Review

Role of sentinel node biopsy in breast cancer: a review

Maria Jesús Pla Farnós1, *, Maria Eulalia Fernández-Montolí1 , Rosalía Pascal Capdevila1 , Amparo García Tejedor1 ,
Míriam Campos Delgado1 , Maite Bajen Lázaro2 , Anna Petit Montserrat3 , Raul Ortega Martínez4 , Evelyn Martínez Pérez5 ,
Sonia Pernas Simón6 , Jordi Ponce Sebastià1
European Journal of Gynaecological Oncology

1
Gynaecology Department, Hospital Universitari de Bellvitge, Idibell, Universitat de Barcelona, 08907 L‘Hospitalet de Llobregat, Barcelona, Spain
2
Nuclear medicine Department Hospital Universitari de Bellvitge, Idibell, Universitat de Barcelona, 08907 L‘Hospitalet de Llobregat, Barcelona, Spain
3
Pathology Department, Hospital Universitari de Bellvitge, Idibell, Universitat de Barcelona, 08907 L‘Hospitalet de Llobregat, Barcelona, Spain
4
Radiology Department, Hospital Universitari de Bellvitge, Idibell, Universitat de Barcelona, 08907 L ‘Hospitalet de Llobregat, Barcelona, Spain
5
Oncological Radiotherapy Department, Institut Català d’Oncologia, Univeristat de Barcelona, 08908 L‘Hospitalet de Llobregat, Barcelona, Spain
6
Medical Oncology Department, Institut Català d’Oncologia, Universitat de Barcelona, 08908 L‘Hospitalet de Llobregat, Barcelona, Spain
*Correspondence: mjpla@bellvitgehospital.cat (Maria Jesús Pla Farnós)
DOI:10.31083/j.ejgo4205147
This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).
Submitted: 31 May 2021 Revised: 2 July 2021 Accepted: 4 August 2021 Published: 15 October 2021

Axillary lymph node involvement is still an important predictor of re- 2. Definition of sentinel node and sentinel
currence and survival in breast cancer. Axillary staging was classi- lymph node biopsy
cally done by axillary lymph node dissection (ALND), but the intro- The sentinel node (SN) is defined as the node that first
duction of sentinel lymph node biopsy (SLNB) has led to a progres- receives tumour drainage to the lymphatic system of a deter-
sive and continuing de-escalation in its use. Therefore, SLNB can now mined anatomical region. This definition implies a sequence
be considered the standard procedure for axillary staging in clinically in the drainage to the lymphatic system of the tumour cells.
N0 patients. Different studies have also begun to report that a posi- There can, therefore, be multiple SNs. The first mention
tive sentinel node does not always require ALND, reducing the mor- of the SN in the literature dates to 1960, when Dr. Gould
bidity derived from this technique. Fears that this sentinel node ap- proposed that the SN predicts the histological state of the
proach might not be accurate for neoadjuvant chemotherapy have rest of the nodes in a determined region. However, it was
been allayed by several studies showing that post-neoadjuvant SLNB
Cabañas in 1977 [2] who stated that tumour cells from a pri-
in clinical N0 patients reduces the rate of ALND. This approach bene-
mary carcinoma migrate through the lymphatic channel to
fits from axillary pathological complete response with an acceptable
a single lymph node before involving further lymph nodes
false-negative rate. By contrast, however, cN1 disease still requires
within that basin [1]. In the 1990s Krag et al. [3] and Giu-
that we optimise the technique to reduce the rate of false negatives.
liano et al. [4] in identified the SN in breast cancer using a
Currently, SLNB is the best method for axillary staging in breast can-
cer, allowing patients to be treated according to risk of recurrence,
radioactive tracer and a vital dye, respectively [5].
and with good evidence that morbidity is lower than with other more A sentinel lymph node biopsy (SLNB) is the procedure
radical techniques. in which the SN is identified, removed and examined to de-
termine the presence of tumour cells. Morton et al. [6]
Keywords first used this technique in patients with cutaneous malignant
Sentinel lymph node biopsy; Breast cancer; Axillary lymph node dissection; melanoma and Giuliano et al. [4] developed and used a mod-
Neoadjuvant chemotherapy; Node positive; Macrometastasis; Micrometastasis ification of lymphatic mapping and sentinel lymphadenec-
tomy to detect axillary lymph node metastasis in patients with
1. Introduction breast cancer. SLNB predicts the axillary state in 95% of pa-
The presence and extent of axillary lymph node involve- tients at low-risk of spread in breast cancer, which means
ment is one of the most powerful predictors of recurrence and that the risk of falsely staging an axillary tumour as negative
survival in breast cancer besides tumour biology [1], mak- is approximately 5% [7]. Therefore, lymphatic mapping by
ing the evaluation of node status crucial to proper therapeu- SLNB instead of systematic ALND is considered appropri-
tic management. Historically, lymph node involvement in ate in early-stage breast cancer with clinically negative axil-
breast cancer was determined solely by axillary lymph node lary lymph nodes [8]. Using this approach, the overall sur-
dissection (ALND), which not only provided high sensitiv- vival (OS), disease-free survival (DFS) and regional control
ity and accuracy of detection but also carried high morbidity for SLNB are statistically equivalent to those for ALND [9].
(e.g., lymphedema, pain or potential injury of vascular and Nevertheless, ALND remains the standard treatment for pa-
brachial plexus). Today, it is accepted that less radical proce- tients with clinically positive axillary nodes who are initially
dures provide adequate staging. treated surgically [8].

