Preoperative systemic therapy inlocoregional management of early breast
cancer: highlights from the Kyoto Breast
Cancer Consensus Conference
Masakazu Toi, John R. Benson, Eric
P. Winer, John F. Forbes, Gunter von
Minckwitz, Mehra Golshan, John
F. R. Robertson, et al.
Breast Cancer Research andTreatment
ISSN 0167-6806
Breast Cancer Res Treat
DOI 10.1007/s10549-012-2333-9

1 23

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Author's personal copy
Breast Cancer Res Treat
DOI 10.1007/s10549-012-2333-9

BRIEF REPORT

Preoperative systemic therapy in locoregional managementof early breast cancer: highlights from the Kyoto Breast Cancer
Consensus Conference
Masakazu Toi • John R. Benson • Eric P. Winer • John F. Forbes •Gunter von Minckwitz • Mehra Golshan • John F. R. Robertson •Hironobu Sasano • Bernard F. Cole • Louis W. C. Chow • Mark D. Pegram •Wonshik Han • Chiun-Sheng Huang • Tadashi Ikeda • Shotaro Kanao •Eun-Sook Lee • Shinzaburo Noguchi • Shinji Ohno • Ann H. Partridge •Roman Rouzier • Mitsuhiro Tozaki • Tomoharu Sugie • Akira Yamauchi •Takashi Inamoto
Received: 22 October 2012 / Accepted: 1 November 2012
Ó Springer Science+Business Media New York 2012

Abstract Data reviewed at the Kyoto Breast Cancer
Consensus Conference (KBCCC) showed that preoperative
systemic therapy (PST) could optimize surgery throughthe utilization of information relating to pre- and post-PST
tumor stage, therapeutic sensitivity, and treatment-inducedchanges in the biological characteristics of the tumor.
As such, it was noted that the biological characteristics ofthe tumor, such as hormone receptors, human epidermal
growth factor receptor-2, histological grade, cell proliferative activity, mainly defined by the Ki67 labeling index,
and the tumor’s multi-gene signature, should be consideredin the planning of both systemic and local therapy.
Furthermore, the timing of axillary sentinel lymph nodediagnosis (i.e., before or after the PST) was also noted to be

M. Toi (&)  T. Sugie
Breast Surgery, Graduate School of Medicine, Kyoto University,
54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japane-mail: info@kyoto-breast-cancer.org; toi@kuhp.kyoto-u.ac.jp

H. Sasano
Pathology, Tohoku University School of Medicine, Sendai,Japan

J. R. Benson
Cambridge Breast Unit, Addenbrooke’s Hospital,
University of Cambridge, Cambridge, UK
E. P. Winer  A. H. Partridge
Breast Oncology Center, Dana-Farber Cancer Institute,
Brigham & Women’s Cancer Center, Harvard Medical School,
Boston, MA, USA
J. F. Forbes
Surgical Oncology, University of Newcastle, Newcastle,
Australia
G. von Minckwitz
German Breast Group, Neu-Isenburg, Germany
M. Golshan
Breast Surgery, Dana-Farber Cancer Institute, Brigham &Women’s Cancer Center, Harvard Medical School, Boston,
MA, USAJ. F. R. Robertson
Breast Surgery, Royal Derby Hospital, Universityof Nottingham, Nottingham, UK

B. F. Cole
College of Engineering and Mathematical Sciences,
University of Vermont, Burlington, VT, USA
L. W. C. Chow
UNIMED Medical Institute, University of Hong Kong,
Hong Kong, Hong Kong
M. D. Pegram
Medical Oncology, Miller School of Medicine,
University of Miami, Miami, FL, USA
W. HanSurgery, Seoul National University Hospital, Seoul, Korea
C.-S. Huang
Surgery, National Taiwan University Hospital, Collegeof Medicine, National Taiwan University, Taipei, Taiwan
T. Ikeda
Surgery, Teikyo University, Tokyo, JapanS. Kanao
Diagnostic Radiology, Kyoto University Graduate Schoolof Medicine, Kyoto, Japan123

