The Future of Targeted Therapies in Ovarian Cancer

Susana Banerjee and Martin Gore

The Oncologist 2009, 14:706-716.
doi: 10.1634/theoncologist.2009-0013 originally published online July 10, 2009

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The online version of this article, along with updated information and services, is
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The

Oncologist

Gynecologic Oncology
The Future of Targeted Therapies in Ovarian Cancer
SUSANA BANERJEE, MARTIN GORE

Key Words. Ovarian cancer Targeted therapy VEGF inhibitors PARP inhibitors
Disclosures: Susana Banerjee: None; Martin Gore: Consultant/advisory role: Roche, Pfizer, Bayer; Honoraria: Roche, Pfizer,
Bayer.
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from
commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer
reviewers.

ABSTRACT
Ovarian cancer is the second most common gynecological malignancy and the leading cause of death from gynecological cancer. Most women present with advanced
disease with little prospect for cure. There have been
some advances in surgical and chemotherapeutic strategies, but these approaches have led to only minor improvements in outcome. There remains a significant
risk for recurrence and resistance to therapy, and hence
there is a need to improve upon the current treatment

options. Molecularly directed therapy aims to target tumor cells and the tumor microenvironment by blocking
specific molecular changes in the cancer. The most
promising agents so far are the antiangiogenic agents
and polyadenosine diphosphate-ribose polymerase inhibitors. This article reviews the various targeted therapeutic approaches under clinical investigation in
ovarian cancer and the challenges facing their future
success in the clinic. The Oncologist 2009;14:706 716

INTRODUCTION

prove upon the current treatment options. Potential strategies for improving outcome in ovarian cancer include the
inhibition of signal transduction pathways and targeting
DNA repair. Novel biologically targeted agents appear successful in a variety of malignancies, such as breast, colon,
lung, and renal cancers. These agents target tumor cells and
the tumor microenvironment by blocking specific molecular changes in the cancer. The promise of targeted therapy is
to selectively exploit molecules that are aberrant in cancers,
thereby sparing normal cells and potentially providing antitumor effects without the toxicity associated with traditional modalities, such as chemotherapy. This article
reviews the various targeted therapeutic approaches under

Ovarian cancer is the second most common gynecological

malignancy and the leading cause of death from a gynecological cancer. There are 204,000 new cases of ovarian
cancer per year worldwide, including about 43,000 cases in
Europe and 22,000 in the U.S. [1]. Most women present
with advanced disease with little prospect for cure [1]. The
current standard of care consists of the combination of radical surgery and platinum-based chemotherapy. There have
been some advances in surgical and chemotherapeutic strategies, but these approaches have led to small improvements
in outcome. There remains a significant risk for recurrence
and resistance to therapy and therefore there is a need to im-

Correspondence: Martin Gore, Ph.D., F.R.C.P., The Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, United Kingdom. Telephone: 44-207-808-2198; Fax: 44-207-808-2475; e-mail: martin.gore@rmh.nhs.uk Received January 22, 2009; accepted for publication June 12, 2009; first published online in The Oncologist Express on July 10, 2009. AlphaMed Press 1083-7159/2009/$30.00/0 doi:
10.1634/theoncologist.2009-0013

The Oncologist 2009;14:706 716 www.TheOncologist.com

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The Royal Marsden Hospital, London, United Kingdom

Banerjee, Gore

clinical investigation in ovarian cancer and the challenges

facing their future success in patients. (See Figure 1.)

TARGETING ANGIOGENESIS AND VASCULAR

ENDOTHELIAL GROWTH FACTOR

THERAPEUTIC APPROACHES BASED ON VEGF

PATHWAY INHIBITION
VEGF-induced angiogenesis may be inhibited by targeting
either the VEGF ligand itself or VEGFRs. Bevacizumab
(Avastin; Genentech, Inc., San Francisco, CA) is an i.v.
administered humanized monoclonal antibody directed
against VEGF-A, and this drug acts by binding and neutralizing all VEGF-A isoforms. In contrast, small-molecule tyrosine kinase inhibitors (TKIs) do not bind to VEGF
directly; they inhibit the activity of VEGFRs and therefore
block downstream signaling pathways activated by
VEGF-A and other members of the VEGF family. Many
TKIs have the advantage of oral bioavailability, but the se-

