Published Ahead of Print on December 1, 2014 as 10.1200/JCO.2014.55.
7827
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.55.7827
JOURNAL OF CLINICAL ONCOLOGY
Jean-Francois Boileau, Mark Basik, and
Andre Lisbona, Montreal Jewish
General Segal Cancer Centre, McGill
University; Louis Gaboury, Isabelle
Trop, Rami J. Younan, Erica Patocskai,
and Andre Robidoux, Centre Hospitalier
de l’Universite de Montreal; Lucas
Sideris, Hopital Maisonneuve Rose-
mont, Universite de Montreal; Sarkis
Meterissian and Atilla Omeroglu, McGill
University Health Centre, Montreal;
Brigitte Poirier and Louise Provencher,
Hopital Saint-Sacrement, Universite
Laval, Quebec City, Quebec; Claire
M.B. Holloway and Frances C. Wright,
Sunnybrook Odette Cancer Centre,
University of Toronto; David R.
McCready, University Health Network,
University of Toronto, Toronto; Angel
Arnaout, Ottawa Hospital, University of
Ottawa, Ottawa; Muriel Brackstone,
London Regional Cancer Program,
University of Western Ontario, London,
Ontario, Canada; and Stephen E. Karp,
Lahey Hospital and Medical Center,
Tufts University School of Medicine,
Boston, MA.
Published online ahead of print at
www.jco.org on December 1, 2014.
Support information appears at the end
of this article.
Clinical trial information: NCT00909441.
Terms in blue are defined in the glos-
sary, found at the end of this article
and online at www.jco.org.
Authors’ disclosures of potential
conflicts of interest are found in the
article online at www.jco.org. Author
contributions are found at the end of
this article.
Corresponding author: Jean-Francois
Boileau, MD, MSc, Jewish General
Hospital Segal Cancer Centre, 3755
Chemin de la Cote-Ste-Catherine, E-710,
Montreal, Quebec, Canada, H3T 1E2;
e-mail: jean-francois.boileau@mcgill.ca.
© 2014 by American Society of Clinical
Oncology
0732-183X/14/3299-1/$20.00
DOI: 10.1200/JCO.2014.55.7827
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Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Copyright 2014 by American Society of Clinical Oncology
O R I G I N A L R E P O R T
Sentinel Node Biopsy After Neoadjuvant Chemotherapy in
Biopsy-Proven Node-Positive Breast Cancer: The SN
FNAC Study
Jean-Francois Boileau, Brigitte Poirier, Mark Basik, Claire M.B. Holloway, Louis Gaboury, Lucas Sideris,
Sarkis Meterissian, Angel Arnaout, Muriel Brackstone, David R. McCready, Stephen E. Karp, Isabelle Trop,
Andre Lisbona, Frances C. Wright, Rami J. Younan, Louise Provencher, Erica Patocskai,
Atilla Omeroglu, and Andre Robidoux
A B S T R A C T
Purpose
An increasing proportion of patients (⬎ 30%) with node-positive breast cancer will obtain an
axillary pathologic complete response after neoadjuvant chemotherapy (NAC). If sentinel node
(SN) biopsy (SNB) is accurate in this setting, completion node dissection (CND) morbidity could
be avoided.
Patients and Methods
In the prospective multicentric SN FNAC study, patients with biopsy-proven node-positive breast
cancer (T0-3, N1-2) underwent both SNB and CND. Immunohistochemistry (IHC) use was
mandatory, and SN metastases of any size, including isolated tumor cells (ypN0[i⫹], ⱕ 0.2 mm),
were considered positive. The optimal SNB identification rate (IR) ⱖ 90% and false-negative rate
(FNR) ⱕ 10% were predetermined.
Results
From March 2009 to December 2012, 153 patients were accrued to the study. The SNB IR was
87.6% (127 of 145; 95% CI, 82.2% to 93.0%), and the FNR was 8.4% (seven of 83; 95% CI, 2.4%
to 14.4%). If SN ypN0(i⫹)s had been considered negative, the FNR would have increased to
13.3% (11 of 83; 95% CI, 6.0% to 20.6%). There was no correlation between size of SN
metastases and rate of positive non-SNs. Using this method, 30.3% of patients could potentially
avoid CND.
Conclusion
In biopsy-proven node-positive breast cancer after NAC, a low SNB FNR (8.4%) can be achieved
with mandatory use of IHC. SN metastases of any size should be considered positive. The SNB IR
was 87.6%, and in the presence of a technical failure, axillary node dissection should be
performed. We recommend that SN evaluation with IHC be further evaluated before being
included in future guidelines on the use of SNB after NAC in this setting.
J Clin Oncol 32. © 2014 by American Society of Clinical Oncology
shown that SNB after NAC has an acceptable accu-
INTRODUCTION
racy.3 An unplanned retrospective analysis of pa-
The surgical management of breast cancer has un- tients from the NSABP (National Surgical Adjuvant
dergone major changes in the last 20 years. The Breast and Bowel Project) B27 protocol supports the
emergence of sentinel lymph node biopsy (SNB) has use of SNB after NAC in patients who present with
eliminated the need for axillary dissection in many clinically node-positive or node-negative disease.4
patients, reducing the morbidities of lymphedema Small series evaluating SNB after NAC in patients
andarmpain.1 SNBhasbeenvalidatedinthecontextof presenting with biopsy-proven node-positive dis-
clinically negative axillae, and the false-negative rate ease have shown highly variable FNRs, some of
(FNR) of SNB has been measured at 9.8%.2 which would be considered prohibitive (from 11%
The use of SNB after neoadjuvant chemother- to 25%).5,6 The identification rate (IR) of SNB in this
apy (NAC) has been the subject of some contro- setting has often been reported as lower than would
versy. A meta-analysis of prospective cohorts has be expected in the absence of NAC.3,4,7,8
© 2014 by American Society of Clinical Oncology 1
132.239.1.231
 Boileau et al

