Original article

Neoadjuvant chemotherapy with sequential anthracyclineedocetaxel

with gemcitabine for large operable or locally advanced breast
cancer: ANZ 0502 (NeoGem)
q
N. McCarthy
a, b,
*
, F. Boyle
c, d
, N. Zdenkowski
e, f
, J. Bull
e
, E. Leong
e
, A. Simpson
g
,
G. Kannourakis
h
, P.A. Francis
i, j
, J. Chirgwin
f, k, l, m
, E. Abdi
n, o
, V. Gebski
p
, A.S. Veillard
p
,
D. Zannino
p
, N. Wilcken
q
, L. Reaby
e
, D.F. Lindsay
e
, H.D. Badger
e
, J.F. Forbes
e, f, r
,
on behalf of the Australia and New Zealand Breast Cancer Trials Group
a
Cancer Care Services, Royal Brisbane and Womens Hospital, Buttereld St, Herston, Brisbane, QLD 4029, Australia
b
University of Queensland, Brisbane, QLD, Australia
c
The Mater Hospital, Sydney, NSW, Australia
d
University of Sydney, Sydney, NSW, Australia
e
Australia and New Zealand Breast Cancer Trials Group, Newcastle, NSW, Australia
f
University of Newcastle, Newcastle, NSW, Australia
g
Wellington Cancer Centre, Wellington Hospital, Wellington, New Zealand
h
Ballarat Oncology and Haematology Service, Ballarat, VIC, Australia
i
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
j
Department of Medicine, St. Vincents Hospital, University of Melbourne, VIC, Australia
k
Box Hill Hospital, Box Hill, VIC, Australia
l
Maroondah Breast Clinic, Maroondah Hospital, Ringwood East, VIC, Australia
m
Monash University, VIC, Australia
n
Tweed Hospital, Tweed Heads, NSW, Australia
o
Grifth University- Gold Coast, Southport, QLD, Australia
p
National Health and Medical Research Council Clinical Trials Centre, Sydney, NSW, Australia
q
Westmead Cancer Care Centre, Westmead Hospital, University of Sydney, NSW, Australia
r
Department of Surgical Oncology, Calvary Mater Newcastle, Newcastle, NSW, Australia
a r t i c l e i n f o
Article history:
Received 18 July 2013
Received in revised form
4 November 2013
Accepted 4 December 2013
Keywords:
Locally advanced breast cancer
Neoadjuvant chemotherapy
Gemcitabine
Phase 2
Pathologic complete response
a b s t r a c t
Background: Neoadjuvant chemotherapy has a sound rationale for use in women with large operable
breast cancer, and achievement of pathological complete response (pCR) is prognostic. Epirubicin and
cyclophosphamide followed by docetaxel is a standard chemotherapy regimen for early breast cancer.
In metastatic breast cancer the combination of gemcitabine and a taxane has shown promising results.
This phase II study investigated the efcacy and safety of incorporating gemcitabine into neoadjuvant
therapy.
Methods: Female patients with operable breast cancer that was clinically T2 (3 cm) or T3-4, N0-1, M0
were enrolled to receive 24 weeks of neoadjuvant chemotherapy using epirubicin and cyclophosphamide
followed by docetaxel and gemcitabine, plus trastuzumab if HER2-positive. The primary endpoint was
the pathological complete response (pCR) rate in the breast in separate HER2-negative and HER2-
positive cohorts. Secondary endpoints included pCR in both the breast and axillary lymph nodes, clin-
ical and radiological response rates, disease free survival and safety.
Results: 81 patients were enrolled: 63 HER2-negative and 18 HER2-positive. 67 (84%) completed all
cycles of chemotherapy, and 78 (96%) proceeded to surgery. pCR was achieved by 12 (20%) patients with
HER2-negative, and 9 (53%) with HER2-positive disease. At the rst interim analysis, addition of pro-
phylactic G-CSF was recommended due to excess neutropenia. The HER2-negative cohort was closed to
accrual because it did not meet the pre-specied target for pCR, and the HER2-positive cohort was closed
q
Presentations: Presented in part at the 34th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 2011.
* Corresponding author. Present address: ICON Cancer Care Wesley, Wesley Medical Centre, 40 Chasely Street, Auchenower, QLD 4066, Australia. Tel.: 61 7
3737 4636; fax: 61 7 3737 4601.
E-mail address: NMcCarthy@iconcancercare.com.au (N. McCarthy).
Contents lists available at ScienceDirect
The Breast
j ournal homepage: www. el sevi er. com/ brst
0960-9776/$ e see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.breast.2013.12.001
The Breast 23 (2014) 142e151
due to slow accrual. At a median follow-up of 24 months, 12 of 81 (15%) patients had experienced a
relapse of their breast cancer.
Conclusion: Neoadjuvant gemcitabine, when added to docetaxel, after epirubicin and cyclophosphamide,
did not reach the pre-specied expectations for pCR rate in HER2-negative tumours. Excess neutropenia
was observed, requiring growth factor support. Addition of gemcitabine to docetaxel in this schedule
cannot be recommended.
Australia and New Zealand Clinical Trials Registry (www.anzctr.org.au) registration number
ACTRN12606000191594.
2013 Elsevier Ltd. All rights reserved.
Introduction
Large operable and locally advanced breast cancers are
associated with a relatively poor prognosis and higher risk of
micrometastatic disease [1] and require multimodality therapy.