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rum half-lives of these agents are considerably shorter than

that of bevacizumab, although this can be compensated for
by daily administration of TKIs. Small-molecule inhibitors
commonly have additional activity against other tyrosine
kinases, and such multitargeting activity may contribute
to their antitumor effects. For example, sorafenib (Nexavar; Bayer Pharmaceuticals, West Haven, CT) inhibits
Raf-1, VEGFR-2, VEGFR-3, and platelet-derived growth
factor receptor (PDGFR)-, potentially targeting proliferation via the Ras extracellular signalrelated kinase pathway in addition to angiogenesis. Other VEGFR TKIs
include vandetanib (Zactima; AstraZeneca Pharmaceuticals, Wilmington, DE), sunitinib (Sutent; Pfizer, Inc.,
New York), BIBF 1120 (Boehringer Ingelheim, Ingelheim,
Germany), and pazopanib (GlaxoSmithKline, Philadelphia). Additional approaches to VEGF inhibition include
the use of soluble receptors such as VEGF Trap (AVE0005,
Aflibercept, Sanofi-Aventis, Paris, France). VEGF Trap is
a recombinant fusion protein of the extracellular ligandbinding domains of VEGFR-1 and VEGFR-2 fused to the
constant region of the immunoglobulin IgG and acts as a
soluble decoy receptor, modulating the availability of ligand to receptors. VEGF Trap, as with bevacizumab, binds
to VEGF-A but also binds to VEGF-B and placental growth
factor. VEGF Trap has a greater affinity for the VEGF ligand than VEGFRs and anti-VEGF monoclonal antibodies
such as bevacizumab. The precise mechanisms by which
angiogenesis inhibition might improve clinical outcome are
not fully understood [8]. Antiangiogenic agents may work
by suppressing tumor vasculature formation, thus depriving
the tumor from nutrients and limiting tumor growth [2]. Another possibility is that antiangiogenic agents transiently
normalize the tumor vasculature, allowing more efficient
oxygen and chemotherapy delivery [9].
Targeting the VEGF pathway has proven to be a successful strategy in a variety of cancers. Randomized phase
III clinical trials of bevacizumab in combination with chemotherapy in patients with colorectal, lung, and breast cancer have all demonstrated a benefit for VEGF inhibition in
terms of either the progression-free survival (PFS) or overall survival duration [10 13]. In renal cancer, VEGF pathway inhibition, either with bevacizumab in combination
with interferon [14] or single-agent VEGFR inhibitors
(sunitinib or sorafenib) [15, 16], has shown dramatic benefits in terms of the PFS time. This has led to U.S. Food and
Drug Administration approval of these anti-VEGF regimens in colon, lung, breast, and renal cancer. Several studies reported an association between high VEGF levels and
prognostic markers such as disease stage, grade, diseasefree survival time, and cancer-related death [1720]. In addition, VEGF blockade inhibited ascites formation in a

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Angiogenesis, the formation of new blood vessels from the

pre-existing vasculature, is a critical component of cancer
growth and metastasis [2]. Tumor angiogenesis is controlled by a number of cytokines and genetic factors.
Among these, vascular endothelial growth factor (VEGF)
and its receptors are thought to play a pivotal role. The
VEGF protein family consists of at least seven structurally
related glycoproteins, of which VEGF-A (commonly referred to as VEGF) is the most well characterized. VEGF
functions are mediated by binding to VEGF tyrosine kinase
receptorsVEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and
VEGFR-3 (Flt-4)leading to receptor dimerization, phosphorylation, and subsequent activation of signaling cascades, including the mitogen-activated protein kinase and
phosphatidylinositol 3 kinase/Akt pathways. The significance of VEGFR-1 in angiogenesis is complex. Under
some circumstances, VEGFR-1 is believed to sequester
VEGF and prevent its interaction with VEGFR-2. The decoy role can also be performed by an alternatively spliced
soluble VEGFR-1 form [3]. VEGFR-2 is thought to mediate the majority of the proangiogenic effects of VEGF [4].
These effects include promotion of endothelial cell proliferation, migration, and invasion, and survival of immature
blood vessels. VEGF also increases vascular permeability
and vasodilation, resulting in interstitial hypertension and a
leaky neovasculature; the delivery of oxygen and therapeutic agents from the bloodstream to tumor cells is subsequently impaired. Furthermore, VEGFR-2 expression has
been reported in ovarian cancer [5, 6]; VEGF could potentially act in an autocrine fashion, influencing the tumor directly by protecting the cells from apoptosis [7], as well as
via angiogenesis.

707

708

preclinical ovarian cancer model [21]. The above data support a role for VEGF in ovarian malignancy, and the success of anti-VEGF treatment in other solid cancers has
generated interest in testing the anti-VEGF approach in
ovarian cancer.