Author's personal copy
Breast Cancer Res Treatcritical in that it may influence the likelihood of axillarypreservation, even in node positive cases. In addition,
axillary diagnosis with ultrasound and concomitant fineneedle aspiration cytology or core needle biopsy (CNB)
was reported to contribute to the construction of a treatment algorithm for patient-specific or individualized axillary surgery. Following PST, planning for breast surgery
should therefore be based on tumor subtype, tumor volume
and extent, therapeutic response to PST, and patient preference. Nomograms for predicting nodal status and drug
sensitivity were also recognized as a tool to support decision-making in the selection of surgical treatment. Overall,
review of data at the KBCCC showed that PST increases
the likelihood of patients receiving localized surgery andindividualized treatment regimens.
Keywords Breast cancer  Preoperative systemic therapy 
Sentinel lymph node  Breast-conserving therapy

Introduction
Preoperative systemic therapy (PST) is the current standardof care for locally advanced breast cancer and stage II
patients who may not be immediately suitable for breastconserving surgery (BCS). Recent clinical trials havedemonstrated that survival outcomes for patients who
received PST are similar to those who received the same
treatment postoperatively [1]. Furthermore, monitoring thetumor response to PST can allow for the selection of both
systemic and surgical treatment according to individual
patient disease characteristics. Indeed, surgical options, as
localized treatment following PST should be consideredbased on the post-PST status of the tumor volume. The
timing of sentinel lymph node (SLN) diagnosis (i.e., before
or after PST) is also an important issue for consideration in
the locoregional management of early breast cancer, as is

E.-S. Lee
Division of Covergence Technology, Center for Breast Cancer,
Research Institute and Hospital, National Cancer Center,
Goyang-si, Gyeonggi-do, South Korea
S. Noguchi
Breast and Endocrine Surgery, Graduate School of Medicine,
Osaka University, Osaka, Japan
S. OhnoDepartment of Breast Oncology, National Kyushu Cancer
Center, Fukuoka, Japan
R. Rouzier
University Pierre et Marie Curie (Paris 6), Tenon Hospital, Paris,
France123

the use of predictive biomarkers for the response to PST
and nomogram/algorithms to estimate the tumor spread. In
addition, information regarding tumor response andbehavior following PST will help further understanding oftumor biology. In this article, we present a summary of
discussions from the 2nd Kyoto Breast Cancer Consensus
Conference (KBCCC) regarding the role of PST in the
management of early breast cancer, which indicated that
PST increases the likelihood of patients receiving localized
surgery and individualized treatment regimens [2].

Purpose of preoperative systemic therapy
PST has a number of purposes in the treatment of primarybreast cancer, including permitting the option of BCS for
patients who may otherwise have required total mastectomy, and monitoring of the therapeutic response to thistreatment. However, it is unclear whether PST is considered for patients who do not opt for BCS. Indeed, PST
could also be considered as a treatment option for patients
who are unlikely to achieve BCS after PST, as it provides
information regarding drug sensitivity. PST may also berecommended for patients who have a family history ofbreast cancer, including BRCA genetic mutations; knowledge of therapeutic sensitivity could be beneficial in thesubsequent treatment of these patients [3]. However,patient preferences must be factored into the clinicaldecision-making process.
Data are now available on the rates of local recurrence
after PST, including findings from the National Surgical
Adjuvant Breast and Bowel Projects (NSABP) B-18 andB-27. There was some evidence from B-18 of a doubling of
local recurrence rates among patients that underwent wide
local excision and who initially required a mastectomy,
however, when all BCS cases were included from theanalysis, the recurrence rates were similar at the 16-year
follow-up (approximately 7.7 vs. 9.9 %). It is worth noting

M. Tozaki
Kameda Medical Center, Kamogawa, Japan
A. Yamauchi
Breast Surgery, The Tazuke Kofukai Medical Research Institute,
Kitano Hospital, Osaka, Japan
T. Inamoto
Department of Breast Surgery, Tenri Hospital, Nara, Japan