Neoadjuvant or induction chemotherapy is the standard treat-
ment for inoperable locally advanced breast cancer and is also
used for large operable cancers to help achieve breast conserva-
tion. Although a survival benet has not been demonstrated with
neoadjuvant compared with adjuvant chemotherapy, there is
sound rationale for using neoadjuvant chemotherapy [2]. Apart
from improving the likelihood of breast conservation [3], neo-
adjuvant chemotherapy provides early treatment to the primary
tumour and micrometastatic disease and also provides an early
indication of the effectiveness of the particular chemotherapeutic
agents [4]. Furthermore, the pathologic complete response (pCR)
rate following neoadjuvant chemotherapy has been shown to be a
strong prognostic measure of long-term disease-free survival
(DFS) and overall survival (OS) [5,6], at least in oestrogen receptor
(ER) negative disease.
Anthracycline-based chemotherapy remains the core of most
pre- and post-operative chemotherapy regimens for women
diagnosed with high risk locally advanced breast cancer. The
addition of a taxane following 4 cycles of an anthracycline-based
regimen has been associated with increased pathologic complete
response rate in the neoadjuvant setting [2] and further incre-
mental survival benet in the adjuvant setting [7]. Standard
treatment for the human epidermal growth factor receptor 2
(HER2) over-expressing breast cancer subgroup now incorporates
trastuzumab, most frequently given concurrently with a taxane
[8]. Gemcitabine, a nucleoside analogue anti-metabolite, has
established safety and efcacy in metastatic breast cancer [9].
Combining gemcitabine with docetaxel is active in patients with
anthracycline pre-treated metastatic disease, without excess
toxicity [10]. Trastuzumab has also been combined successfully
with taxanes and gemcitabine either alone or in combination,
with promising results in patients with HER2 positive metastatic
disease [11,12].
We therefore sought to test the feasibility and activity of a
neoadjuvant regimen consisting of a standard anthracycline-based
regimen followed by a combination of gemcitabine and docetaxel,
with or without trastuzumab (depending on HER2 status), in this
Phase II study in women with large operable or locally advanced
breast cancer.
Materials and methods
Patient selection
Patients with histologically conrmed unilateral, operable or
locally advanced (at initial presentation) T2 (3 cm), T3-4, N0-1,
M0 primary breast cancer were eligible. Other eligibility criteria
included age 18 years, no prior chemotherapy or hormonal
therapy for breast cancer or other invasive cancer and ECOG per-
formance status 0e2. Eligible patients were required to have
adequate bone marrow, neurological, hepatic, renal and cardiac
function. Patients with inoperable, inammatory or metastatic
breast cancer were excluded.
Study design
This was a Phase II study with a planned enrolment of 147
patients across two cohorts, 84 HER2-negative and 63 HER2-
positive. All enrolled patients were planned to receive combined
epirubicin (E) and cyclophosphamide (C) followed by combined
docetaxel (Taxotere

, D) and gemcitabine (Gemzar

, G) chemo-
therapy in the neoadjuvant setting. Patients with HER2 positive
tumours also received trastuzumab (Herceptin

, H) in combina-
tion with DG followed by adjuvant H for a total of 1-year. The
primary endpoint of the study was the pCR rate of the primary
tumour in the breast after neoadjuvant chemotherapy, at the time
of surgery. Secondary endpoints were (i) pCR rate in both the
breast and axillary lymph nodes, (ii) clinical and radiological
complete response rates following neoadjuvant anthracycline
chemotherapy and after all neoadjuvant chemotherapy, (iii)
disease-free and overall survival and (iv) safety prole of this
neoadjuvant chemotherapy regimen.
The study was conducted in accordance with Good Clinical
Practice guidelines and the tenets of the Declaration of Helsinki.
Participants provided written, informed consent. It was approved
by local Human Research Ethic Committees, underwent review by
the Consumer Advisory Panel of the ANZBCTG and was registered
with the Australia and New Zealand Clinical Trials Registry (www.
anzctr.org.au), registration number ACTRN12606000191594.
Treatment plan
Neoadjuvant chemotherapy consisted of a rst phase of E
90 mg/m [2] and C 600 mg/m [2] both intravenous (IV) on day 1 of
a 21-day cycle for 4 cycles (Appendix A). This was followed by a
second phase of chemotherapy starting 3 weeks after the start of
the 4th cycle of EC and consisting of D 75 mg/m[2] IV on day 1 and
G 1000 mg/m [2] (30 min IV infusion) on days 1 and 8 of a 21-day
cycle for 4 cycles. In HER2-positive patients, H was commenced
with the taxane phase of chemotherapy using a loading dose of
4 mg/kg followed by 2 mg/kg IV weekly for 12 weeks. This tras-
tuzumab schedule was used based on the prevailing neoadjuvant
literature, in which weekly trastuzumab was combined with
concurrent chemotherapy [13]. After surgery, H was administered
at 6 mg/kg IV every 3 weeks up to a total of one year.
Patients with oestrogen (ER) and/or progesterone receptor (PgR)
positive tumours were recommended to receive adjuvant endo-
crine therapy, as chosen by the investigator, for a minimum of 5
years. An aromatase inhibitor, tamoxifen, or a sequential combi-
nation of the two was recommended for postmenopausal women.
Tamoxifen was recommended for premenopausal women.
N. McCarthy et al. / The Breast 23 (2014) 142e151 143
Tamoxifen could be combined with ovarian suppression in locally
advanced cases, in line with national guidelines.