T0-T3 breast cancer Neoadjuvant SNB + completion node

N1-2 biopsy proven
(FNA or core biopsy)
Clinical examination No. 1
Axillary ultrasound No. 1
chemotherapy
Clinical examination No. 2
Axillary ultrasound No. 2
dissection
Fig 1. SN FNAC (Sentinel Node Biopsy
Following Neoadjuvant Chemotherapy)
study design. FNA, fine-needle aspiration;
SNB surgical form SNB, sentinel node biopsy.
Pathology form

(N = 153)

The American Society of Clinical Oncology Clinical Practice
Guideline Update Committee considers the current reported FNR of
SNB after NAC in patients who present with involved axillary nodes
(from 10% to 30%) unacceptable and will take into consideration any
new information regarding this specific patient population, for which
there is insufficient data.9 Currently, for most patients with biopsy-
proven node-positive breast cancer who receive NAC, completion
node dissection (CND) is recommended, regardless of their response
to treatment; 22% to 35% of these patients will have no residual
disease in the axilla (axillary pathologic complete response [pCR])
after NAC.5,10 With better selection of patients for NAC and improved
effectiveness of targeted therapy, these rates are likely to increase. CND
could potentially be avoided in a large number of node-positive pa-
tients if SNB were shown to be accurate at identifying those who have
achieved an axillary pCR after NAC.
In the absence of NAC, the size of sentinel node (SN) metastases
is correlated with the probability of non-SN involvement, and low-
volume disease in SNs does not always mandate CND when adjuvant
radiotherapy and systemic therapy are planned.11 Therefore, most
guidelines do not support, in the absence of NAC, the routine use of
immunohistochemistry (IHC) and recommend against CND when
only SN isolated tumor cells (pN0[i⫹]) or micrometastases (pN1mi)
are identified.1 After NAC, the relevance of SN ypN0(i⫹) or ypN1mi
and the value of IHC are not well established.
The primary objective of the SN FNAC (Sentinel Node Biopsy
Following Neoadjuvant Chemotherapy) trial was to evaluate the ac-
curacy of SNB after NAC in patients presenting with biopsy-proven
node-positive breast cancer. It was hypothesized that the FNR would
be ⱕ 10%, similar to the rate reported in the NSABP B-32 trial.12 The
other main objective of this study was to evaluate the IR of SNB in this
setting (estimated at ⱖ 90%). The secondary objective was to evaluate
and compare the accuracy of clinical examination, axillary ultrasound,
and SNB in identifying patients with axillary pCR after NAC.
PATIENTS AND METHODS
The SN FNAC study was a prospective multicentric phase II trial aimed at
evaluating the accuracy of SNB after NAC in patients with biopsy-proven
node-positive disease at presentation. Ten academic university-affiliated cen-
ters in Canada and the United States participated in the study.
The protocol and consent forms were approved by the scientific com-
mittee or research ethics board of each participating center. Patients accrued to
the trial were required to sign the study consent before their surgery date.
Eligibility Criteria
Patients with stage II to IIIa (T0-T3, N1-2, M0-X) biopsy-proven node-
