Ann Surg Oncol
DOI 10.1245/s10434-011-1666-7

ORIGINAL ARTICLE – BREAST ONCOLOGY

Identifying Gaps in the Locoregional Management of Early Breast
Cancer: Highlights from the Kyoto Consensus Conference
Masakazu Toi, MD1, Eric P. Winer, MD2, Takashi Inamoto, MD3, John R. Benson, MD4, John F. Forbes, MD5,
Michihide Mitsumori, MD6, John F. R. Robertson, MD7, Hironobu Sasano, MD8, Gunter von Minckwitz, MD9,
Akira Yamauchi, MD3, and V. Suzanne Klimberg, MD10
Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan; 2Breast Oncology
Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 3Department of Breast Surgery, Kitano
Hospital, Osaka, Japan; 4Cambridge Breast Unit, Addenbrooke’s Hospital and University of Cambridge, Cambridge, UK;
5
Department of Surgical Oncology, University of Newcastle, Newcastle, Australia; 6Department of Radiation Oncology
and Image-Applied Therapy, Graduate School of Medicine at Kyoto University, Kyoto, Japan; 7Professorial Unit ofSurgery, Division of Breast Surgery, University of Nottingham, Nottingham, UK; 8Department of Pathology, Tohoku
University School of Medicine, Sendai, Japan; 9Department of Gynecology and Obstetrics, Goethe University, Frankfurt
am Main, Germany; 10Division of Breast Surgical Oncology, Rockefeller Cancer Institute, University of Arkansas for
Medical Sciences, Little Rock, AR
1

ABSTRACT A consensus conference was held to investigate issues related to the local management of early breast
cancer. Here, we highlight the major topics discussed at theconference and propose ideas for future studies. Regarding
axillary management, we examined three major issues.
First, we discussed whether the use of axillary reverse
mapping could clarify the lymphatic system of breast andwhether the ipsilateral arm might help avoid lymphedema.
Second, the use of an indocyanine green fluorescent navigation system was discussed for intraoperative lymphatic
mapping. These new issues should be examined further inpractice. Finally, some agreement was reached on theimportance of ‘‘four-node diagnosis’’ to aid in the diagnostic accuracy of sentinel nodes. Regarding breast
treatment, there was general agreement that the clinicalvalue of surgical margins in predicting local failure wasdependent on the tumor’s intrinsic biology and subtypes.
For patients treated with preoperative chemotherapy, lessThis study is conducted on behalf of the 2009 Kyoto Breast Cancer
Consensus Conference panelists.
Ó Society of Surgical Oncology 2011
First Received: 8 December 2010
M. Toi, MD
e-mail: toi@kuhp.kyoto-u.ac.jp

extensive excision may be feasible in those who respond tosystemic therapy in an acceptable manner. Most trials of
preoperative chemotherapy lack outcome data on local
recurrence. Therefore, there is a need for such data foroverview analysis. We also agreed that radiation after
mastectomy may be beneficial in node-positive cases
where more than four nodes are involved. Throughout thediscussions for both invasive and noninvasive disease, theinvestigation of nomograms was justified for major issues
in the decision-making process, such as the presence orabsence of microinvasion and the involvement of nonsentinel nodes in sentinel node-positive patients.

When the paradigm for breast cancer treatment shiftedfrom the localized Halstedian view to Fisher’s systemic
vision, the role of surgery in the local management of breast
cancer changed simultaneously. Appropriate local management is critical for the effective treatment of early breast
cancer, because local recurrence might be a marker for thedevelopment of distant disease. In addition, reducing the
failure of local treatment might result in the reduction ofsystemic treatment failure. Understanding the biologicaland pathological phenotype of breast cancer helps in constructing systemic therapeutic plans as well as in achieving
successful individualized local management strategies.
Among the aspects of breast cancer treatment that haverecently drawn attention, we have focused on the local

M. Toi et al.

management of primary noninvasive and invasive breast
cancer, including: breast conservation in conjunction withpreoperative systemic treatments; axillary management;
radiation therapy for the breast, chest wall, and regional
lymph nodes; and the pathological assessment of excised
tissues. At the Kyoto Breast Cancer Consensus Conference,
held in 2009, we clarified these issues for purposes of
discussion and sought to reach a consensus.