Prophylactic anti-emetics were administered according to
institutional guidelines. In the initial protocol, secondary pro-
phylaxis with granulocyte-colony stimulating factor (G-CSF) was
permitted, using subcutaneous lgrastim 5 mg/kg day 2 to day 7,
after an episode of febrile neutropenia or delayed neutrophil
count recovery beyond day 21. If the neutrophil count was 0.5e
1.0 10
9
/L when day 8 G was due, G was given, and peglgrastim
6 mg was added on day 9, or lgrastim 5 mg/kg was added from
day 9 to day 15 of that cycle. Gemcitabine was omitted if the
neutrophil count on day 8 was <0.5 10
9
/L. Gemcitabine dose
was reduced after rst and subsequent episodes of febrile neu-
tropenia, and study treatment was discontinued after a third
episode. After an interim safety analysis showed a high rate of
grade 3/4 neutropenia, a protocol amendment mandated primary
lgrastim 5 mg/kg day 2 to day 7 with each cycle of DG.
Comprehensive dose modication recommendations are shown
in Appendix B.
Patients proceeded to surgery following completion of the 4
cycles of DG/DGH, preferably within 4 weeks. The decision to
proceed to mastectomy or breast conserving surgery (BCS) was at
the discretion of the breast surgeon and the patient. Axillary sur-
gery consisted of standard axillary dissection.
Patients who underwent BCS received radiotherapy to the
whole breast with a boost to the primary site. Post-mastectomy
radiotherapy was recommended in patients with at least clinical
stage III disease or clinical tumour size 5 cm at diagnosis,
pathological involvement of 4 axillary lymph nodes post-
chemotherapy or at the discretion of the treating radiation oncol-
ogist if other risk factors were present.
Patient assessments
Before study entry, radiological investigations of the breast
(mammogram, ultrasound), and staging investigations (CT chest/
abdomen/pelvis, bone scan) were undertaken. Women of child-
bearing potential were required to have a negative pregnancy test
and to use adequate contraception for the duration of study
treatment. A core biopsy from the breast tumour was performed
in all patients before treatment. HER2 status was determined by
immunohistochemistry (IHC) and conrmed with either chro-
mogenic or uorescent in situ hybridization if IHC equivocal (2).
Repeat core biopsy of persisting breast or axillary tumour was
collected following completion of 2 cycles of EC for translational
research purposes. History, physical examination (including clin-
ical tumour response), recording of toxicity and blood tests were
performed before each chemotherapy cycle and 21 days after the
last cycle of DG/DGH. Full blood count, liver function and elec-
trolyte tests were required prior to day 1 of each chemotherapy
cycle and prior to day 8 of each cycle of DG. Repeat left ventricular
ejection fraction (LVEF) measurement and breast ultrasound were
performed after the 4th cycle of EC and after the 4th cycle of DG/
DGH.
The primary endpoint of pCR was dened as no histologic evi-
dence of invasive cancer cells in the surgical breast specimen (ypT0/
is), based on the National Surgical Adjuvant Breast and Bowel
Project (NSABP) denition [14]. The secondary endpoint of pCR in
both breast and axillary nodes was dened as no histologic
evidence of invasive cancer cells in the surgical breast specimen
and axillary nodes (ypT0/is, ypN0). A minimum of 10e15 parafn
blocks from the primary site were examined before assigning a
response of pCR. Clinical response was dened as complete: no
palpable disease; partial: >50% decrease in the product of the di-
ameters of the tumour; stable disease: between 50% decrease and
25% increase in size; progressive disease: more than 25% increase in
the size of the lesion or appearance of new ipsilateral adenopathy.
Radiological responses using ultrasound, were dened as com-
plete: complete disappearance of lesions; partial: more than 50%
reduction in the product of the perpendicular diameters of the
tumour; stable: between 50% decrease and 25% increase in size;
progressive: more than 25% increase in size (Appendix C). Toxicities
were graded according to the National Cancer Institute Common
Toxicity Criteria version 3.0 [15].
Statistical considerations
Enrolled patients who received at least 1 cycle of chemotherapy
were evaluable for efcacy and safety. The study had a Simon two-
stage design with the decision to proceed to the second stage based
on interim analysis of efcacy in patients in each cohort in the rst
stage. The combination of EC followed by DG/DGH chemotherapy
was expected to achieve a pCR rate of 35% in the HER2-negative
cohort and 39% in the HER2-positive cohort, with the lowest limit
of therapeutic efcacy being a pCR rate of 22% in the HER2-negative
cohort and 24% in the HER2-positive cohort. Based on these as-
sumptions, 84 HER2-negative and 63 HER2-positive patients were
required to detect evidence of treatment activity based on a power
of 80% and 95% level of signicance. The 95% condence intervals
for pCR rates were based on the Wilson method. Statistical analyses
were carried out using Statistical Analysis System (SAS Version 9.2)
software.
An interim efcacy analysis was planned. Seven or more
responses (pCR) among the rst 27 evaluable patients in the HER2-
negative cohort were required to complete recruitment of 84
patients. Five or more responses (pCR) among the rst 17 evaluable
patients in the HER2-positive cohort were required to continue
recruitment of 63 patients. Planned interim safety analyses were
scheduled with consideration being given by the Independent Data
and Safety Monitoring Committee (IDSMC) to modify or stop the
protocol if the number of dened adverse events exceeded the
thresholds listed in Table 1 [16].
Results
Patient characteristics
From August 2006 to April 2009, 81 patients were enrolled
from 14 institutions in Australia and New Zealand. Baseline de-
mographic and clinical patient characteristics are summarised in
Table 2. Median age was 49 years (range 28e71 years). Median
primary tumour size on physical examination was 6.0 cm (range
3.0e15.0 cm), 31 (38%) were grade III, 63 (78%) were HER2-
negative and 18 (22%) were HER2-positive. Overall, 44 (54%)
were hormone receptor (ER and/or PgR) positive/HER2 negative,
19 (23%) hormone receptor (HR) negative/HER2-negative (triple
negative), 8 (10%) HR-negative/HER2-positive and 10 (12%) HR-
positive/HER2-positive. The CONSORT diagram (Fig. 1) shows the
number of patients who completed assigned treatments.