positive breast cancer selected to receive NAC were eligible for this study.
Exclusion criteria included clinical T4 or N3 breast cancer, prior axillary
surgery (including SNB before NAC), and neoadjuvant radiotherapy to the
breast or axilla.
Clinical Examination and Axillary Ultrasound
Clinical staging and axillary ultrasound before and after NAC were
obtained. Physicians performing clinical examination and radiologists re-
sponsible for the axillary node assessment after NAC were asked to pro-
spectively record the size and presence of residual nodal involvement.
Timelines for the clinical examination, ultrasound evaluation, and surgery
are shown in Figure 1.
Surgical Technique
All patients accrued to this trial were required to undergo SNB followed
by CND. The SNB technique was left to the discretion of the operating sur-
geon, but the use of radioisotope was mandatory. The use of blue dye (lymp-
hazurin, patent blue, or methylene blue) and the sites of blue dye and
radioisotope injection were recorded prospectively. An SN was defined as the
hottest node (ie, node with highest count using gamma probe), any node with
counts of ⬎ 10% of those of the hottest node, any blue node, or any palpable
suspicious node.
Pathologic Evaluation
The number of SN specimens and the total number of SNs were
recorded. SNs were sliced at intervals of ⱕ 2 mm. Hematoxylin and eosin
(HE) stain was used, and if negative, IHC was mandatory. The size of the
largest nodal metastasis was recorded. The nodes retrieved from CND were
analyzed by standard institutional guidelines, usually bivalved and stained
by HE. Pathology (SNB plus CND slides) were prepared, evaluated on site,
and shipped for central review, which was performed by a single patholo-
gist at the trial coordinating site. SNs with metastases of any size were
considered positive, including IHC-only– detected ypN1mi (⬎ 0.2 to 2
mm) and ypN0(i⫹) [ⱕ 0.2 mm].
Sample-Size Calculation and Expected Accrual Period
With an expected FNR of 10%, 95% CI, and expected axillary pCR rate of
40% to 50%, sample size was calculated to be 230 to 276 patients. The target
accrual was set at 300 patients for an expected accrual period of 3 years. A
higher rate of axillary pCR than previously published10 was used to take into
account the fact that patients with a higher probability of axillary pCR (oper-
able human epidermal growth factor receptor 2 (HER2) –positive and triple-
negative breast cancers) were more likely to participate in this trial.
Unplanned Interim Analysis and Early Closure
In December 2012, results from the ACOSOG (American College of
Surgeons Oncology Group) Z1071 trial,13 which had a similar study design,
were reported at the San Antonio Breast Cancer Symposium. At that time, the
SN FNAC study had reached 51% of its targeted accrual in a period of 3.75
years. It was estimated, using the most recent accrual rates, that a minimum of
2 years would be needed to reach our accrual target. An unplanned interim
analysis was performed, which yielded results similar to those presented by the
ALLIANCE group. Because of the similarities between the two trials and the

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132.239.1.231
 SN FNAC Study