TABLE 1 Pathological factors to be recorded while analyzing breast
cancer specimens
Tumor size
Measured microscopically in orthogonal directions including thelargest size of invasion
Margin
Method used to assess (orange peel or perpendicular cut)Definition of positive margin
Distance of margin from cut edge (mm)

PATHOLOGICAL ANALYSIS

Additional treatment in positive cases (re-excision or boost RT)
Biological markers
ER (%)

Tumor extension to the surgical margins of the resected
specimen should be examined meticulously using appropriate inking protocols. Ductal carcinoma in situ (DCIS)
found at an inked margin should be considered as a positive
margin. The best method of manipulating the specimen toreveal the status of the margin (e.g., the use of a perpendicular cut versus Carter’s orange peel technique) is
controversial. Furthermore, no consensus was attained on thedefinition of negative margin. The definitions of a negative
margin ranged from no tumor at the inked margin to aninvasive tumor at a minimum of 5 mm from the edge. In
addition, even greater margins have been proposed for DCIS
when postoperative radiation therapy was not performed.
There was a lack of agreement about the number oflevels of a frozen section required to adequately examine
the sentinel lymph nodes. Other points of discussion
included the appropriate use of cytokeratins and the type of
methodology used (e.g., molecular or immunohistochemical analysis) (Table 1). Despite the differences in thedefinition of isolated tumor cells (ITC) and micrometastasis (MIC), there was general agreement that the presence of
ITC should be considered node negative, whereas thepresence of MIC (0.2–2 mm) should be considered node
positive for staging purposes.1
In addition to histological grading according to theNottingham criteria, the analysis of the status of cellproliferation using biomarkers such as the MIB1/Ki67
index provides important prognostic information.2 To
collect the data necessary to reach a consensus regarding
controversial issues such as the definition of positive
margins, it is recommended that each institution maintainprecise records.

AXILLARY SURGERY
Sentinel lymph node biopsy (SLNB) partially reduces thecomplications related to axillary staging by avoiding level I
axillary lymph node dissection (ALND), level II ALND, andfull ALND in the case of sentinel node-negative patients
based on the reports of the ALMANAC experience.3

PR (%)
HER-2 (IHC or FISH)
MIB1/Ki67 index (%)
Other conventional factors
Nuclear grade
Vessel invasion
Fixation
Time to fixation
Time for fixation
Sentinel lymph nodes (SLNs)
Techniques to identify SLNs (RI, dye, fluorescent or others)
Method of diagnosis (HE, IHC, molecular analysis or others)
Definition of metastasis
Number of excised SLNs
Number of positive SLNs
Number of frozen sections
Was ALND performed?
PR progesterone receptor, IHC immunohistochemistry, FISH fluorescent in situ hybridization, HE hematoxylin and eosin

Lymphatic Mapping
SLNB causes arm lymphedema in approximately 5–8%
of patients, even when they are assessed at 6 months
postoperatively. The axillary reverse mapping (ARM)
procedure, which can clarify the anatomical relationshipbetween the lymphatic system of the breast and the ipsilateral arm, may provide a method to avoid thiscomplication.4 In nearly 98% of primary breast cancer
cases, the lymphatics from the arm, which were identified
with a subcutaneous injection of blue dye in the volar
surface of the upper arm, did not drain into the sentinel
lymph node of the breast. This method should be standardized for common practice.
Another novel and highly sensitive method for visualizing the lymphatic system and the sentinel lymph nodes
involved indocyanine green fluorescent (ICGf) navigation.5
A photodynamic eye that recognizes fluorescence emission
from protein-binding ICG enables real-time mapping of thelymphatic network. It was generally agreed that further

Local Management of Early Breast Cancer

studies, such as clinical trials and long-term outcome
studies, are needed to elucidate the issue of lymphatic
mapping and determine the ultimate impact of thesemodalities on the incidence of lymphedema. It is necessary
to determine more precisely the value of combination of
ICGf with radioisotope (RI) in prospective studies.
Number of Nodes Required for Diagnosis
Non-SLN metastases have been reported in 4–7% of
SLN-negative cases.6 It is crucial to consider the number ofnodes that should be excised for diagnosis and staging andfrom the perspective of the therapeutic benefit of local
control.7–11 We agreed that examination of four SLNcontaining nodes was sufficient to determine the status ofmetastases in the axilla. There were indications that fournode diagnosis would help to avoid unnecessary ALND
and may enable less extensive axillary surgery (Fig. 1).
Another important issue discussed was lymph node dissection for SLN-positive patients. Several studies haveindicated that it may be possible to avoid subsequent
axillary dissection in certain subgroups of node-positive
patients.12–14 Table 2 summarizes these options.

