Cancer Treatment Reviews 39 (2013) 622–631
Contents lists available at SciVerse ScienceDirect
Cancer Treatment Reviews
journal homepage: www.elsevierhealth.com/journals/ctrv
Anti-Tumour Treatment
HER2-targeted therapy in breast cancer: A systematic review
of neoadjuvant trials
Susan Dent a,1, Basak Oyan b,2, Arnd Honig c,3, Max Mano d,4, Sacha Howell e,⇑
a
The Ottawa Hospital Cancer Centre, Division of Medical Oncology, Department of Medicine, The University of Ottawa, 501 Smyth Road, Box 912, Ottawa, Ontario, Canada
Medical Oncology Section, Yeditepe University Hospital, Devletyolu, Ankara Cad 102-104, Istanbul, Kozyatagi 34752, Turkey
c
University of Wuerzburg, Josef-Schneider Str. 4, 97080 Würzburg, Germany
d
Instituto do Câncer do Estado de São Paulo, University of São Paulo, Av. Dr. Arnaldo, 251 Cerqueira César, São Paulo/SP, Brazil
e
The University of Manchester, Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom
b
a r t i c l e
i n f o
Article history:
Received 23 July 2012
Received in revised form 7 January 2013
Accepted 10 January 2013
Keywords:
Neoadjuvant breast cancer
Pathological complete response
Trastuzumab
Lapatinib
Pertuzumab
Novel agents
HER2
a b s t r a c t
Targeting human epidermal growth factor receptor 2 (HER2) during or in sequence with chemotherapy
improves overall survival in metastatic and early HER2-overexpressing breast cancer. In this paper we
systematically review neoadjuvant clinical trial data in HER2-positive breast cancer and discuss key
unanswered clinical questions.
All trials of HER2-targeted neoadjuvant therapy were identiﬁed through non-date-limited searches of
PubMEDÒ and BiosisÒ and congress abstract book searches from 2000–2011. Eligible trials were prospective, had at least 10 patients and a clear deﬁnition of pathological complete response (pCR) rate.
A total of 50 trials fulﬁlled the eligibility criteria; 41 single-arm phase II studies were identiﬁed, 37 with
trastuzumab and 4 with lapatinib, with signiﬁcant variability in baseline tumour characteristics and pCR
rates (range 12–66.7%). Of 9 randomised phase II/III trials, 4 assessed the addition of trastuzumab to
chemotherapy and a further 5 randomised trials assessed different HER2-targeting approaches. Four of
these studies assessed dual HER2-targeting approaches, which universally increased pCR at the expense
of increased non-cardiac toxicity when lapatinib, but not pertuzumab, was added to trastuzumab.
Signiﬁcant advances have been made in HER2 targeting, resulting in a marked increase in the number
of breast cancer patients experiencing tumour pCR. Mature data from randomised neoadjuvant and adjuvant studies are awaited for survival outcomes with combination targeted approaches. Unanswered
questions centre on the individualisation of therapy and include; which, if any, chemotherapy backbone
should be used, and which patients need dual HER2 blockade?
Ó 2013 Elsevier Ltd. All rights reserved.
Introduction
Neoadjuvant therapy in women with early breast cancer improves rates of operability in locally advanced disease and breast
conservation in women who would otherwise require a mastectomy.1,2 However, meta-analyses of neoadjuvant trials have not
shown an improvement in disease-free (DFS) or overall survival
⇑ Corresponding author. Address: The University of Manchester, Department of
Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United
Kingdom. Tel.: +44 161 4463721; fax: +44 161 4468564.
E-mail addresses: [email protected] (S. Dent), [email protected]
(B. Oyan), [email protected] (A. Honig), [email protected] (M. Mano),
[email protected] (S. Howell).
1
Tel.: +1 613 737 7700; fax: +1 613 247 3511.
2
Tel.: +90 216 578 4085; fax: +90 216 578 4969.
3
Tel.: +49 179 944 3540; fax: +49 931 201 25406.
4
Tel.: +55(11)38932619; fax: +55(11)38933504.
0305-7372/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ctrv.2013.01.002
(OS) compared to similar treatment delivered after breast
surgery.1,2 Nevertheless, the neoadjuvant approach offers additional advantages in the assessment of response to both standard
therapies and novel agents requiring in vivo validation.
Several classiﬁcation systems deﬁning the histopathological
effects of chemotherapy on breast cancer have been published.3–7
In clinical trials, pathological complete response (pCR) has been
used as a surrogate marker for clinical outcome (including OS)
for patients receiving neoadjuvant treatment. Inconsistencies in
the deﬁnition of pCR have resulted in signiﬁcant variations reported in the literature.8,9 The most widely accepted deﬁnition
of pCR is no residual invasive carcinoma in the breast and axillary
lymph nodes. Differences in the deﬁnition of pCR hinge on the
requirement for clearance of ductal carcinoma in situ in addition
to invasive cancer only from the breast, and invasive disease from
axillary lymph nodes. Ideally, to aid in the critical evaluation of
results, a standardised deﬁnition of pCR should be utilised for
all clinical trials.
S. Dent et al. / Cancer Treatment Reviews 39 (2013) 622–631
Human epidermal growth factor receptor 2 (HER2) ampliﬁcation is seen in approximately 20% of breast cancers and is associated with more aggressive disease and worse prognosis.10
Trastuzumab, a monoclonal antibody against the extracellular
component of the HER2 protein, results in improved DFS and OS
in patients with HER2-overexpressing tumours in both the adjuvant and metastatic settings.11–13 In the neoadjuvant setting, the
achievement of pCR with chemotherapy plus trastuzumab has
been shown to correlate well with improved survival outcomes.14
More recently, additional HER2-targeted therapies including lapatinib (a tyrosine kinase inhibitor) and pertuzumab (a humanised
anti-HER2 monoclonal antibody) have shown promising results
in metastatic breast cancer leading to the exploration of dual
blockade with a combination of targeted therapies in the neoadjuvant setting.
In this article, we systematically review the literature detailing
HER2-targeted approaches in neoadjuvant clinical trials. Pathological complete response rates achieved with a wide range of regimens
in phase II and III studies are tabulated and toxicity proﬁles, particularly in phase III studies, are discussed. Consideration is given to
key questions that remain unanswered such as the optimal
management of women with residual cancer post-neoadjuvant
therapy and strategies to tailor therapy and increase pCR rates.