of SNB in this setting was 87.6% (127 of 145; 95% CI, 82.2% to
Table 1. Patient Demographic, Clinicopathologic, and Treatment
Characteristics (N ⫽ 153) 93.0%). In the presence of a technical failure, the rate of positive nodal
involvement was 66.7% (12 of 18). The axillary pCR rate was 34.5%
Characteristic No. %
(50 of 145). A total of 30.3% (44 of 145) of patients eligible to partic-
Age, years
ipate in the SN FNAC study could have potentially avoided node
Median 50
Range 26-75
dissection if SNB only had been used after NAC.
Clinical T stage at presentation The average number of SNs removed was 2.7. The impact of the
T0 5 3 size of SN metastases on FNR, NPV, and accuracy of post-NAC SNB is
T1 8 5 summarized in Table 2. If ypN0(i⫹) SNs had been considered nega-
T2 76 50 tive, the FNR would have increased to 13.3% (11 of 83; 95% CI, 6.0%
T3 61 40
to 20.6%). There was no direct correlation between the size of SN
NA 3 2
Clinical N stage at presentation
metastases and the rate of positive non-SNs (Table 3). The average
N0 26 17 number of positive nodes in the CND after a positive ypN0(i⫹),
N1 113 74 ypN1mi, or ypN1 SN after neoadjuvant therapy was 0.7, 0.5, and 2.8,
N2 10 6 respectively (Appendix Table A1, online only). A total of 20.5% (17 of
NA 4 3 83) of patients had ⱖ four positive nodes in the CND, all in the
Clinical tumor subtype
presence of ypN1 SNs. The use of IHC increased the detection of
ER positive and/or PR positive, HER2 negative 87 57
Triple negative 23 15
small SN metastases in this setting; 63% of micrometastases and
HER2 positive 43 28 100% of isolated tumor cells were detected by IHC (Appendix
Neoadjuvant chemotherapy regimen Table A2, online only).
Anthracycline plus taxane 147 96 If only one SN was obtained, the FNR increased to 18.2%, and
Anthracycline based 1 1 accuracy decreased to 87.5%. In the presence of ⱖ two SNs, the FNR
Taxane based 3 2
of SNB decreased to 4.9%, and accuracy increased to 96.8% (FNR P ⫽
NA 2 1
.076; Table 2). SNB mapping with dual tracers (isotope and blue dye)
Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor
receptor 2; NA, not available; PR, progesterone receptor.
was associated with an FNR of 5.2% (three of 58), whereas single-
agent isotope use had an FNR of 16.0% (four of 25; P ⫽ .190; Table 2).
In the presence of a false-negative SNB, the average number of positive
non-SNs was 1.3 (Appendix Table A1, online only). The impact of
comparable methodology and results, it was decided to close the trial to accrual clinical stage at presentation on the FNR and NPV is summarized in
on December 5, 2012.
Table 2. Accuracy of clinical examination, axillary ultrasound, and
SNB at identifying residual axillary disease after NAC was 45%, 62%,
Statistical Analysis
The two-tailed Fisher’s exact test was used to compare frequencies be- and 95% respectively (Table 4). Positive predictive value of clinical
tween two groups. The Freeman-Halton extension of Fisher’s exact test was examination and axillary ultrasound was 89% (17 of 19) and 81% (44
used to compare three groups. Two-sided 95% CIs were calculated for the FNR of 54), respectively.
and IR.

RESULTS DISCUSSION

From March 2009 to December 2012, 153 patients were accrued to the
SN FNAC study. Median age was 50 years (range, 26 to 75 years). A
total of 40% of patients had tumors ⬎ 5 cm in size; 74% had clinical
N1 disease at presentation; 15% had triple-negative breast cancer, and
28% had HER2-positive breast cancer; 96% of patients in the study
had received anthracycline and taxane– based chemotherapy regi-
mens, and all patients with HER2-positive breast cancer had received
neoadjuvant trastuzumab. Demographic, clinicopathologic, and
treatment characteristics are listed in Table 1.
The results for the primary objectives of the study are summa-
rized in Figure 2. Using the information obtained from the central
review of pathology, the FNR of SNB after NAC for patients with
biopsy-proven node-positive breast cancer was 8.4% (seven of 83;
95% CI, 2.4% to 14.4%). Using the data provided from the participat-
ing institutions, the FNR was 9.6% (eight of 83; 95% CI, 3.3% to
15.9%). A patient with ypN0(i⫹) found on HE staining in a single
non-SN node, in the presence of a negative SN, was reclassified from
false negative to true negative (ypT0N0[i⫹]) after central review. The
negative predictive value (NPV) of SNB was 86.3% (44 of 51). The IR
In the SN FNAC study, patients who presented with biopsy-proven
node-positive breast cancer had a post-NAC SNB FNR of 8.4%, meet-
ing the study prespecified end point of ⱕ 10%. The ACOSOG Z1071
trial, results of which were recently published,13 followed a similar
methodology, except that the use of IHC was not mandatory, and SNs
with metastases ⱕ 0.2 mm (ypN0[i⫹]) were considered node nega-
tive. The reported FNR of SNB when ⱖ two SNs were examined was
12.6%, which exceeded their prespecified threshold of 10%. The au-
thors concluded that changes in approach or patient selection would
be necessary to support the use of SNB in this setting.
The SENTINA (Sentinel Neoadjuvant) study evaluated SNB in
592 patients presenting with clinically node-positive breast cancer (by
physical and ultrasound evaluations) that converted to clinically
node-negative disease after NAC.14 IHC was not mandatory, and the
FNR was 14.2%. The design of the trial required patients who re-
mained clinically node positive after NAC to proceed directly to axil-
lary node dissection. This is supported by the high positive predictive
values of physical examination (89%) and axillary ultrasound (81%)
obtained in the SN FNAC study.