Sentinelnodes

Para-sentinel
nodes

Regional
nodes

Lymphatic metastasis

Removal of lymph nodes

Limited dissection

FIG. 1 Limited axillary lymph node dissection

TABLE 2 Impact of four-node diagnosis for sentinel nodes onsubsequent ALND
No. of involved nodes

Requirement for completion of ALND

0 (ITC included)

Avoidable

1–3
More than 3

Avoidable (individually)
Inevitable

ITC isolated tumor cells

SLNB Prior to Systemic Therapy
Although SLNB before preoperative systemic therapy(PST) under local anesthesia is difficult, we concluded at
the meeting that it is useful for the purpose of confirming
the nodal status, especially in clinically node-negative
cases. In clinically node-positive cases, SLNB before PST
is controversial. The nodal information is important for
designing and individualizing therapeutic plans for local
and systemic treatment, because the nodal status can bealtered by the treatment.
SLNB after PST is also controversial.15 The major
concerns are the relatively high false-negative rate and theuncertainty in the conversion of the positive nodes tonegative. Future studies are warranted to clarify theaccuracy of lymphatic mapping after PST, including antihuman epidermal growth factor receptor 2 (HER2) therapies, and to develop nomograms to facilitate the decisionmaking process (Table 3).
SLNB in DCIS
SLN metastases were identified by RI lymphatic mapping in approximately 1.4% of 854 patients with pure
DCIS.16 Most of these patients underwent complete
ALND, and only one of these patients exhibited additional
positive axillary lymph nodes. Several studies investigating
the long-term outcomes of local control in proven DCIS
cases determined that local failures were rare.17 During theconference, there was general agreement that SLNB can berecommended for patients with DCIS who undergo mastectomy and for those diagnosed with invasive carcinoma
upon final pathology. In addition, there was agreement thatSLNB should be avoided in patients with needle biopsyproven DCIS and without high risk factors for invasivecancer who undergo breast-conserving surgery (BCS).
Therefore, the development of an algorithm to predict
potential invasion and thus avoid SLNB for needle biopsyproven DCIS (Table 3) is warranted.18
BREAST SURGERY
Ipsilateral Breast Tumor Recurrence (IBTR)
It is difficult to decide upon one margin width that is
appropriate for all patients.19 Opinions about the minimal
acceptable margin in local breast cancer resection varied
from less than 5 mm to more than 20 mm. The recommendations were divided into three major categories basedon tumor location: within 5 mm, tumor within 2 mm, andtumor at the margin. With respect to the re-excision criteria
in the case of BCS, the consensus was that a 2 mmradial margin was satisfactory and should not prompt

M. Toi et al.
TABLE 3 Nomogram for breast cancer
Decisionfactors

Decision goal

DCIS

To determine whether SLNB is required by examining
possible microinvasion46

PST

To determine the type of surgery required byexamining possible pCR47

IBTR

To determine whether RT or re-excision is necessary48

SLNB

To determine whether ALND is required by predicting
non-SLN metastasis18,49–52

re-excision.20 For a close margin (i.e., 2–5 mm), boost
irradiation can be considered.
The 20-year follow-up data from the National Surgical
Breast and Bowel Project (NSABP) B-06 trial showed that
39.2% of the patients who received wide local excision
without radiotherapy developed ipsilateral breast tumor
recurrence (IBTR), as compared with 14.3% of those who
received postoperative radiotherapy. Some believe that
IBTR does not influence overall survival and that it can beconsidered a marker of distant metastases rather than acause; its presence therefore cannot change the intrinsic
risk of distant disease.21 However, according to a metaanalysis performed by the Early Breast Cancer Trialists’Collaborative Group (EBCTCG), the impact of local
radiation therapy (RT) to prevent local recurrence, either tothe breast following BCT or to the chest wall after mastectomy, exhibited overall survival benefit in patients withgreater than 10% risk of local recurrence, but it did notshow any benefit in patients with less than 10% risk of
local recurrence.22 An analysis of hazard ratios for distantmetastases in patients who had undergone breast-conservation surgery with or without postoperative radiotherapy
indicated that local recurrence might be a cause of distantmetastases.23 These results suggested that the group with ahigh risk for locoregional recurrence gained a survival
benefit from local radiotherapy. In addition, local relapse
could be a crucial psychological stressor for a patient even
if her long-term survival was unaffected.
PST
In the case of sequential chemotherapeutic regimens suchas doxorubicin and cyclophosphamide (AC) followed by ataxane, the pathological complete remission (pCR) rates arehigher in patients who responded to the preceding regimen
than in nonresponders. Furthermore, combining chemotherapy with an anti-HER2 treatment such as trastuzumab
resulted in even higher pCR rates in HER2-positive cases.24
A multidisciplinary team, which included an attending surgeon, a radiologist, a medical oncologist, and a pathologist,
was indispensable in making appropriate decisions regarding