Efcacy
Of the 81 enrolled patients, 78 (96%) proceeded to surgical
resection after neoadjuvant chemotherapy. Of the 3 patients who
did not undergo surgery, one was ineligible for inclusion in the
study due to inoperable disease at baseline; one stopped
chemotherapy due to multiple adverse events from DG (grade 3
fatigue, mucositis, myalgia) and withdrew consent for surgery;
and one withdrew consent for surgery after completing all
chemotherapy cycles. In addition, one patient withdrew consent
N. McCarthy et al. / The Breast 23 (2014) 142e151 144
for DG after completing 4 cycles of EC, and 3 patients withdrew
consent for further DG after receiving at least one cycle. These
patients all proceeded to surgery and were evaluable for study
outcomes. Sixty one (78%) of those who underwent resection
were HER2-negative, and 17 (22%) HER2-positive. Breast
conserving surgery was performed in 20 patients (26%). Of the 78
patients who underwent surgical resection, 21 (27%) achieved
pCR (Table 3) including 12/61 (20%) in the HER2-negative cohort
and 9/17 (53%) in the HER2-positive cohort. Within the HER2-
negative cohort who underwent resection, 5/43 (12% [95%CI:
5%e24%]) with HR-positive tumours achieved pCR compared
with 7/18 (39% [95% CI: 20%e61%]) with triple negative tumours.
Of the assessable patients with HR-positive HER2-positive tu-
mours, 5/10 (50% [95%CI: 24%e76%]) achieved a pCR.Four out of
seven (57% [95%CI: 25%e84%]) with HR-negative HER2-positive
tumours achieved a pCR. Of the 21 patients who had pCR in
the breast, 2 had positive axillary lymph nodes resulting in a total
of 19 patients (24%) with pCR in both the breast and axillary
nodes.
After 40 patients had completed neoadjuvant therapy and
undergone surgical resection, a planned efcacy analysis showed
that 3 of the 27 patients (11%) with HER2-negative tumours had
achieved a pCR. Within this cohort, 3 of 9 (33%) who had a triple
negative tumour achieved a pCR and none of the 18 patients who
had HR-positive HER2-negative tumours had achieved a pCR. On
the basis that a pre-dened futility boundary had been crossed, the
IDSMC recommended that the HER2-negative cohort be closed to
accrual. The steering committee also elected to close the HER2-
positive cohort due to slow accrual.
Following all cycles of neoadjuvant chemotherapy, 52 patients
(64%) had a clinical response, 27 (33%) of which were complete
clinical responses. Objective radiological response was observed
in 38 (47%) patients of which 8 (10%) were complete radiological
responses. A pCR was observed in 5 of the 8 patients with a
complete radiological response in the breast and axilla, while 14
patients had a pCR but did not achieve a conrmed complete
radiological response. Following the EC cycles, 40 patients (49%)
had a clinical response, 11 (14%) of which were complete clinical
responses. Twenty eight patients (35%) had a radiological
response, only 1 (1%) of which was a complete radiological
response. Four patients had clinical progressive disease during EC,
one of whom changed to DG after 2 cycles, while the remaining 3
completed 4 cycles of EC. These patients all had clinical responses
after completing 4 cycles of DG. Four patients had clinical or
radiological progressive disease after 4 cycles of DG and one
stopped DG after 3 cycles due to clinical progression and pro-
ceeded to surgery.
Toxicity
A protocol amendment mandated G-CSF for each cycle of DG
after an interim safety analysis found 22 (96%) of 23 patients had
experienced grade 3 neutropenia. After primary G-CSF was star-
ted, the rate of grade 3/4 neutropenia decreased from 75% to 60%,
while the rate of febrile neutropenia remained relatively stable, at
9% before and 12% after the amendment. Overall, grade 3/4 febrile
neutropenia was experienced by 10% of patients, while grade 3/4
neutropenia was recorded in 70% of patients (Table 4). Grade 3/4
fatigue was experienced by 15% of patients. Apart from fatigue and
haematological toxicity, 47% of patients experienced at least grade
3 toxicity (41% grade 3, 6% grade 4). Gemcitabine was omitted or
delayed in 38% of patients on at least one occasion due to haema-
tologic toxicity. After primary G-CSF was started, the relative dose
intensity of gemcitabine increased from 84 to 92% and the relative
dose intensity of docetaxel remained stable at 99%. No treatment-
related deaths occurred.
Survival
After median follow-up of 24 months, DFS for the evaluable
population was 86%. In HER2-negative patients, the DFS was 87%
(95% CI 76e93%) compared with 83% (95% CI 57e94%) in HER2--
positive patients (Fig. 2). At the time of analysis, 10 patients (12%)
had relapsed: 3 were HR-positive/HER2-negative, 4 were triple
negative, 1 was HR-positive/HER2-positive, and 2 were HR-nega-
tive/HER2-positive. The relapses were local only in 2 patients,
distant only in 6 patients and both local and distant in 2 patients. Of
the local recurrences, 3 patients had in-breast recurrences after
breast conserving surgery; one had a chest wall recurrence after
mastectomy. In addition to those patients who relapsed, two pa-
tients withdrew consent for surgery after completion of chemo-
therapy. Both patients had residual disease and subsequently
developed local progression, and one developed distant metastases
and died. Overall survival at 24 months was 94% with 5 deaths
Table 1
Planned interim safety analyses.