Author's personal copy
Breast Cancer Res Treat

that the addition of taxanes to the B-27 study regimen
increased the pathological complete response (pCR) but
did not improve overall BCS rates [1].
According to the NSABP B-27 study, clinical nonresponders to anthracycline did not derive any survival
advantage from addition of a taxane to the treatment regimen [1], while clinical responders showed increased pCRrates and increased survival. These data all suggest thatcross-resistance/sensitivity mechanisms might exist, eventhough the pCR rates and survival benefits do not appear todemonstrate cross-resistance in vitro.
Recent studies have demonstrated that pCR rates inducedby multi-drug cytotoxic chemotherapy tend to be highest
in rapidly proliferating tumor subtypes, such as in the nonluminal human epidermal growth factor receptor-2 (HER2)
type and triple negative diseases [4, 5]. It is unlikely that pCRwill be achieved in luminal-type A diseases that are notcharacterized by rapid cell proliferation [6]. However, noestablished biomarkers currently exist to predict tumor
responses to specific chemotherapeutic agents, which represents therapeutic and research challenges in the translational study of breast cancer. In particular, persisting criticalissues for targeted therapies include the selection of patientsthat could respond to PST and the prediction of survival
outcomes (i.e., disease-free and overall survival).

Biological features of tumors and response to systemic
therapyIn the subgroups of non-luminal HER2 type and triple-negative cancers, patients who achieved pCR following preoperative chemotherapy were usually associated with morefavorable prognoses compared to patients without pCR [5, 7–10]. In addition, patients that became axillary node negative
following PST had significantly better prognoses comparedwith patients that remained node positive [11]. This finding
may also apply to patients with luminal-type B disease.
Although the definition of luminal-type A and B and the criteria for pCR varied among investigators, a large number ofattempts to select systemic treatment based on individual
tumor biology, with the aim of increasing pCR rates, havebeen reported. Indeed, several methods designed to distinguish between luminal-type A and B are currently available,
including the most promising and widely applicable Ki67/
MIB1 labeling index (Ki67LI) and/or multi-gene assays (e.g.,
PAM50, Oncotype DXÒ and MammaprintÒ), together withthe assays to evaluate ER and HER2 status and the histologic
grade of the tumor. Efforts are also underway to clarify tumor
subtypes using multiple biological parameters; most of themethods for multi-gene profiles introduced in the market arelinked to genes associated with the cellular proliferative andinvasive activity of a tumor [12]. As the downregulation of cellproliferation often results in tumor response and favorable
survival outcome [13], it is important to sequentially monitor
the tumor phenotype, for markers of cell proliferation, before
and after PST. In particular, the biomarker status of tumors ischanged by treatment in some cases [14, 15]. As a result,increased numbers of biomarkers involving basal tumors,
BRCAness, the PI3KCA/AKT, mitogen-activated protein
kinase pathway and mTOR are likely to be intensively
examined in the coming years [16–19].

Assessment of tumor volume and tumor extent
before and after PST
Objective evaluation of the pretreatment status with respect
to tumor volume and tumor extent, including potential
multifocality of any apparent unifocal lesions and nodal
involvement, is critical in the use of PST for the locoregional management of early breast cancer. Mammography,
ultrasound (US), and magnetic resonance imaging (MRI)
are in general useful for monitoring tumor response totreatment. The maximum diameter of a tumor, its volume,and contrast kinetic patterns could be evaluated using MRI.
MRI is currently the most sensitive tool for detecting
intraductal components or small residual tumors after
chemotherapy. However, it should be noted that MRI tends
to detect false-positive lesion(s) and may increase mastectomy rates by over-estimating the extent of the intraductal component. Nonetheless, it is useful for monitoring
treatment-induced changes, especially tumor volume
shrinkage from a quantitative aspect [20–22]. Additional
MRI-guided biopsies may be necessary in some circumstances for evaluation of additional lesions detected on
MRI alone (limited specificity) and these further biopsies
may help reduce unnecessary mastectomies.
Tumor shrinkage generally encourages patients tocontinue with their scheduled systemic treatment. Marked
clinical responses increase the probability of pCR, particularly in those tumors with biological features that areassociated with pCR [1]. Approximately half to two-thirdsof patients with a complete clinical response will havea pCR and one-third of patients with a pCR will haveradiological evidence of a residual tumor. Therefore,
relying on the combination comprising the biologicalcharacteristics of the tumor and the clinical therapeutic
response tends to increase the predictive accuracy forpathological response [23, 24]. Recently, several studies
have shown that dynamic MRI or PET-CT scan after the
1st or 2nd cycle of PST can provide additional information
for predicting pathological tumor response to conventional
factors [25, 26]. In addition, serial tumor biopsies can beincorporated into protocols to increase understanding oftreatment-induced changes to the tumor biology. Tumor

123

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regression and shrinkage patterns in response to PST
should be analyzed in relation to tumor subtype, rates of
BCS and local control rates after surgery [27–29].