BCS after PST. The findings also led to the recommendationthat long-term outcome data, particularly data related to local
recurrence rates, and methodologies for assessing the
response and success of treatment should be collected, analyzed, and clarified at each institution.25
The large majority of the attendees agreed that neoadjuvant endocrine treatment (NAET) is an acceptableapproach for certain patients, including those with lowgrade, estrogen receptor (ER)-positive breast cancers andpostmenopausal patients. Recent studies have suggested
that NAET provides higher breast-conservation rates.
Nevertheless, because of a lack of randomized clinical trial
data, especially on local recurrence, this issue remains to bestudied with respect to the tailoring of treatment using
biomarkers.26 Future studies are required to investigate thefactors that are predictive of a shrinkage pattern in tumorsthat have responded to NAET and to determine their
postoperative prognosis.
Hereditary Breast Cancer
There was some consensus that patients at higher risk
for local recurrence or development of breast cancer in thecontralateral breast due to genetic mutations (e.g., BRCA1
or BRCA2) require a more aggressive surgery than BCS.
Although this is a controversial topic, the risks of IBTR andof developing contralateral breast cancer may be higher inpatients with BRCA abnormalities. Therefore, performing abilateral mastectomy may be preferable to BCS. In addition, performing a bilateral mastectomy would avoid use of
RT in a majority of patients. Fifteen years of follow-up
data from postoperative radiotherapy in BRCA patientssuggested that there is a higher risk of radiation toxicity inthese patients. Taking these data together, bilateral mastectomy for this specific subgroup could result in reducing
cancer recurrence in the affected breast, decreasing newbreast cancer development in the unaffected breast, andavoiding the late toxicity of radiotherapy.27–29
BCS for DCISThe Van Nuys Prognostic Index (VNPI), originallyproposed and validated by Silverstein et al., is a scoring
system for predicting the risk of IBTR in DCIS patients
undergoing BCS. Three major factors—margin status, highhistological grade, and young age—were recognized as
significant risk factors for IBTR after resection of DCIS.
The distribution of the opinions as to the proper marginneeded for DCIS was similar to that for invasive ductal
carcinoma (IDC).
Several retrospective studies have suggested that RT after
BCS is useful in avoiding IBTR, especially in patients withhigh-risk DCIS.30,31 Tamoxifen in combination with RT has

Local Management of Early Breast Cancer

also been reported to decrease IBTR in DCIS.32 Prospective
trials of neoadjuvant therapies for DCIS using trastuzumab
or lapatinib have recently been initiated. These trials may
elucidate the effect of anti-HER2 treatments on the local
management of HER-2-neu-overexpressing DCIS.
Dunne et al. performed a meta-analysis of 4,660 cases
identified from Medline with regard to the margins
required for DCIS and RT. They found that a negative
margin significantly reduced the risk of IBTR comparedwith a close margin, and a 2-mm margin was superior to amargin less than 2 mm. However, they observed no significant differences in the IBTR rates with margins over
2 mm.33 Fisher et al. demonstrated the benefit of tamoxifenin the treatment of DCIS in NSABP B-24, a randomized
controlled trial.34 Because these data suggest that BCS
alone is insufficient to prevent IBTR after surgery for
DCIS, there was consensus at the meeting that RT and/or
endocrine therapy is necessary after BCS.
RADIATION THERAPY
RT as a Component of the Local Management of Breast
CancerPostoperative RT reduces the risk of locoregional
recurrence to approximately one-third of that without RT.
Although the baseline risks have varied among existing
reports, depending on the method of surgery and thepathological evaluation, the relative risk reduction related
to RT was consistent.22
For each group of patients who received BCS, there
have been continual efforts to find a subgroup of patients
who do not require RT.32,35–38 Unfortunately, such a subgroup had not yet been identified in a prospective trial.
However, the eligibility criteria and systemic treatment
used in early clinical trials were suboptimal in comparison
with today’s standards.32 A clinical trial in a selected groupof patients, which included individuals over 70 years old
with hormone-responsive tumors treated with a suitable
resection margin and appropriate hormonal therapy, demonstrated that the absolute reduction in the risk of local
recurrence due to RT, although significant, was smallenough that omission of RT could be considered.32 It issuggested that the intrinsic subtype of breast cancer might
be an independent predictive factor related to the benefit of
postoperative RT.39,40 At the meeting it was indicated thatthese findings should be verified in prospective trials.
Trends in Postoperative Irradiation for the Conserved
BreastBoth hypofractionated whole-breast RT and accelerated
partial-breast irradiation (APBI) were increasingly used

