breast cancer. Biologics 2007;1(1):19-31.
162. Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med
2007;357(1):39-51.
163. Mir O, Berveiller P, Pons G. Trastuzumab--mechanism of action and use. N Engl J Med 2007;
357(16):1664-1665; author reply 1665-1666.
164. Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD,
Hudis CA, Moore J. Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with
HER2/neu-overexpressing metastatic breast cancer. Semin Oncol 1999; 26:78-83.
165. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V,
Shak S, Lieberman G, Slamon DJ. Multinational study of the efficacy and safety of humanized antiHER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that
has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999; 17(9):2639-2648.
166. Baselga J, Carbonell X, Casta˜neda-Soto NJ. Phase II study of efficacy, safety, and
pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule.J Clin Oncol
2005; 23(10):2162–2171.
167. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy
M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M. Efficacy and safety of trastuzumab as
a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol
2002; 20(3):719-726.
168. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bejamonde A, Fleming T, Eiermann W,
Wolter J, Pegram M, Beselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against
HER2 for metastatic breast cancer that overexpress HER2. N Engl J Med 2001; 344(11):783-792.
169. Burstein HJ, Kuter I, Campos SM, Gelman RS, Tribou L, Parker LM, Manola J, Younger J,
Matulouis U, Bunnell CA, Partridge AH, Richardson PG, Clarke K, Shulman LN, Winer EP. Clinical
activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast
cancer. J Clin Oncol 2001; 19(10):2722-2730.
170. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D,
Anton A, Lluch A. Randomized phase II trial of the efficacy and safety of trastuzumab combined
with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast
cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005; 23:42654274.
171. Gasparini G, Gion M, Mariani L, Papaldo P, Crivellari D, Filippelli G, Morabito A, Silingardi V,
Torino F, Spada A. Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus
Medicinal Research Reviews 2012, 32(1), 166–215
weekly paclitaxel as first-line therapy of patients with positive advanced breast cancer. Breast
Cancer Res Treat 2007; 101:355-365.
172. Petrelli F, Cabiddu M, Cazzaniga ME, Cremonesi M, Barni S. Targeted therapies for the treatment of
breast cancer in the post-trastuzumab era. Oncologist 2008; 13(4):373-381.
173. Burstein HJ, Kuter I, Campos SM, Gelman RS, Tribou L, Parker LM, Manola J, Younger J,
Matulonis U, Bunnell CA. Clinical activity of trastuzumab and vinorelbine in women with HER2overexpressing metastatic breast cancer. J Clin Oncol 2001; 19:2722-2730.
174. Burstein HJ, Harris LN, Marcom PK, Lambert-Falls R, Havlin K, Overmoyer B, Friedlander RJ, Jr.,
Gargiulo J, Strenger R, Vogel CL, Ryan PD, Ellis MJ, Nunes RA, Bunnell CA, Campos SM, Hallor
M, Gelman R, Winer EP. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing
metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor
markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 2003; 21(15):28892895.
175. Papaldo P, Fabi A, Ferretti G, Mottolese M, Cianciulli AM, Di Cocco B, Pino MS, Carlini P, Di
Cosimo S, Sacchi I. A phase II study on metastatic breast cancer patients treated with weekly
vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history
of HER2-positive disease. Ann Oncol 2006; 17:630-636.
176. De Maio E, Pacilio C, Gravina A, Morabito A, Di Rella F, Labonia V, Landi G, Nuzzo F, Rossi E,
Silvestro P. Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer: a singlecentre phase
2 trial. BMC Cancer 2007; 7 :50.
177. Burris H, 3rd, Yardley D, Jones S, Houston G, Broome C, Thompson D, Greco FA, White M,
Hainsworth J. Phase II trial of trastuzumab followed by weekly paclitaxel/carboplatin as firstline
treatment for patients with metastatic breast cancer. J Clin Oncol 2004; 22:1621-1629.
178. Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R,
Cobleigh M. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with
trastuzumab and paclitaxel in women with -overexpressing metastatic breast cancer. J Clin Oncol
2006; 24:2786-2792.
179. Fujimoto-Ouchi K, Sekiguchi F, Kazushige M. Preclinical study of continuous administration of
trastuzumab as combination therapy after disease progression with trastuzumab monotherapy. Proc
Am Assoc Cancer Res 2005; 46:[Abstr 5062].
180. Fountzilas G, Razis E, Tsavdaridis D, Karina M, Labropoulos S, Christodoulou C, Mavroudis D,
Gogas H, Georgoulias V, Skarlos D. Continuation of trastuzumab beyond disease progression is
feasible and safe in patients with metastatic breast cancer: a retrospective analysis of 80 cases by the
hellenic cooperative oncology group. Clin Breast Cancer 2003; 4:120-125.
181. Gelmon KA, Mackey J, Verma S, Gertler SZ, Bangemann N, Klimo P, Schneeweiss A, Bremer
Soulieres D, Tonkin K. Use of trastuzumab beyond disease progression: observations from a
retrospective review of case histories. Clin Breast Cancer 2004; 5:52-58.
182. Tripathy D, Slamon DJ, Cobleigh M, Arnold A, Saleh M, Mortimer JE, Murphy M, Stewart SJ.
Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin
Oncol 2005; 22:1063-1070.