CLINICAL STUDIES OF VEGF

PATHWAY INHIBITION
Bevacizumab

morphism had a statistically significant lower response rate

than those homozygous T/T (19% versus 50%; p .006)
[28]. IL-8 is believed to mediate angiogenesis independently of VEGF and may contribute to resistance to bevacizumab-based chemotherapy [28]. IL-8 may be a potential
molecular predictor of response to bevacizumab. The combination of bevacizumab with chemotherapy appears to be
even more active than bevacizumab alone and is consistent
with studies in colon and breast cancers [11, 29, 30]. However, phase III randomized trials are necessary to validate
this observation. A phase II trial evaluated bevacizumab
with the epidermal growth factor receptor (EGFR) inhibitor
erlotinib (Tarceva; OSI Pharmaceuticals, Inc., Melville,
NY) in recurrent ovarian cancer. There was no early indication that this combination was superior to bevacizumab
alone, and two patients had fatal gastrointestinal (GI) perforations, resulting in the closure of the study [31]. As discussed above, normalization of the vasculature resulting in
increased cytotoxic agent delivery is widely believed to be
the principal mechanism of the antitumor effect of antiangiogenic agents [9]. However, the significant single-agent
activity does not provide support for this hypothesis and
suggests the possibility of additional mechanisms. The
presence of VEGFRs on ovarian cancer cells raises the possibility that as well as inhibiting angiogenesis, bevacizumab may directly inhibit cancer cells via an autocrine
loop [5]. The clinical efficacy of single-agent bevacizumab
in ovarian cancer demonstrated by phase II trials is considerably greater than that observed in colorectal (3%) [30]
and breast (6.7%) cancers [29] and suggests that this agent
could potentially have a significant impact in ovarian cancer. Prospective trials of bevacizumab as a single agent and
as combination therapy are summarized in Table 1.
Toxicities
The major toxicities seen in the phase II trials of bevacizumab in ovarian cancer are similar to those observed in
other solid tumors and include hypertension, thrombosis,
proteinuria, hemorrhage, and GI perforation. Six patients
(9.7%) developed grade 3 hypertension, two patients had
venous thromboses (1.6%), one patient had grade 4 proteinuria (1.6%) that was reversible upon discontinuation of bevacizumab, and no patient had grade 1 hemorrhage or GI
perforations in the GOG 170D trial [23]. In contrast, the
AVF 2949 study was stopped after accruing 44 patients because of a higher than expected incidence of bowel perforation (11%); five patients developed GI perforation, one of
which was fatal [22]. Serious adverse events occurred in
41% of patients and were most commonly arterial thromboembolic events, GI perforation, or obstruction, and three
deaths (myocardial infarction, GI perforation, and hyper-

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The results of prospective, phase II clinical trials of bevacizumab (as a single agent and in combination with chemotherapy) were recently reported and suggest that anti-VEGF
therapy is a promising strategy in recurrent ovarian cancer
[2224]. The two studies that demonstrated the significant
efficacy of single-agent bevacizumab both involved
women with relapsed ovarian cancer and used a regimen of
15 mg/kg every 21 days. The Gynecology Oncology Group
(GOG) 170D study, reported by Burger and colleagues, recruited 62 patients with either platinum-sensitive disease
(6 month platinum-free interval) or platinum-resistant
disease (6 month platinum-free interval) who were limited to no more than two prior chemotherapy regimens [23].
The AVF 2949 trial, reported by Cannistra and colleagues,
recruited 44 patients and differed from the GOG 170D
study; entry was restricted to patients with platinum-, topotecan-, or liposomal doxorubicinresistant disease, and patients could have received up to three prior chemotherapy
regimens [22]. Burger et al. [23] reported an objective response rate of 21% and stable disease in a further 52% of
patients. Forty percent were free from progression at 6
months, and the median PFS and overall survival times
were 4.7 months and 16.9 months, respectively. Cannistra
et al. [22] demonstrated a response rate of 16%, median PFS
duration of 4.4 months, and median survival duration of
10.7 months at study termination.
Four prospective phase II trials suggested that bevacizumab in combination with chemotherapy (carboplatin
paclitaxel, cyclophosphamide, or topotecan) is efficacious
in advanced ovarian cancer [24 27]. A phase II trial reported on the combination of bevacizumab (10 mg/kg on
days 1, 8, and 15 and then every 2 weeks) and metronomic
chemotherapy with cyclophosphamide (50 mg/day). The
study population included patients with platinum-sensitive
and platinum-resistant disease who had received no more
than three prior chemotherapy regimens. Garcia et al. [24]
reported a response rate of 24%, stable disease rate of 63%,
and 56% 6-month PFS rate. The median time to progression
and median survival time were 7.2 months and 16.9
months, respectively [24]. Interestingly, patients genotyped
A/A or A/T for the Interleukin (IL)-8 T-251A gene poly-