after BCT. Hypofractionated whole-breast RT demonstrated equivalent tumor control and cosmetic resultscompared with conventional fractionation.41,42 In the consensus conference, we discussed hypofractionation as an
option for certain patients, such as those who are margin
free. However, APBI is still considered an experimental
treatment.
Indication for Boost to the Tumor Bed after BCT
Although a large randomized clinical trial demonstrated
a significant reduction of IBTR in patients with a negative
margin, we were unable to reach a consensus on the indications for an RT boost. The most important issue to beresolved was the definition of a ‘‘positive’’ margin after
BCS. This definition varied by country and region.43
Therefore, it should be further examined whether patientswith positive margins benefit from routine administrationof boost irradiation after whole-breast radiation therapy. At
the consensus conference, approximately half of the participants responded that boost irradiation is not necessary if
the margin is greater than 5 mm.
In addition to the dose dependency of the ipsilateraltumor control, the European Organisation for Research andTreatment of Cancer (EORTC) 22881-10882 trial clearly
demonstrated that younger patients receive a greater benefit
from boost irradiation secondary to their greater baseline
risk of IBTR. However, in this consensus conference,
approximately half of the participants answered that young
age alone in not a sufficient criterion for providing a boost,
if the margin is widely clear. To resolve this issue, we muststandardize the definition of a positive margin, clarify the
relationship between the distances required for a clear
margin, and understand the magnitude of the effect ofboost irradiation.
Survival Benefit of Postoperative RT for Breast Cancer
Meta-analyses performed by EBCTCG demonstrated
that a reduction in the risk of locoregional recurrence at
5-year postoperative follow-up could eventually lead to a
reduction in death from all causes at 15-year postoperative
follow-up.30 This survival benefit was attributed to prevention of secondary dissemination from local recurrence.
However, the benefit was substantial only if the absoluterisk reduction of the locoregional recurrence at 5 years
exceeded 10%.
Currently, patients with four or more positive lymph
nodes are regarded as being at high risk for local recurrence. Postoperative RT to the supraclavicular lymph nodes
and the chest wall and breast are recommended in thisgroup after both breast-conserving surgery and mastectomy. Furthermore, meta-analyses of existing trials have

M. Toi et al.

suggested that patients with one to three positive
lymph nodes might also receive a survival benefit frompostoperative RT, although a randomized clinical trial
investigating this hypothesis is ongoing. Patients withnegative axillary lymph nodes generally exhibit a low riskof local recurrence. These patients do not benefit from such
RT and may have increased risks of radiation side-effects if
RT is given. Of note, the number of positive axillary lymph
nodes in this context is only a surrogate for the risk ofisolated locoregional recurrence. The indication for postoperative RT should ultimately be based on the absoluterisk of local recurrence.
Postoperative Radiation Therapy in Patients Receiving
PST
Recently, PST has been offered not only to patients withadvanced disease but also to patients with early-stage
breast cancer. The expansion of this practice has unveiled a
new clinical question: What is the optimal RT dose forpatients who respond favorably to PST? Randomized trials
are needed to answer this question. However, the generalconsensus was that, for all patients who receive PST and
BCS, postoperative RT is recommended. Retrospective
studies of patients who received a mastectomy after PST
showed that RT significantly improved local control evenin patients with pCR after PST.44 These investigators also
found that RT improved survival in patients at higher riskof locoregional recurrence after PST and mastectomy.45
These results provide insight that the decision to offer RT
should be based on both the pretreatment assessment andthe final pathologic findings. Postoperative RT is recommended for patients initially diagnosed as having a highrisk of locoregional recurrence, regardless of their response
