Invited review

Surgical treatment of primary breast cancer in the

neoadjuvant setting
S. Kmmel
1
, J. Holtschmidt
1
and S. Loibl
2,3
1
Kliniken Essen Mitte, Klinik fr Senologie, Essen,
2
German Breast Group, Neu-Isenburg, and
3
Sana Klinikum Offenbach, Offenbach, Germany
Correspondence to: Professor S. Loibl, German Breast Group, GBG Forschungs GmbH, Martin-Behaim-Strasse 12, 63263 Neu-Isenburg, Germany
(e-mail: sibylle.loibl@germanbreastgroup.de)
Background: Neoadjuvant chemotherapy (NACT) is a standard treatment option for primary operable
breast cancer when adjuvant chemotherapy is indicated.
Methods: This article reviews the use of NACT in breast cancer treatment.
Results: Pathological complete response (pCR) rates of up to 60 per cent have been reached for
certain breast cancer subgroups. Patients achieving a pCR have a lower locoregional recurrence rate.
Nevertheless, the rate of breast-conserving surgery seems to be stable at around 6570 per cent, although
more than 80 per cent of patients respond to NACT. The risk of local relapse does not appear to be higher
after NACT, which supports the recommendation to operate within the new margins, as long as there
is no tumour in the inked area of the surgical specimen. However, tumours do not shrink concentrically
and the re-excision rate is higher after NACT. Mastectomy rates for lobular carcinomas remain high
irrespective of tumour response. The role of sentinel lymph node biopsy (SLNB) in the context of NACT
has been studied in recent years, and it is not yet completely clear which type of axillary staging is the
most suitable. SLNB before NACT in clinically node-negative patients has been the preferred option.
However, this practice is currently changing, and it seems advisable to have the SLNB after NACT to
reduce the risk of a false-negative SLNB.
Conclusion: Overall, patients do beneft fromNACT, especially those with human epidermal growth fac-
tor receptor 2-positive and triple-negative breast cancer, but surgical/local procedures need to be adapted.
Cutting edge articles are invited by the BJS Editorial Team, and focus on how current research and
innovation will affect future clinical practice.
Paper accepted 2 April 2014
Published online 19 May 2014 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9545
Introduction
Neoadjuvant therapy has become a standard option in the
treatment of primary operable and locally advanced breast
cancer
1
. Initially developed for use in locally advanced
tumours, the concept of neoadjuvant chemotherapy
(NACT) has now also been adopted in the setting of early
breast cancer. The evolution of modern chemotherapy
regimens has led to a steady rise in pathological complete
response (pCR) rates over recent decades in patients with
early breast cancer. Tailored systemic therapy can be
administered according to the tumour subtype and nodal
status, and the effectiveness monitored using the primary
lesion as an in vivo chemosensitivity test (Fig. 1). The
safe use and advantages of NACT, in downstaging dis-
ease within the breast and axilla, have long been described.
As shown by the National Surgical Adjuvant Breast and
Bowel Project (NASBP) B-18 trial
2,3
, a signifcantly higher
rate of breast-conserving surgery (BCS) and downstaging
of axillary involvement can be achieved without jeopar-
dizing disease-free (DFS) and overall (OS) survival at a
follow-up of 15 years. These results date from a time when
the concomitant use of taxanes and biologicals had not
yet been implemented. Nowadays, pCR rates of 2025
per cent can be achieved by NACT alone. A combina-
tion of NACT with targeted agents, such as trastuzumab,
two agents targeted against human epidermal growth fac-
tor receptor (HER) 2 or bevacizumab, has led to pCR rates
of up to 4080 per cent, especially in HER2-positive and
triple-negative breast cancer
410
.
Although NACT regimens have been refned, leading
to high pCR rates, the rate of BCS has remained stable
(Tables 13)
1133
. Follow-up results from earlier studies
imply that the use of BCS after NACT is safe in terms
of local control as rates of locoregional recurrence (LRR)
are low following NACT and surgery
30,34
. Surgery in new
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Surgical treatment of primary breast cancer in the neoadjuvant setting 913
S
p
e
c
im
e
n
S
p
e
c
im
e
n
S
p
e
c
im
e
n
S
p
e
c
im
e
n
Adjuvant
therapy
Adjuvant
therapy
Possibility to monitor
treatment effect
Yes No Yes Partly
Breast cancer
diagnosis
Surgery
Neoadjuvant treatment
Breast cancer
diagnosis
Continue
same regimen
Change
regimen
Clinical response
Pathological
response
No clinical response
Tumour typing
and staging
Surgery
Surgery Surgery
Pathological
response
Pathological
response
Neoadjuvant treatment Adjuvant treatment
Fig. 1 Use of chemotherapy in breast cancer treatment. Boxes indicate points at which tumour samples can be collected to monitor
effects
margins adjusted for the tumour response after NACT
hence seems feasible, and is recommended
1
. However,
several questions remain to be addressed in future studies.
Can clinical assessment with magnetic resonance imaging
(MRI) or jet biopsy be used to predict a pCR reliably? Is
a further reduction in surgical radicality for disease within
the breast safe, analogous to the trend towards conservative
axillary surgery? What is the prognostic impact of such a
change in the trend of breast cancer treatment?