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132.239.1.231
 Boileau et al

Patients with T0-3, N1-2

(biopsy proven) Ineligible (n = 7)
breast cancer Withdrew (n = 1)
(N = 153)

Study eligible
(n = 145)

SNB + CND Technical failure (n = 18)

Identification rate
(n = 127 of 145) Axillary pCR (n = 44) CND potentially avoided
(87.6%; 95% CI, 82.2% to 93.0%) (n = 44 of 145; 30.3%)

Node positive False-negative rate

after NAC and (n = 7 of 83)
False negative (n = 7)
SNB + CND (8.4%; 95% CI, 2.4% to 14.4%)
(n = 83)

Fig 2. SN FNAC (Sentinel Node Biopsy Following Neoadjuvant Chemotherapy) trial: Results of central pathology review. CND, completion node dissection; NAC,
neoadjuvant chemotherapy; pCR, pathologic compete response; SNB, sentinel node biopsy.

On the basis of the three trials, it is clear that harvesting only one with an increased FNR in the absence of NAC.15 Patients with only one
SN is associated with a high FNR (SN FNAC, 18.2%; ACOSOG Z1071, SN represented 26.5% (22 of 83) of patients in the SN FNAC study,
31.5%; SENTINA, 24.3%). This finding is not specific to the neoadju- 20.4% (78 of 382) in the ACOSOG Z1071 trial, and 31.0% (70 of 226)
vant setting; obtaining a single SN is a well known factor associated in the SENTINA study. The limitations of this finding is that if we

Table 2. Impact of No. of SNs Removed, Method of SN Identification, Definition of Positive SN, and Clinical Stage at Presentation on FNR, NPV, and Accuracy
of SNB After Neoadjuvant Chemotherapy
FNR NPV Accuracy

Factor No. % No. % No. % P

No. of SNs removed .076
1 4 of 22 18.2 11 of 15 73.3 29 of 33 87.9
ⱖ2 3 of 61 4.9 32 of 35 91.4 90 of 93 96.8
Method of lymph node mapping .190
Isotope only 4 of 25 16.0 10 of 14 71.4 31 of 35 88.6
Dual tracers (isotope and blue dye) 3 of 58 5.2 34 of 37 91.9 89 of 92 96.7
Definition of positive SN
Any size (ypN0[i⫹] ⫹ ypN1mi ⫹ ypN1) 7 of 83 8.4 44 of 51 86.3 120 of 127 94.5
⬎ 0.2 mm (ypN1mi ⫹ ypN1) 11 of 83 13.3 44 of 55 80.0 116 of 127 91.3
⬎ 2 mm (ypN1) 14 of 83 16.9 44 of 58 75.9 113 of 127 89.0
Clinical stage at presentation
T stage
T0 1 of 4 25.0 1 of 2 50.0 4 of 5 80.0
T1 0 of 7 0.0 1 of 1 100.0 8 of 8 100.0
T2 1 of 37 2.7 27 of 28 96.4 63 of 64 98.4
T3 5 of 35 14.3 15 of 20 75.0 45 of 50 90.0
N stage
N0 0 of 11 0.0 3 of 3 100.0 14 of 14 100.0
N1 7 of 67 10.4 38 of 45 84.4 98 of 105 93.3
N2 0 of 4 0.0 3 of 3 100.0 7 of 7 100.0

Abbreviations: FNR, false-negative rate; NPV, negative predictive value; SN, sentinel node; SNB, sentinel node biopsy.