to PST.
ACKNOWLEDGMENT We thank Dr. Masahiro Hiraoka, Chairman of the Department of Radiation Oncology and Image-applied
Therapy at Kyoto University, the executive advisor to this project. We
are also grateful to Dr. Fabrizio Michelassi, Chairman of the
Department of Surgery at New York Presbyterian Hospital, Weill
Cornell Medical Center, for providing guidance regarding the consensus questionnaire. We thank the Kyoto University Foundation for
their generous donation of funds. The conference was part of a program, ‘‘Raising Proficient Oncologists,’’ run by the Japanese Ministryof Education, Culture, Sports, Science, and Technology. We
acknowledge the kind support of the Japan Breast Cancer Society. We
express sincere thanks to the doctors who completed the consensus
questionnaire. We are grateful to Dr. Hiroshi Ishiguro for his valuable
help and scientific advice. We also thank Ms. Aya Morotomi,
Mr. David Graham, Ms. Mihoko Yamamoto, Ms. Nastajia Burke,
Ms. Chisa Takano, and Ms. Nobuko Yagi for their invaluable support.
Moderators: S. K. Apple (University of California, Los Angeles),J. R. Benson (Addenbrooke’s Hospital and University of Cambridge,
Cambridge), W. C. Chow (UNIMED Medical Institute/Hong Kong
University, Hong Kong), J. F. Forbes (The University of Newcastle,
Newcastle), M. Golshan (Dana-Farber Cancer Institute, Brigham &Women’s Cancer Center, Boston), T. Inamoto (Kitano Hospital,
Osaka), V. S. Klimberg (University of Arkansas for Medical Sciences, Arkansas), M. Mitsumori (Kyoto University, Kyoto), S.
Noguchi (Osaka University, Osaka), J. F. R. Robertson (The University of Nottingham, Nottingham), D. H. Roukos (University of
Ioannina, Ioannina), H. Sasano (Tohoku University, Sendai), E.
A. Strom (The University of Texas M.D. Anderson Cancer Center,
Houston), M. Toi (Kyoto University, Kyoto), G. Von Minckwitz (TheCentre for Gynecology and Obstetrics at the University of Frankfurt,Frankfurt), E. P. Winer (Dana-Farber Cancer Institute, Brigham &Women’s Cancer Center, Boston), and A. Yamauchi (Kitano Hospital, Osaka). Discussants and organizers: S. Akashi-Tanaka (National
Cancer Center Hospital, Tokyo), R. Arriagada (Karolinska institute,
Stockholm/Institut Gustave-Roussy, Paris), J. Chen (Cancer Hospitalof Fudan University, Shanghai), S.C. Chen (Chang Gung University,
Taoyuan), S.W. Ha (Seoul National University Hospital, Seoul),
S. Han (Inje University Sanggye Paik Hospital, Kyungnam), C.
S. Huang and T. Ikeda (Teikyo University, Tokyo), S. Imoto (Kyorin
University, Tokyo), H. Inaji (Osaka Medical Center for Cancer andCardiovascular Diseases, Osaka), T. Iwase (The Cancer InstituteHospital of JFCR, Tokyo), H. Iwata (Aichi Cancer Center, Nagoya),
R. V. Jakesz (University of Vienna, Vienna), H. Jinno (Keio University, Tokyo), H. Kawabata (Toranomon Hospital, Tokyo), T.
Kinoshita (National Cancer Center Hospital, Tokyo), T. Kitai (NaraSocial Insurance Hospital, Nara), N. Kohno (Tokyo Medical University, Tokyo), I. E. Krop (Dana-Farber Cancer Institute, Brigham
and Women’s Cancer Center, Boston), I. Kunkler (University of
Edinburgh, Edinburgh), J. Kurebayashi (Kawasaki Medical University, Kurashiki), K. Kuroi (Tokyo Metropolitan Cancer and Infectious
Disease Center, Tokyo), E. S. Lee (Korea University Anam-Hospital,
Seoul), S. J. Lee (Yeungnam University, Gyeongsan), N. Masuda(Osaka National Hospital, Osaka), Y. Mikami (Kyoto University,
Kyoto), S. Nakamura (St. Luke’s International Hospital, Tokyo),
D. Y. Noh (Seoul National University, Seoul), S. Ohno (National
Kyushu Cancer Center, Fukuoka), N. S. Paik (Konkuk University
Medical Center, Seoul), M. D. Pegram (University of Miami, Miller
School of Medicine, Miami), T. Saeki (Saitama Medical University,
Saitama), M. Shafir (Mount Sinai Hospital and School of Medicine,
New York), H. Takei (Saitama Cancer Center, Saitama), H. Sonoo(Kawasaki Medical School Hospital, Kurashiki), T. Sugie (Kyoto
University, Kyoto), M. Takada (Kyoto University, Kyoto), Y. Tanaka(Kyoto University, Kyoto), T. Ueno (Kyoto University, Kyoto), T.
Varughese (Lakeshore Hospital and Research Centre, Cochin), and K.
Yamagami (Shinko Hospital, Kobe).