Methods
Eligible trials were identiﬁed through searches of PubMEDÒ,
BiosisÒ and manual searches of congress abstract books from the
American Society of Clinical Oncology (ASCO), San Antonio Breast
Cancer Symposium (SABCS), European Cancer Organisation (ECCO),
European Society for Medical Oncology (ESMO), European Breast
Cancer Conference (EBCC) and St. Gallen International Breast Cancer Conference (St. Gallen). No time limit was stipulated for the
PubMED searches. Conference proceedings from 2005 to 2011
were searched initially and the search expanded to 2000 to 2005
post hoc.
The PubMED search terms were: [HER2+, or HER-2+, or HER-2+, or HER2-positive, or HER2 positive, or HER-2 positive, or ErbB-2
positive, or ERbB2 positive] AND [trastuzumab, or pertuzumab, or
T-DM1, or lapatinib, or neratinib, or HER2-targeted treatment, or
anti-HER-2 treatment, or anti-HER2 treatment, or any of the previous terms with ‘therapy’ substituted for ‘treatment’] AND [breast
cancer, or breast neoplasm] AND [neoadjuvant, or preoperative,
or pre-operative, or primary systemic]. Search limits were set to:
clinical trials, randomised trials, meta-analyses, phase II, or phase
III.
PubMED was searched for evidence of subsequent publication
of conference abstracts using the senior author as the search term.
Abstracts without evidence of prospective enrolment of at least 10
patients into a phase II or III trial were excluded, as were studies
with no clear deﬁnition of pCR unless clariﬁcation could be obtained from the conference poster or presentation. If multiple reports on the same dataset were found, only the most recent
update was included. Two authors (Sacha Howell and Basak Oyan)
reviewed the resulting lists of studies to be included, and consensus was obtained from all authors for disagreements. Pathological
complete response rates were transcribed as presented if adequate
account was made of all recruited patients in the text of the abstract/publication. Where there was discrepancy, the number recruited was used as the denominator to provide intent-to-treat
analysis. In addition to pCR rates, data were collected on tumour
size, stage, endocrine receptor status, presence of inﬂammatory
breast cancer, chemotherapy/targeted agent regimen, as well as
treatment schedule and duration. ClinicalTrials.gov was also
searched for ongoing trials for discussion.
623
Results
Summary of neoadjuvant trastuzumab studies
The search criteria identiﬁed 358 studies although 308 did not
meet the eligibility criteria (Fig. 1). Fifty articles met the eligibility
criteria and were included in the review. The majority (37 articles)
reported on single-arm phase II studies15–51 of different chemotherapy backbones with trastuzumab (Supplementary Table 1). A
further four single-arm phase II trials examining the role of single
HER2 blockade with lapatinib are summarised in Table 1.52–55 Four
randomised trials evaluated the role of single-agent trastuzumab
added to a chemotherapy backbone versus the same chemotherapy
alone (Table 2).56–59 A further ﬁve randomised trials evaluated the
beneﬁt of other HER2 blockade approaches, including four studies
on dual-HER2 blockade (Table 3).60–64
Single-arm phase II trastuzumab trials
In the single-arm phase II studies (Supplementary Table 1),
which evaluated chemotherapy backbones on a background of single-agent trastuzumab, pCR rates varied widely (range 12–76%).15–
51
Cross-trial comparison of the relative activity of these regimens
has many pitfalls given the variability in disease stage, oestrogen
receptor (ER) status, deﬁnitions of pCR, as well as the many potential biases inherent to non-randomised studies. Despite these caveats, these trials demonstrated that trastuzumab is active when
given in combination with a wide range of different chemotherapy
regimens. In addition, they raised important questions for testing
in randomised clinical trials, including the role of anthracyclines
in sequence or combination with trastuzumab, the optimal taxane
partner for trastuzumab, the role of other non-taxane, non-anthracycline agents and novel targeted therapies.
Single-arm lapatinib trials
Two single-arm studies have explored the combination of lapatinib and trastuzumab (Table 1).52,53 Chang et al. treated women
with relatively large tumours (median tumour size 6 cm) with
12 weeks of lapatinib and trastuzumab without the addition of
chemotherapy.52 Women with ER-positive cancers also received
letrozole with or without goserelin in order to block ER/HER crosstalk. The overall rate of pCR in the breast was 28%. Despite treatment with endocrine therapy, patients with ER-positive tumours
achieved a lower pCR rate (21%) compared to those with ER-negative expression (42%). The omission of chemotherapy was associated with a good toxicity proﬁle.
Callahan et al. presented preliminary safety and efﬁcacy data on
the combination of trastuzumab and lapatinib with docetaxel and
carboplatin for six q3-weekly cycles.53 In the ﬁrst 21 patients
(including six in a dose escalation phase), the pCR rate of 43%
was achieved with ‘manageable’ toxicity. In two small trials
(involving 30 and 32 patients, respectively), lapatinib was added
to a taxane (nab-paclitaxel or paclitaxel) chemotherapy backbone
with pCR rates of 17.9% and 9.4%, respectively.54,55
Randomised trials of chemotherapy ± trastuzumab
A total of four randomised (phase II and III) clinical trials have
investigated the addition of trastuzumab to neoadjuvant chemotherapy (Table 2).56–59 Overall, these trials reported an increase
in pCR rates with the addition of trastuzumab to chemotherapy
(pCR 26–65%), compared to chemotherapy alone (pCR 19–27%).
This appears to be relatively independent of the type of chemotherapy employed. In the ﬁrst of these studies (MDACC), women
624
S. Dent et al. / Cancer Treatment Reviews 39 (2013) 622–631
Fig. 1. HER2 = human epidermal growth factor receptor 2, pCR = complete pathological response (deﬁned as no invasive tumour in breast and axilla, if not otherwise
speciﬁed), EBC = early breast cancer, DCIS = ductal carcinoma in situ, ST1 = supplementary table 1, T1 = table 1, T3 = table 3.
Table 1
Single-arm lapatinib trials.
Ref.