Interim analysis
1 2 3
Number of patients completing at least
8 cycles of chemotherapy
20 30 40
Minimum number of non-haematological
toxicities (expected rate 20% grade 3/4)
7 10 13
Minimum number of events of pneumonitis
(expected rate 5% grade 2)
3 4 5
Minimum number of cardiac events
(expected rate 4% grade 3/4)
2 3 4
Minimum number of grade 2, 3 or 4 toxicities required to be observed before
consideration will be given to either modifying the regimen or ceasing accrual [16].
Table 2
Baseline characteristics.
HER2 negative HER2 positive Total
n 63 (78%) n 18 (22%) n 81 (100%)
Demographic data
Median age at registration
(range)
50 (28e71) 44 (32e64) 49 (28e71)
ECOG 0 58 (92%) 18 (100%) 76 (94%)
ECOG 1 5 (8%) 0 (0%) 5 (6%)
Clinical TNM
Tumour Stage
cT2 23 (37%) 9 (50%) 32 (40%)
cT3 36 (57%) 8 (44%) 44 (54%)
cT4 4 (6%) 1 (6%) 5 (6%)
Axillary lymph node status
cN0 24 (38%) 3 (17%) 27 (33%)
cN1 39 (62%) 15 (83%) 54 (67%)
Breast cancer diagnosis
Histopathologic type
Inltrating ductal
carcinoma
46 (73%) 17 (94%) 63 (78%)
Inltrating lobular
carcinoma
13 (21%) 0 (0%) 13 (16%)
Other 4 (6%) 1 (6%) 5 (6%)
Histologic grade
Unable to be assessed 28 (44%) 5 (28%) 33 (41%)
G1: Low 0 (0%) 1 (6%) 1 (1%)
G2: Intermediate 16 (25%) 0 (0%) 16 (20%)
G3: High 19 (30%) 12 (67%) 31 (38%)
Hormone receptor status at diagnosis
ER and/or PgR positive 44 (70%) 10 (56%) 54 (67%)
ER and PgR negative 19 (30%) 8 (44%) 27 (33%)
N. McCarthy et al. / The Breast 23 (2014) 142e151 145
Fig. 1. CONSORT diagram.
N. McCarthy et al. / The Breast 23 (2014) 142e151 146
recorded, all attributed to breast cancer. All 5 patients had docu-
mented metastatic disease from breast cancer prior to death. Three
of these patients had triple negative disease, while 2 had HR-
negative HER2-positive disease.
Discussion
This Phase II study was designed when there was great
enthusiasm for the improved pCR rates seen when docetaxel was
added following adriamycin and cyclophosphamide in NSABP B-
27, and the increasing evidence for the prognostic signicance of
pCR. A chemotherapy doublet in the metastatic setting had also
shown superior response rates and progression free survival with
the addition of either capecitabine to docetaxel [17], or gemci-
tabine to paclitaxel [18]. Our study showed that the addition of
another cytotoxic agent gemcitabine to docetaxel, which
required a docetaxel dose reduction compared to docetaxel
monotherapy, did not result in pCR rates sufcient to justify
further study.
Recent studies in the neoadjuvant and adjuvant setting have
reported similar ndings. In the randomised NSABP B-38 study,
4894 patients were treated with either TAC or dose dense AC
followed by paclitaxel gemcitabine in the adjuvant setting and
there was no signicant difference in OS or DFS [19]. The UK
tAnGo trial, which randomised 3152 patients to EC followed by
P G, did not demonstrate an advantage for the addition of G
[20]. Adjuvant trials adding capecitabine to docetaxel have also
been negative [21]. In the randomised Neo-tAnGo study, the
addition of G to paclitaxel (P) either before or after EC, did not
markedly improve pCR rates (15% vs 20%) [22]. The NSABP B-40
study randomised 1206 patients with operable HER-2 negative
breast cancer. G did not improve the pCR rate when added to D,
followed by AC, at a cost of increased toxicity [23]. Thus, in this
study in the neoadjuvant setting, adding an additional cytotoxic
agent to a taxane did not show an advantage compared with the
signicant improvement in pCR rates seen with the addition of
targeted therapy in patients with HER2 positive breast cancer
[8].
When the NeoGem protocol was developed, the low pCR rate
associated with hormone receptor (HR) positive breast cancer,
particularly the luminal A subtype, was not well established.
However, a pooled analysis of neoadjuvant studies has since
shown a low 13% pCR rate in those women with ER positive tu-
mours, which did not correlate with DFS or OS [24]. Our un-
planned subset analysis by ER, PgR and HER2 involves small
numbers, but the pCR rates seen are consistent with published
reports [24]. We cannot comment on intrinsic subtype, as Ki-67
was not assessed. The low pCR rate (19%) seen in the 53 patients
(65%) with HR positive disease reduced the overall pCR rate in the
HER2 negative cohort and was a major factor in the trials early
closure. Future neoadjuvant trials should be designed to assess
HER2 positive, triple negative and hormone receptor positive
HER2 negative cohorts separately.
Neoadjuvant therapy may be advantageous for large or locally
advanced HR positive breast cancers in order to obtain breast
conservation. We found no advantage from adding an additional
cytotoxic agent in this group, and alternative strategies are
needed. The relatively low rate of breast conserving surgery in our
population (26%) is likely to relate to the large median tumour size
of 6 cm. In addition, despite becoming eligible for breast
conserving surgery after neoadjuvant chemotherapy, many pa-
tients and/or surgeons will opt for a mastectomy [25]. We did not
collect data on patient preference or suitability for breast
conserving surgery.