REFERENCES
1. de Mascarel I, Macgrogan G, Deblet M, et al. Distinction
between isolated tumor cells and micrometastasis in breast cancer. Cancer. 2008;112:1672–8.
2. Yerushalmi R, Woods R, Ravdin PM, et al. Ki67 in breast cancer:
prognostic and predictive potential. Lancet Oncol. 2010;11:
174–83.
3. Clarke D, Khonji N, Mansel R. Sentinel node biopsy in breast
cancer: ALMANC trial. World J Surg. 2001;25;819–22.
4. Boneti C, Korourian S, Bland K, et al. Axillary reverse mapping:mapping and preserving arm lymphatics may be important inpreventing lymphedema during sentinel lymph node biopsy. J Am
Coll Surg. 2008;206:1038–44.
5. Kitai T, Inomoto T, Miwa M, et al. Fluorescence navigation withindocyanine green for detecting sentinel lymph nodes in breast
cancer. Breast Cancer. 2005;12:211–15.
6. Yi M, Meric-Bernstam F, Ross MI, et al. How many sentinel
lymph nodes are enough during sentinel lymph node dissection
for breast cancer? Cancer. 2008;113:30–7.

Local Management of Early Breast Cancer
7. Dabbs DJ, Johnson R. The optimal number of sentinel lymph nodes
for focused pathologic examination. Breast J. 2004;10:186–9.
8. Zavagno G, De Salvo GL, Bozza F, et al. Number of metastatic
sentinel lymph nodes as predictor of axillary involvement inpatients with breast cancer. Breast Cancer Res Treat. 2004;86:
171–9.
9. Barranger E, Coutant C, Flahault A, et al. An axilla scoring
system to predict non-sentinel lymph node status in breast cancer
patients with sentinel lymph node involvement. Breast Cancer
Res Treat. 2005;91:113–9.
10. Boileau JF, Easson A, Escallon JM, et al. Sentinel nodes in breast
cancer: relevance of axillary level II nodes and optimal number ofnodes that need to be removed. Ann Surg Oncol. 2008;15:1710–6.
11. Rubio I, Pedreira F, Roca I, et al. Removal of all radioactive
sentinel nodes in breast cancer improves the detection of positive
sentinel nodes. Clin Transl Oncol. 2008;10:347–50.
12. Veronesi U, Galimberti V, Paganelli G, et al. Axillary metastases
in breast cancer patients with negative sentinel nodes: a follow-up
of 3548 cases. Eur J Cancer. 2009;45:1381–8.
13. Layeequr Rahman R, Siegel E, Boneti C, et al. Stage migration withsentinel node biopsy in breast cancer. Am J Surg. 2009;197:491–6.
14. Benson JR, della Rovere GQ; Axilla Management Consensus
Group. Management of the axilla in women with breast cancer.
Lancet Oncol. 2007;8:331–48.
15. Mamounas EP, Brown A, Anderson S, et al. Sentinel node biopsy
after neoadjuvant chemotherapy in breast cancer: results from
National Surgical Adjuvant Breast and Bowel Project Protocol
B-27. J Clin Oncol. 2005;23:2694–702.
16. Intra M, Rotmensz N, Veronesi P, et al. Sentinel node biopsy is
not a standard procedure in ductal carcinoma in situ of the breast:
the experience of the European institute of oncology on 854
patients in 10 years. Ann Surg. 2008;247:315–9.
17. Julian TB, Land SR, Fourchotte V, et al. Is sentinel node biopsy
necessary in conservatively treated DCIS? Ann Surg Oncol.
2007;14:2202–8.
18. Katz A, Smith BL, Golshan M, et al. Nomogram for the prediction of having four or more involved nodes for sentinel lymph
node-positive breast cancer. J Clin Oncol. 2008;26:2093–8.
19. Morrow M. Trends in the surgical treatment of breast cancer.
Breast J. 2010;16(Suppl 1):17–9.
20. Sabel MS. Surgical considerations in early-stage breast cancer:
Lessons learned and future directions. Semin Radiat Oncol.
2011;21:10–9.
21. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow up of arandomized trial comparing total mastectomy, lumpectomy andlumpectomy plus irradiation for the treatment of invasive breast
cancer. N Eng J Med. 2002;347:1233–41.
22. Clarke M, Collins R, Darby S, et al. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy andof differences in the extent of surgery for early breast cancer on
local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366:2087–106.
23. Nguyen PL, TaghianAG, Katz MS, et al. Breast cancer subtype
approximated by estrogen receptor, progesterone receptor, andHER-2 is associated with local and distant recurrence after
breast-conserving therapy. J Clin Oncol. 2008;26:2373–8.
24. Romond EH, Perez EA,, Bryant J, et al. Trastruzumab plus
adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84.
25. Komoike Y, Akiyama F, Iino Y, et al. Ipsilateral breast tumor
recurrence (IBTR) after breast-conserving treatment for earlybreast cancer: risk factors and impact on distant metastases.
Cancer. 2006;106:35–41.
26. Cheang MC, Chia SK, Voduc D, et al. Ki67 index, HER2 status,and prognosis of patients with luminal B breast cancer. J NatlCancer Inst. 2009;101:736–50.