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 SN FNAC Study

Table 3. Size of Postneoadjuvant SN Metastases and Rate of
Positive Non-SNs
ypN1mi
ypN0(i⫹) (⬎ 0.2 to ypN1
[ⱕ 0.2 mm] 2 mm) (⬎ 2 mm)
Positive
Non-SNs No. % No. % No.
Rate 4 of 7 57 3 of 8 38 34 of 61
NOTE. P ⫽ .637.
Abbreviation: SN, sentinel node.
follow the standard definition of what constitutes an SN,2 it is not
possible to create more SNs if only one is present. Harvesting more
nodes (ie, blind node sampling) to increase the number of SNs to
ⱖ two was not evaluated in any of the trials and should not
be recommended.
An unplanned retrospective analysis from the ACOSOG Z1071
trial reported that placing clips in suspicious nodes at the time of
biopsy could possibly decrease the FNR of SNB.16 At the time of node
biopsy, 32.8% (172 of 525) of patients had clip placement. The clips
were found in the SNs at the time of surgery in 55.8% (96 of 172) of
cases. Patients in whom the clips were found had an FNR of 7.4% (v
14.0% if clips were not found and 13.6% if clips were not placed). It is
difficult to recommend this technique as a solution to increase the
accuracy of SNB after neoadjuvant therapy, because it would only
benefit approximately half of patients. This should be considered as an
exploratory analysis. Nodal clip placement was not evaluated in the SN
FNAC trial.
One of the most important findings of the SN FNAC trial is that
after NAC, SN metastases of any size are significant and should be
considered positive. At the time of pathologic evaluation, SNs that
were negative on HE staining were submitted to mandatory IHC
staining. ypN1mi and ypN0(i⫹) SNs were more likely to be identified
primarily by IHC staining. In the absence of NAC, the rate of positive
non-SNs increased with the size of SN metastases.17 After NAC, at least
for patients with biopsy-proven node-positive disease at presentation,
the rate of positive non-SNs was high and independent of the size of
SN metastases.
The FNR for patients with ⱖ two SNs and SN metastases ⬎ 0.2
mm was 11.5% (seven of 61), comparable to the FNR of 12.6% (39 of
310) reported in the ACOSOG Z1071 trial in similar patients. By
including IHC in the pathologic evaluation of the SNs and considering
SN metastases of any size as positive, an FNR of ⬍ 10% can be
achieved (8.4% in this trial) without excluding patients. Using this
method, 30.3% of patients who present with biopsy-proven node-
positive disease could potentially be spared CND. One of the limita-
tions of this trial is the relatively small sample size, which explains the
large CI around the FNR that overlaps the 10% value. To confirm the
importance of IHC in the evaluation of SNs in this setting, we recom-
mend reanalyzing the results of the ACOSOG Z1071 trial using IHC
and considering SN metastases of any size as node positive.
% In the SN FNAC trial, the use of dual tracers (isotope and blue
56
dye) was associated with a three-fold decrease in the FNR, when
compared with isotope alone (5.2% v 16.0%; P ⫽ .190). This was not
statistically significant, possibly because of the small sample size. Two-
fold decreases in the FNR have been previously reported with the use
of dual tracers in similar settings.13,14 The use of a single tracer using
blue dye alone was not permitted in the this study.
The IR (87.6%) was lower than the prespecified rate (ⱖ 90%). In
the presence of a technical failure, CND is warranted, because 66.7%
of these patients will have positive nodal metastases. A lower IR is a
common finding when SNB is performed after NAC,3,4,7,8,13,14 but
this should not preclude its use in patients with biopsy-proven node-
positive disease, because the default treatment would be an axillary
node dissection that could potentially be spared. SNB is more accurate
than clinical examination and axillary ultrasound at identifying pa-
tients who have achieved an axillary pCR.
In the presence of a false-negative SNB, the disease burden in the
non-SNs was minimal (average, 1.3 nodes positive). Although this was
not recorded prospectively, in most of the participating centers, pa-
tients with biopsy-proven node-positive disease undergoing neoadju-
vant therapy received regional node irradiation (RNI) regardless of
SNB result. The AMAROS (After Mapping of the Axilla: Radiotherapy
or Surgery?) trial compared CND versus RNI in patients with a posi-
tive SNB and found comparable adequate regional control rates be-
tween the two modalities, but the trial excluded patients with tumors
⬎ 5 cm and patients who had received neoadjuvant therapy.18 The
significance of leaving even a minimal amount of residual disease in
the axilla after neoadjuvant therapy is not known, especially if RNI is
administered. Patients in the SN FNAC study are not being observed
beyond their surgery and are not an appropriate cohort for answering
this question, because all patients in the trial underwent CND. The
relevance of residual axillary disease after neoadjuvant therapy, the
role of RNI in the presence of axillary pCR, and the need for CND and
RNI versus RNI alone in the presence of a positive SNB after NAC are
questions being addressed in ongoing clinical trials.19
In conclusion, a low FNR (8.4%) of SNB after NAC in biopsy-
proven node-positive breast cancer can be achieved with mandatory
use of IHC for SN evaluation. SN metastases of any size, including
micrometastases and isolated tumor cells, should be considered posi-
tive and are associated with a significant rate of involved non-SNs.
This is the most convenient and inclusive method to decrease the FNR
of SNB below the threshold of 10% and should be further evaluated