Targeted Therapies in Ovarian Cancer

Banerjee, Gore

709

Table 1. Reported phase II trials of bevacizumab in ovarian cancer

n of patients
Prior
Study
treated
regimens
Treatment
Burger et al. (2007) [23]
Cannistra et al. (2007) [22]
Micha et al. (2007) [25]
Garcia et al. (2008) [24]
Nimeiri et al. (2008) [31]

62
44
20
70
13

2
23b
0
3a,b
2b
a,b

BV
BVc
BVc, carboplatin, paclitaxel
BVd, cyclophosphamide
BVc, erlotinib

OR

SD

PFS (mos)

21%
16%
80%
24%
15%

52%
25%
5%
63%
54%

4.7
4.4
NR
7.2 (TTP)
4.1

Platinum sensitive.
Platinum resistant.
c
15 mg/kg every 3 weeks.
d
10 mg/kg every 2 weeks.
Abbreviations: BV, bevacizumab; NR, not reported; OR, overall response; PFS, progression-free survival; SD, stable
disease; TTP, time to progression.
b

BevacizumabOngoing Trials
The GOG 218 trial is a phase III, three-arm, placebo-controlled, randomized clinical study involving 2,000 patients
with stage III/IV epithelial ovarian cancer who have undergone a suboptimal (1 cm residual disease) tumor debulking procedure. The trial compares i.v. paclitaxel and
carboplatin alone with the same treatment plus bevacizumab (15 mg/kg every 21 days) for six courses followed
by placebo or an additional 48 weeks (16 courses) of bevacizumab as maintenance therapy. The trial has been modified to include optimally debulked patients who have some
residual disease that is palpable or visible at the end of surgery. The second phase III trial (International Collaborative
Ovarian Neoplasm Trial 7, ICON-7), run by the Gynecologic Cancer Intergroup, is an open-label, randomized
study of patients with high-risk or advanced epithelial ovarian or primary peritoneal cancer. This is a nonplacebocontrolled, two-arm trial. Patients are randomized to
receive either i.v. carboplatin and paclitaxel alone or the
same treatment plus bevacizumab (7.5 mg/kg every 21

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days) for six cycles. Patients in the bevacizumab arm receive a further 12 cycles of bevacizumab after chemotherapy. The ICON-7 and GOG 218 trials are designed to
address the benefit of bevacizumab in combination with
chemotherapy as well as maintenance therapy. PFS is the
primary endpoint of both trials. The GOG 213 trial is a
phase III bifactorial randomized study of taxane and carboplatin with or without bevacizumab followed by bevacizumab and secondary surgical cytoreduction in patients
with platinum-sensitive recurrent disease. That trial is designed to determine (a) if surgical secondary cytoreduction
in addition to adjuvant chemotherapy with or without bevacizumab leads to a longer overall survival time in recurrent, platinum-sensitive disease and (b) if the addition of
bevacizumab to the second-line and maintenance phases of
treatment leads to a longer overall survival time than with
second-line paclitaxel and carboplatin alone. Bevacizumab is
also being assessed in combination with other cytotoxic
agents. The Ovarian Cancer Education Awareness Network
(OCEANS) trial is a placebo-controlled, randomized, multicenter phase III study evaluating the efficacy of bevacizumab
administered in combination with carboplatin and gemcitabine in women with platinum-sensitive recurrent epithelial
ovarian, primary peritoneal, or fallopian tube carcinoma.

VEGF Trap
Preclinical studies provided evidence suggesting that
VEGF Trap may reduce malignant ascites in addition to tumor burden [34, 35]. Preliminary results from a phase II
trial of VEGF Trap in patients with recurrent, platinumresistant ovarian cancer demonstrated a partial response in
8% of patients, a clinical benefit rate of 41% at 4 weeks, and
resolution of ascites in 29% of patients [36]. The most frequent grade 3 or 4 adverse events reported with VEGF Trap
therapy were hypertension (18%), proteinuria (7%), and

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tensive encephalopathy) were suspected to be related to bevacizumab treatment. The reasons for the differences in
toxicity profile are not entirely clear, but the fact that patients in the AVF 2949 study were more heavily pretreated
and all had platinum-resistant disease may be important.
The rate of GI perforation appears substantially higher in
ovarian cancer (5%) than in other tumors [32]; the incidence is 2.4% in colorectal cancer [33]. Data are limited to
retrospective studies and phase II trials in ovarian cancer
and better estimates of GI perforation risks with bevacizumab in ovarian cancer will be provided by the ongoing
phase III trials. Pre-existing small bowel obstruction and
platinum-resistant disease are potential predisposing factors to perforation in ovarian cancer.