Assessment of pathological response
As pathological assessment of the tumor response canpredict survival outcomes, it is important that competent,
board certified pathologists working in accredited institutions evaluate the tumor specimens. Thorough sectioningof the resected specimens is mandatory to determine
pathological response. In the majority of cases, the examination based on hematoxylin and eosin-stained slides is
considered sufficient; however, additional immunohistochemical evaluation with pan-cytokeratin, cytokeratins 5/6
and p63 may be required occasionally, to precisely confirm
the presence or absence of tumor cells and the non-invasivenature of carcinoma cells. For the remaining cancer cells,
examination of Ki67LI should be also considered.
Multiple classification systems, for assessment of thepathological response, have been reported in the literature[30, 31]. The absence of invasive tumor in the breast (pNoninv) and macro/micrometastases or isolated tumor cells in
the axillary nodes has been commonly used to define pCR
following PST. However, other criteria have been also used,such as pTotal (no tumor cells remaining). The criteria forassessing pathological response must be clearly enunciatedalong with monitoring of quality control and assurance
within each institution. Immunohistochemical evaluationmust be performed to insure that there are no residual
carcinoma cells after the therapy as described. Most classifications have been developed in relation to cytotoxic
chemotherapy and it might be necessary to also develop amethodology to confirm pCR for preoperative anti-HER2
containing therapy. Tumor biological features may change
in response to the modes of treatment. For instance, theshort-term changes in Ki67LI over a two-week period are
predictive of longer-term survival outcomes in endocrine
treatment [32, 33]. Low levels of KI67 expression following
PST are a predictor of a favorable prognosis. There are otherinvestigational parameters related to the immune system andtumor angiogenesis, which are potential components oftherapy-induced biological changes [34].

Breast surgery
The original tumor volume and extent, biological features
and therapeutic response are three major factors that
influence decision-making for breast surgery after PST(Fig. 1). For instance, a triple-negative tumor with awell-defined margin before PST and an excellent clinical123

response consistent with concentric shrinkage may betreated with limited resection after PST, if negative surgical margins are attainable. For luminal-type tumors, especially type B, a different treatment approach may berequired because the likelihood of achieving pCR varies
between individuals and the overall pCR rate is modest[35, 36]. At the KBCCC, it was elucidated that the surgicalprocedure and precise resection volume should be based on
both pre-and post-PST tumor volume and extent forluminal-type tumors, while for non-luminal tumors it
should be planned according to post-PST tumor status. For
clinical CR cases with non-luminal tumor subtype, very
limited resections tended to be performed. Intraoperative
identification of residual tumors may be difficult. Microclip
placement, tattooing, and photographs are quite useful for
localizing the tumor after treatment with chemotherapy.
In terms of prediction of response, Ki67LI might be usefulfor determining the probability of pCR (e.g., low proliferative
activity may relate to less chemo sensitivity), however, local
quality control of the assay needs to be performed routinely
and cut-points need to be carefully considered for each endpoint. In addition, high scores by multigene assays would be
helpful for predicting pCR in luminal subtypes [37]. Radiotherapy cannot be omitted and cannot substitute for surgery inthe majority of the cases; this is associated with doubling of
local recurrences. According to recent studies, the effectiveness of radiation therapy for local controls differs between
luminal and non-luminal disease subtypes [38]. For planning
surgical margins, different radiosensitivity among different
subtypes must be considered.

Axillary surgery
Definitive axillary treatment should be based on the initial
nodal status. US-guided fine needle biopsy/CNB is usefulfor the identification of nodal metastasis, particularly macrometastasis, before performing SLN biopsy (Table 1;
Fig. 2). SLN biopsy can be considered prior to PST forclinically node negative patients and those with a negativeneedle nodal biopsy, because the patients would have areasonably high chance of axillary preservation.
When SLN biopsy is performed before PST, surgicaltreatment of the axilla can be guided according to therecommendations shown in Table 2. Although it is necessary to discuss with the patients the uncertainty of metastasis in para- or non-SLNs for those patients with a positive
SLN, axillar lymph node dissection (ALND) can be individualized in those cases with micrometastasis or limited
macrometastatic involvement e.g., metastatic ratio \50 %(number of metastatic nodes/number of examined nodes).
The tumor response and other factors, such as age, need tobe taken into account in this situation [39–41].