183. Bartsch R, Wenzel C, Hussian D, Pluschnig U, Sevelda U, Koestler W, Altorjai G, Locker GJ, Mader
R, Zielinski CC. Analysis of trastuzumab and chemotherapy in advanced breast cancer after the
failure of at least one earlier combination: an observational study. BMC Cancer 2006; 6:63.
184. Montemurro F, Donadio M, Clavarezza M, Redana S, Jacomuzzi ME, Valabrega G, Danese S,
Vietti-Ramus G, Durando A, Venturini M. Outcome of patients with HER2-positive advanced breast
cancer progressing during trastuzumab-based therapy. Oncologist 2006; 11:318-324.
185. Bartsch R, Wenzel C, Gampenrieder SP, Pluschnig U, Altorjai G, Rudas M, Mader RM, Dubsky P,
Rottenfusser A, Gnant M, Zielinski, CC, Steger, GG. Trastuzumab and gemcitabine as salvage
therapy in heavily pre-treated patients with metastatic breast cancer. Cancer Chemother Pharmacol.
2008;62(5):903-910.
Medicinal Research Reviews 2012, 32(1), 166–215
186. O'Shaughnessy J, Blackwell KL, Burstein H, Storniolo AM, Sledge G, Baselga J, Koehler M, Laabs
S, Florance A, Roychowdhury D. A randomized study of lapatinib alone or in combination with
trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab
therapy. J Clin Oncol (Meeting Abstract) 2008; 26:1015.
187. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C,
Kaufmann M, Bauer W. Trastuzumab beyond progression in human epidermal growth factor
receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 0305 study. J Clin Oncol 2009; 27:1999-2006.
188. Park IH, Ro J, Lee KS, Nam BH, Kwon Y, Shin KH. Trastuzumab treatment beyond brain
progression in HER2-positive metastatic breast cancer. Ann Oncol 2009; 20(1):56-62.
189. Spielmann M, Roché H, Humblet Y, Delozier T, Bourgeois H, Serin D, Romieu G, Canon JL,
Monnier A, Piot G. 3-year follow-up of trastuzumab following adjuvant chemotherapy in node
positive HER2-positive breast cancer patients: results of the PACS-04 trial. San Antonio Breast
Cancer Symposium 2007;[abstr 72].
190. Baselga J, Perez EA, Pienkowski T, Bell R. Adjuvant Trastuzumab: A Milestone in the Treatment of
-Positive Early Breast Cancer. The Oncologist 2006;11(suppl 1):4–12
191. Dahabreh IJ, Linardou H, Siannis F, Fountzilas G, Murray S. Trastuzumab in the adjuvant treatment
of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials.
Oncologist 2008; 13(6):620-630.
192. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Jr., Davidson NE, Tan-Chiu E, Martino S,
Paik S, Kaufman PA. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast
cancer. N Engl J Med 2005; 353:1673-1684.
193. Perez EA, Suman VJ, Davidson N. NCCTG N9831. May 2005 update. Slide presentation at the 41st
American Society of Clinical Oncology Annual Meeting, Orlando, Florida, May 13–17, 2005.
Available
at
http://www.asco.org/ac/1,1003,_12-002511-00_18-0034-00_19-005815-00_21001,00.asp. Accessed June 7, 2006.
194. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L,
Baselga J, Bell R, Jackisch C. Trastuzumab after adjuvant chemotherapy in HER2-positive breast
cancer. N Engl J Med 2005; 353:1659–72.
195. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Pawlicki M, Chan A, Smylie M, Liu M,
Falkson C. BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and
cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide
followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab
(TCH) in Her2neu positive early breast cancer patients. San Antonio Breast Cancer Symposium
2006; [Abstr 52].
196. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R,
Hemminki A, Tarkkanen M. Adjuvant docetaxel or vinorelbine with or without trastuzumab for
breast cancer. N Engl J Med 2006; 354:809-820.
197. Price-Schiavi SA, Jepson S, Li P, Arango M, Rudland PS, Yee L,Carraway KL.
Rat Muc4
(sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell
surfaces, a
potential mechanism for herceptin resistance. Int J Cancer 2002, 99:783-791.
198. Nagy P, Friedlander E, Tanner M, Kapanen AI, Carraway KL, Isola J, Jovin TM. Decreased
accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing
breast cancer cell line. Cancer Res 2005, 65:473-482.
199. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. Insulin-like growth factor-I receptor signaling and
resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001; 93:1852-1857.
200. Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human
epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast
cancer cells. Cancer Res 2005; 65:11118-11128.
Medicinal Research Reviews 2012, 32(1), 166–215
201. Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Evans
DP, Maiese K. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth.
Cancer Cell 2002; 2:127-137.
202. Motoyama AB, Hynes NE, Lane HA: The efficacy of ErbB receptor- targeted anticancer therapeutics
is influenced by the availability of epidermal growth factor-related peptides. Cancer Res 2002;
62:3151-3158.
203. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT,
Hortobagyi GN, Hung MC, Yu D. PTEN activation contributes to tumor inhibition by trastuzumab,
and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004;6(2):117-127.