#
Study name, phase
N
Regimen
Neo tx
duration,
weeks
Stage
HR
negative,%
pCR,%
52
TBCRC 006 RP2 Chang, et al. J
Clin Oncol 2011
66
12
>3 cm or
>2 cm and
cN+
38
28 (61 cm residual invasive
tumour in breast)
ER+: 21
ER-: 42
53
RP2 Callahan, et al. Cancer Res
2010
20
21
IIA 40%
IIB 35%
IIIA 10%
IIIB 15%
40
43
54
Kaklamani, et al. Breast Cancer
Res Treat 2012
30
12
17.9
P2 Boussen, et al. J Clin Oncol
2010
32
I 13.3%
II 63.3
III 23.4%
IIIB 44%
IIIC 34%
IVa 22%
IBC = 100%
60
55
T + L ± gosrelin
12 (Tqwk) + L 1000 mg for 12 weeks
If ER+, postmenopausal: letrozole
If ER+, premenopausal:
letrozole + gosrelin
T + L DCar + T + L
1 (Tq3wk + L 1000 mg, 3 wks) ? 6
(Tq3wk) + 6
(L 1000 mg/d, q3wk) + 6 (D 75 mg/m2
Car AUC: 5–6, q3wk)
Nab-P + L
4 (Nab-P 260 mg/m2, q3wk) + (L
1000 mg/d 12 weeks)
L?L+P
L 1500 mg for 2 weeks ? L 1500 mg + 12
(P 80 mg/m2, qwk)
Not given
9.4%
14
Ref. # = reference number, Neo tx = neoadjuvant treatment, HR = hormone receptor, pCR = pathological complete response (deﬁned as no invasive tumour in breast and axilla,
if not otherwise speciﬁed), RP2 = randomised phase II study, T = trastuzumab, L = lapatinib, Tqwk = 4 mg/kg loading then 2 mg/kg every week, wks = weeks, ER = oestrogen
receptor, D = docetaxel, Car = carboplatin, Tq3wk = 8 mg/kg loading then 6 mg/kg every 3 weeks, q3wk = every 3 weeks, AUC = area under the concentration–time curve,
Nab-P = nanoparticle albumin-bound paclitaxel, P2 = phase II study, P = paclitaxel, qwk = every week.
a
All patients planned for surgery before starting therapy.
were randomised to block sequential taxanes and anthracycline
chemotherapy with or without trastuzumab throughout treatment.56 This approach re-explored the concept of concurrent
administration of anthracycline and trastuzumab, which had largely been abandoned after high rates of cardiac failure were seen
in the metastatic setting.11,56 The pCR rate in the combination
arm was 65% compared to only 26% in those receiving chemother-
apy alone, resulting in early closure of the study (n = 42). Safety
data were relatively reassuring. The high pCR rates were shown
to be reproducible in a small expansion phase of the trial and the
regimen was shown to be feasible outside of a clinical trial
setting.56,65,66
In the larger NOAH study (randomised phase III), 235 patients
with HER2-positive, locally advanced breast cancer (including
625
S. Dent et al. / Cancer Treatment Reviews 39 (2013) 622–631
Table 2
Randomised trials of chemotherapy ± trastuzumab.
Ref.
#
Study name, phase,
citation
56
MDACC RP3 Buzdar,
et al. J Clin Oncol
2005
57
NOAH RP3 Gianni,
et al. Lancet 2010
58
RP2 Pierga, et al.
Breast Cancer Res
Treat 2010
59
ABCSG-24 RP3
Steger, et al. Cancer
Res 2009
N
42
235
120
90
Regimen
Neo tx
duration,
weeks
Stage
HR
negative,%
pCR,%
Arm A: P ? FEC
Arm B: P + T ? FEC + T
4 (P 225 mg/m2 over 24 h, q3wk) ± 12
(Tqwk) ? 4 (FEC 500[d1,4]/75/500 mg/m2, q3wk) ± 12 (Tqwk)
Arm A: AP ? P ? CMF
Arm B: AP + T ? P + T ? CMF + T
3 (AP 60/150 mg/m2, q3wk) ? 3 (P 175 mg/m2, q3wk) ? 3
(CMF 600/40/600 mg/m2 d1,8, q4wk) ± Tq3wk with AP and P,
q4wk with CMF
24
T1 10%
T2 67%
T3 21% T4 2%
43
Arm A: 26
Arm B: 65.2
P = 0.016
40
T3N1 or
T4 or any
T N2,3
T4a-c 42.5%
IBC = 26.5%
64
Total pCR Arm A:
19%
Arm B: 38%
Arm A: EC ? D
Arm B: EC ? D + T
4 (EC 75/750 mg/m2, q3wk) ? 4 (D 100 mg/m2, q3wk) + 12
(Tqwk)
Arm A: ED ± Cap
Arm B: ED ± Cap + T
6 (ED 75/75 mg/m2 q3wk) ± 6
(Cap 1000 mg/m2 bid, d1–14, q3wk) ± 6 (Tq3wk)
24
T2 > 4 cm N0T2 49%
T3 36
T4 15%
T1 19%
T2 52%
T3 25%
T4 4%
41
18
40
P = 0.001 Breast pCR
Arm A: 22%
Arm B: 43%
P = 0.0007
Arm A: 19
Arm B: 26 P = not
given
Arm A: 26.
Arm B: 40 P = 0.369
pCR deﬁnition not provided.
Ref. # = reference number, Neo tx = neoadjuvant treatment, HR = hormone receptor, pCR = pathological complete response (deﬁned as no invasive tumour in breast and axilla,
if not otherwise speciﬁed), RP3 = randomised phase III study, P = paclitaxel, FEC = 5-ﬂuorouracil, epirubicin, and cyclophosphamide, T = trastuzumab, q3wk = every 3 weeks,
Tqwk = 4 mg/kg loading then 2 mg/kg every week, d = day, A = doxorubicin, CMF = cyclophosphamide, methotrexate, and 5-ﬂuorouracil, q4wk = every 4 weeks,
Tq3wk = 8 mg/kg loading then 6 mg/kg every 3 weeks, IBC = inﬂammatory breast cancer, RP2 = randomised phase II study, E = epirubicin, C = cyclophosphamide, D = docetaxel, Cap = capecitabine, bid = twice daily.
inﬂammatory breast cancer) were randomised to receive epirubicin/taxane/CMF-based chemotherapy with or without trastuzumab, concurrent with all chemotherapy.57 The primary
endpoint was event-free survival (EFS), which was improved with
the addition of trastuzumab (3-year EFS 71% vs. 56%, hazard ratio
0.59 [95% CI, 0.38 to 0.90]; P = 0.013), as was the secondary endpoint of pCR rate (total pCR: 38% vs. 19%, P = 0.001; breast pCR:
43% vs. 22%, P = 0.0007). The investigational arm appeared to be
safe, with no major short term cardiac issues reported. The patients
in the NOAH trial had more advanced disease than those in the
MDACC trial (69%57 had T4 and/or inﬂammatory breast cancer
compared with 67%56 with T2 disease in the MDACC trial), which
may explain the lower pCR rates observed.