Author's personal copy
Breast Cancer Res Treat*ACOS Z11 could be taken into account if node-positive.

Fig. 1 Decision-making for local therapy after PST** Tumor response should be considered. Residual tumors are resistant to the treatment
generally.
*** Nomogram / mathematical algorithm are used occasionally.

Table 1 Axillary diagnosis, sentinel lymph node biopsy
Subject

Points of discussion and remarks

Indication of SLN
biopsySNB is not contraindicated for surgery of‘‘high-risk DCIS’’ (e.g., high-grade DCIS
with comedo necrosis)
SLN biopsy should be appropriate forextensive and/or high-grade DCIS
requiring mastectomy
SLN biopsy is a standard of care for staging
the axilla in clinically node-negative
invasive breast cancer patients with T0-3,
and with multifocal/multicentric tumors

Method of SLN
biopsyAxillary ultrasound(US) diagnosis

US: Ultrasound, FNA: fine needle aspiration, CNB: Core needle biopsy

Fig. 2 Algorithm of axillary management for PST. *ACOSGZ0011
could be considered if node-positive. **Tumor response should beconsidered. ***Mathematical algorithm are used occasionally. US
ultrasound, FNA fine needle aspiration, CNB core needle biopsy

Table 2 Axillary lymph node dissection before and after PST
Nodal status
SLN diagnosis before PSTBlue dye and radioisotope (RI) method is agold standard in the method

Node negative including
ITC*

Not recommend

Micrometastasisa orlimitedmacrometastasisb

Individualized (Other factors have to betaken into account to avoid ALNDc)

Other node positive

Recommend

Several new methodologies, such as
indocyanine green fluorescence (ICGf)
method, are used in common practice
locally

SLN diagnosis after PST

Diagnostic sensitivity increases depending
on increase in tumor size

Node negative including
ITC

Avoidable (Other factors have to betaken into accountc)

Cortex thickness (e.g., [2.5 mm) helps topredict nodal metastasis

Micrometastasis orlimitedmacrometastasis

Recommend (No data support the
avoidance, but worthwhile forinvestigation)

Other node positive

Recommend

Usefulness of intraoperative US diagnosis in
detecting non-SLN is under investigation
FNA cytology/CNB

Completion of ALND

False-positive rate of FNA would be around2%
False-negative rates of FNA increasedepending on the decrease in the numberof involved nodes
If FNA or CNB positive, SLN biopsy could
be unnecessary
If FNA or CNB negative, SLN biopsy
should be considered

Several issues on axillary diagnosis were summarized

If SLN biopsy is conducted after preoperative chemotherapy, it is reasonable to infer that any remaining tumor
cells within the axillary nodes are resistant to therapy,

ITC isolated tumor cellsaMicrometastasis: size of metastasized tumor is 200 lm–2 mm

b

The metastatic rate, number of positive nodes/number of examined
nodes, \50 %cTotal mastectomy or partial mastectomy, multifocality, subtype,
lymphatic invasion and tumor response (after PST)

therefore, ALND would be indicated. If micrometastases
are only evident after PST, ALND should be recommended; however, clinical trials investigating omission of
ALND in these circumstances are warranted. If there areresidual SLN metastases post-PST, these are partially or
wholly resistant to chemotherapy and the same is presumably true of non-sentinel nodes. Patients do not usually123Author's personal copy
Breast Cancer Res Treat

Fig. 3 Nomogram/algorithm before, during, and after PST

receive any further chemotherapy, but may receive adjuvant systemic hormonal therapy, which could further
downstage non-sentinel nodes in node-positive disease if
completion ALND is not undertaken. At the KBCCC, there
was some hesitation in recommending ALND when there
was a clinical CR. This would apply to patients undergoing
either mastectomy or BCS.
Axillary management, including indications and methodology for SLN biopsy, is summarized in Table 2. It is
possible to perform a repeat SLN biopsy after PST, and thisis being explored in the German SENTINA trial. Intraoperative US examination is a potential technique for identifying metastases in non-SLNs.
The American College of Surgeons Oncology Group(ACOSOG) Z0011 trial is a phase 3 non-inferiority trial thatcompared observation only with completion ALND in breast
cancer patients with T1–T2 tumors and no palpable axillary
lymph nodes [42]. No significant differences in loco-regional
control or disease-free survival were noted between the twogroups at a median follow-up of 6.3 years. Patients with 1 or
2 SLNs (i.e., \/= 3) containing macro- or micrometastases
who underwent BCS followed by radiation therapy andsystemic therapy were randomized to observation orcompletion ALND. It was therefore suggested that non-PST
patients who met the Z0011 trial conditions could have achance of omitting completion ALND.