710

headache (4%). The incidence of GI perforations was relatively low (1%). However, at present, it is unknown
whether the risk for bowel perforation is lower with VEGF
Trap than with bevacizumab. The efficacy of VEGF Trap in
recurrent ovarian cancer, in terms of clinical response and
survival, in combination with docetaxel is being evaluated
in a phase I/II trial. Furthermore, VEGF Trap as a treatment
for recurrent malignant ascites in patients with ovarian cancer is being investigated in the phase II/III setting.

VEGFR TKIs

therapy), concurrent cediranib, and concurrent and

maintenance cediranib (total duration of cediranib, up to 18
months). The PDGF and fibroblast growth factor (FGF)
pathways have been implicated in resistance to anti-VEGF/
VEGFR agents, and counteracting compensatory mechanisms by multitargeting other proangiogenic pathways may
improve the efficacy of anti-VEGF therapies [43]. BIBF
1120 targets VEGFR, PDGFR, and FGFR tyrosine kinases.
Recent preliminary results of a randomized, placebo-controlled, phase II study of continuous maintenance treatment
with BIBF 1120 following chemotherapy in patients with
relapsed ovarian cancer are encouraging, The 36-week PFS
rates were 15.6% for BIBF 1120 and 2.9% for placebo, and
suggest that maintenance BIBF 1120 could delay disease
progression [44]. In summary, several VEGFR TKIs (vandetanib, pazopanib, cediranib, sorafenib, sunitinib, and
BIBF 1120) are under evaluation either as monotherapy or
in combination therapy in recurrent ovarian cancer. The optimal schedule and clinical scenario for these agents are currently unknown. In addition to targeting VEGFRs using
TKIs, IMC-1121B, a monoclonal antibody directed against
VEGFR-2 has entered a phase II trial in recurrent ovarian
cancer.

Targeting DNA RepairPolyadenosine

Diphosphate-Ribose Polymerase Inhibitors
An increased understanding of DNA repair pathways has
led to the development of drugs designed specifically to
target this process. Targeting the base excision repair pathway with polyadenosine diphosphate-ribose polymerase
(PARP) inhibitors appears promising in ovarian cancer, in
particular in the BRCA-associated subtype. Heterozygous
carriers of germline BRCA1 or BRCA2 mutations have a
highly elevated risk for developing ovarian cancer (10%
40% lifetime risk). The BRCA1 and BRCA2 proteins are
critical for the maintenance of genome integrity and have
important roles in the repair of DNA double-strand breaks
by the pathway of homologous recombination [45]. As a result, tumor cells arising in carriers of BRCA1 or BRCA2
mutations are defective in DNA repair by homologous recombination. PARP is a nuclear enzyme that signals the
presence of DNA damage by catalyzing the addition of
ADP-ribose units to DNA, histones, and DNA repair enzymes, and it facilitates the repair of single-strand breaks
via the base excision pathway. PARP inhibitors work by
generating specific DNA lesions that require functional
BRCA1 and BRCA2 for DNA repair [46]. In vitro studies
demonstrated that cell lines lacking wild-type BRCA1 or
BRCA2 were extremely sensitive to potent PARP inhibitors
[47, 48], compared with heterozygous mutant or wild-type
cells. Patients with BRCA-associated cancers lack wild-

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Several VEGFR TKIs are under investigation in patients

with recurrent ovarian cancer. Preliminary results from two
phase II trials of sorafenib in recurrent ovarian cancer, one
as a single agent and the other in combination with gemcitabine, suggest that sorafenib has activity in ovarian cancer
[37, 38]. In addition to the toxicities previously seen with
anti-VEGF agents, grade 3 or 4 handfoot syndrome occurred. The combination of sorafenib and bevacizumab was
evaluated in a phase I study of patients with advanced solid
tumors. Partial responses were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 22
months). The regimen was not well tolerated, and the majority of patients required dose reductions [39]. However,
these results suggest that the vertical approach of VEGF
inhibitiontargeting both the ligand and receptoris
worth further exploration in ovarian cancer.
Preliminary results of a phase II trial suggest that pazopanib has activity in terms of cancer antigen (CA)-125 response in recurrent ovarian cancer. CA-125 responses were
seen in seven of 15 patients (47%), and stable disease was
observed in four patients (27%) [40].
Another VEGFR TKI, cediranib (AZD2171, AstraZeneca Pharmaceuticals, Wilmington, DE) has also shown encouraging results in ovarian cancer. A phase II trial of
single-agent cediranib in recurrent ovarian cancer (platinum-sensitive and platinum-resistant) reported a partial response in six of the 32 patients and stable disease in four
patients [41]. Another phase II study of cediranib in recurrent ovarian, peritoneal, or fallopian tube cancer reported a
clinical benefit rate of 41% in platinum-sensitive disease
and 29% in platinum-resistant disease. The median time to
progression (TTP) and median survival time for all patients
were 4.1 months and 11.9 months, respectively, and there
was no difference in TTP or survival between the platinumsensitive and platinum-resistant groups [42]. Cediranib is
currently being evaluated in the phase III ICON-6 trial.
ICON-6 is a randomized, placebo-controlled study in
which patients with platinum-sensitive recurrent ovarian
cancer are randomized to one of three treatment arms: standard treatment (six cycles of carboplatinpaclitaxel chemo-