In a French randomised phase II trial, 120 patients with stage II
and III HER2-positive breast cancer were randomised to receive
epirubicin/cyclophosphamide followed by docetaxel with or without concurrent trastuzumab.58 In this trial, pCR rates favoured the
experimental arm (26% vs. 19%), with no major safety issues reported. Similarly, in ABCSG-24, a subgroup of 90 patients with
HER2-positive, locally advanced disease were randomised to receive epirubicin/docetaxel or epirubicin/docetaxel/capecitabine
with or without trastuzumab, and a statistically non-signiﬁcant increase in pCR was observed with the addition of trastuzumab (40%
vs. 26.7%).59
These results have led to the adoption of combination
chemotherapy and trastuzumab as the standard of care in the
neoadjuvant setting for women with HER2-overexpressing nonmetastatic breast cancer.67–69
Strategies to improve on trastuzumab-based therapy
Despite the improved pCR rates seen with the addition of trastuzumab to chemotherapy (Table 2), the majority of patients with
breast cancer do not experience a pCR and even if this is achieved
a small minority still experience relapse.14 Thus in cancers where
the HER2 pathway is the key driver of cell proliferation and cell
survival, primary and acquired resistance to trastuzumab are key
issues. Some potential mechanisms of resistance and strategies to
overcome them are presented in Table 4. Dual blockade with a
combination of targeted therapies has been explored as an alternative treatment strategy to overcome resistance. Although several
novel agents targeting HER2 have been developed, the most mature data are available for lapatinib and pertuzumab (Table 152–
55
and Table 3.60–64)
Randomised trials comparing HER2-targeting approaches
Five randomised neoadjuvant trials that compared HER2-targeted agents individually or in combination were identiﬁed (Table 3).60–64 The targeted therapies in each study were combined
with conventional chemotherapy backbones comprising taxanes
and/or anthracyclines. In the open-label NeoALTTO trial, patients
received paclitaxel with lapatinib, trastuzumab, or the combination.60 The pCR rate in the breast and axilla with the combination
of lapatinib and trastuzumab (46.8%) was signiﬁcantly superior to
that of trastuzumab alone (27.6%; P = 0.0007). No signiﬁcant difference in pCR rates was seen between the lapatinib (20%) and trastuzumab (27.6%) arms despite one-third (33.8%) of patients treated
with lapatinib not completing therapy (vs. 8% in the trastuzumabonly arm) primarily due to increased grade 3 diarrhoea (23.4% vs.
2.0%) and liver enzyme alterations (17.5% vs. 7.4%). In contrast,
the GeparQuinto study examined the addition of trastuzumab or
lapatinib to anthracycline-/taxane-based chemotherapy, and demonstrated a signiﬁcantly superior pCR rate in patients treated with
trastuzumab (30.3% vs. 22.7%; odds ratio 0.68 [95% CI, 0.47 to
0.97]; P = 0.04).61 Dose reductions were again more common with
lapatinib than trastuzumab (32% vs. 1%; P < 0.0001) and the protocol was amended to mandate a reduction in lapatinib dose from
1250 mg to 1000 mg. However, when patients without dose reductions were compared, a similar difference in the pCR rates was seen
in favour of trastuzumab. A STEPP analysis performed by the investigators demonstrated no effect on pCR rates with lapatinib doses
from 700 to 1250 mg.
Two smaller neoadjuvant studies have compared targeted therapy with trastuzumab, lapatinib or the combination added to a
chemotherapy backbone.62,63 In both of these studies, treatment
626
S. Dent et al. / Cancer Treatment Reviews 39 (2013) 622–631
Table 3
Randomised trials comparing HER2-targeting approaches.
Ref.
#
Study name, phase,
citation
N
Regimen
Neo tx
duration,
weeks
Stage
60
NeoALTTO RP3 Baselga,
et al. Lancet 2012
455
18
>2 cm
T2 58%
T3/4 42%
49
Arm A:
27.6
Arm B:
20.0
Arm C:
46.8
61
GeparQuinto, GBG 44 RP3
Untch, et al. Lancet Oncol
2012
615
Arm A: T ? T + P
6 (Tqwk) ? 12 (Tqwk) + 12 (P 80 mg/m2, qwk)
Arm B: L ? L + P
L 1500 mg/d 6 weeks ? (L 1500 mg/d 12 weeks) + 12 (P 80 mg/m2,
qwk)
Arm C: T + L ? T + L + P
6 (Tqwk) + (L 1500 mg/d 6 weeks) ? 18 (Tqwk) + (L 1000 mg/
d 18 weeks) + 12 (P 80 mg/m2, qwk)
Arm A: EC + T ? D + T
4 (EC 90/600 mg/m2, q3wk) + 4 (Tq3wk) ? 4 (D 100 mg/m2, q3wk) + 4
(Tq3wk)
Arm B: EC + L ? D + L
4 (EC 90/600 mg/m2, q3wk) + (L 1000–1250 mg/d 12 weeks) ? 4 (D
100 mg/m2, q3wk) + (L 1000–1250 mg/d 12 weeks)
24
44
Arm A:
30.3
Arm B:
22.7
P = 0.04
62