Pathological complete response: a good
prognostic factor
Historically, breast cancer was understood to be a localized
disease that requires radical surgery to achieve a cure.
Since the time of radical mastectomy as postulated by
Halsted in 1894, a tremendous amount of information
has been gathered, leading to a different understanding
of the disease. Breast cancer is nowadays regarded as a
systemic disease with broad biological heterogeneity. The
implementation of systemic therapies in addition to the
crude resection of affected tissue has long been shown to
improve the prognosis as measured by DFS and OS
35,36
. If
adjuvant systemic therapy is capable of eradicating minimal
residual/disseminated disease after resection of the primary
lesion, clinically occult dissemination of tumour cells must
already have taken place before surgery.
The pCR is a strong prognostic marker for supe-
rior DFS and OS, especially in the hormone receptor-
negative subgroups (either HER2-positive or -negative)
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914 S. Kmmel, J. Holtschmidt and S. Loibl
Table 1 Comparison of neoadjuvant chemotherapy regimens regarding their outcome in terms of pathological complete response and
breast-conserving surgery rates: neoadjuvant trials and trials comparing preoperative versus postoperative administration
Trial Preoperative therapy n ypT0/Tis ypN0 (%) BCS (%)
GeparDo
11
* dd A Doc 4 126 95 69
dd A Doc 4 +Tam 122 57 69
GeparDuo
12
* dd A Doc +Tam 453 102 66
A C4 then Doc +Tam 454 192 75
GeparTrio pilot
13
* TAC6 252 190 n.a.
TAC2 then 4N X 33 6 n.a.
GeparTrio
14,15
* TAC6 1085 187 68
TAC8 686 290 69 responders
57 non-responders
TAC2 then N X4 301 69 60
GeparQuattro
10,16
*
HER2-negative E C4 then Doc 4 343 187 68*
E C4 then Doc +X4 345 165 67
E C4 then Doc 4 then X4 362 191 64
HER2-positive CHT+H for HER2-positive 445 413
AGO-1
17
* E Pac 4 335 66 58
dd E3 then dd Pac 4 333 132
PREPARE
18
* E C4 then Pac 4 370 146 67
dd E3 then dd Pac 3 then CMF3 363 204 65
SWOG 0012
19
A C5 every 3 weeks then Pac 12 179 207 n.a.
A15 weekly +C daily then Pac 12 177 243
MDACC
20
FAC4 100 90 n.a
dd FAC4 99 13
CALGB 40603
21
Pac 12 then dd A C4 108 390 n.a.
+ Bev 9 every 2 weeks 110 430
+ Cb6 every 3 weeks 113 490
+ Cb+Bev 112 600
Older trials comparing preop.
and postop. administration
NSABP B-18
3
A C4 747 67
Primary surgery 759 60
ABCSG-07
22
CMF3 203 59 bpCR 66
Primary surgery 195 60
EORTC 10902
23
FEC4 350 40 35
Primary surgery 348 22
*Numbers are based on original data used for meta-analysis; data in study publication may be different. ypT or N, pathological tumour or node category
after chemotherapy; BCS, breast-conserving surgery; dd, dose dense; A, doxorubicin; Doc, docetaxel; Tam, tamoxifen; C, cyclophosphamide; TAC,
docetaxel doxorubicincyclophosphamide; n.a., not available; N, vinorelbine; X, capecitabine; E, epirubicin; HER, human epidermal growth factor
receptor; CHT, chemotherapy; H, trastuzumab; AGO, Arbeitsgemeinschaft fr Gynkologische Onkologie; Pac, paclitaxel; PREPARE, Preoperative
Epirubicin Paclitaxel Aranesp Study; CMF, cyclophosphamidemethotrexate5-fuorouracil; SWOG, Southwest Oncology Group; MDACC, MD
Anderson Cancer Center; FAC, 5-fuorouracil doxorubicincyclophosphamide; CALGB, Cancer and Leukemia Group B; Bev, bevacizumab; Cb,
carboplatin; NSABP, National Surgical Adjuvant Breast and Bowel Project; ABCSG, Austrian Breast and Colorectal Cancer Study Group; bpCR, breast
pathological complete response; EORTC, European Organization for Research and Treatment of Cancer; FEC, 5-fuorouracil epirubicin
cyclophosphamide.
as the correlation with survival is best in these groups. It
has therefore been used as the primary endpoint for many
trials of neoadjuvant therapy
3741
.
The introduction of targeted therapies such as
trastuzumab has had further impact on pCR rates and
outcome
27
. For patients with HER2-overexpressing
tumours a further improvement in the effcacy of NACT
is conceivable based on the results of the NeoSphere
8
and TRYPHAENA
4,5
trials. A signifcant increase in
pCR, defned as the absence of invasive neoplastic cells in
the breast (pathological status after neoadjuvant therapy
(yp) T0/Tis), was observed in the NeoSphere trial
8
by
addition of neoadjuvant pertuzumab to trastuzumab and
docetaxel. The TRYPHAENA trial
4
evaluated cardiac
safety and reported pCR (ypT0/Tis) rates above 60 per
cent. These results led to the US Food and Drug Adminis-
tration (FDA) approval of pertuzumab for the neoadjuvant
treatment of breast cancer
42
. In the past, new chemothera-
peutic agents had to be tested in the adjuvant setting before
approval. Adjuvant studies require years of follow-up of
clinical outcome and are therefore protracted and costly.