Nomograms and algorithms
Nomograms and algorithms are being increasingly used inbreast oncology clinics, to provide information for patientsand providers, standardize treatment, and provide tools for
informed selection of treatment. Specific examples include
tools for the prediction of pathological response to PST,
estimation of the number of involved nodes, and thepresence or absence of metastasis in non- or para-SLNs.
For PST, nomograms and algorithms should be used inconjunction with clinical information, such as tumor

123

response rates in a pathway of treatment as shown in
Fig. 3. In a case study discussed at the KBCCC (2011), it
became apparent that information from nomograms orother mathematical model predictions could significantly
influence clinical decision-making. In particular, whentreatment decisions may depend on quality-of-life considerations, or if there is a trade-off between treatment toxicity
and subsequent delay in disease progression, decisionmaking may be aided by a nomogram that shows the
expected quality-adjusted time gained (or lost) according
to different valuations that patients may place on the timespent experiencing treatment toxicity and the time spent
following disease progression [43]. It is important toimprove the predictive accuracy of these nomograms andalgorithms in prospective clinical trials and better define
indications for their clinical use. As described at the
KBCCC (2011), accuracy may be improved through theuse of meta-analysis and other methods for pooling datafrom multiple studies.

Conclusions
Review of PST shows that information relating to tumor
status, biological characteristics, and therapeutic responses
must be integrated to formulate decisions regarding surgery
and other treatment procedures. Furthermore, the timing of
SLN biopsy, before PST or after PST, can be individualized for each patient according to nodal status at presentation. Incorporation of nomograms or mathematicalalgorithms into clinical practice is a worthwhile area ofstudy that requires further investigation.

Discussants and local organizers
Akashi-Tanaka S (National Cancer Center Hospital,
Tokyo), Chang KJ (Cheng Chin Hospital, Taichung,Taiwan), Inaji H (Osaka Medical Center for Cancer andAuthor's personal copy
Breast Cancer Res Treat

Cardiovascular Diseases, Osaka), Iwase H (Kumamoto
University Hospital, Kumamoto), Iwata H (Aichi Cancer
Center, Nagoya), Kataoka M (Kyoto University Hospital,
Kyoto), Kawabata H (Toranomon Hospital, Tokyo), Kitai
T (Kyoto University, Kyoto), Kuroi K (Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome
Hospital, Tokyo), Lee SJ (Yeungnam University Hospital,
Daegu), Masuda N (Osaka National Hospital, Osaka),
Nakamura S (Showa University, Tokyo), Nishimura R(Kumamoto City Hospital, Kumamoto), Paik NS (Konkuk
University Medical Center, Seoul), Saeki T (Saitama
Medical University, Saitama), Yamagami K (Shinko Hospital, Kobe), Yamauchi H (St Luke’s International Hospital, Tokyo), Ogaki K (Kyoto Police Hospital, Kyoto),
Takada M (Kyoto University, Kyoto).
Acknowledgments We would like to express our sincere gratitude
to Professor Masahiro Hiraoka, Dr. Michihide Mitsumori, Dr. Hiroshi
Ishiguro, Dr. Takayuki Ueno, Ms. Aya Morotomi, Ms. Mihoko
Yamamoto, Ms. Chisa Takano, and Mr. David Graham for theirassistance with the preparation of this manuscript. We would also liketo thank the Commemorative Organization for the Japan World
Exposition (1970). The conference was part of a program, ‘‘Raising
Proficient Oncologists,’’ organized by the Japanese Ministry of
Education, Culture, Sports, Science, and Technology. Finally, we
would like to acknowledge the kind support of the Japan Breast
Cancer Society.
Conflict of interest

None.

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