27. Fatouros M, Baltoyiannis G, Roukos DH. The predominant roleof surgery in the prevention and new trends in the surgicaltreatment of women with BRCA1/2 mutations. Ann Surg Oncol.
2008;15:21–33.
28. Ziogas D, Roukos DH. Genetics and personal genomics for
personalized breast cancer surgery: progress and challenges in
research and clinical practice. Ann Surg Oncol. 2009;16:1771–82.
29. Garcia-Etienne CA, Barile M, Gentilini OD, et al. Breast-conserving surgery in BRCA1/2 mutation carriers: are we approachingan answer? Ann Surg Oncol. 2009;16:3380–7.
30. Bijker N, Meijnen P, Peters JL. Breast-conserving treatment withor without radiotherapy in ductal carcinoma-in-situ: ten-year
results of European Organisation for Research and Treatment ofCancer randomized phase III trial 10853—a study by the EORTC
Breast Cancer Cooperative Group and EORTC RadiotherapyGroup. J Clin Oncol. 2006;24:3381–7.
31. Viani GA, Stefalo EJ, Afonso SL, et al. Breast-conserving surgery with or without radiotherapy in woman with ductal
carcinoma in situ: a meta-analysis of randomized trials. Radiation
Oncol. 2007;2:28–39.
32. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus
tamoxifen with or without irradiation in women 70 years of age
or older with early breast cancer. N Engl J Med. 2004;351:971–7.
33. Dunne C, Burke JP, Morrow M, et al. Effect of margin status on
local recurrence after breast conservation and radiation therapy
for ductal carcinoma in situ. J Clin Oncol. 2009;27:1615–20.
34. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of
intraductal breast cancer: National Surgical Adjuvant Breast andBowel Project B-24 randomised controlled trial. Lancet. 1999;
353:1993–2000.
35. Fisher B, Bryant J, Dignam JJ, et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence
after lumpectomy in women with invasive breast cancers of one
centimeter or less. J Clin Oncol. 2002;20:4141–9.
36. Forrest AP, Stewart HJ, Everington D, et al. Randomised controlled trial of conservation therapy for breast cancer: 6-year
analysis of the Scottish trial. Scottish Cancer Trials Breast Group.
Lancet. 1996;348:708–13.
37. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with orwithout breast irradiation in women 50 years of age or older withearly breast cancer. N Engl J Med. 2004;351:963–70.
38. Lim M, Bellon JR, Gelman R, et al. A prospective study ofconservative surgery without radiation therapy in select patientswith Stage I breast cancer. Int J Radiat Oncol Biol Phys. 2006;
65:1149–54.
39. Kyndi M, Sorensen FB, Knudsen H, et al. Estrogen receptor,
progesterone receptor, HER-2, and response to postmastectomy
radiotherapy in high-risk breast cancer: the Danish Breast Cancer
Cooperative Group. J Clin Oncol. 2008;26:1419–26.
40. Saverio SD, Catena F, Santini D, et al. 259 Patients with DCIS ofthe breast applying USC/Van Nuys prognostic index: a retrospective review with long term follow up. Breast Cancer Res
Treat. 2008;109:405–16.
41. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy
hypofractionation for treatment of early breast cancer: a randomised trial. Lancet. 2008;371:1098–107.
42. Whelan T, MacKenzie R, Julian J, et al. Randomized trial ofbreast irradiation schedules after lumpectomy for women withlymph node-negative breast cancer. J Natl Cancer Inst. 2002;
94:1143–50.
43. Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher
radiation dose on local control and survival in breast-conserving
therapy of early breast cancer: 10-year results of the randomized
boost versus no boost EORTC 22881-10882 trial. J Clin Oncol.
2007;25:3259–65.

M. Toi et al.
44. McGuire SE, Gonzalez-Angulo AM, Huang EH, et al. Postmastectomy radiation improves the outcome of patients with locallyadvanced breast cancer who achieve a pathologic complete
response to neoadjuvant chemotherapy. Int J Radiat Oncol Biol
Phys. 2007;68:1004–9.
45. Huang EH, Tucker SL, Strom EA, et al. Postmastectomy radiation improves local-regional control and survival for selectedpatients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy. J Clin Oncol. 2004;22:4691–9.
46. O’Flynn EA, Morel JC, Gonzalez J, et al. Prediction of thepresence of invasive disease from the measurement of extent ofmalignant microcalcification on mammography and ductal carcinoma in situ grade at core biopsy. Clin Radiol. 2009;64:178–83.
47. Colleoni M, Bagnardi V, Rotmensz N, et al. A risk score to
predict disease-free survival in patients not achieving a pathological complete remission after preoperative chemotherapy forbreast cancer. Ann Oncol. 2009;20:1178–84.
48. Bilimoria KY, Bentrem DJ, Hansen NM, et al. Comparison ofsentinel lymph node biopsy alone and completion axillary lymph

node dissection for node-positive breast cancer. J Clin Oncol.
2009;27:2946–53.
49. Van Zee KJ, Manasseh DM, Bevilacqua JL, et al. A nomogramfor predicting the likelihood of additional nodal metastases inbreast cancer patients with a positive sentinel node biopsy. Ann
Surg Oncol. 2003;10:1140–51.
50. Gur AS, Unal B, Johnson R, et al. Predictive probability of four
different breast cancer nomograms for nonsentinel axillary lymph
node metastasis in positive sentinel node biopsy. J Am Coll Surg.
2009;208:229–35.
51. Amanti C, Lombardi A, Maggi S, et al. Is complete axillary
dissection necessary for all patients with positive findings on
sentinel lymph node biopsy? Validation of a breast cancer
nomogram for predicting the likelihood of a non-sentinel lymph
node. Tumori. 2009;95:153–5.
52. Coutant C, Olivier C, Lambaudie E, et al. Comparison of models
to predict nonsentinel lymph node status in breast cancer patientswith metastatic sentinel lymph nodes: a prospective multicenter
study. J Clin Oncol. 2009;27:2800–08.