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Surgical treatment of primary breast cancer in the neoadjuvant setting 915
Table 2 Comparison of neoadjuvant chemotherapy regimens regarding their outcome in terms of pathological complete response and
breast-conserving surgery rates: targeted therapy trials
Trial Preoperative therapy n ypT0/Tis ypN0 (%) BCS (%)
Buzdar et al.
24
Pac 4 then FEC4 19 26 53
Pac 4 then FEC4+H24 weekly 23 65 57
(164 planned)
NSABP B-41
25
A C4 then Pac 12
+ H weekly 177 494 n.a.
+ L 171 474 n.a.
+ H weekly +L 171 602 n.a.
CHER-LOB
26
Pac 12 then FEC4
+ H weekly 36 25 67
+ L 39 26 58
+ H+L 46 47 69
NOAH
27,28
A+Pac 3 then Pac 4 then CMF3
HER2-negative 99 16 n.a.
HER2-positive 118 190 13
HER2-positive +H11 every 3 weeks 117 380 23
Neo ALTTO
6
6 weeks L then 12Pac +L 154 247 43
6 weeks H then 12Pac +H 149 295 39
6 weeks L+H then 12P+H+L 152 513 41
TRYPHAENA
4
FEC+H+P3 then Doc +H+P3 73 56 n.a.
FEC3 then Doc +H+P3 75 55 n.a.
Doc +Cb+H+P6 77 64 n.a.
NeoSphere
8
Doc 4 +H every 3 weeks 107 215 n.a.
Doc 4 +H+P every 3 weeks 107 393 n.a.
H+P every 3 weeks 107 112 n.a.
Doc +P every 3 weeks 96 18 n.a.
TECHNO
9
* E C4 then Pac +H4 217 390 64
GeparQuinto
5,29
*
HER2-positive E C4 then Doc 4+H 309 446 64
E C4 then Doc 4 +L 311 302 59
HER2-negative E C4 then Doc 4 +Bev 956 217 62
E C4 then Doc 4 969 183 62
NSABP B-40
7
Doc 4 then A C4 392 258 46
Doc 4 +X then A C4 393 232 43
Doc 4 +Gem then AC4 390 269 50
Bev 6 for half of all patients 230 with Bev n.a.
276 no Bev
*Numbers are based on original data used for meta-analysis; data in study publication may be different . ypT or N, pathological tumour or node category
after chemotherapy; BCS, breast-conserving surgery; Pac, paclitaxel; FEC, 5-fuorouracil epirubicincyclophosphamide; H, trastuzumab; NSABP,
National Surgical Adjuvant Breast and Bowel Project; A, doxorubicin; C, cyclophosphamide; n.a., not available; L, lapatinib; CHER-LOB,
Chemotherapy, Herceptin and Lapatinib in Operable Breast cancer; NOAH, NeOAdjuvant Herceptin; CMF, cyclophosphamide
methotrexate5-fuorouracil; HER, human epidermal growth factor receptor; Neo ALTTO, Neoadjuvant Lapatinib and/or Trastuzumab Treatment
Optimization; P, pertuzumab; Doc, docetaxel; Cb, carboplatin; TECHNO, Taxol Epirubicin Cyclophosphamide Herceptin Neoadjuvant; E, epirubicin;
Bev, bevacizumab; X, capecitabine; Gem, gemcitabine.
Pertuzumab was the frst drug for which an accelerated
approval was granted based on the results of a NACTstudy.
In May 2012 the FDA published draft guidance to alter this
procedure of approval
43
. The objective of this draft was the
regulation for use of pCR as an endpoint in study design to
predict and confrm clinical beneft, and the establishment
of a homogeneous defnition of pCR. Thus, the avail-
ability of new therapies for patients with high-risk early
breast cancer can be accelerated, while the confrmation of
approval is still pending.
Recently, Sikov and colleagues
21
presented preliminary
results of the Cancer and Leukemia Group B (CALGB)
40603 trial (NCT00861705) in which neoadjuvant carbo-
platin with or without bevacizumab was added to conven-
tional taxane and anthracycline-containing NACT. The
addition of carboplatin led to a signifcant increase in pCR
(ypT0/is, N0), but the increase observed with addition of
bevacizumab did not reach signifcance.
Pathological complete response
and breast-conserving surgery rates
Despite increasing pCRrates, the rate of BCS has remained
stable, irrespective of the tumour subtype (Tables 13). Too
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916 S. Kmmel, J. Holtschmidt and S. Loibl
Table 3 Comparison of neoadjuvant chemotherapy regimens regarding their outcome in terms of pathological complete response and
breast-conserving surgery rates: trials investigating taxane regimens
Trial Preoperative therapy n ypT0/Tis ypN0 (%) BCS (%)
NSABP B-27
2,30
A C4 1606 115 62
A C4 then Doc 4 805 218 64
Aberdeen
31
CVAP4 then CVAP4 52 15 bpCR 67
CVAP4 then Doc 4 52 31 bpCR 48
CVAP4 (no clinical response) then Doc 4 55 2 bpCR n.a.
