New drugs for breast cancer
Laura Tookman, and Rebecca Roylance*
Centre for Molecular Oncology and Imaging, Barts and the London School of Medicine and
Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK
Recently there have been significant advances in rational drug design for the
treatment of breast cancer, especially in the area of targeted drug therapy.
These include drugs which target the HER2 receptor and angiogenesis and the
novel class of drug the PARP inhibitors. Some of these agents, for example,
trastuzumab used in the treatment of HER2 positive breast cancer are already
established as the standard of care. However, the duration of adjuvant
trastuzumab, whether to continue it beyond progression in metastatic disease
and the mechanism for developing trastuzumab resistance, remain to be
determined. There is also much still to be learnt regarding other targeted
therapies; the efficacy of different agents, the optimal duration of use and
combination of therapies. Many of these agents are already in clinical trials, the
results of which are likely to change clinical practice.
Keywords: targeted therapy/breast cancer/HER2/angiogenesis/PARP
inhibitors
Accepted: August 7, 2010
Introduction
Over the last two decades, breast cancer research has lead to significant
progress in the understanding of this disease. Increasingly it is recog-
nized that breast cancer encompasses a range of diseases with different
behaviors, which require different treatments. Gene expression studies
have made a significant contribution to our understanding with the
identification of different intrinsic subtypes. These include the luminal
A subtype, which are mostly oestrogen receptor positive and histologi-
cally low grade; the luminal B subtype, which are also mostly oestrogen
receptor positive but frequently high histological grade; the HER2-
positive subtype characterized by amplification and overexpression of
the HER2 gene and the basal-like subtype, which are mostly oestrogen
receptor, progesterone receptor and HER2 negative and therefore at
present lack any specific therapeutic target. This area is the focus of
intensive current research.
British Medical Bulletin 2010; 1–19
DOI:10.1093/bmb/ldq029
& The Author 2010. Published by Oxford University Press.
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*Correspondence address.
E-mail: r.roylance@qmul.
ac.uk
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The non-surgical management of breast cancer depends on che-
motherapy and endocrine therapy with not all patients requiring both
modalities. However, with the greater understanding of the underlying
biology considerable advances have been made in the development of
targeted therapies resulting in a wider range of therapeutic options.
This review will focus on these new targeted therapies. Agents which
target the HER2 receptor, angiogenesis and the recently described
PARP inhibitors will be discussed. While many of these new biological
and targeted therapies remain under development and/or entering clini-
cal trials, some have already become the standard of care.
HER2 targeted therapy
Overexpression of HER2 occurs in approximately 25% of breast
cancers and is predominantly due to amplification of the HER2 gene.
Overexpression is correlated with a more aggressive phenotype and
worse prognosis.1 HER2 (also known as ErbB2) is a member of the
epidermal growth factor receptor family of tyrosine kinases (TK),
which in humans consists of four members: HER1, 2, 3 and 4 (also
called epidermal growth factor receptors EGFR or ERB1, 2, 3 and 4,
respectively). Each one is a transmembrane TK receptor with partial
homology that normally regulates cell growth and survival, as well as
adhesion, migration, differentiation and other cellular responses.2 Each
receptor consists of an extracellular-binding domain, a transmembrane
lipophilic segment and (except for HER3) a functional intracellular TK
domain. The TK domains are activated by both homo-and hetero-
dimerization, generally induced by ligand binding, although no natural
ligand for HER2 has been identified to date. Dimerization in the
absence of ligand can occur by the extracellular domain of HER2
adopting a fixed conformation resembling a ligand-activated state,3
and by receptor overexpression and mutation. Once activated, the
signal transduction cascades of these receptors promote cellular pro-
liferation, through the RAS-MAPK pathway and survival by inhibiting
cell death through the phosphatidylinositol 30-kinase-AKT-mammalian
target of rapamycin (mTOR) pathway.4 Clinically overexpression is
detected using immunohistochemistry (IHC), with an antibody directed
against the HER2 receptor or by FISH (fluorescence in situ hybridiz-
ation), which uses a fluorescently labelled DNA probe to the ERBB2
gene to detect gene copy number. A scoring system from 0 to 3þ is
employed for IHC, where 3þ is positive, 0/1 is negative and 2þ is
indeterminate, requiring FISH confirmation of gene amplification.