Table 4. Evaluation of Residual Nodal Disease After Neoadjuvant Therapy: FNR, NPV, PPV, and Accuracy of Clinical Examination, Axillary Ultrasound, and SNB
FNR NPV PPV

Modality No. % No. % No. % Accuracy (%)

Clinical examination 77 of 94 82 48 of 125 38 17 of 19 89 45
Axillary ultrasound 39 of 83 47 36 of 75 48 44 of 54 81 62
SNB 7 of 83 8 44 of 51 86 83 of 83 100 95

Abbreviations: FNR, false-negative rate; NPV, negative predictive value; PPV, positive predictive value; SNB, sentinel node biopsy.

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132.239.1.231
 Boileau et al

before being included in future guidelines on the use of SNB after

NAC in node-positive breast cancer.
Confirming previously published reports, the FNR of SNB after
NACwasdecreasedwiththeuseofdualtracers(isotopeandbluedye)and
when ⬎ one SN was removed. The IR of SNB after NAC (87.6%) was
slightly inferior to 90%. In the presence of a technical failure, axillary node
dissection is warranted. By using SNB after NAC, axillary node dissection
could potentially be avoided in ⱖ 30% of patients who present with
node-positive breast cancer. In an era where RNI is increasingly used, the
relevance of leaving residual disease in the undissected axilla of patients
after NAC is unknown and is currently being investigated.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Conception and design: Jean-Francois Boileau, Stephen E. Karp, Andre
Robidoux
Administrative support: Jean-Francois Boileau
Provision of study materials or patients: Jean-Francois Boileau, Brigitte
Poirier, Mark Basik, Claire M.B. Holloway, Muriel Brackstone, David R.
McCready, Stephen E. Karp, Andre Lisbona, Frances C. Wright, Rami J.
Younan, Louise Provencher
Collection and assembly of data: Jean-Francois Boileau, Brigitte Poirier,
Mark Basik, Claire M.B. Holloway, Lucas Sideris, Sarkis Meterissian,
Angel Arnaout, Muriel Brackstone, David R. McCready, Isabelle Trop,
Andre Lisbona, Frances C. Wright, Louise Provencher, Erica Patocskai,
Atilla Omeroglu, Andre Robidoux
Data analysis and interpretation: Jean-Francois Boileau, Claire M.B.
Holloway, Louis Gaboury, Lucas Sideris, Sarkis Meterissian, Frances C.
Wright, Rami J. Younan, Andre Robidoux
Manuscript writing: All authors
Final approval of manuscript: All authors

7. Gimbergues P, Abrial C, Durando X, et al: motherapy in patients with node-positive breast

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Support
Supported by the Quebec Breast Cancer Foundation, Cancer Research Society, Week-end to End Women’s Cancers, and Montreal Jewish
General Segal Cancer Centre.
■ ■ ■