Diras et al.
32
A Pac 4 133 160 58
A C4 67 10 45
ACCOG
33
A C6 180 160 20
A Doc 6 183 120 20
ypT or N, pathological tumour or node category after chemotherapy; BCS, breast-conserving surgery; NSABP, National Surgical Adjuvant Breast and
Bowel Project; A, doxorubicin; C, cyclophosphamide; Doc, docetaxel; CVAP, cyclophosphamidevincristinedoxorubicinprednisone; bpCR, breast
pathological complete response; n.a., not available; Pac, paclitaxel; ACCOG, Anglo-Celtic Cooperative Oncology Group.
many women still undergo mastectomy, even when a pCR
is obtained. This problem is particularly evident among
patients with lobular carcinoma, in whom a pCR is less
likely, but long-term outcome is superior to that in patients
with ductal carcinoma
44
. The described high rate of elec-
tive mastectomy might be due to the poorer response to
NACT. Smaller retrospective studies
45,46
have addressed
the question of whether rates of negative resection mar-
gins achieved by BCS following NACT are comparable to
those after upfront BCS. Positive margin rates were not
infuenced by NACT, and the rate of detection of residual
tumour in re-excision specimens was not signifcantly dif-
ferent. An overall association between lobular subtype and
margin involvement was described; yet, the administration
of NACT itself before surgery for lobular carcinoma did
not have an impact on the probability of residual tumour
in resection margins
45
.
A study
47
concerning the infuence of resection margin
width during BCS in the adjuvant setting on LRR rates
has been published recently. Data from 535 triple-negative
tumours were analysed retrospectively according to mar-
gin width. For patients with triple-negative tumours and
an increased risk of LRR, no signifcant infuence of mar-
gin width on local recurrence, LRR or distant recurrence
was observed. The local recurrence rate was 47 per cent if
resection margins were 2 mmor less compared with 37 per
cent for margins greater than 2 mm after a follow-up of 60
months. All patients received adjuvant whole-breast irra-
diation (WBI) and 80 per cent were allocated to adjuvant
chemotherapy, which might have contributed to local con-
trol. No data are available fromprospective trials regarding
margin width and oncological safety following NACT. A
subgroup analysis of the neoadjuvant Arbeitsgemeinschaft
fr Gynkologische Onkologie (AGO) 1 study
48
showed
superior DFS after a median follow-up of 69 months for
patients who had BCS compared with those who had mas-
tectomy after NACT. The St Gallen International Expert
Consensus on the Primary Therapy of Early Breast Can-
cer 2013
49
confrmed the minimal acceptable margin as no
tumour on the inked area of the specimen and stated that,
if BCS is desired, the only absolute contraindications are
inability to achieve clear margins after multiple resections
and inability to deliver adjuvant breast radiotherapy (RT).
Bearing in mind the trend towards increasing pCR rates
and the reduction in local therapy, the reasons for the con-
tinuing high mastectomy rates after NACT are unclear.
Thorough preoperative clinical assessment is needed in
the planning of breast surgery. The extension of resec-
tion should be adapted to the clinical tumour response, and
obstacles that hinder BCS should be identifed.
For instance, the tumour site should be marked ade-
quately. With rising pCRrates, clip placement at the begin-
ning of NACT is of paramount importance. Patients with
locally advanced breast cancer, who are scheduled primarily
for mastectomy after NACT, should be spared a mutilating
procedure when BCS with the new post-NACT margins
seams feasible. In the case of clinical complete remission,
the possibility of BCS is jeopardized if no clip is placed.
This approach is in accordance with the current guidelines
of the German gynaeco-oncological association
50
.
One problem seems to be the accurate description
of lesion size after NACT. The amount of residual
non-invasive tumour tissue is comparatively greater in
patients with HER2-positive disease than in those with
HER-2-negative tumours
51
. MRI can be used to assess
actual tumour size following NACT. In a meta-analysis
52
of preoperative MRI after NACT, only a slight overesti-
mation of tumour size was found, but levels of agreement
between measured tumour size and pathological tumour
size were still wide. Moreover, preoperative ultrasound
assessment performed comparably, but was not compared
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Surgical treatment of primary breast cancer in the neoadjuvant setting 917
directly with MRI
12
. To the authors knowledge, there are
still no available data showing a positive infuence of preop-
erative use of MRI on BCS rates. The accurate prediction
of tumour response, especially the reliable detection of
residual tumour, could be used to guide surgery and avoid
unnecessary mastectomy and reoperations for positive
margins, especially in patients with lobular carcinoma
53
.
Further studies aiming to determine the best clinical
assessment of pathological tumour response to NACT are
required. This would allow the improvements in NACT
that have resulted in higher pCR rates to be translated into
a higher BCS rate and improved cosmetic outcome.