204. Saez R, Molina MA, Ramsey EE, Rojo F, Keenan EJ, Albanell J, Lluch A, Garcia-Conde J, Baselga
J, Clinton GM. p95 predicts worse outcome in patients with HER-2-positive breast cancer. Clin
Cancer Res 2006; 12(2):424-431.
205. Colomer R, Montero S, Lluch A, Ojeda B, Barnadas A, Casado A, Massuti B, Cortes-Funes H,
Lloveras B. Circulating HER-2 extracellular domain and resistance to chemotherapy in advanced
breast cancer. Clin Cancer Res 2000; 6:2356-2362.
206. Leitzel K, Teramoto Y, Konrad K, Chinchilli VM, Volas G, Grossberg H, Harvey H, Demers L,
Lipton A. Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of
breast cancer. J Clin Oncol 1995; 13:1129-1135.
207. Yamauchi H, O’Neill A, Gelman R, Carney W, Tenney DY, Hosch S, Hayes DF. Prediction of
response to antiestrogen therapy in advanced breast cancer patients by pretreatment circulating levels
of extracellular domain of the HER-2/c-neu protein. J Clin Oncol 1997; 15:2518-2525.
208. Hayes DF, Yamauchi H, Broadwater G, Cirrincione CT, Rodrigue SP, Berry DA, Younger J, Panasci
LL, Millard F, Duggan DB. Cancer and Leukemia Group B: Circulating HER-2/erbB-2/c-neu (HER2) extracellular domain as a prognostic factor in patients with metastatic breast cancer: Cancer and
Leukemia Group B Study 8662. Clin Cancer Res 2001; 7:2703-2711.
209. Christianson TA, Doherty JK, Lin YJ, Ramsey EE, Holmes R, Keenan EJ, Clinton GM. NH2terminally truncated HER-2/neu protein: relationship with shedding of the extracellular domain and
with prognostic factors in breast cancer. Cancer Res 1998; 58:5123-5129.
210. Molina MA, Saez R, Ramsey EE, Garcia-Barchino MJ, Rojo F, Evans AJ, Albanell J, Keenan EJ,
Lluch A, Garcia-Conde J. NH2-terminal truncated HER-2 protein but not full-length receptor is
associated with nodal metastasis in human breast cancer. Clin Cancer Res 2002; 8:347-353.
211. Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J. Trastuzumab (Herceptin), a
humanized anti-HER2 receptor monoclonal antibody, inhibits basal and activated HER2 ectodomain
cleavage in breast cancer cells. Cancer Res 2001; 61:4744-4749.
212. Esteva FJ, Cheli C, Fritsche HA, Fornier M, Slamon DJ, Thiel RP, Luftner D, Ghani F. Clinical
utility of circulating HER-2/neu in monitoring and prediction of progression-free survival in
metastatic breast cancer patients undergoing trastuzumabbased therapy. Breast Can Res Treat 2004;
88:6001.
213. Kostler WJ, Schwab B, Singer CF, Neumann R, Rucklinger E, Brodowicz T, Tomek S, Niedermayr
M, Hejna M, Steger GG. Monitoring of serum HER-2/neu predicts response and progression-free
survival to trastuzumab-based treatment in patients with metastatic breast cancer. Clin Cancer Res
2004; 10:1618-1624.
214. Fornier MN, Seidman AD, Schwartz MK, Ghani F, Thiel R, Norton L, Hudis C: Serum HER-2
extracellular domain in metastatic breast cancer patients treated with weekly trastuzumab and
paclitaxel: association with HER2 status by immunohistochemistry and fluorescence in situ
hybridization and with response rate. Ann Oncol 2005; 16:234-239.
215. Nahta R, Esteva FJ. HER-2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer
Res 2006; 8(6):215.
Medicinal Research Reviews 2012, 32(1), 166–215
216. Le XF, Claret FX, Lammayot A, Tian L, Deshpande D, LaPushin R, Tari AM, Bast RC Jr. The role
of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell cycle arrest
and tumor growth inhibition. J Biol Chem 2003; 278:23441-23450.
217. Nahta R, Takahashi T, Ueno NT, Hung MC, Esteva FJ: P27 (kip1) down-regulation is associated
with trastuzumab resistance in breast cancer cells. Cancer Res 2004, 64:3981-3986.
218. Adams CW, Allison DE, Flagella K, Presta L, Clarke J, Dybdal N, McKeever K, Sliwkowski MX.
Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization
inhibitor, pertuzumab. Cancer Immunol Immunother 2006; 55(6):717-727.
219. Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights into ErbB
signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 2004; 5:317–28.
220. Fendly BM, Winget M, Hudziak RM, Lipari MT, Napier MA, Ullrich A. Characterization of murine
monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER-2/neu
gene product. Cancer Res 1990; 50:1550–8.
221. Agus DB, Gordon MS, Taylor C, Natale RB, Karlan B, Mendelson DS, Press MF, Allison DE,
Sliwkowski MX, Lieberman G, Kelsey SM, Fyfe G. Phase I clinical study of pertuzumab, a novel
HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 2005; 23(11):2534-2543.
222. Yamamoto N, Yamada Y, Fujiwara Y, Yamada K, Fujisaka Y, Shimizu T, Tamura T. Phase I and
Pharmacokinetic Study of HER2-targeted rhuMAb 2C4 (Pertuzumab, RO4368451) in Japanese
Patients with Solid Tumors. Jpn J Clin Oncol 2009; 39(4)260–266.