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 SN FNAC Study

GLOSSARY TERMS

immunohistochemistry: the application of antigen-
antibody interactions to histochemical techniques. Typically, a
tissue section is mounted on a slide and incubated with antibod-
ies (polyclonal or monoclonal) specific to the antigen (primary
reaction). The antigen-antibody signal is then amplified using a
second antibody conjugated to a complex of peroxidase-
antiperoxidase, avidin-biotin-peroxidase, or avidin-biotin alka-
line phosphatase. In the presence of substrate and chromogen,
the enzyme forms a colored deposit at the sites of antibody-
antigen binding. Immunofluorescence is an alternate approach to
visualize antigens. In this technique, the primary antigen-
antibody signal is amplified using a second antibody conjugated
to a fluorochrome. On ultraviolet light absorption, the fluoro-
chrome emits its own light at a longer wavelength (fluorescence),
thus allowing localization of antibody-antigen complexes.
neoadjuvant therapy: the administration of chemotherapy prior
to surgery. Induction chemotherapy is generally designed to decrease
the size of the tumor prior to resection and to increase the rate of com-
plete (R0) resections.
pathologic complete response: the absence of any residual tu-
mor cells in a histologic evaluation of a tumor specimen.
sentinel lymph node: the lymph node that is anatomically located such
that it is the first site of lymph drainage from the location of the primary tumor.
It is suspected and assumed that if a malignancy is going to disseminate via the
lymphatic system, metastases will first be evident in the sentinel lymph node. In
this manner, this lymph node is said to stand guard or sentinel over the meta-
static state of the tumor. For many cancers, the sentinel lymph node is biopsied
as part of the staging process and presence of macro- or micrometastases in the
sentinel lymph node is a negative prognostic factor.

www.jco.org © 2014 by American Society of Clinical Oncology 7

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Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
132.239.1.231
 Boileau et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Sentinel Node Biopsy After Neoadjuvant Chemotherapy in Biopsy-Proven Node-Positive Breast Cancer: The SN FNAC Study
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Jean-Francois Boileau Stephen E. Karp
No relationship to disclose No relationship to disclose
Brigitte Poirier Isabelle Trop
No relationship to disclose No relationship to disclose
Mark Basik Andre Lisbona
No relationship to disclose No relationship to disclose
Claire M.B. Holloway Frances C. Wright
No relationship to disclose No relationship to disclose
Louis Gaboury Rami J. Younan
No relationship to disclose
No relationship to disclose
Lucas Sideris
Louise Provencher
No relationship to disclose
No relationship to disclose
Sarkis Meterissian
No relationship to disclose Erica Patocskai
No relationship to disclose
Angel Arnaout
No relationship to disclose Atilla Omeroglu
No relationship to disclose
Muriel Brackstone
No relationship to disclose Andre Robidoux
No relationship to disclose
David R. McCready
No relationship to disclose

© 2014 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
132.239.1.231
 SN FNAC Study

Acknowledgment
Presented at the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, IL, May 31-June 4, 2013, and ASCO
Breast Cancer Symposium, San Francisco, CA, September 7-9, 2013.

Appendix

Table A1. Impact of Post-NAC Size of SN Metastases and False-Negative SNs on Average No. of Positive SNs and Non-SNs in CND

Status of SN After NAC Mean No. of Positive SNs Mean No. of Positive Nodes in CND
ypN0(i⫹) [n ⫽ 7] 1.3 0.7
ypN1mi (n ⫽ 8) 1.4 0.5
ypN1 (n ⫽ 61) 2.3 2.8
False negative (n ⫽ 7) 0 1.3

Abbreviations: CND, completion node dissection; NAC, neoadjuvant chemotherapy; SN, sentinel node.

Table A2. Impact of Post-NAC Size of Largest SN Metastasis on Rate of Positive SNBs Detected by IHC

ypN0(i⫹) ypN1mi ypN1

[ⱕ 0.2 mm] (⬎ 0.2 to 2 mm) (⬎ 2 mm)

Positive SNBs Detected by IHC No. % No. % No. %

Rate 6 of 6 100.0 5 of 8 63 26 of 55 47

NOTE. P ⫽ .037.
Abbreviations: IHC, immunohistochemistry; NAC, neoadjuvant chemotherapy; SN, sentinel node; SNB, sentinel node biopsy.

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