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Trastuzumab
The advent of trastuzumab (HerceptinTM), a recombinant humanized
monoclonal antibody (mAb) targeting the extracellular domain of the
HER2 receptor, has changed the treatment paradigm for HER2-
positive breast cancer. Trastuzumab consists of two antigen-specific
sites that bind to the juxtamembrane portion of the extracellular
domain of the HER2 receptor and prevents the activation of its intra-
cellular TK. The remainder of the antibody is human IgG with a con-
served Fc portion. Several possible mechanisms by which trastuzumab
might decrease signaling include prevention of the HER2-receptor
dimerization, increased endocytotic destruction of the receptor, inhi-
bition of shedding of the extracellular domain and immune activation.5
In the metastatic setting, a pivotal randomized Phase III trial com-
pared chemotherapy with or without trastuzumab in 469 HER2-
positive patients. Chemotherapy naı¨ve patients received either doxoru-
bicin or epirubicin in combination with weekly trastuzumab, whereas
patients who had received an anthracycline in the adjuvant setting
received paclitaxel with weekly trastuzumab. Trastuzumab plus che-
motherapy was associated with a significant improvement in median
time to disease progression (7.4 months versus 4.6 months, P, 0.001),
response rates (50% versus 32%, P, 0.001) and median survival
(25.1 months versus 20.3 months P ¼ 0.01) compared with chemother-
apy alone.6
However, cardiotoxicity was a clinically significant and unexpected
side effect, seen in 27% of patients receiving anthracycline plus trastu-
zumab, compared with 8% with anthracycline alone, 13% with pacli-
taxel and trastuzumab and 1% with paclitaxel alone. This led to the
recommendation that concomitant anthracyclines and trastuzumab
should be avoided. The mechanism of cardiotoxicity remains to
be elucidated, but animal studies suggest signaling through the
HER2 pathway may be important for maintenance of normal cardiac
function.7
Following the outcome of the pivotal study, trastuzumab has been
tested in the adjuvant setting in four large multicentre trials:
the National Surgical Adjuvant Breast and Bowel Project trial [B-31],
the North Central Cancer Treatment Group trial [N9831], the
Trastuzumab Adjuvant trial [HERA] and the Breast Cancer
International Research Group trial 006 [BCIRG-006]. Altogether these
trials involved over 12 000 women. Results are available from three of
these studies (HERA,8,9 NSABP B-3110 and N983110) with to date, the
fourth only published in the abstract form (BCRIG00611,12). The
results from the first three trials were so significant that the respective
data and safety monitoring committees stopped the trials after the
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interim analyses and trastuzumab was offered to all patients in the
control groups.
Both NSABP B-31 and the NCCTG N9831 included node-positive
and N9831 also included high-risk node-negative patients.10 B-31 com-
pared four cycles of doxorubicin and cyclophosphamide followed by
paclitaxel with and without weekly trastuzumab starting on day 1 of
paclitaxel and continued for 12 months. The N9831 trial compared
three regimens, four cycles of doxorubicin and cyclophosphamide fol-
lowed by 12 cycles of weekly paclitaxel. Trastuzumab was either given
concurrently starting on day 1 of paclitaxel or on completion of che-
motherapy for a total of 12 months. The control arms of both trials
together with the concurrent chemotherapy trastuzumab arms differed
in only minor details, therefore an NCI and FDA approved joint analy-
sis was undertaken (however this was not a preplanned analysis). It
should be noted that the sequential treatment arm in N9831 was
excluded from this interim analysis and has just reported in the abs-
tract form.12,13 The interim analysis resulted in a significant difference
between groups resulting in early trial stoppage as discussed above. A
total of 2043 patients were enrolled in B-31 with a median follow-up
of 2.4 years. There were 1633 patients in the analysis arms of N9831
with a median follow-up of 1.5 years. In the combined analysis there
were 133 events in the trastuzumab arm and 261 in the control group.
The hazard ratio (HR) for a first event in the trastuzumab group com-
pared with control was 0.48 (95% CI: 0.39 to 0.59; P, 0.0001). The
percentage of patients alive and disease free at 3 years were 75.4 and
87.1% in the control and trastuzumab groups, respectively (absolute
difference: 11.8%; 95% CI: 8.1–15.4%). The absolute survival rate at
3 years was 94.3% in the trastuzumab group compared with 91.7% in
the control group (absolute difference: 2.5%; 95% CI: 0.1–5.0%).10
The 3 year cumulative incidence in congestive cardiac failure or death
from cardiac causes was 4.1 and 2.9% in the B-31 trial and N9831
trial, respectively.