223. Cortes L, Baselga J, Kellokumpu-Lehtinen P, Bianchi G, Cameron D, Miles D, Salvagni S, Wardley
A, Goeminne JC, Gianni L. Open label, randomized, phase II study of pertuzumab in patients with
metastatic breast cancer with low expression of HER-2. J Clin Oncol 2005; 23 suppl 16:[abstract
3068].
224. Gelmon KA, Fumoleau P, Verma S, Wardley AM, Conte PF, Miles d, Giani L, McNally VA, Ross
G, Baselga J. Results of a phase II trial of trastuzumab (H) and pertuzumab (P) in patients (pts) with
HER2-positive metastatic breast cancer (MBC) who had progressed during trastuzumab therapy. J
Clin Oncol 2008; 26 suppl 15:[abstract 1026].
225. A Study to evaluate Pertuzumab + Trastuzumab + Docetaxel Vs. Placebo + Trastuzumab +
Docetaxel in previously untreated Her2-positive Metastatic Breast Cancer (CLEOPATRA)NCT00567190 [Roche]. www.pressportal.de.
226. Mendelsohn J. Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer
therapy. Clin Cancer Res 1997; 3(12 pt 2):2703–2707.
227. Thomas SM, Grandis JR. Pharmacokinetic and pharmacodynamic properties of EGFR inhibitors
under clinical investigation. Cancer Treat Rev 2004; 30(3):255-268.
228. Masui H, Kawamoto T, Sato JD, Wolf B, Sato G, Mendelsohn J. Growth inhibition of human tumor
cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res
1984; 44:1002–1007.
229. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008; 358:1160-1174.
230. Fan Z, Lu Y, Wu X, Mendelsohn J. Antibody-induced epidermal growth factor receptor dimerization
mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells. J Biol Chem
1994;269:27595–27602.
231. Wu X, Rubin M, Fan Z, DeBlasio T, Soos T, Koff A, Mendelsohn J. Involvement of p27 KIP1 in G1
arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody. Oncogene
1996;12:1397–1403.
232. Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J. Growth stimulation of A431 cells
by EGF: identification of high affinity receptors for epidermal growth factor by an anti-receptor
monoclonal antibody. Proc Natl Acad Sci U S A 1983; 80(5):1337–1341.
233. Gill GN, Kawamoto T, Cochet C, Le A, Sato JD, Masui H, MacLeod C, Mendelsohn J. Monoclonal
anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor
Medicinal Research Reviews 2012, 32(1), 166–215
binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol
Chem 1984; 259:7755–7760.
234. Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric
antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Can Res
1995; 1:1311–1318.
235. Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS. Neutralizing antibodies
against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular
endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for
signal transduction therapy of solid tumors. Am J Pathol 1997;151(6):1523–1530
236. Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve BY, Hicklin DJ, Radinsky R, Dinney CP. 1999
Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell
carcinoma growing orthotopically in nude mice. Clin Cancer Res 1999; 5(2):257–265.
237. Normanno N, Bianco C, De Luca A, Maiello MR, Salomon DS. Target-based agents against ErbB
receptors and their ligands: a novel approach to cancer treatment. Endo Rel Can 2003; 10: 1-21.
238. Modi S, D'Andrea G, Norton L, Yao TJ, Caravelli J, Rosen PP, Hudis C, Seidman AD. A phase I
study of cetuximab/paclitaxel in patients with advanced-stage breast cancer. Clin Breast Cancer
2006; 7(3):270-277.
239. O’Shaughnessy J, Weckstein DJ, Vukelja SJ, Melyntyre K, Krebow L, Holmes FA Preliminary
results of rarandomized phase II study of weekly irinotecan/carboplatin with or without cetuximab in
patients with metastatic breast cancer. Breast Cancer Res Treat 2007;106(suppl 1):[abstract S32].
240. Carey L, Rugo HS, Marcom P, Irvin W, Ferraro M, Burrows E, He X, Perou CM, Winer EP. TBCRC
001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple negative (basal-like)
breast cancer. J Clin Oncol 2008; 26 suppl 15:[abstract 1009].
241. Hobday T, Stella P, Fitch T, Jaslowski A, LaPlant B, Ames MM, Goetz MP, Perez EA. N0436: A
phase II trial of irinotecan plus cetuximab in patients with metastatic breast cancer and prior
anthracycline and/or taxane-containing therapy. J Clin Oncol 2008; 26 suppl 15:[abstract 1081].
242. Spector N, Xia W, El-Hariry I, Yarden Y, Bacus S. Small molecule tyrosine kinase inhibitors.
Breast Cancer Res 2007; 9(2):204-210.
243. Allen LF, Lenehan PF, Eiseman IA, Elliott WL, Fry DW. Potential benefits of the irreversible panerbB inhibitor, CI-1033, in the treatment of breast cancer. Semin Oncol 2002; 11:11-21.
244. Xia W, Liu L-H, Ho P, Spector NL. Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin
through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase
inhibitor GW572016. Oncogene 2004, 23:646-653.