Surgical complications following neoadjuvant
chemotherapy
An aspect of NACT that has not yet been investigated
thoroughly is the effect of preoperative treatment on sur-
gical complications. The infuence of new agents such
as biologicals and dose-dense therapies on postoperative
wound healing, wound infection, haematoma formation
and the need for reoperation has still scarcely been stud-
ied. In a recent retrospective analysis
54
, data were collected
from 44 533 patients after breast surgery. A multivariable
regression analysis was performed to identify predictors
of postoperative wound complications; 2006 patients had
received NACT before surgery. Wound complication rates
were generally low and comparable in the neoadjuvant
treatment and primary surgery groups (34 versus 31 per
cent). It was concluded that NACT does not infuence
postoperative wound healing, although there was a trend
towards a higher rate of wound complications (40 per
cent) among patients who had mastectomy and immedi-
ate reconstruction after NACT. However, these rates may
be an underestimate as postoperative complications requir-
ing reoperation were excluded. It is understandable that
mastectomies with immediate or delayed reconstruction
have higher postoperative complication rates than BCS
55
.
In smaller series
5658
of immediate breast reconstruction
following NACT, complication rates after mastectomy and
immediate autologous or expander/implant reconstruction
with or without preceding NACT were compared, and
reported to be similar. Bearing in mind the small sample
sizes, NACTdid not, however, seemto affect postoperative
complication rates.
Some reports have raised doubt about whether the use
of preoperative bevacizumab is safe
59
. Bevacizumab in
addition to chemotherapy increases the pCR rate
5,7
. The
GeparQuinto study
60
reported a non-signifcant increase
in overall surgical complications after preoperative addi-
tion of bevacizumab (11 versus 153 per cent; P =012), but
revealed an increased risk for patients who required two
or more operations to achieve clear margins for BCS
61
.
Bear and colleagues
40
documented a signifcant increase in
non-infectious wound healing complications when beva-
cizumab was administered before and after surgery accord-
ing to the NSABP B-40 protocol (overall non-infectious
wound complication rate 106 and 43 per cent with
and without bevacizumab). Complication rates doubled in
patients who had mastectomy and reconstruction. In both
studies surgery was allowed no earlier than 4 weeks after the
last administration of bevacizumab. The additional adju-
vant administration of ten cycles of bevacizumab in the
NSABP B-40 protocol might be a plausible explantion for
the reported increase in wound healing problems.
Golshan and colleagues
62
reported an increased
complication rate when performing immediate breast
reconstruction using expanders. In a single-arm study,
with only 51 patients enrolled, that evaluated neoadjuvant
cisplatinum plus bevacizumab, no signifcant increases
in wound healing complications following BCS were
observed compared with the results of a previous study
in which cisplatinum was given without bevacizumab.
Nevertheless, loss of the reconstruction (implant or
expander) was reported in four of eight patients. A further
study
63
reported no difference in overall surgical com-
plication rate among patients treated with neoadjuvant
doxorubicincyclophosphamidepaclitaxel with or with-
out bevacizumab. Patients in the two cohorts undergoing
mastectomy with or without reconstruction (autologous
tissue or implant/expander) were compared. Again, the
rate of complications was higher when implants/expanders
were used for immediate reconstruction following admin-
istration of bevacizumab in a cohort of 119 patients.
Locoregional recurrence after neoadjuvant
chemotherapy
In a meta-analysis
64
of nine randomized clinical trials, the
clinical outcome of 3861 patients receiving the same sys-
temic therapy either before or after surgery was compared.
No signifcant difference in cancer-related death, disease
progression or distant disease recurrence was reported. A
signifcant increase in LRRrate was observed in the neoad-
juvant treatment arm(relative risk 122; P =0015). Four of
the nine studies included in this meta-analysis allowed RT
alone, without any breast surgery, when a complete clinical
response was achieved. The NACT regimens administered
in those studies are not comparable with those of the cur-
rent standard of care, and clinical response was assessed
by palpation and X-ray mammography. Imaging systems
have since been refned (breast MRI). In addition, complete
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918 S. Kmmel, J. Holtschmidt and S. Loibl
response was not proven histologically by biopsy before the
decision to omit surgery was taken. Thus an increase in
LRR in the neoadjuvant arm is understandable.
Long-term follow-up results of the NSABP B-18 and
B-27 trials have been published recently
30
. These two stud-
ies included a total of 3088 patients undergoing NACT
or adjuvant chemotherapy. All underwent surgery in the
course of treatment. RT was limited to WBI following
BCS. Chest wall RT following mastectomy or RT of
regional lymph nodes was not allowed in the trial protocols,
so an infuence of unstandardized RT on locoregional con-
trol was avoided. The 10-year cumulative LRR rate after
NACT was 123 per cent for patients who had a mastec-
tomy and 103 per cent for those treated with BCS and
consecutive WBI. Clinical tumour size greater than 5 cmin
patients who had a mastectomy and age below 50 years in
the BCS group had a signifcant impact on the risk of LRR
by 10 years. Clinically node-positive (cN+) disease before
NACT and pathological nodal involvement after NACT
were independent predictors of LRR, irrespective of type
of surgical therapy. Patients who failed to achieve down-
staging of the axilla (cN+to ypN0) and breast pCR were
at higher risk of LRR. Unfortunately, data concerning hor-
mone receptor and HER2 status were not available, and
it not could not therefore be determined whether certain
subgroups may beneft more, or may be at increased risk
of LRR after NACT. Moreover, the direct comparison of
LRR rates between the two groups in NSABP B-18, which
received the same type of chemotherapy (1 group before
and 1 after surgery), was not reported.