The role of neoadjuvant endocrine therapy appears promising
[26], but needs further evaluation. This Iranian group randomised
101 patients to CAF chemotherapy with or without concurrent
letrozole. Encouragingly, the pCR rate with combination therapy
was 31%, compared with 10% with chemotherapy alone, in the 62
Table 3
Pathological response.
pCR breast
a
pCR breast and
axillary nodes
b
n (%) 95% CI n (%) 95% CI
HER2-negative, HR-positive 5/43 (12) 5e24 4/43 (9) 4e22
HER2-negative, HR-negative
(TNBC)
7/18 (39) 20e61 7/18 (39) 20e61
Total HER2 negative 12/61 (20) 12e31 11/61 (18) 10e29
HER2-positive, HR-positive 5/10 (50) 24e76 5/10 (50) 24e76
HER2-positive, HR-negative 4/7 (57) 25e84 3/7 (43) 16e75
Total HER2 positive 9/17 (53) 31e74 8/17 (47) 26e69
Total
c
21/78 (27) 18e38 19/78 (24) 16e35
a
No histologic evidence of invasive carcinoma in the surgical breast specimen.
b
No evidence of invasive carcinoma in the breast or axillary lymph nodes.
c
3 patients did not proceed to surgery: ER and/or PgR positive/HER2-negative
(n 2), ER and PgR negative/HER2-positive (n 1).
Table 4
Adverse events.
HER2 negative HER2 positive Total
n 63 (%) n 18 n 81
No. of patients (%) No. of patients (%) No. of patients (%)
Toxicity Any
Grade
Grade
3e4
Any
Grade
Grade
3e4
Any
Grade
Grade
3e4
Fatigue 60 (95) 11 (17) 17 (94) 1 (6) 77 (95) 12 (15)
Febrile
neutropenia
5 (8) 5 (8) 3 (17) 3 (17) 8 (10) 8 (10)
Infection and
Grade 3/4
neutrophils
5 (8) 3 (5) 2 (11) 1 (6) 7 (9) 4 (5)
Neutropenia 63 (100) 45 (71) 18 (100) 12 (67) 81 (100) 57 (70)
Thrombocytopenia 63 (100) 5 (8) 18 (100) 1 (6) 81 (100) 6 (7)
Rash 24 (38) 2 (3) 7 (39) 1 (6) 31 (38) 3 (4)
Mucositis/
stomatitis
40 (63) 5 (8) 11 (61) 1 (6) 51 (63) 6 (7)
Diarrhoea 45 (71) 4 (6) 13 (72) 3 (17) 58 (72) 7 (9)
Pain 54 (86) 5 (8) 14 (78) 2 (11) 68 (84) 7 (9)
Toxicity graded using NCI CTCAE V3.0 [15], 3% (total) G3/4 shown.
Fig. 2. Disease-free survival.
N. McCarthy et al. / The Breast 23 (2014) 142e151 147
patients with ER positive tumours. Other potential strategies
include combining letrozole with a cyclin dependent kinase
(CDK) 4/6 inhibitor [27] or targeting the PI3K-Akt-mTOR pathway
in combination with endocrine therapy [28,29].
Patients with HER2 positive or triple negative breast cancer
(TNBC) have higher response rates to neoadjuvant therapy. pCR
correlates with prognosis and may be useful as a surrogate
endpoint in clinical trials [24]. Our denitions of pathological,
clinical and radiological response were based on those used by the
NSABP [14], however pCR in the breast and axilla has subsequently
been shown to be a more robust predictor of outcome [24]. Rather
than adding cytotoxic agents, the use of dual HER2-targeted ther-
apy with pertuzumab [30] or lapatinib [31] has been shown to
improve pCR rates. The inherent heterogeneity of TNBC makes
targeted therapy a challenge and a number of newagents are being
tested [32e34].
In the NeoGem study, the addition of G to D after EC increased
haematological toxicity, requiring primary growth factor support
to maintain dose intensity. In 38% of patients, one or more doses
of gemcitabine were omitted or delayed due to haematological
toxicity. This led to concern that efcacy may have been
compromised due to insufcient exposure to gemcitabine. After
primary G-CSF was added to the protocol, relative dose intensity
increased.
The rate of haematological toxicity in this study was compara-
tively high. In SUCCESS and NSABP B38, two large studies using
secondary G-CSF with adjuvant taxane G following an
anthracycline-containing regimen, the rate of febrile neutropenia
was 4% in the gemcitabine arm [19,35]. Low rates of neutropenia
(G3/4 11%) and febrile neutropenia (1%) were achieved in a study
using peglgrastim as primary prophylaxis with a dose dense
neoadjuvant triplet G (2000 mg/m
2
), E (50 mg/m
2
) and albumin-
bound paclitaxel (175 mg/m
2
) [36]. However, in a rst-line meta-
static study using G with a taxane, grade 3/4 neutropenia was
between 39.3% and 56.5% [37]. Peglgrastim has been shown to be
superior to lgrastim at preventing febrile neutropenia, which may
reect better compliance with a simpler dosing schedule [38].
Alternate scheduling, such as that used in sarcoma, using gemci-
tabine D1 then gemcitabine and docetaxel D8, may have optimised
dose intensity due to less neutropenia-related chemotherapy
omission at D8 [39].
Apart from ER, PgR and HER-2, established predictive breast
cancer biomarkers are lacking. NeoGem biomarker substudies are
yet to be completed, but we hope to identify a subset of patients
who may benet from the addition of gemcitabine, for incorpora-
tion into future trials. A Ki-67 of >20% or a basal-like PAM50 sub-
type have been shown to predict for benet when G is added to a
taxane-containing regimen [40,41].