245. Walter HJ Ward, PNC, Slater AM, Huw Davies D, Holdgate GA, Leslie R. Epidermal growth factor
receptor tyrosine kinase investigation of catalytic mechanism, structure based searching and
discovery of a potent inhibitor Biochem Pharmacol 1994; 48:659–666.
246. Wakeling AE, Guy SP, Woodburn JR, Ashton SE, Curry BJ, Barker AJ, Gibson KH. ZD1839
(Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer
therapy. Cancer Res 2002; 62(20):5749–54.
247. Sirotnak FM, Zakowski MF, Miller VA, Scher HI, Kris MG. Efficacy of cytotoxic agents against
human tumour xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor
of EGFR tyrosine kinase. Clin Cancer Res 2000; 6:4885–92.
248. Moasser MM, Basso A, Averbuch SD, Rosen N. The tyrosine kinase inhibitor ZD1839 (Iressa)
inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressingtumour cells.
Cancer Res 2001; 61:7184–8.
249. Moulder SL, Yakes Fm, Muthuswamy SK, Bianco R, Sampson JF, Arteaga CL. Epidermal growth
factor receptor (HER-1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/Neu (ErbB2)
overexpressing breast cancer cells invitro and invivo. Cancer Res 2001;61:8887-8895.
Medicinal Research Reviews 2012, 32(1), 166–215
250. Basso A, Averbach SD, Rosen N, Moasser MM. Inhibition of PI3 kinase/ Akt pathway mediates
antitumour effects of ZD1839 (Iressa) in HER2-overexpressing tumours. Proc Am Soc Clin Oncol,
Abstract #1662; 2002.
251. Ciardiello F, Caputo R, Bianco R, Damiano V, Pomatico G, De Placido S, Bianco AR, Tortora G.
Antitumour effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839
(Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res
2000; 6:2053–63.
252. Huang SM, Li J, Harari PM. Modulation of radiation response and tumour-induced angiogenesis
following EGFR blockade by ZD1839 (Iressa) in human squamous cell carcinoma. Proc Am Soc
Clin Oncol 2001;[abstr #259]
253. Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S, De Placido S, Bianco AR,
Tortora G. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839
(Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 2001;
7:1459–65.
254. Miller VA, DJ, Heelan RT, Pizzo BA, Perez WJ, Bass A, Kris MG, Ochs J, Averbuch S, Pilot A.
Trial demonstrates the safety of ZD1839 (‘Iressa’, an oral epidermal growth factor receptor tyrosine
kinase inhibitor (EGFR-TKI), in combination with carboplatin (C) and paclitaxel (P) in previously
untreated advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001;abstr
[1301].
255. Baselga J, Albanell J, Ruiz A, Lluch A, Gascon P, Guillem V, Gonzalez S, Sauleda S, Marimon I,
Tabernero JM, Koehler MT, Rojo F. Phase II and tumor pharmacodynamic study of Gefitinib in
patients with advanced breast cancer. J Clin Oncol 2005; 23(23):5323-5333.
256. Von Minckwitz G, Jonat W, Fasching P, du Bois A, Kleeberg U, Luck HJ, Kettner E, Hilfrich J,
Eiermann W, Torode J, Schneeweiss A. A multicentre phase II study on Gefitinib in taxane- and
anthracycline-pretreated metastatic breast cancer. Breast Cancer Res Treat 2005; 89(2):165-172
257. Ciardiello F, Troiani T, Caputo F, De Laurentiis M, Tortora G, Palmieri G, De Vita F, Diadema MR,
Orditura M, Colantuoni G, Gridelli C, Catalano G, De Placido S, Bianco AR. Phase II study of
Gefitinib in combination with docetaxel as first-line therapy in metastatic breast cancer. Br J Cancer
2006; 94(11):1604-1609.
258. Dennison SK, Jacobs SA, Wilson JW, Seeger J, Cescon TP, Raymond JM, Geyer CE, Wolmark N,
Swain SM. A phase II clinical trial of ZD1839 (Iressa) in combination with docetaxel as first-line
treatment in patients with advanced breast cancer. Invest New Drugs 2007; 25(6):545-551.
259. Buzdar A. Anastrozole as adjuvant therapy for early-stage breast cancer: implications of the ATAC
trial. Clin Breast Cancer 2003;4 Suppl 1:S42-48.
260. Buzdar AU. 'Arimidex' (anastrozole) versus tamoxifen as adjuvant therapy in postmenopausal
women with early breast cancer--efficacy overview. J Steroid Biochem Mol Biol 2003;86(3-5):399403.
261. Polychronis A, Sinnett HD, Hadjiminas D, Singhal H, Mansi JL, Shivapatham D, Shousha S, Jiang J,
Peston D, Barrett N, Vigushin D, Morrison K, Beresford E, Ali S, Slade MJ, Coombes RC.
Preoperative Gefitinib versus Gefitinib and anastrozole in postmenopausal patients with oestrogenreceptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: a doubleblind placebo-controlled phase II randomised trial. Lancet Oncol 2005; 6(6):383-391.