If subgroups at increased risk of LRR could be identi-
fed, this knowledge could be included when deciding on
surgical treatment. In a recent meta-analysis
65
of 12 592
patients with breast cancer treated with initial surgery (BCS
or mastectomy) it was stated that the risk of LRR may vary
between tumour subtypes. Patients with triple-negative
breast cancer or a HER2-positive phenotype have a higher
risk of LRR than patients with luminal tumours. Lowery
and co-workers
65
reported a LRR rate of 71 per cent for
BCS and 90 per cent for mastectomy at a median follow-up
of 57 months for patients with HER2-positive breast can-
cer, these patients showing the highest risk of LRR. Keep-
ing in mind that these data were collected before the era of
trastuzumab and that all NACT was excluded, these rates
may not apply to modern NACT regimens. All patients
who had BCS underwent adjuvant RT, and 44 per cent of
those having a mastectomy received chest wall RT. Adju-
vant chemotherapy was administered to 48 per cent of all
patients.
Young age is also a risk factor for increased risk of local
recurrence. However, it seems that this is especially true for
young patients without a pCR. In one study
66
, of women
who did not achieve a pCR, the LRR rate among those
aged 35 years or less was signifcantly higher than that
among women aged 3650 years (P =0024). However,
there was no age-related difference among women who
achieved a pCR.
Is it possible that microscopic residual tumour is left
behind when BCS is performed within new margins? It
could be speculated that such resistant residual tumour
could increase the overall risk of LRR. The main target of
NACT is shifting from merely downstaging to monitoring
tumour response, and tailoring therapy and predicting
clinical outcome. At the San Antonio Breast Cancer Sym-
posium 2011, the German Breast Group presented data
from a meta-analysis
34
of seven prospective neoadjuvant
trials with a total of 6377 patients. LRR rates were anal-
ysed according to initial tumour stage, intrinsic tumour
subtype, type of surgery, pCR rate and nodal status. At
a median follow-up of 462 months, 485 patients had
experienced LRR. LRR rates for BCS were signifcantly
lower than those for mastectomy. Not surprisingly, the
percentage of women undergoing BCS declined with
increasing initial clincial tumour (cT) category (ranging
from 777 per cent for cT1 to 191 per cent for cT4d),
and LRR rate rose with increasing tumour size after
NACT (from 47 per cent for ypT0 to 312 per cent
for ypT4d). The LRR rate was higher among patients
with non-invasive residual disease (99 versus 37 per
cent). Comparing tumour subtypes, despite achieving a
pCR, luminal B/HER2-positive tumours had a higher
LRR rate (81 per cent) than all other subtypes. Among
patients who did not achieve a pCR, triple-negative
and non-luminal-like HER2-positive tumours both
displayed an extraordinary LRR rate of about 18 per cent.
Weksberg and colleagues
67
investigated the prognostic
outcome of salvage therapy in patients with local recur-
rence after NACT and BCS. Data were analysed retro-
spectively for 1589 patients, of whom 448 had undergone
surgery after NACT. Among these, 26 per cent of patients
initially treated with BCS, and 58 per cent treated with
NACTand subsequent BCS, experienced LRRat a median
follow-up of 91 months. Higher nuclear grade, higher
tumour stage and larger number of involved lymph nodes
in the NACT group may account for the difference in
LRR rate itself. No signifcant differences in DFS, OS and
locoregional control were detected in the two groups fol-
lowing salvage treatment for isolated LRR.
Therefore, resection within new margins after NACT
is safe and should be offered to more patients, enabling
translation of the increasing pCR rates into higher BCS
rates and avoidance of unnecessary mastectomies.
2014 BJS Society Ltd www.bjs.co.uk BJS 2014; 101: 912924
Published by John Wiley & Sons Ltd
Surgical treatment of primary breast cancer in the neoadjuvant setting 919
Treatment of the axilla in the era of
neoadjuvant chemotherapy
Before the NSABP B-04 trial, axillary lymph node
dissection (ALND) had been a standard procedure in
the surgical treatment of breast cancer for many years
68
.