Holmes, et al. J Clin Oncol
2011
100
T3/4a-d or
HR-,
T2 N+and
HR+,
T1 pNSLN+
HR+,
cT4 – 18%
IBC = 2.5%
II-III
63
CHER-LOB RP2 Guarneri,
et al. J Clin Oncol 2012
80
64
NeoSphere RP2 Gianni,
et al. Lancet Oncol 2012
417
Arm A: T ? FEC + T ? P + T
2 (Tqwk) ? 4 (FEC 500/75/500 mg/m2, q3wk) + 12 (Tqwk) ? 12 (P
80 mg/m2, qwk) + 12 Tqwk)
Arm B: L ? FEC + L ? P + L
(L 1250 mg/d 2 weeks) ? 4 (FEC 500/75/500 mg/m2, q3wk) + (L
1250 mg/d 12 weeks) ? 12 (P 80 mg/m2, qwk) + (L 1250 mg/
d 12 weeks)
Arm C: T + L ? FEC + T + L ? P + T + L
2 (Tqwk) + (L 750 mg/d 2 wk) ? 4 (FEC 500/75/500 mg/m2, q3wk) + 12
(Tqwk) + (L 750 mg/d 12 weeks ? 12 (P 80 mg/m2, qwk) + 12
(Tqwk) + (L 750 mg/d 12 weeks)
Arm A: P + T ? FEC + T
12 (P 80 mg/m2, qwk) + 12 (Tqwk) ? 4 (FEC 500/75/500 mg/m2, q3wk) +
12 (Tqwk)
Arm B: P + L ? FEC + L
12 (P 80 mg/m2, qwk) + (L 1250 mg/d 12 weeks) ? 4 (FEC 500/75/
500 mg/m2, q3wk) + (L 1250 mg/d 12 weeks)
Arm C: P + T + L ? FEC + T + L
12 (P 80 mg/m2, qwk) + 12 (Tqwk) + (L 750 mg/d 12 weeks) ? 4 (FEC
500/75/500 mg/m2, q3wk) + 12 (Tqwk) + (L 750 mg/d 12 weeks)
Arm A: D + T
4 (D 75–100 mg/m2, q3wk) + 4 (Tq3wk)
Arm B: D + T + Pert
4 (D 75–100 mg/m2, q3wk) + 4 (Tq3wk) + 4 (Pert 840 ? 420 mg/m2,
q3wk)
Arm C: T + Pert
4 (Tq3wk) + 4 (Pert 840 ? 420 mg/m2, q3wk)
Arm D: D + Pert
4 (D 75–100 mg/m2, q3wk) + (Pert 840 ? 420 mg/m2, q3wk)
26
HR
negative,%
Not given
pCR,%
⁄⁄
Arm
A: 54
Arm B:
45
Arm C:
74
24
IIA 32%
IIB 50%
IIIA 18%
41
Arm A:
25
Arm B:
26.3
Arm C:
46.7
12
II-III
LABC = 32%
IBC = 7%
52
Arm
21.5
Arm
39.3
Arm
11.2
Arm
17.7
A:
B:
C:
D:
pCR deﬁnition not provided.
Ref. # = reference number, Neo tx = neoadjuvant treatment, HR = hormone receptor, pCR = pathological complete response (deﬁned as no invasive tumour in breast and axilla,
if not otherwise speciﬁed), RP3 = randomised phase III study, T = trastuzumab, P = paclitaxel, Tqwk = 4 mg/kg loading then 2 mg/kg every week, qwk = every week,
L = lapatinib, wk = week, E = epirubicin, C = cyclophosphamide, D = docetaxel, q3wk = every 3 weeks, Tq3wk = 8 mg/kg loading then 6 mg/kg every 3 weeks, IBC = inﬂammatory breast cancer, FEC = ﬂuorouracil, epirubicin, and cyclophosphamide, RP2 = randomised phase II study, Pert = pertuzumab, LABC = locally advanced breast cancer.
comprised sequential blocks of taxane then anthracycline-containing chemotherapy. The study of Holmes et al.62 reported very high
pCR rates although did not deﬁne pCR (trastuzumab 54%; lapatinib
45%; trastuzumab combined with lapatinib 74%), whereas in the
CHER-LOB study63 the rates of pCR (trastuzumab 25%; lapatinib
26%; trastuzumab combined with lapatinib 47%) were comparable
to those in the shorter taxane-only regimen of NeoALTTO,60 highlighting the importance of adequate endpoint deﬁnition to aid
comparisons between trials.
The four-arm randomised phase II NeoSphere study64 (Table 3)
compared the combination of pertuzumab and trastuzumab with
or without docetaxel and single-agent trastuzumab or pertuzumab
in combination with docetaxel. Treatment was given for a total of
12 weeks prior to surgery and all patients then received additional
anthracycline-based chemotherapy postoperatively. The pertuzumab and trastuzumab combination without docetaxel induced
pCR in breast and axilla in 11.2% and in breast alone in 16.8% of
women. The combination of dual HER2 targeting with chemotherapy resulted in a signiﬁcantly higher pCR rate (39.3%) when compared with the same chemotherapy and single agent
trastuzumab (21.5%; P = 0.014) or pertuzumab (17.7%; P = 0.003).
Importantly, the addition of a second, targeted anti-HER2 agent
did not increase toxicity signiﬁcantly. In the adjuvant setting, the
combination of pertuzumab and trastuzumab with chemotherapy
is being evaluated in the international, multicentre, randomised
phase III BIG 4-11 trial (APHINITY; NCT01358877).
Two further neoadjuvant studies are exploring single-agent
versus combination lapatinib and trastuzumab in the neoadjuvant
setting on a paclitaxel backbone, either with (NSABP-B4170) or
without (CALGB 40601; NCT00770809) preoperative anthracycline
prior to commencing HER2-targeted therapy. NSABP-B41 reported
initial results after the searches for this article were conducted, and
demonstrated high rates of breast and axillary pCR with AC-paclitaxel in combination with either trastuzumab (pCR 52.5%) or
S. Dent et al. / Cancer Treatment Reviews 39 (2013) 622–631
627
Table 4
Mechanisms of resistance to trastuzumab and strategies to overcome resistance.