262. Cristofanilli M, Valero V, Mangalik A, Rabinowitz I, Arena FP, Kroener JF, Curcio E, Watkins C,
Magill P. A phase II multicenter, double blind, randomized trial to compare anastrozole plus
Gefitinib with anastrazole plus placebo in postmenopausal women with hormone receptor positive
metastatic breast cancer. J Clin Oncol 2008;26 suppl 15:[abstract 1012].
263. Raymond E, Faivre S, Armand JP. Epidermal growth factor receptor tyrosine kinase as a target for
anticancer therapy. Drugs 2000; 60 Suppl 1:15-23; discussion 41-12.
264. Bulgaru AM, Mani S, Goel S, Perez-Soler R. Erlotinib (Tarceva): a promising drug targeting
epidermal growth factor receptor tyrosine kinase. Expert Rev Anticancer Ther 2003; 3(3):269-279.
Medicinal Research Reviews 2012, 32(1), 166–215
265. Britten CD. Targeting ErbB receptor signaling: a pan-ErbB approach to cancer. Mol Cancer Ther
2004; 3 10):1335-1342
266. Dickler MN, Rugo HS, Eberle CA, Brogi E, Caravelli JF, Panageas KS, Boyd J, Yeh B, Lake DE,
Dang CT, Gilewski TA, Bromberg JF, Seidman AD, D'Andrea GM, Moasser MM, Melisko M, Park
JW, Dancey J, Norton L, Hudis CA. A phase II trial of Erlotinib in combination with bevacizumab in
patients with metastatic breast cancer. Clin Cancer Res 2008; 14 (23):7878-7883.
267. Kaur H, Silverman P, Singh D, Cooper BW, Fu P, Krishnamurthi S, Remick S, Overmoyer
B.Toxicity and outcome data in a phase II study of weekly docetaxel in combination with Erlotinib in
recurrent and/or metastatic breast cancer (MBC). J Clin Oncol 2006; 24 suppl 18:10623.
268. Gaul MD, Guo Y, Affleck K, Cockerill GS, Gilmer TM, Griffin RJ, Guntrip S, Keith BR, Knight
WB, Mullin RJ, Murray DM, Rusnak DW, Smith K, Tadepalli S, Wood ER, Lackey K. Discovery
and biological evaluation of potent dual ErbB-2/EGFR tyrosine kinase inhibitors: 6thiazolylquinazolines. Bioorg Med Chem Lett 2003; 13 (4):637-640.
269. Rusnak DW, Affleck K, Cockerill SG, Stubberfield C, Harris R, Page M, Smith KJ, Guntrip
SB,Carter MC, Shaw RJ. The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase
inhibitors: potential therapy for cancer. Cancer Res 2001; 61:7196-7203.
270. Rusnak DW, Lackey K, Affleck K, Wood ER, Alligood KJ, Rhodes N, Keith BR, Murray DM,
Glennon K, Knight WB, Mullin RJ, Gilmer TM. The Effects of the Novel, Reversible Epidermal
Growth Factor Receptor/ErbB-2 Tyrosine Kinase Inhibitor, GW2016, on the Growth of Human
Normal and Tumor-derived Cell Lines in Vitro and in Vivo. Mol Cancer Ther 2001;1(2):85-94.
271. Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, Di Cosimo S, Matias-Guiu X, Ramony
Cajal S, Arribas J. Expression of p95HER2, a truncated form of the HER2 receptor,and response to
anti-HER2 therapies in breast cancer. J Natl Cancer Inst 2007; 99 :628-638.
272. Burstein HJ, Storniolo AM, Franco S, Forster J, Stein S, Rubin S, Salazar VM, Blackwell KL. A
phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2negative advanced or metastatic breast cancer. Ann Oncol 2008; 19(6):1068-1074.
273. Burris HA, 3rd, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O'Neil B, Marcom PK, Ellis MJ,
Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL. Phase I
safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual
inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with
metastatic carcinomas. J Clin Oncol 2005; 23(23):5305-5313.
274. Dees EC, Burris H, Hurwitz H, Dowlaty A, Smith D, Koch K, Stead A, Mangum S, Harris J, Spector
N. Clinical Summary of 67 heavily pretreated patients with metastatic breast carcinomas treated with
GW572016 in a phase Ib study. Proc Am Soc Clin Oncol 2004;23:241.
275. Blackwell K, Pegram MD, Tan-Chiu E, Schwartzberg LS, Arbushites MC, Maltzman JD, Forster JK,
Rubin SD, Stein SH, Burstein HJ. Single- agent lapatinib for HER 2 overexpressing advanced or
metstatic breast cancer that progressed on first- or second- line trastuzumab- containing regimens.
Ann Oncol 2009; 20(6): 1026-1031.
276. Gomez H, Doval DC, Chavez MA, Ang PC, Aziz Z, Nag S, Ng C, Franco SX, Chow LW, Arbushites
MC, Casey MA, Berger MS, Stein SH, Sledge GW,. Efficacy and safety of lapatinib as first line
therapy for ErbB2-amplified locally advanced or metastatic breast cancer. J Clin Oncol 2008; 26(18):
2999-3005.
277. Spielmann M, Roche H, Delozier T, Canon JL, Romieu G, Burgeois H, Extra JM, Serin D, Kerbrat
P, Mechiels JP, Lortholary A, Orfeuvre H, Campone M, Hardy-Bessarcl AC, Coudert B, Maerevoet
M, Piot G, Karaman A, Martyn AL, Penault-Llorea F. Trastuzumab for patients with axillary-nodepositive breast cancer: results of FNCLCC- PACS 04 trial. J Clin Oncol 2009;27(36):6129-6134.