The current standard for axillary staging is sentinel lymph
node biopsy (SLNB). The false-negative rate (FNR) in
most studies is below 10 per cent
69
. Given these results,
clinically node-negative patients can be spared ALND,
avoiding postoperative morbidity such as lymphoedema
and arm movement impairment. In particular, patients
with no metastatic lymph nodes found on ALND can
avoid a non-benefcial procedure. Moreover, based on
results from the American College of Surgeons Oncology
Group (ACOSOG) Z0011 trial
70
in 2010, ALND can be
omitted under certain preconditions (tumour smaller than
5 cm, cN0, M0, planned WBI for BCS) in patients with
affected sentinel lymph nodes (SLNs) without altering
LRR signifcantly. In this randomized trial, initial BCS
and SLNB was performed. Additional axillary metastases
were detected by ALND in 27 per cent of the patients
who had a positive SLNB. Adjuvant opposing tangential
feld WBI and adjuvant systemic therapy was mandatory
in that setting. At median follow-up of 63 years, possible
undetected remaining axillary disease in these patients
did not translate into a signifcant difference in local
recurrence or OS rate.
These conclusions apply to breast cancer in an adju-
vant treatment plan, but are they exportable to the neoad-
juvant setting? Is SLNB similarly safe when performed
after NACT? Is SLNB a reasonable surgical procedure for
patients who present with a clinically downstaged axilla?
Are SLN detection rates, sensitivity and FNRs reliable
after NACT? Is a second SLNB feasible after NACT for
patients who already had one before neoadjuvant treat-
ment? This would allow patients whose axillary lymph
nodes were cleared of tumour cells to be identifed and
avoid ALND. Two recent prospective multicentre trials
have addressed some of these questions.
The ACOSOG Z1071 trial
71
enrolled 701 patients with
non-metastatic breast cancer of any T category and con-
frmed axillary involvement. Patients underwent SLNB
followed by immediate ALND after completion of NACT.
The objective was to assess the FNR of SLNB following
NACT. At least one SLN was detected in 927 per cent,
and a FNR of 126 per cent was reported (39 patients with
a negative SLN among 310 with residual axillary disease).
This was slightly above the predefned goal of a FNRbelow
10 per cent, and applied only to patients in whom two or
more SLNs were detected. If only one SLN was detected,
the FNR increased to 31 per cent (17 patients with a neg-
ative SLN among 54 with residual axillary disease). Even
though dual-agent mapping (blue dye and radiotracer) was
used in most patients, in only 809 per cent were two or
more SLNs detected. If the system requires three or more
sentinel nodes to be collected to achieve a FNR of less than
10 per cent, two questions arise. Is a secondary ALND
necessary in 439 per cent of patients, if in only 571 per
cent more than three SLNs are detected and the additional
harvesting of some neighbouring lymph nodes is not vali-
dated? Is the initial idea of SLNB compromised if fve or
more SLNs are removed in over 20 per cent of patients?
A possible infuence could be related to the fact that all
patients were eligible for SLNB after NACT, even those
with clinical residual disease in the axilla. Low detection
rates and a raised FNR might be due to remaining tumour
burden in the desired lymph nodes. Therefore, the feasi-
bility of SLNB following NACT remains uncertain based
on these results.
Asecond prospective multicentre study that evaluated the
reliability of SLNB after NACT is the SENTINA study
72
.
A total of 2234 patients scheduled to receive NACT were
enrolled in the trial and data from 1737 were used in
the fnal analysis. Clinically node-negative patients (palpa-
tion and ultrasonography) were staged by SLNB before
NACT (arm A+B) and clinically node-positive patients
went straight to NACT (arm C+D). Patients who were
node-negative, clinically and by SLNB, received no further
axillary surgery (arm A). In those with a positive SLNB, a
second SLNB and ALND were carried out after NACT
(arm B). Re-SLNB (arm B) had the lowest detection rate
(SLN detected in only 608 per cent) and proved to be
false-negative in over 50 per cent. Patients who converted
to clinically node-negative disease after NACT received
SLNB plus immediate ALND (arm C), whereas those with
persistent clinical axillary disease received ALND (arm D).
The SLN detection rate was 801 per cent in arm C with
an overall FNR of 142 per cent (243 per cent if 1 SLN
removed, 185 per cent if 2 SLNs removed and less than 10
per cent if more than 2 SLNs removed). Interestingly, the
FNR was only 86 per cent if combined mapping (blue dye
and radiotracer) was used, although this was not signifcant
compared with the rate when radiotracer alone was used.
According to Kuehn and colleagues
72
, a re-SLNB biopsy
should not be done after NACT(armB), because the detec-
tion rate and FNR are unfavourable after the initial lym-
phatic drainage of the tumour bed has been discontinued
at primary surgery. In arm C, the lymph node detection
rate after NACT was signifcantly lower than that in arm
A+B (801 versus 99 per cent), possibly owing to the tis-
sue reaction to NACT. Unfortunately, an additional arm
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920 S. Kmmel, J. Holtschmidt and S. Loibl
investigating SLNB in patients with cN0 disease only after
NACT was not included in this study design. Therefore,
a direct comparison between detection rates of SLNB in
the cN0 situation before and after NACT cannot be made,
and the best timing of SLNB in clinical practice remains
unclear.