Conclusion
This schedule of gemcitabine, added to a taxane and
anthracycline-containing neoadjuvant regimen, cannot be rec-
ommended. The pathological response rate was lower than ex-
pected, particularly in patients with ER positive HER2 negative
tumours. It was difcult to maintain dose intensity due to a high
rate of neutropenia, requiring G-CSF support. Alternative strategies
are required to continue to improve outcomes, including better
patient selection, and evaluation of novel agents in the neo-
adjuvant setting.
Role of the funding source
This study was sponsored by the Australia and New Zealand
Breast Cancer Trials Group (ANZBCTG) and the National Health
and Medical Research Council (project grant ID 455513). Roche
Products, Pty Limited (Australia) and Eli Lilly Australia gave
research grants and study drugs and Sano-Aventis supplied
study drug. Data was collected by the ANZBCTG and analysed in
collaboration with the National Health and Medical Research
Council Clinical Trials Centre. All authors had full access to the
data and had nal responsibility for the decision to submit for
publication.
Contributors
Australia and New Zealand Breast Cancer Trials Group and
supporting staff (2004e2012).
Principal investigator: Nicole McCarthy.
Administrative ofce: Dianne Lindsay, Heath Badger, Lauren
Macnab, Kristy Taubman, Rose Lucas, Former staff: Kristy Schmidt.
Statisticians: Val Gebski, Anne-Sophie Veillard, Diana Zannino.
Steering Committee: N McCarthy, F Boyle, JF Forbes, G Kan-
nourakis, C Underhill, J Chirgwin, B Robinson, C Shannon, P Francis,
B Mann, R Snyder, E Abdi, A Simpson, MPitcher, S Guthrie, V Gebski,
R Sutherland, D Lindsay, H Badger.
Collaborators
Names in brackets show co-investigators and trial coordinators.
G Kannourakis (H Francis, R Bond, C Carden, L Cartledge, R
Cotton, A Ewan) Ballarat Oncology and Haematology Services.
C Underhill (P Bilinski, KClarke, R Eek, B Francis, D Kee, C Steer, C
Hodgkins) Border Medical Oncology.
J Chirgwin (D Campbell, S Chua, G Goss, R Masters, L Pellegrini, J
Dryden, D Rapson) Box Hill Hospital.
B Robinson (B Fitzharris, D Gibbs, D Harris, I Henderson, M
Jeffery, A Landers, A Rahman, P Tan, B Egan, A Smith, L Thompson)
Christchurch Hospital.
J Chirgwin (S Chua, G Goss, J Dryden, J Flynn) Maroondah
Hospital.
C Shannon (P Mainwaring, M Xavier, N Arnold, G Crosbie, J
Marshall, M Pawsey) Mater Adult Hospital, Brisbane.
F Boyle (S Baron-Hay, D Bell, K Moore, J Page, A Spillane, M
Sywak, D Dash, K Sheather) Mater Hospital, Sydney.
P Francis (F Day, K Field, R Jennens, D Kee, E Lim, G Mallasara, L
Mileshkin, KA Phillips, N Potasz, J Power, A Marshall, N Roylance)
Peter MacCallum Cancer Centre.
N McCarthy (G Beadle, A Hadley, B Hughes, P Inglis, D Wyld, A
Earley, C Fletcher, W Pritchard, N Roberts) Royal Brisbane and
Womens Hospital.
B Mann (S Ananda, D Carden, J Collins, R de Boer, M Green, G
Lindeman, J Miller, C Murphy, C Scott, J Tie, M Lieschke, C Master-
son, A Sherman) The Royal Melbourne Hospital.
R Snyder (I Burns, A Dowling, P Francis, SA McLachlan, G
Newnham, A Wirth, D Gaitanis, L Pasanen, N Ranieri, S Vickery) St
Vincents Hospital, Melbourne.
E Abdi (H AL-Saig, B Brigham, D Martin, J Polong, R Srivastav, C
Chorlton) The Tweed Hospital.
A Simpson (C Barrow, J Edwards, B King, B Luey, A ODonnell, K
Clarke, J Bowers, M Kler) Wellington Hospital.
M Pitcher (R de Boer, M Green, C Oakman, S Wong, L Wilkinson)
Western Hospital.
Authorship
Each author has signicantly contributed to the study.
N. McCarthy et al. / The Breast 23 (2014) 142e151 148
Conict of interest statement
Prudence Francis: Education travel assistance from Sano-
Aventis.
No other authors have a conict of interest to declare, including
employment, consultancies, stock ownership, honoraria, paid
expert testimony, patent applications/registrations and grants or
other funding.
Acknowledgements
We thank the women who participated in the study, their
doctors and the research teams at each of the participating hospi-
tals; the Australia and New Zealand Breast Cancer Trials Group ANZ
0502 Study Team; the NeoGem steering committee, and the Na-
tional Health and Medical Research Council of Australia (project
grant ID 455513). Roche Products, Pty Limited (Australia) (drug,
research grants), Eli Lilly Australia (drug, research grant), Sano-
Aventis (drug), supported the trial and commented on ndings of
this study, but had no input into data analysis or interpretation.