278. Gomez HL, Doval DC, Chavez MA. Efficacy and safety of lapatinib as first-line therapy for ErbB2amplified locally advanced or metastatic breast cancer. J Clin Oncol 2008; 26:2940–42.
279. Lin NU, Carey LA, Liu MC, Younger J, Come SE, Ewend M, Harris GJ, Bullitt E, Abbeele ADV,
Henson JW, Li X, Gelman R, Burstein HJ, Kasparian E, Kirsch DG, Crawford A, Hochberg F, Winer
Medicinal Research Reviews 2012, 32(1), 166–215
EP. Phase II Trial of Lapatinib for Brain Metastases in Patients With Human Epidermal Growth
Factor Receptor 2–Positive. Breast Can Jr Clin Oncol 2008; 28(12):1993-1999
280. Johnston S, Trudeau M, Kaufman B, Boussen H, Blackwell K, Lo Russo P, Lombardi DP, Ben
Ahmed S, Citri DL, De Silvio ML, Harris J, Westlund RE, Salazar V, Zaks TZ, Spector NL. Phase II
study of predictive biomarker profiles for response targeting human epidermal growth factor receptor
2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol 2008;
26(7): 1066-1072.
281. Kaufman B, Trudeau M, Awada A, Blackwell K, Bachelot T, Salazar V, DeSilvio M, Westlund R,
Zaks T, Spector N, Johnston S. Lapatinib monotherapy in patients with HER2-overexpressing
relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+
cohort in EGF103009, a phase II study. Lancet Oncol 2009; 10(6):581-588.
282. Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, Hopper TM, Miller
CG, Harrington LE, Onori JA, Mullin RJ, Gilmer TM, Truesdale AT, Epperly AH, Boloor A,
Stafford JA, Luttrell DK, Cheung M. Pharmacokinetic-pharmacodynamic correlation from mouse to
human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and
antiangiogenic activity. Mol Cancer Ther 2007;6(7):2012-2021.
283. Slamon D, Gomez HL, Kabbinavar FF, Amit O, Richie M, Pandite L, Goodman V. Randomised
study of pazopanib + lapatinib vs. lapatinib alone in patients with HER2-positive advanced or
metastatic breast cancer . J Clin Oncol 2008; 26 Suppl 15:[abstact 1016].
284. Rugo HS, Franco S, Munster P, Stopeck A, Ma W, Lyandres J, Lahiri S, Arbushites M, Koehler M,
Dickler MN. A phase II evaluation of lapatinib (L) and bevacizumab (B) in HER2+ metastatic breast
cancer (MBC). J Clin Oncol 2008; 26 Suppl 15:[abstract 1042].
285. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE.
Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;
357:2666-2676.
286. Miles D, Chan A, Romieu G, Dirix LY, Cortes J, Pivot X, Tomczak P, Taran T, Harbeck N, Steger
GG. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel
or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast
cancer (MBC): AVADO. J Clin Oncol 2008;26: abstr LBA1011.
287. Blackwell KL, Burstein HJ, Storlinio Am, Rugo H, Sledge G, Kochler M, Ellis C, Casey m, Vukelja
S, Bischoff J, Baselga J, O’Shaughnessy J. Randomised Study of Lapatinib alone or in Combination
with Trastuzumab in Women with ErbB2 positive, Trastuzumab-Refractory Metastatic Breast
Cancer. J Clin Oncol 2010 [In Press].
288. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown
J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S,
Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med
2006; 355(26):2733-2743.
289. Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld
A, Kaufman B, Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI,
Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE. A phase
III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with
advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses.
Breast Cancer Res Treat 2008;112(3):533-543.
290. Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC, Guerrera SF, Koehler M, Oliva
C, Stein SH, Williams LS, Dering J, Finn RS, Press MF. Phase III, double-blind, randomized study
comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic
breast cancer. J Clin Oncol 2008;26(34):5544-5552.
291. Xia W, Bacus S, Hegde P. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase
inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A
2006; 103:7795–800.
Medicinal Research Reviews 2012, 32(1), 166–215
292. Chu I, Blackwell K, Chen S, Slingerland J. The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016),
cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression
in antiestrogen-resistant breast cancer. Cancer Res 2005; 65:18–25.
293. Chowdhury S, Pickering LM, Ellis PA. Lapatinib: a novel dual tyrosine kinase inihibitor. Targ
Oncol 2007; 2:107–12.
294. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X,
Chamness GC. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer
Inst 2008; 100:672-679.
295. Gray JW, Das D, Wang N, Kuo W, Press MF, Di Leo A, Ellis C, Arbushites M, Williams L, Koehler
M. Identification of a 6 gene molecular predictor of lapatinib related benefit: from breast cancer cell
lines to a phase III trial. J Clin Oncol 2008; 26: 1043.
296. Allen LF, Lenehan PF, Eiseman IA, Elliott WL, Fry DW. Potential benefits of the irreversible panerbB inhibitor, CI-1033, in the treatment of breast cancer. Semin Oncol 2002;29(3) Suppl 11:11-21.