Targeted Therapies in Ovarian Cancer

Banerjee, Gore

Targeting Human Epidermal Growth

Factor Receptors
The human epidermal growth factor receptor (HER) family
of proteins consists of four distinct tyrosine kinase receptors: HER-1 (commonly referred to as EGFR), HER-2,
HER-3, and HER-4. Members of the HER family are capable of dimerizing with each other forming hetero- and homodimers, and this impacts receptor function. For example,
HER-2 and HER-3 are functionally incomplete receptors
by themselves; HER-2 has an extracellular domain, but
lacks ligand-binding activity, whereas HER-3 has a nonfunctional kinase domain and hence has no catalytic kinase

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activity. However, heterodimerization between HER-2 and

HER-3 allows signal transduction. A number of downstream pathways regulating processes including differentiation, migration, proliferation, and survival are activated in
response to extracellular ligands (e.g., EGF, transforming
growth factor ). There are two main approaches used to
inhibit members of the HER family: monoclonal antibodies
and TKIs. The TKIs include gefitinib (Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE) and erlotinib, targeting EGFR, and lapatinib (Tykerb; GlaxoSmithKline,
Philadelphia), which targets both EGFR and HER-2.
Cetuximab (Erbitux; ImClone Systems, Inc., New York)
is a monoclonal antibody directed at the extracellular domain of EGFR, and trastuzumab (Herceptin; Genentech,
Inc., South San Francisco, CA) is a monoclonal antibody
against HER-2 that has shown strong activity in HER-2
breast cancer [54]. Pertuzumab (Omnitarg; Genentech,
Inc., South San Francisco, CA) disrupts the interaction of
HER-2 with HER-1 and HER-3, therefore blocking HER2 driven downstream signaling.
There is strong preclinical evidence suggesting that the
EGFR and HER-2 pathways are functional in epithelial
ovarian cancer [5558]. A wide range of EGFR and HER-2
overexpression rates have been reported in ovarian cancer
(EGFR, 55%98%; HER-2, 1.8%76% [59, 60]) that reflect differences in study sizes and detection techniques. A
study of 1,420 samples reported a 16% HER-2 positivity
rate, as assessed by immunohistochemistry [61]. Furthermore, both EGFR and HER-2 overexpression have been reported to be correlated with poor survival in ovarian cancer
[62 64]. These results, taken together with the clinical success of EGFR and HER-2 inhibitors in other malignancies,
provided the impetus for testing inhibitors of the HER family in ovarian cancer patients.
Results from phase II trials of erlotinib [65] and gefitinib (EGFR inhibitors) [66 68], trastuzumab (HER-2 inhibitor) [69], and pertuzumab (HER-2 dimerization
inhibitor) [70] have, overall, been relatively disappointing
and are summarized in Table 2. A phase II study (GOG
170C) of gefitinib monotherapy in relapsed ovarian cancer
(unselected on the basis of EGFR status) demonstrated minimal activity one of 27 (4%) patients with an objective response and four of 27 (15%) patients free from progression
at 6 months. Interestingly, the only patient with an objective
response was later shown to have a mutation in the catalytic
domain of EGFR [66]. The GOG 160 phase II trial evaluated trastuzumab in ovarian cancer and reported an overall
response rate of 7.3% in the 41 eligible patients with HER-2
overexpression. The clinical effectiveness of trastuzumab
in recurrent ovarian cancer is limited by the low frequency
of HER-2 overexpression (11% of patients) and low rate of