Resistance mechanism
Potential strategies to overcome resistance
Obstacles for trastuzumab binding to HER2
Masking of epitope by mucin 4 and CD44-hyaluronan complex
Expression of truncated HER2 protein: p95 ErbB2
Competition with circulating extracellular domain of HER2
Stabilisation and shuttling of HER2 to the cell membrane
HSP activity
Upregulation of HER2 downstream signalling pathways
HER tyrosine kinase inhibitor (lapatinib, neratinib, afatinib)
PTEN loss
PI3k mutation
Downregulation of p27 (Cdk inhibitor)
Signalling through alternate pathways
IGF-1R
c-met
Signalling through other members of HER family (HER2:HER3
dimerisation)
Failure to trigger immune-mediated mechanisms to destroy tumour cells
Low afﬁnity polymorphic forms of Fcc
Epitope masking
HSP inhibitors
Inhibiting downstream pathways (PI3k/Akt, mTOR inhibitors), or increasing
cytotoxicity of trastuzumab (T-DM1), or increasing immunity (ertumaxomab)
Inhibiting activity of other receptors
IGF-1R inhibitors
c-met inhibitors
Inhibition of dimerisation (pertuzumab)
HER3 or pan-HER inhibitors (neratinib, afatinib)
Increasing immunity (ertumaxomab, HER2 vaccines)
HER2 = human epidermal growth factor receptor 2, HSP = heat shock protein, PTEN = phosphatase and tensin homolog, PI3k = phosphatidylinositol 3-kinase, Akt = protein
kinase B, mTOR = mammalian target of rapamycin, IGF-1R = insulin-like growth factor-1 receptor.
lapatinib (pCR 53.2%).70 There was no statistically signiﬁcant difference in pCR rate with chemotherapy and trastuzumab alone
vs. the combination of lapatinib and trastuzumab (52.5% vs. 62%
P = 0.095).
Targeted agents and toxicity
Cardiac toxicity
Cardiac toxicity was the predominant adverse effect identiﬁed
with trastuzumab in the metastatic breast cancer clinical trials
(CHF 27%11,12). However, unlike the irreversible, dose-dependent
apoptosis and necrosis of cardiomyocytes induced by anthracyclines,71 trastuzumab induced cardiac toxicity appears to be largely
reversible. Similarly, the effects of lapatinib on the myocardium
appear largely reversible, not cumulative or dose related, and
ultrastructural myocardial changes are not generally seen.72 Pertuzumab has been generally well tolerated by patients enrolled in
ongoing clinical trials, with a low incidence of cardiac dysfunction.73 The potential clinical beneﬁt of concurrent administration
of anthracyclines and trastuzumab has been re-explored in the
neoadjuvant setting in several randomised studies with no apparent detrimental impact on cardiac health. One should remain cautious however when considering adoption of this approach outside
of the clinical trial setting, given the small numbers of highly selected patients enrolled in these studies and the short duration
of follow-up.29,56,57,59,61–64
Cardiotoxicity in trials of dual HER2 inhibition – trastuzumab with
lapatinib or pertuzumab
In the NeoALLTO study (Table 3), patients received anthracycline-based chemotherapy postoperatively with concurrent
administration of lapatinib, or trastuzumab, or both. No major cardiac dysfunction has been reported to date.60 Similarly in GeparQuinto, the concurrent administration of trastuzumab or lapatinib
with epirubicin/cyclophosphamide-docetaxel resulted in low levels of symptomatic cardiotoxicity (1%).61 In the NeoSphere study,
the addition of pertuzumab to trastuzumab resulted in only one
reported case of congestive heart failure in a woman with a history
of coronary stents and cardiac treatment with digitalis for an
unrelated cardiac problem.64 Changes in left ventricular ejection
fraction were within 15% in all of the trastuzumab, pertuzumab,
and combination groups, suggesting that the addition of pertuzumab over a short course of four cycles of chemotherapy did
not add signiﬁcantly to short term cardiotoxicity.64 These results
are encouraging; however, we await the longer term safety data,
in particular from the adjuvant portion of this trial in which anthracyclines were delivered with concurrent trastuzumab following
surgery.
Most recently, the TRYPHAENA study73 tested the addition of
pertuzumab and trastuzumab to both anthracycline and taxane
portions of neoadjuvant chemotherapy or to the taxane portion
only. The primary endpoint of the study was cardiac safety. The results showed no increase in cardiotoxicity when targeted treatment was delivered with the anthracycline portion concurrently.
Similarly, low levels of short-term cardiotoxicity were seen in this
study with six cycles of non-anthracycline chemotherapy and
trastuzumab plus pertuzumab.
To date, the limited data available on dual targeted therapies
does not suggest an increase in cardiac toxicity. This is reﬂected
in the change in the trastuzumab label to include its use in the neoadjuvant setting in combination with chemotherapy. However, the
duration of follow-up has been relatively short and as such, the
widespread adoption of concurrent anthracyclines with trastuzumab in a ‘real world’ setting is premature. Bozovic-Spasojevic
et al.74 undertook a combined analysis of 3 neoadjuvant trials29,56,57
in which anthracyclines were combined with trastuzumab. The
concurrent use of anthracycline-based chemotherapy and trastuzumab was associated with a trend towards an increased risk of
cardiac toxicity (OR 1.95, 95% CI 1.16–3.29; P = 0.36), thus highlighting the need for extra vigilance when considering the adoption
of this treatment approach in the non-clinical trial setting.
Non-cardiac toxicity with HER2-targeted therapies
While most attention has focused on the potential cardiac toxicity of HER2-targeted therapies, several signiﬁcant non-cardiac
toxicities have been observed in phase II/III clinical trials. In NeoALLTO, women randomised to the lapatinib-containing arms experienced signiﬁcant grade 3/4 diarrhoea (21% lapatinib; 23%
628
S. Dent et al. / Cancer Treatment Reviews 39 (2013) 622–631
lapatinib/trastuzumab).60 Similar rates of diarrhoea have been reported in smaller phase II neoadjuvant trials,54,63 necessitating extra vigilance in toxicity monitoring and supportive care measures.
In the run-in portion of the GeparQuinto trial,61 82% of the 60 patients enrolled in the lapatinib arm experienced grade 3/4 neutropenia necessitating the mandatory administration of growth
factors for patients randomised to lapatinib and docetaxel in the
main study. In addition, 34.5% of patients in the run-in phase discontinued treatment early, leading to a reduction in the dose of
lapatinib from 1250 mg/day to 1000 mg/day in the main study.
In NeoSphere, the addition of pertuzumab to trastuzumab in
combination with docetaxel did not signiﬁcantly increase toxicity.64 There were numerically more cases of grade 3/4 asthenia
(2% vs. 0%) in the triple therapy arm but the incidence of grade
3/4 neutropenia was lower (45% vs. 57%). The incidence of febrile
neutropenia (7% vs. 8%) as well as grade 3/4 diarrhoea (6% vs.