297. Slichenmyer WJ, Elliott WL, Fry DW. CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin Oncol
2001;28(5) Suppl 16:80-85.
298. Nemunaitis J, Eiseman I, Cunningham C, Senzer N, Williams A, Lenehan PF, Olson SC, Bycott P,
Schlicht M, Zentgraff R, Shin DM, Zinner RG. Phase 1 clinical and pharmacokinetics evaluation of
oral CI-1033 in patients with refractory cancer. Clin Cancer Res 2005; 11(10):3846-3853
299. Zinner RG, Nemunaitis J, Eiseman I, Shin HJ, Olson SC, Christensen J, Huang X, Lenehan PF,
Donato NJ, Shin DM. Phase I clinical and pharmacodynamic evaluation of oral CI-1033 in patients
with refractory cancer. Clin Cancer Res 2007; 13(10):3006-3014.
300. Dewji MR. Early phase I data on an irreversible pan-erb inhibitor: CI-1033. What did we learn? J
Chemother 2004; 16 Suppl 4:44-48.
301. Calvo E, Tolcher AW, Hammond LA, Patnaik A, de Bono JS, Eiseman IA, Olson SC, Lenehan PF,
McCreery H, Lorusso P, Rowinsky EK. Administration of CI-1033, an irreversible pan-erbB tyrosine
kinase inhibitor, is feasible on a 7-day on, 7-day off schedule: a phase I pharmacokinetic and food
effect study. Clin Cancer Res 2004; 10(21):7112-7120
302. Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD,
Nilakantan R, Overbeek E, Reich MF, Shen R, Shi X, Tsou HR, Wang YF, Wissner A. Antitumor
activity of HKI-272, an orally active, irreversible inhibitor of the tyrosine kinase. Cancer Res 2004;
64(11):3958-3965.
303. Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL,
Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher
KJ, Settleman J, Haber DA. Irreversible inhibitors of the EGF receptor may circumvent acquired
resistance to Gefitinib. Proc Natl Acad Sci U S A 2005; 102(21):7665-7670.
304. Wissner A, Mansour TS. The development of HKI-272 and related compounds for the treatment of
cancer. Arch Pharm (Weinheim) 2008; 341(8):465-477.
305. Wong KK, Fracasso PM, Bukowski RM, Lynch TJ, Munster PN, Shapiro GI, Janne PA, Eder JP,
Naughton MJ, Ellis MJ, Jones SF, Mekhail T, Zacharchuk C, Vermette J, Abbas R, Quinn S, Powell
C, Burris HA. A Phase I Study with Neratinib (HKI-272), an Irreversible Pan ErbB Receptor
Tyrosine Kinase Inhibitor, in Patients with Solid Tumors. Clin Cancer Res 2009; 15(7):2552-2558.
306. Burstein HJ, sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, Awada A, Ranade A, Jiao S, Schwartz
G, Abbas R, Powell C, Turnbull K, Vermetti J, Zacharchuk C, Badwe R. Neratinib, an ireeversible
ErbB receptor tyrosine kinase inhibitopr in patients with advanced ErbB2 positive breast cancer. J
Clin Oncol 2010 [In Press].
307. Fan M, Yan PS, Hartman-Frey C, Chen L, Paik H, Oyer SL, Salisbury JD, Cheng ASL, Li L, Abbosh
PH. Diverse gene expression and DNA methylation profiles correlate with differential adaptation of
breast cancer cells to the antiestrogens tamoxifen and fulvestrant. Canc Res 2006; 66:11954–11966.
308. Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S,
Wakeling AE, Nicholson RI. Insulin-like growth factor-I receptor signalling and acquired resistance
Medicinal Research Reviews 2012, 32(1), 166–215
to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 2004;
11(4):793–814.
309. Silverman AP, Levin AM, Lahti JL and Cochran JR. Engineered Cystine-Knot Peptides that Bind
αvβ3 Integrin with Antibody-Like Affinities. J Mol Biol 2009; 385:1064–1075.
310. Zhang M, Rosen JM. Stem cells in the etiology and treatment of cancer. Curr Opin Genet Dev
2006;16(1):60-64.
Ms. Ruchi Saxena has done Masters in Biochemistry from the Department of Biochemistry,
University of Lucknow, India and is presently pursuing Ph.D. under the supervision of Dr. Anila
Dwivedi at the Division of Endocrinology at Central Drug Research Institute. She has qualified
national level Entrance and Fellowship exams of Council of Scientific and Industrial Research
and Indian Council of Medical Research. She is working as a Junior Research Fellow in a
project on identification and development of novel therapeutic agent(s) for breast cancer.
Dr Anila Dwivedi is a senior research scientist in the Division of Endocrinology at Central
Drug Research Institute, Lucknow. She did her Masters in Biochemistry from Lucknow
University and obtained Ph.D. in the area of Reproductive Biochemistry and Endocrinology from
CDRI in 1986. Currently, she is pursuing research projects on Endocrine Related Cancers and
Reproductive Biology. Her research projects are supported by Ministry of Health and Family
Welfare, Govt of India and Indian Council of Medical Research, New Delhi, India. She has more
than 50 peer- reviewed publications and three national / international patents.