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type BRCA1 or BRCA2 in tumor cells, but normal cells retain a single wild-type copy of the relevant gene. This
difference between tumor and normal cells means that
PARP inhibitors can kill tumor cells specifically while
sparing normal cells. This approach uses the concept of
synthetic lethality, which describes the situation whereby
two pathway defects acting individually allow cell viability, but in combination become lethal [45]. Because of this,
it has been suggested that this approach could have a large
therapeutic index [45].
The profound sensitivity of BRCA mutant cells to PARP
inhibitors led to the design of clinical trials to test this strategy. Five PARP inhibitors are currently in cancer clinical
trials. Preliminary observations from patients with BRCA
mutations and ovarian cancer in a phase II, international,
multicenter, single-arm trial of the PARP inhibitor
AZD2281 (AstraZeneca Pharmaceuticals, Wilmington,
DE) are very encouraging and indicate low toxicities and
promising radiological and serological clinical responses
[49]. The objective response rate (ORR) and clinical benefit
rate (ORR and/or confirmed 50% decline in CA-125)
were 33% and 57.6%, respectively, in 33 evaluable patients
with hereditary ovarian cancer receiving AZD2281 (400
mg twice daily orally). Toxicities were generally mild.
Grade 3 toxicity was infrequent and included nausea (7%)
and leukopenia (5%). In addition to patients with tumors
with specific genetic defects, such as BRCA mutations,
PARP inhibitors may also be effective in tumors with
BRCAness [50]. This property of phenotypic similarity
of sporadic cancers to those with BRCA mutations has been
proposed to be present in a subset of ovarian cancers. For
example, up to 15% of sporadic ovarian cancers harbor
BRCA1 promoter methylation. BRCA1 protein expression
is undetectable in many of these tumors, which suggests silencing of the BRCA1 gene [51, 52]. Taken together up to
40% of high-grade ovarian cancers may have defects conferring sensitivity to PARP inhibition [45, 53], suggesting
wide applicability of this approach.

711

Targeted Therapies in Ovarian Cancer

712

Table 2. Published phase II trials of nonantiangiogenic-based targeted therapy in ovarian cancer

n of
Study
patients Target
Treatment
Result
Schilder et al. (2005) [66]
Wagner et al. (2007) [67]
Posadas et al. (2007) [68]
Gordon et al. (2005) [65]
Bookman et al. (2003) [69]
Gordon et al. (2006) [70]
Smyth et al. (2007) [75]

27
56
24
34
41
61
42

Gefitinib
Gefitinib tamoxifen
Gefitinib
Erlotinib
Trastuzumab
Pertuzumab
Letrozole

ER (via aromatase)
ER (via aromatase)
CA-125

Letrozole
Letrozole
Oregovomab versus
placebo

OR, 4%
OR, 0%; SD, 29%
OR, 0%; SD, 37%
RR, 6%; SD, 44%
RR, 7.3%
RR, 4.3%; SD, 6.8%; PFS, 6.6 wks
RR: CT, 9%; CA-125, 17%; SD:
CT, 42%
RR, 9%; SD, 26%
RR, 15%; SD, 18%
No difference

a
Phase III trial.
Abbreviations: CA, cancer antigen; CT, computed tomography; EGFR, epidermal growth factor receptor; ER, estrogen
receptor; HER-2, human epidermal growth factor receptor 2; OR, overall response; PFS, progression-free survival; RR,
response rate; SD, stable disease.

Figure 1. Targeted therapy agents under evaluation in phase IIIII trials of epithelial ovarian cancer.
Abbreviations: EGFR, epidermal growth factor receptor; HER-2, human epidermal growth factor receptor 2; Hsp, heat shock
protein; PARP, polyadenosine diphosphate-ribose polymerase; PDGFR, platelet-derived growth factor receptor; PKC, protein
kinase C; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

objective response among patients with HER-2 overexpression [69]. It has been suggested that HER-2 activation may
be a better indicator of response. In support of this theory,
Gordon et al. [70] suggested that patients with HER-2 phos-

phorylation (pHER-2) had a better outcome following

pertuzumab than patients with pHER-2 tumors (PFS time,
20.9 weeks versus 5.8 weeks; p .14). Efficacy data of
lapatinib in ovarian cancer are pending. EGFR or HER-2

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Bowman et al. (2002) [74]

60
Papadimitriou et al. (2004) [78] 27
373
Berek et al. (2008) [80]a

EGFR
EGFR, ER
EGFR
EGFR
HER-2
HER-2 dimerization
ER (via aromatase)

Banerjee, Gore

inhibitors combined with chemotherapy [71] may enhance

the effects of chemotherapy, but final results from clinical
trials are not yet available.

Targeting the Estrogen Receptor

Other Targeted Strategies

Monoclonal antibodies against tumor antigens such as the
folate receptor (FR) and CA-125 are also under evaluation
[79]. FR is overexpressed in 90% of ovarian cancers. The
monoclonal antibody against FR, MORab-003 (farletuzumab, Morphotek Inc., Exton, PA) is being evaluated in a
phase II trial of recurrent platinum-sensitive disease. Oregovomab (OvaRex MAb B43.13; United Therapeutics Corporation, Silver Spring, MD) is a monoclonal antibody
directed against CA-125 being studied as consolidation
therapy after adjuvant treatment for ovarian cancer. Recently, the results of a phase III study of oregovomab monotherapy maintenance after first-line therapy failed to show
any clinical benefit [80]. Other drugs under clinical development in ovarian cancer include dasatinib (Src inhibitor),
imatinib (PDGFR, c-Kit inhibitor), enzastaurin (protein kinase C inhibitor), and tanespimycin (heat shock protein-90
inhibitor).

