Treatment of HER2-positive breast cancer
Maria Cristina Figueroa-Magalhães1, Danijela Jelovac1, Roisin M. Connolly,
Antonio C. Wolff*
Breast Cancer Program, The Johns Hopkins Kimmel Comprehensive Cancer Center, 1650 Orleans Street, CRB1-189, Baltimore, MD 21287, USA
a r t i c l e i n f o
Received 24 January 2013
Received in revised form
23 September 2013
Accepted 24 November 2013
HER2-positive breast cancer
a b s t r a c t
The human epidermal growth factor receptor 2 gene (HER2) is overexpressed and/or amplified in w15%
of breast cancer patients and was identified a quarter century ago as a marker of poor prognosis. By 1998,
antibody therapy targeting the HER2 pathway was shown to demonstrably improve progression-free and
overall survival in metastatic disease, and in 2005 evidence of improvement in disease-free and overall
survival from the first generation of trastuzumab adjuvant trials became available. However, not all
patients with HER2 overexpression benefit from trastuzumab. Second-generation studies in metastatic
disease led to the approval of several new HER2-targeted therapies using small molecule tyrosine kinase
inhibitors such as lapatinib, new HER2/HER3 antibodies such as pertuzumab, and the new antibody
chemotherapy conjugate ado-trastuzumab emtansine. These successes supported the launch of second-
generation adjuvant trials testing single and dual HER2-targeted agents, administered concomitantly or
sequentially with chemotherapy that will soon complete accrual. HER2-positive breast cancer in the
setting of HER2-targeted therapy is no longer associated with poor prognosis, and recent guidance by the
US Food and Drug Administration suggests that pathologic response to HER2-targeted therapy given
preoperatively may allow an earlier assessment of their clinical benefit in the adjuvant setting. An
adjuvant trial of trastuzumab in patient whose tumors express normal levels of HER2 and trials of single/
dual HER2-targeting without chemotherapy are also ongoing. In this article, we review the current data
on the therapeutic management of HER2-positive breast cancer.
? 2013 Elsevier Ltd. All rights reserved.
Breast cancer is now recognized as a heterogeneous disease
characterized by various biologic drivers and related clinical out-
comes. The use of systemic therapy including chemotherapy for
higher proliferation tumors, endocrine therapy for patients with
estrogen receptor (ER)-positive disease, and HER2-targeted therapy
for all patients whose tumors overexpress HER2 likely accounts for
over half of the observed reduction in breast cancer mortality in
recent history . The HER2-positive phenotype observed in about
15% of patients is of great scientific interest as HER2 overexpression
is associated with worse clinical outcome (worse prognosis) in the
absence of therapy . HER2 gene amplificationwas first associated
with worse clinical outcomes in the late 1980s by Slamon and col-
leagues, who went on to describe HER2 protein overexpression as a
potential predictive tool for clinical use [2,3]. Fast forward a decade,
and in 1998 the clinical course of HER2-positive disease was
fundamentally altered upon the release of the first-generation trial
of trastuzumab added to chemotherapy in metastatic breast cancer
(MBC) . By 2005, the natural historyof this breast cancer subtype
in the adjuvant setting was forever changed with the release of the
findings from the first generation adjuvant trials combining tras-
tuzumab with chemotherapy, concomitantly or sequentially [5e8].
Historically, new treatments are tested first in the metastatic
disease and then evaluated in the preoperative (or neoadjuvant)
setting. In this context, lapatinib in 2007, then pertuzumab in 2012
and ado-trastuzumab emtansine in 2013 were approved in the US
and elsewhere based on evidence showing an improvement in
survival outcomes in patients with mostly trastuzumab-naïve
trastuzumab emtansine) metastatic disease [9,10]. The clinical
benefit demonstrated by those drugs in advanced disease has now
triggered several adjuvant trials testing them in combination with
chemotherapy, but also without conventional chemotherapy, using
single or dual HER2-targeting drugs.
A key first step in appropriately deciding on the use of HER2-
targeted therapy is the accurate determination of HER2 over-
expression . A few studies have observed as much as 25%
discordance between test results from the primary and metastatic
sites [12e14]. The reasons for this might include a change in biology
* Corresponding author.
E-mail address: email@example.com (A.C. Wolff).
1Both authors equally contributed to this manuscript.
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The Breast 23 (2014) 128e136
[15e17], tumor heterogeneity , and analytical variability .
Available evidence suggests no benefit from HER2-targeted therapy
in patients with HER2-negative metastatic disease . However,
unplanned retrospective assessment from two of the adjuvant
trastuzumab trials suggest a possible benefit from trastuzumab in
patients with HER2-negative disease [21,22], and this is now being
prospectively tested in trial NSABP B47 for patients with normal
levels of HER2 expression (NCT01275677).
This review article discusses current treatment options for
breast cancer patients with HER2-positive disease in the adjuvant,
neoadjuvant, and metastatic setting, along with the fast moving
landscape of HER2-targeted agents in clinical development.
Thus far, four separate HER2-targeted agents (trastuzumab,
lapatinib, pertuzumab and ado-trastuzumab emtansine) have been
approved for treatment of HER2-positive MBC patients. Much of
their current use is driven by the design of the studies that led to
their regulatory approval, but much remains unknown about their
optimal use, alone or in combination.
The approval of trastuzumab in the first-line combined with
patientswith HER2-positive breastcancerandmetastatic disease to
an anthracycline regimen (or paclitaxel if prior anthracycline) with
or without concomitant trastuzumab . There was a significant
p < 0.001), overall response rate (ORR, 50% vs 32%, p < 0.001), and
median overall survival (OS, 25.1 vs 20.3 months; p ¼ 0.046), along
with an unacceptably high risk of cardiotoxicity with the concom-
itant administration of trastuzumab and an anthracycline.