The HERA trial had a three-way randomization to observation fol-
lowing standard institution defined (neo-) adjuvant treatment or to
trastuzumab given on a three weekly schedule for 12 or 24 months in
patients with HER2-positive node-positive or high-risk node-negative
breast cancer.8 Randomization was performed within 7 weeks of day 1
of the last cycle of chemotherapy or within 6 weeks from the end of
definitive surgery or radiotherapy whichever was last. The rationale for
the prolonged treatment group was several fold; a major peak in the
rate of relapse occurs 18–24 months after surgery, effective treatment
of HER2-positive breast cancer may need prolonged attenuation of
HER2 activity and using an analogy with tamoxifen, also a targeted
therapy, it has proven to be more effective with therapy up to 5 years.
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After median follow-up of 2 years, the 12 month trastuzumab
arm versus observation was updated, but with insufficient events for
a comparison of 24 versus 12 months.9 There were 1703 and 1698
women in the 12 month treatment and observation arms, respect-
ively. There were 218 events in the trastuzumab arm and 321 in
the observation group. The unadjusted HR for the risk of an event
in the trastuzumab group compared with the observation group was
0.64 (95% CI: 0.54–0.76; P, 0.0001 log rank test), which corre-
sponds to an absolute DFS benefit of 6.3% (80.6 versus 74.3%) at
3 years. Severe cardiotoxicity was only seen in 0.6% of women
receiving trastuzumab.
The Breast Cancer International Research Group (BCIRG) 006 trial
has reported the third interim safety and efficacy analysis.11 In this
Phase III trial the control arm was four cycles of doxorubicin and
cyclophosphamide (AC) followed by 4 cycles of docetaxel (T) com-
pared with two experimental arms AC followed by T plus trastuzumab
(H) weekly during chemotherapy and then subsequently three weekly
for 12 months (ACTH) or six cycles of docetaxel (T) plus carboplatin
(C) plus trastuzumab (H) for 12 months (TCH). This third arm was
designed to obviate the need for anthracyclines thereby potentially
eliminating cardiotoxicity. A total of 3222 patients were randomized
and at a median of 65 months follow-up, there were 185 events in the
ACTH arm, 214 events in the TCH arm and 257 in the control arm.
The HR for the risk of an event in the ACTH arm was 0.64 (95% CI:
0.53–0.78; P, 0.001) and 0.75 (95% CI: 0.63–0.90 P ¼ 0.04) for
TCH compared with the observation group, which corresponds to an
absolute DFS improvement of 9% for ACTH (84 versus 75%) and 6%
for TCH (81 versus 75%). Although there was no statistically signifi-
cant difference between the two trastuzumab containing arms, there
was a trend towards the TCH arm doing less well, but the incidence of
cardiotoxicity was greater in the ACTH compared with the control and
TCH arms.
In contrast, the FNCLCC-PACS 04 trial has shown no significant
advantage for adjuvant trastuzumab (Table 1). This trial randomized
528 HER2-positive patients to 1 year of trastuzumab or observation
following completion of adjuvant chemotherapy (either six cycles of
FE(100)C or six cycles of epirubicin and docetaxel).14 After 47-month
median follow-up, the trastuzumab arm was associated with a non-
significant 14% reduction in the risk of relapse (HR 0.86; 95% CI:
0.61–1.22; P ¼ 0.41) but with no difference in the 3 year DFS, which
was 78% (95% CI: 72.3–82.5) and 81% (95% CI: 75.3–85.4) in the
observation and trastuzumab arms, respectively. Possible explanations
for this negative result may be the small sample size and/or the sequen-
tial versus concurrent administration of trastuzumab.
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Table 1 Summary of the adjuvant trastuzumab trials.
Trial Median follow-up (months) Treatment regimes per arm Number of
patients/arm
DFS (%) HR P-value OS (%) HR P-value
HERA9 24 CT!observation 1698 74 90
CT! H �12 months 1703 81 0.64 ,0.001 92 0.66 0.11
CT! H �24 months 1689 Arm not yet reported
NSABP B-31 and N-983110 24 (28.8 months in B-31,
18 months in N9831)
AC! P 1679 75.4 91.7
AC! P þ H 1672 87.1 0.48 ,0.001 94.3 0.67 0.02
BCIRG 00611 65, third analysis AC! T 1073 75 92
AC! T þ H! H 1074 84 0.64 ,0.001 91 0.63 ,0.001
TCH 1075 81 0.75 0.04 87 0.77 0.038
FinHER19 62 V or T! FE(60)C 116 73 82.3
V or Tþ H! FE(60)C 116 83.3 0.65 0.12 91.3 0.55 0.094
PACS-O414 47 FE(100)C or ED! Observation 268 78 96
FE(100)C or ED! H 260 81 0.86 0.41 95 1.27
CT, chemotherapy institution choice; H, herceptin; AC, doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2; P, paclitaxel 175 mg/m2; T, docetaxel 100 mg/m2; TC,
docetaxel 75 mg/m2 carboplatin AUC6, V, vinorelbine 25 mg/m2; FE(60)C, 5-fluorouracil 600 mg/m2 epirubicin 60 mg/m2 cyclophosphamide 600 mg/m2; FE(100)C, 5-
fluorouracil 500 mg/m2 epirubicin 100 mg/m2 cyclophosphamide 500 mg/m2; ED, epirubicin 75 mg/m2 docetaxel 75 mg/m2.