4%) was similar in both arms. In contrast, the addition of pertuzumab to trastuzumab and docetaxel in the metastatic setting resulted in signiﬁcantly more grade 3/4 diarrhoea (7.9% vs. 5.0%),75
possibly reﬂecting the longer duration of exposure in this trial. In
NeoSphere, the combination of pertuzumab plus trastuzumab
without docetaxel was very well tolerated, with only 7% of patients
experiencing any grade 3/4 toxicity, conﬁrming that the majority
of side effects of combination therapy are due to the cytotoxic
agents.64
It is imperative that we continue to prospectively collect information on the toxicities of these targeted therapies not only in the
clinical trial setting but also in clinical practise. Longer follow-up of
targeted therapy trials, particularly in those patients treated with
curative intent, are needed to establish the long-term safety of
these agents.
Novel HER2-targeted agents in ongoing neoadjuvant clinical trials
Neratinib
Neratinib, similar to lapatinib, is an oral, dual-activity but irreversible pan-inhibitor of epidermal growth factor receptor (EGFR)
tyrosine kinases. It targets EGFR, HER2, and HER4,76 and is an active agent in patients whose disease has progressed following
trastuzumab-based therapy.77 A randomised phase II study (NSABP
FB-7) of neratinib versus trastuzumab in combination with weekly
paclitaxel, followed by doxorubicin and cyclophosphamide as neoadjuvant therapy is currently recruiting women with HER2-positive, locally advanced breast cancer (NCT01008150). Neratinib is
also one of several investigational agents to be tested in the neoadjuvant I-SPY 2 trial on a backbone of paclitaxel followed by doxorubicin/cyclophosphamide (NCT01042379).
Trastuzumab-emtansine (T-DM1)
T-DM1 is a novel agent, comprised of trastuzumab, a stable linker, and emtansine, a potent microtubule inhibitor.78,79 Upon binding to HER2, T-DM1 is internalised and emtansine is released
intracellularly, causing direct cytotoxicity80 thus T-DM1 requires
only HER2 expression for activity not a functional HER2 signalling
pathway. A phase II trial evaluating the safety and efﬁcacy of TDM1 in the neoadjuvant/adjuvant setting after the completion of
anthracycline-based chemotherapy in patients with early HER2positive breast cancer has completed accrual (NCT01196052) and
a neoadjuvant comparison of T-DM1 versus trastuzumab in combination with endocrine therapy is actively recruiting
(NCT01745965).
Afatinib (BIBW 2992)
Afatinib is a potent, irreversible receptor tyrosine kinase inhibitor targeting HER1 and HER2. The drug has been tested in a small,
three-arm neoadjuvant study as a single-agent compared with
lapatinib or trastuzumab (each given for 6 weeks prior to deﬁnitive
breast surgery) and results are pending (NCT00826267). A second
single arm study, currently recruiting is assessing the efﬁcacy
and safety of afatinib in combination with trastuzumab and paclitaxel prior to an anthracycline and trastuzumab combination and
breast surgery (NCT01594177).
Discussion
The addition of HER2-targeted agents to a chemotherapy backbone in the neoadjuvant setting, has resulted in improved pCR
rates (26–65%) over the same chemotherapy partner alone (19–
28%) in women with HER2-ampliﬁed breast cancers.56–59 However,
a number of women treated with this approach (single HER2
blockade/chemotherapy) will not achieve a pCR and it is in this
population that dual HER2 blockade may be beneﬁcial. Several trials have demonstrated the clinical beneﬁt of dual HER2 blockade in
addition to a chemotherapy backbone.60,62–64 Mature data from
these and ongoing adjuvant trials such as ALTTO (NCT00490139)
and APHINITY (NCT01358877) are needed to establish the value
of dual HER2 blockade on DFS and OS. In addition, the feasibility
of dual HER2 blockade in the non-clinical trial setting is dependent
on the toxicity proﬁle of these combinations as discussed
previously.
A number of clinical trials have tested the combination of anthracyclines given concurrently with anti-HER2 therapy, a practise
largely abandoned due to high rates of cardiac toxicity observed
with this approach in the metastatic setting. None of these trials
have shown signiﬁcant increase in short-term cardiac toxicity57
and the trastuzumab label has recently been changed by the European Medicines Agency (EMA)80 to include treatment ‘in combination with neoadjuvant chemotherapy’, which could contain an
anthracycline. However, no study has yet shown a signiﬁcant
improvement in pCR rate or any survival endpoint with the addition of a HER2-targeted agent to both the anthracycline and taxane
portion of a regimen versus the taxane portion alone, or indeed to
taxane-based chemotherapy plus a HER2-targeted agent in the absence of an anthracycline. Indeed in TRYPHAENA73 the pCR rates
and incidence of short-term cardiotoxicity were comparable in
all three arms. Until the time that such outcome data, and indeed
longer term cardiotoxicity data are available, regimens that employ concurrent anthracycline and HER2-targeted agents should
be reserved for patients who fulﬁl the strict entry criteria and monitoring requirements of the studies in which these regimens were
tested.
The optimal duration of neoadjuvant therapy is not clear.
Although six to eight cycles of chemotherapy prior to surgery is
established practise, the impressive pCR rate with only 12 weeks
of dual HER2-targeted agents plus chemotherapy in the NeoSphere64 and NeoALTTO60 studies suggest that shorter durations
of highly active regimens may be feasible. As all patients had treatment postoperatively to balance out the chemotherapy regimens
in these trials, future studies will be required to determine the
optimal duration of neoadjuvant therapy. The optimal duration
of trastuzumab therapy has not been established. Current guidelines suggest that completion of 1 year of HER2-targeted therapy
is considered standard.67,68 Shorter durations may be similarly efﬁcacious81 but further trials are underway to test this hypothesis
such as SOLD (NCT00593697), PERSEPHONE (NCT00712140), and
PHARE (NCT00381901). Preliminary results from PHARE, designed
to test 6 months vs. 12 months of adjuvant trastuzumab using a
non-inferiority design, were recently presented.82 The conclusion
was that 6 months of treatment could not be classed as non-inferior to 12 months statistically. Retrospective sub-group analysis
suggested that the 6-month regimen may be inferior in women
S. Dent et al. / Cancer Treatment Reviews 39 (2013) 622–631
with ER-negative disease who received sequential chemotherapy
then trastuzumab, although this did not reach statistical
signiﬁcance.