Appendix A
Appendix B
Patient assessments
Before study entry, all patients had a history, physical exami-
nation (including ECOG score, and breast and axilla clinical tumour
measurement), haematology and biochemistry blood tests, radio-
logical investigations of the breast (mammogram, ultrasound),
evaluation of cardiac function (ECG and echocardiogram or multi-
ple gated acquisition (MUGA)) and staging investigations (CT chest/
abdomen/pelvis, bone scan). A core biopsy from the breast tumour
was performed in all patients before treatment. A biopsy was also
obtained from the axilla if there were clinically or radiologically
suspicious axillary nodes. Repeat core biopsy was collected
following completion of 2 cycles of EC for translational research
purposes (to be reported elsewhere). History, physical examination
(including clinical tumour response), recording of toxicity and
blood tests were performed before each chemotherapy cycle and 21
days after the last cycle of DG/DGH. Repeat LVEF measurement and
breast ultrasound were performed after the 4th cycle of EC and
after the 4th cycle of DG/DGH.
Dose modications
Granulocyte-colony stimulating factor (G-CSF) was permitted
for treatment of febrile neutropenia and for delayed recovery of
Study schema.
N. McCarthy et al. / The Breast 23 (2014) 142e151 149
neutrophil count at day 21. It was also permitted for secondary
prophylaxis in patients with a prior episode of febrile neutropenia
or infection or with delayed recovery of neutrophil count after 28
days in an earlier cycle. Treatment was delayed in the event of
neutrophil count <1.2 10
9
/L on day 21 until recovery to
1.2 10
9
/L, platelet count <100 10
9
/L, or grade 2 non-
haematological toxicities (other than alopecia and nausea). Dose
reductions were made in the event of delayed recovery of neutro-
phil count (after day 28), >1 episode of febrile neutropenia (except
G, where dose was only reduced after the rst episode of febrile
neutropenia), platelet count <100 10
9
/L on day 21, grade 2
vomiting, any grade 2 non-haematological toxicity (other than al-
opecia and nausea) that resulted in treatment delay, grade 3 non-
haematological toxicities.
Additional treatment modications were recommended for E, D,
G and H. E was ceased in the event of symptoms of signs of
congestive cardiac failure, persistent arrhythmia, or LVEF falling
below normal range or by >15% from baseline. D was withheld in
the event of grade 2 neurosensory toxicity lasting 3 weeks, and
dose-reduced if persisting for >3 weeks, or in the event of grade 3e
4 neurosensory toxicity. It was also stopped after recurrent grade 3,
or a single episode of grade 4, anaphylactoid and hypersensitivity
reactions. The day 8 dose of G was omitted if the day 8 neutrophil
count was <0.5 10
9
/L, platelet count <75 10
9
/L or for grade 2
non-haematological toxicity (except alopecia and nausea). Finally,
H was ceased in the event of a symptomatic cardiac event, which
included congestive cardiac failure, grade 3 or 4 arrhythmia, or
grade 3 or 4 ischaemia or infarction. It was also stopped if LVEF
remained persistently below 45% or persistently 10% below
baseline.
Appendix C
Response denitions
Pathologic response
The pathologic complete response (pCR) will be determined
following examination of tissue (breast and nodes) removed at the
time of surgery.
In keeping with new international trial standards, a minimum of
10e15parafnembeddedblocks fromtheinitial primarysitemust be
examined before assigning a response of pCR. Rates of pCR may
uctuate between trials due to variability of the extent of tissue
sampling for histopathologic examination at the time of denitive
surgery. Less extensive sampling will result in falsely high pCR rates.
pCR denition is based on that used by the NSABP [2].
Clinical response
Baseline clinical measurements will be recorded and the
response rate will be calculated and recorded after the completion
of four cycles of EC and at the End of Chemotherapy (EOC) visit (pre-
surgery). Clinical measurements may be performed and recorded
before each cycle of chemotherapy. Response in the primary breast
mass and axillary mass (if present) will be recorded separately.
Clinical response denition is based on that used by the
NSABP [14].
Radiological response
An ultrasound of the affected breast and axilla (if disease pre-
sent) will be performed and measurements recorded at baseline,
after four cycles of EC and at the end of chemotherapy visit.
Response in the primary breast mass and axillary mass (if present)
will be recorded separately. Bi-dimensional measurements should
be recorded if possible.
Radiological response denition is based on that used by the
NSABP [14].
Appendix D
Pathologic complete response (pCR) No histologic evidence of invasive
cancer cells in the surgical breast
specimen
Pathologic complete response in breast
and axillary nodes
(pCR breast nodes)
No histologic evidence of invasive
cancer cells in the surgical breast
specimen and axillary nodes
Pathologic persistent disease (pINV) Residual histologic evidence of
invasive cancer in the surgical
breast specimen
Clinical complete response
(cCR)
No residual palpable mass in
breast or axilla
Clinical partial response
(cPR)
50% reduction of the tumour area
compared to pre-treatment measurements.
Area is measured as the product of the two
longest perpendicular diameters of the
tumour
Clinical stable disease (cSD) Patients who do not meet criteria for cPD
or cPR and show <25% increase in tumour
area compared with pretreatment
Clinical progressive disease
(cPD)
25% increase in the tumour area
compared to pre-treatment measurement
or appearance of new clinically
suspicious ipsilateral axillary adenopathy
Complete response (rCR): Complete disappearance of lesion(s)
Partial response (rPR): 50% reduction of the tumour area
compared to pre-treatment measurements.
Area is measured as the product of the two
longest perpendicular diameters of the tumour
Stable disease (rSD): patients who do not meet criteria for rPD or
rPR and show <25% increase in tumour area
compared with pretreatment
Progression (rPD): 25% increase in the tumour area compared
to pre-treatment measurement or appearance
of new disease
Disease-free survival by subtype.
N. McCarthy et al. / The Breast 23 (2014) 142e151 150
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