www.TheOncologist.com

CHALLENGES
A major challenge facing the use of anti-VEGF therapy in
ovarian cancer is the lack of predictive markers. Circulating
angiogenic factors such as VEGF and soluble VEGFRs are
under investigation as surrogate endpoints and need further
validation [81]. A preliminary report in refractory ovarian
cancer suggested that IL-8 and VEGF polymorphisms
could be potential markers of clinical outcome following
bevacizumab-based chemotherapy [28]. The traditional
measurement of response rates, such as the Response Evaluation Criteria in Solid Tumors, used in the majority of clinical trials is unlikely to be the best predictor of therapeutic
efficacy in trials of antiangiogenic agents. These agents appear to slow or arrest tumor growth rather than cause cell
death and tumor shrinkage. Therefore, functional and dynamic imaging using dynamic contrast-enhanced magnetic
resonance imaging (MRI), MRI spectroscopy, and position
emission tomography may be preferential modalities to
more directly monitor the activity of the drug and provide
an early means of demonstrating response. Pharmacodynamic studies using reliable biomarkers are important to define the optimal dose of antiangiogenic agents.
Disease stabilization may be achieved with antiVEGF therapy, but this is transient and eventually followed by tumor progression. The mechanisms related to
resistance to VEGF-targeted therapy are not fully understood. Tumors may adapt to evade blockade of angiogenesis by VEGF inhibitors by the following mechanisms:
upregulation of proangiogenic signals such as FGF, matrix metalloproteinase 9, and stromal cell derived factor
1; protection of the tumor vasculature by increasing
pericyte coverage; recruitment of bone marrow derived
proangiogenic cells; and increased invasiveness of tumor
cells to co-opt normal vasculature without obligate neovascularization [43, 82]. Strategies such as combining
multiple antiangiogenic agents or combining antiangiogenic agents with classical agents or other targeted
agents may overcome resistance.
There are a number of other important issues including whether or not bevacizumab or other anti-VEGF
agents have a role in early-stage and/or advanced disease. Moreover, will combination with chemotherapy be
more effective than treatment with antiangiogenic agents
alone? Will maintenance therapy with anti-VEGF agents
prove beneficial? Will VEGFR TKIs be as effective or
even better than bevacizumab? Is it possible to identify
those patients at risk for bevacizumab-related bowel perforation? It is noteworthy that, unlike in breast, colon,
and lung cancer, bevacizumab as a single agent has
shown significant activity in ovarian cancer. These and

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Although 70% of epithelial ovarian cancers express estrogen and/or progesterone receptors, treatment with tamoxifen or luteinizing-hormone-releasing hormone
agonists has shown minimal activity. A Cochrane review of
tamoxifen in ovarian cancer concluded that 9.6% of patients achieved an objective response to tamoxifen alone,
although the range within individual studies was 0%56%.
An additional 32% of patients achieved stable disease for
periods 4 weeks, and less heavily pretreated patients appear to show greater response [72]. Aromatase inhibitors
(AIs) have recently been investigated in phase II trials of
patients with recurrent ovarian cancer. Response rates were
modest, but disease stabilization rates of 18% 42% were
achieved [7378]. A phase II trial of letrozole (Femara;
Novartis Pharmaceuticals Corporation, East Hanover, NJ)
in estrogen receptor (ER) patients with relapsed ovarian
cancer reported that, according to CA-125 criteria, 17% of
patients responded and 26% achieved disease stabilization
at 6 months. Furthermore, CA-125 response was associated
with high ER expression [75]. The efficacy of AIs in combination with biological agents (e.g., EGFR and HER-2 inhibitors) remains to be determined. Given the limited
treatments in ovarian cancer and relative favorable tolerability of AIs, further investigation of the role of these agents
in prolonging the platinum-free interval in recurrent ovarian cancer is warranted.

713

714

Targeted Therapies in Ovarian Cancer

other issues will be addressed in ongoing phase III trials

of antiangiogenic therapy.
The antiangiogenic strategy is showing encouraging activity in ovarian cancer. PARP inhibitors are an exciting approach and hold promise for the future of ovarian cancer
therapy. Understanding the molecular changes driving
ovarian cancer is critical for the selection of appropriate

candidate agents and for the success of these agents in improving clinical outcome.

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Conception/Design: Susana Banerjee, Martin Gore

Collection/assembly of data: Susana Banerjee
Manuscript writing: Susana Banerjee, Martin Gore
Final approval of manuscript: Susana Banerjee, Martin Gore

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