What conclusions can be drawn based on the results of
these two studies? Under certain preconditions (use of dual
mapping) a SLN can be detected in about 90 per cent
of patients having SLNB after NACT. An overall FNR
above 10 per cent is to be expected, and a much higher
FNR when only one SLN is harvested. However, whether
these patients with undetected residual axillary disease are
at increased risk of recurrence remains unclear. In the adju-
vant setting, the results of the ACOSOG Z0011 trial sug-
gest that possible undetected remaining axillary disease in
27 per cent of patients does not lead to a signifcant increase
in local recurrence rate after 63 years of follow-up. This
rate of undetected residual axillary tumour roughly equals
the FNR if one SLN was resected in the SENTINA and
ACOSOGZ1071 trials. Can residual tumour be left behind
after NACT without altering the prognosis? In contrast
to the patients who had SLNB after NACT, 58 per cent
of patients in the ACOSOG Z0011 study received adju-
vant chemotherapy and all were scheduled for adjuvant
WBI. In the event of BCS, subgroups undergoing SLN
alone and those having SLNB followed by ALND would
both have WBI, which would presumably further reduce
the tumour burden in the axilla. Patients undergoing mas-
tectomy with a good tumour response but a false-negative
SLNB after NACT might be at increased risk, because
they would receive neither further chemotherapy nor
adjuvant RT.
Long-term data from these studies are needed to deter-
mine how many of the patients with a false-negative SLNB
would develop LRR as frst tumour recurrence and how
this would affect OS. New studies addressing these issues
are upcoming, such as the German Intergroup Sentinel
Mamma (INSEMA) trial.
So far it is unclear whether patients who convert fromany
node-positive disease before chemotherapy to ypN0 during
NACT require further RT of the lymphatic basins. The
ACOSOG Z1071 trial
71
has reported that such a switch
from cN+to ypN0 can be obtained in 41 per cent. Cur-
rently the NSABP B-51 trial (NCT01872975) is recruiting
patients with T13, biopsy-proven node-positive breast
cancer undergoing NACT, who have negative axillary
nodes at the time of surgery (ypN0 verifed by ALND
or SLNB) (http://www.nsabp.pitt.edu/B-51.asp). Patients
undergoing BCS are being randomized to WBI with or
without regional nodal RT. Those receiving mastectomy
are being randomized to chest wall RT plus regional
nodal RT or no RT at all. The protocol allows SLNB
without ALND after NACT. In this study protocol, for
patients with histologically proven axillary involvement
before NACT, a broad spectrum of further multimodal
therapy is envisaged.
Conclusion
An increasing number of patients are being treated in the
neoadjuvant setting. Knowledge on early response-guided
therapy and the prognostic impact of pCR on survival
has increased in recent years. With NACT regimens
becoming more and more effective, the need for surgical
therapies is beginning to be questioned. For example, the
question of whether irradiation alone, without any surgical
resection of the primary tumour, is an option following a
pCR has been raised
73
. No breast surgery at all for patients
achieving a pCR is provocative, but might become an
option in the future. Still, the crucial question remains:
by what means can these patients be identifed reliably
among those with minimal residual tumour? Previous
studies
74,75
that have analysed this option retrospectively
used palpation to assess for complete clinical response.
The fndings concerning DFS and OS after RT alone
are interesting. Owing to small sample sizes, the prog-
nostic impact did not reach statistical signifcance, and
a substantial number of patients had to undergo salvage
mastectomy. Before prospective trials investigating this
matter can be undertaken, a reliable method for pre-
dicting pCR has to be evaluated. Promising additional
post-neoadjuvant therapies for patients who fail to achieve
a pCR are currently being investigated. For example,
the KATHERINE study (NCT01772472) is recruiting
patients with HER2-positive residual tumour after NACT
who will be randomized to treatment with adjuvant
standard trastuzumab versus adjuvant trastuzumab emtan-
sine (http://clinicaltrials.gov/ct2/show/record/NCT0177
2472)
76
. Based on available data, surgery within new
margins seems to be safe, although not tested in a
prospective randomized clinical trial, and should result
in a higher BCS rate. However, many questions still
remain and need to be addressed in future clinical
trials.
Acknowledgements
The authors thank B. Lederer, German Breast Group
headquarters, for editorial support.
Disclosure: The authors declare no confict of interest.
2014 BJS Society Ltd www.bjs.co.uk BJS 2014; 101: 912924
Published by John Wiley & Sons Ltd
Surgical treatment of primary breast cancer in the neoadjuvant setting 921
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BJS Special Issue on Surgical Innovations: Call for Papers
This special issue of BJS for 2015 will focus on surgical innovation in its broadest meaning. It will
include a number of invited reviews on topics ranging from cutting edge gene and nanotechnology,
all the way to new surgical techniques. Authors are encouraged to submit articles on this theme and
the closing date for submissions is 30
th
June 2014. The issue will be digital-only and we invite
simultaneous submission of videos and other digital material to maximize the use of this media. BJS
referee standards and process will remain, and all successful authors will be required to produce a
podcast to enhance their publication.
Please refer to Instructions to Authors on the BJS website (www.bjs.co.uk). Your article should be
submitted via our online system ScholarOne Manuscripts (http://mc.manuscriptcentral.com/bjs).
2014 BJS Society Ltd www.bjs.co.uk BJS 2014; 101: 912924
Published by John Wiley & Sons Ltd