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Following publication of the B-31, N9831 and HERA trials, which
had all demonstrated an approximate 50 and 33% improvement in
DFS and OS, respectively, by the addition of trastuzumab, regardless of
the chemotherapy regimen or sequence of its delivery, trastuzumab was
FDA approved for the adjuvant treatment of HER2-positive disease.
However, there remain significant unanswered questions. Firstly,
should trastuzumab be given sequentially or concurrently with cyto-
toxic chemotherapy? While there are basic data both in vitro and
in vivo to suggest that it enhances the proapoptotic activity of che-
motherapy,15–17 the mechanism is not fully understood. The compara-
tive analysis of the treatment arms in the N9831 trial was designed to
address this question. Recently reported three were 174 events in the
sequential arm compared with 138 in the concurrent arm. Although
there is a strong trend for a reduction in risk towards concurrent versus
sequential treatment, this did not reach preplanned statistical signfi-
cance.13 Conversely the relative risk reduction in HERA using sequen-
tial treatment, is of a similar magnitude to that seen in the US trials,
and furthermore, while in HERA 95% of patients received trastuzumab
within 6 months of chemotherapy, many had a delay of several months
from chemotherapy and an analysis of the effect of timing of trastuzu-
mab may provide further information regarding this issue.
Secondly what is the optimal duration of treatment with trastuzu-
mab? The results of the extended duration of trastuzumab from the
HERA trial are still awaited. An intriguing trial is the FinHER study,18
which examined the use of just 9 weeks of trastuzumab. A total of
1010 women with node-positive or node-negative breast cancer with a
tumor .20 mm, were randomized to receive either taxotere or vinorel-
bine followed by FEC (5-fluorouracil, epirubicin, cyclophosphamide).
Patients with ERBB2 amplification (23% of patients) underwent a
second randomization to receive 9 weekly cycles of trastuzumab conco-
mitantly with either taxotere or vinorelbine, or no trastuzumab. After
a median follow-up of 62 months the results from the subgroup of
patients with HER2-positive disease showed that patients treated with
just 9 weeks of trastuzumab had a non-significant improvement in
distant DFS compared with chemotherapy alone (HR 0.65; 95% CI:
0.38–1.12; P ¼ 0.12).19 The question of trastuzumab duration is cur-
rently being addressed in clinical trials.
Despite its success in the treatment of both early and advanced stage
HER2-positive breast cancer, a proportion of patients who receive tras-
tuzumab containing adjuvant therapy will relapse and nearly all
patients receiving trastuzumab for metastatic disease will progress. A
number of potential mechanisms underlying trasuzumab resistance
have been proposed either affecting the receptor or its downstream sig-
naling pathways. These include inhibition of trastuzumab interaction
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with its target protein; shedding of the extracellular receptor domain
leaving behind the truncated form (p95), which retains kinase
activity;20 cross-talk or heterodimerization between HER2 and IGF-1R
or other HER family members,21 and decreased levels of PTEN
expression and/or activation of the PI3K/AKT signaling proteins.22,23
Ultimately, a clearer and better understanding of the molecular mech-
anisms of resistance is needed as it will allow development of further
treatment strategies for HER2-positive breast cancer.
Lapatinib
Lapatinib is an orally active reversible tyrosine kinase inhibitor (TKI),
which inhibits the TK of HER1 and 2. A pivotal randomized Phase III
study compared capecitabine plus lapatinib with capecitabine alone in
324 women with progressive, HER2 positive, locally advanced or
metastatic breast cancer who had been treated with an anthracycline, a
taxane and trastuzumab.24 An increased time to progression was seen
in the combination arm (8.4 months compared with