Much has been discussed about a potential clinical synergism
between platinum drugs and trastuzumab. In vitro data suggests
that trastuzumab modulates platinum resistance  but the
clinical experience has been mixed. Adding carboplatin to trastu-
zumab plus paclitaxel led to a greater ORR (52% vs 36%, p ¼ 0.04)
and progression-free survival (PFS 10.7 vs 7.1 months, p ¼ 0.03), but
not OS (35.7 vs 32.2 months, p ¼ 0.76) . In contrast, no TTP,
response rate (RR), or OS benefit was observed in trial BCIRG 007
with the addition of carboplatin to docetaxel and trastuzumab .
Trastuzumab can be safely combined with drugs like vinorelbine,
 docetaxel , and capecitabine, [28,29] with observed tox-
icities driven primarily by the chemotherapy drug.
Pertuzumab targets the dimerization of HER2 and HER3 and has
clinical activity beyond the first line setting. A small multicenter
single-arm trial showed that pertuzumab plus trastuzumab is an
active and safe combination in patients with HER2-positive MBC
whose disease progressed after prior trastuzumab , while a
separate trial showed no benefit from pertuzumab in patients with
HER2-negative disease . Recently, the CLEOPATRA trial tested
the concept of dual versus single HER2-targeting with the addition
of pertuzumab to trastuzumab and docetaxel chemotherapy as
first-line therapy in over 800 patients with HER2-positive MBC
patients, where less than half of the patients had prior adjuvant
chemotherapy and only w10% had prior adjuvant trastuzumab
. There was a significant improvement in PFS (18.5 vs 12.4
months, HR ¼ 0.62, p < 0.001) and OS (HR ¼ 0.66, p ¼ 0.008)
without an apparent increase in cardiac toxicity, though with a
greater risk of febrile neutropenia and diarrhea.
Of interest when examining future trials that lacked a cross over
design (including the recent CLEOPATRA trial of first-line pertu-
zumab), the clinical benefit from trastuzumab in the first pivotal
MBC trial was observed despite a planned cross-over from the
control arm to trastuzumab upon progression. Later on, a disease-
free survival (DFS) benefit was also observed in the adjuvant
HERA adjuvant trial  following late cross-over to the trastuzu-
mab arm upon release of the primary efficacy data from this trial.
These findings serve to highlight the impact of trastuzumab on the
natural history of HER2-positive breast cancer.
In total, these findings led to the recommendation by some that
for patients with disease progression after trastuzumab-based
therapy without pertuzumab, a line of therapy with trastuzumab
plus pertuzumab (with or without a cytotoxic agent like vinor-
elbine or taxane) should be considered, though further research is
needed regarding the optimal sequencing of anti-HER2 therapy
. Futhermore, biomarker analyses from the CLEOPATRA trial
suggest mutations in PI3K were associated with a poor prognosis in
both arms, while an abstract presentation suggest that the clinical
benefit from pertuzumab was more substantial in patients with
tumors showing wild-type PI3K . These data have been pre-
sented in abstract form and require further confirmation.
Subsequent lines of therapy
Several recent randomized trials have demonstrated benefit
with continuing trastuzumab therapy following disease progres-
sion on a trastuzumab-containing regimen [35,36]. One such study
(GBG-26) tested capecitabine with or without trastuzumab after
prior progression on trastuzumab. While it closed due to poor
accrual after 156 patients and reported no significant difference in
OS , a post-hoc analysis showed a better post-progression
survival favoring continuation of trastuzumab without added
toxicity. Another trial evaluated lapatinib plus capecitabine after
prior anthracycline/taxane and progression on trastuzumab-based
therapy [38,39], and reported a significant improvement in TTP
(6.2 vs 4.3 months, p < 0.001), ORR (24% vs 14%, p ¼ 0.017), and
possibly less central nervous system (CNS) events (6% vs 2%,
p ¼ 0.045), favoring the addition of lapatinib to capecitabine.
Preliminary results of BOLERO-3 trial have been presented thus
far in abstract form. It evaluated the role of everolimus combined
with vinorelbine plus trastuzumab in reversing trastuzumab-
resistance in heavily pretreated HER2-positive MBC patients .
Initial findings suggest an improvement in survival, but longer
follow-up and formal peer-review of these data are needed.
Ado-trastuzumab emtansine (T-DM1) combines an antibody
targeting HER2 with an anti-microtubule drug . A phase 1 study
in 24 heavily pretreated patients with HER2-positive MBC that had
progression on trastuzumab showed a clinical benefit rate (CBR)
from ado-trastuzumab emtansine of 73% . Observed side effects
included mild, reversible thrombocytopenia, elevation of trans-
aminases, and fatigue, but not cardiac toxicity. Ado-trastuzumab
emtansine is active after prior exposure to lapatinib [43,44] and
has also been tested in the first line setting [45,46]. Finally, the
EMILIA registration trial randomized 991 patients previously
treated with trastuzumab and a taxane to ado-trastuzumab
emtansine versus lapatinib plus capecitabine.  There was a
significant improvement in PFS favoring the ado-trastuzumab
emtansine arm (9.6 vs 6.4 months, HR ¼ 0.65, p < 0.001), OS
(30.9 vs 25.1 months, HR ¼ 0.68, p < 0.001), and ORR (43.6% vs
30.8%, p < 0.001), and a favorable toxicity profile except for
thrombocytopenia and elevation of transaminases.
Dual HER2-targeting metastatic regimens
A phase 3 study of 296 patients tested lapatinib versus lapatinib
plus trastuzumab in those extensively pre-treated with regimens
containing trastuzumab and chemotherapy, and observed a
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