Perhaps the greatest challenge in breast oncology is the personalisation of therapy through identiﬁcation of predictive biomarkers
of tumour sensitivity. In the neoadjuvant setting, dynamic changes
in biomarkers can also be assessed either through serial tumour
biopsy, blood draw for circulating tumour cells (CTCs) and other
markers or molecular imaging to assess tumour metabolic pathways or drug distribution. All of these approaches are currently under investigation in neoadjuvant trials of HER2-targeted agents.
Although it is beyond the scope of this paper to review all such
data, some examples merit special mention. In the study of Holmes
et al. all patients had core needle biopsies at baseline and 2 weeks
into HER2-targeted therapy (Table 3).62 Results were analysed
based on the subsequent achievement of pCR in the breast and
demonstrated that resistant tumours were signiﬁcantly more
likely to have intact PI3K, autophagy and stem cell proliferation
pathways. Differences between treatment arms (trastuzumab vs.
lapatinib vs. combination) were also detected although patient
numbers were small and these results will require veriﬁcation in
the translational studies of larger trials such as NeoALTTO,60
GeparQuinto61 and NeoSphere.64
Translational results from the GeparQuinto study have already
been published for circulating biomarkers.83 In particular, a decrease in levels early after therapy initiation was predictive of response to lapatinib-based but not trastuzumab-based treatment.
CTCs may also be useful biomarkers of prognosis and response to
therapy, however they are only detectable in a minority of patients
undergoing neoadjuvant therapy, limiting their clinical utility with
current detection methods. Intriguingly, in the GeparQuattro neoadjuvant study, of the 22% (46/213) of patients with P1 CTC/
7.5 mL sample, HER2-overexpressing CTCs were found in 8 patients with HER2-negative primary tumours.84 Similarly, CTCs
scored HER2-negative or weakly HER2-positive before or after neoadjuvant therapy in 11 of 21 patients with HER2-positive primary
tumours, potentially identifying a mechanism of trastuzumab
resistance.84 There was no correlation between CTC levels and
pCR in this or the NeoALTTO study, in which a similar low percentage of patients had detectable CTCs.85
The neoadjuvant setting provides an ideal testing ground for
agents, where relatively small trials, with carefully conducted
sequential biopsy and correlative biomarker studies, are taking
us closer to the goal of personalised medicine. Perhaps the best
example of this is the I-SPY 2 Trial (Investigation of Serial Studies
to Predict Your Therapeutic Response with Imaging and Molecular
Analysis 2; NCT01042379), which seeks to identify improved treatment regimens for subsets of patients on the basis of molecular
characteristics (biomarker signatures) of their disease. The trial design is adaptive such that regimens that show a high Bayesian predictive probability of being more effective than standard therapy
will graduate from the trial with their corresponding biomarker
signature(s) and regimens will be dropped if they show a low probability of improved efﬁcacy. Imaging in the I-SPY 2 trial is with serial magnetic resonance imaging, which shows high sensitivity.
There may be even greater utility in pursuing molecular imaging
techniques such as positron emission tomography/computed
tomography although preclinical data suggest that the more established radio-isotopes such as 18FDG may be suboptimal and clinical
data are currently awaited.85,86
One ﬁnal consideration is the approach to the patient with
residual cancer at surgery after ‘state of the art’ neoadjuvant therapy. Analysis of residual tumour for predictive biomarkers is a priority for future studies as these patients are known to have a poor
prognosis, although a signiﬁcant proportion will not relapse
despite the lack of pCR. Few data are available on the molecular
629
characteristics of residual disease so far although Mittendorf
et al. examined 25 post-treatment tumours for HER2 expression
by ﬂuorescence in situ hybridisation and found that 8 (32%) were
HER2 negative, suggesting that alternate therapeutic strategies
may be required in this subpopulation.87 The GeparQuinto study
has explored this phenomenon pragmatically in women with
triple-negative tumours without pCR randomising to weekly
paclitaxel ± everolimus, patients without pCR to neoadjuvant chemotherapy were randomised to weekly paclitaxel ± everolimus.88
In a similar fashion, a randomised trial of T-DM1 versus continued
post-operative trastuzumab is planned in women with HER2positive primary breast cancers and residual disease after neoadjuvant therapy.
Conclusions
Overall, the future is looking brighter for patients diagnosed
with HER2-positive breast cancer with combinations of HER2-targeted agents showing great promise in improving outcomes. The
neoadjuvant setting provides an ideal testing ground for novel
agents, where relatively small trials, with carefully conducted
sequential biopsy and correlative biomarker studies, are taking
us closer to the goal of personalised medicine.
Conﬂict of interest statement
The authors take full responsibility for the content of this review article. Support for editorial assistance was provided by F.
Hoffmann-La Roche, Ltd., Basel, Switzerland. The authors did not
receive ﬁnancial compensation for this review article.
Sacha Howell has received travel grants and honoraria for advisory boards from F. Hoffmann-La Roche Ltd. Arnd Honig has received travel grants and honoraria for advisory boards from, and
acted as a consultant for, F. Hoffmann-La Roche Ltd. Susan Dent
has received honoraria for speaking engagements and advisory
boards from F. Hoffmann-La Roche Ltd. Max Mano has received
honoraria for speaking engagements and travel grants from F. Hoffmann-La Roche Ltd. Basak Oyan has received travel grants from F.
Hoffmann-La Roche Ltd. The authors have no other conﬂicts to
declare.
Author contributions
Literature search: Sacha Howell and Basak Oyan Conception and
design: All authors.
Collection and assembly of data: All authors.
Data analysis and interpretation: All authors.
Manuscript writing: All authors.
Final approval of manuscript: All authors.
Acknowledgements
We would like to acknowledge editorial assistance and literature searching provided by Gardiner-Caldwell Communications,
support for which was provided by F. Hoffmann-La Roche Ltd.,
Basel, Switzerland.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.ctrv.2013.01.002.
630
S. Dent et al. / Cancer Treatment Reviews 39 (2013) 622–631
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