Eur. J. Gynaecol. Oncol. 2021 vol. 42(5), 982-995

©2021 The Author(s). Published by IMR Press.
 Table 1. Current indications and contraindications for SLNB of the breast.
Indications Contraindications Other indications
(Past contraindications)
Infiltrative carcinoma T1, T2 or T3, cN0 (clin- Breast cancer with N1–N2 Multifocal or multicentric tumours [17]
ically and echographically negative) [16]
Intraductal or in situ carcinoma if: Inflammatory Carcinoma (T4d) [16] Previous tumourectomy
- indication of mastectomy Previous plastic mammary surgery
- high risk of infiltration (high histological Previous breast or axilla radiotherapy
grade or comedonecrosis; Ø ≥3 cm; associated Mammary recurrence after previous conservative surgery with SLNB [18]
with a palpable or nodular lesion) Before or after neoadjuvant treatment in cN0 patients [19–22]
Pregnant, puerperal or lactating woman [23, 24]
- Use of minimal possible dose, the same day of surgery
- Vital colourants still contraindicated
- Stop breastfeeding for 24 h
T4b breast carcinoma in selected cases with focal changes

3. The SLNB technique in breast cancer Other techniques for localising sentinel lymph nodes are
Several techniques are used to localise SNs during surgery. currently being investigated, focusing on the possible benefits
Two of the most frequently used are: vital colourant (Iso- for centres without access to a nuclear medicine service. Two
sulfan Blue Dye or Patent Blue Dye) and radioactive colloid of these techniques have the greatest amount of supporting
(Technetium labelled albumin). These are not mutually ex- data. The first uses Indocyanine Green (ICG) injections be-
clusive and can complement each other, depending on local fore localising the SN with a fluorescent imaging system [13].
availability and the experience and preferences of the surgical The second uses an injection of Superparamagnetic Iron Ox-
team [10]. ide (SPIO) and locates the sites with a magnetometer [11]. A
meta-analysis has showed that using Sienna + as an SPIO and
When Blue Dye is used, 2–5 mL of blue dye is injected
detecting it by magnetometer was non-inferior to the stan-
around the tumour periphery, avoiding intratumoral injec-
dard methods of SLNB for mapping [14].
tion and/or injecting the dye into the seroma cavity sec-
ondary to breast biopsy, which could lead to a failure of map-
4. Current indications and contraindications
ping [11]. The time from injection to axillary incision varies
for SLNB
from 3 to 8 minutes depending on the size of the patient and
location of the tumour. Breast massage is usually performed SLNB is an unstandardised procedure in continuous evo-
at the site of the blue dye injection until the incision is made, lution. Indeed, many controversies remain concerning the
theoretically helping the dye reach the SNs [12]. The axillary technique and its indications and contraindications [15]. The
fascia is entered through an inferior incision in the axilla, and current indications and contraindications of SLNB are sum-
all blue lymphatic nodes or any at the end of a blue lymphatic marised in Table 1 (Ref. [16–24]), together with a third col-
channel are removed and designated as SNs. Suspicious pal- umn that lists past contraindications. Note that there is no
pable nodes are also removed. The two most common tech- evidence for SLNB to be indicated in cases of previous plastic
nical errors are failure to consider the node at the end of a mammary surgery or previous breast or axilla radiotherapy,
blue lymphatic channel and failure to identify the blue node and that this recommendation is only based on expert con-
most proximal to the tumour [11]. sensus.
When radiocolloid is used, close cooperation between nu-
clear medicine and the surgeon is essential to ensure that in- 5. Pathological examination of SNs
formation is shared about changes in the injection technique Frozen SN sections are examined pathologically to de-
[12]. The proportion of successful mappings is significantly tect tumour cell deposits that can be classified by their size
higher in studies using radioactive colloid rather than blue in isolated tumour cells, micrometastasis and macrometas-
dye alone [11]. The principal advantages of this approach are tasis. Isolated tumour cells refer to deposits ≤0.2 mm, des-
the provision of an anatomical map of the lymphatic drainage ignated pN0 (i+) in the Tumour, Node, Metastasis (TNM)
of every patient, finding both axillary and extra-axillary SNs, system, and these do not worsen the prognosis compared
and the identification of the most adequate site to perform the to a negative SLNB [25]. Micrometastases are 0.2–2.0 mm
surgical incision [10]. The nodes are identified by a sensitive clusters of tumour cells and are designated as pN1mic in the
hand-held gamma probe, and in the operating room, a small American Joint Committee on Cancer (AJCC) staging system
skin incision is made over the suspected nodal area and the [25]. These can be associated with non-SN involvement, al-
probe is used to guide the surgeon to the labelled lymphatic though even then, there is not enough evidence to support
nodes [11]. ALND [26–28]. Micrometastases are associated to a worse

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long-term prognosis, and evidence suggests that affected pa- tivity interference from the primary tumour [32]. Lym-
tients may benefit from systemic treatment [27]. Finally, phoscintigraphy studies suggest that approximately 30% of
macrometastases refer to any tumour cell cluster >2 mm and medial tumours and 15% of lateral tumours drain primar-
are a well-established independent predictor of a poor out- ily to these nodes, while surgical series have indicated that
come [25]. there is a higher risk of their involvement in cases of medial
Immunohistochemistry (IHC) staining with cytokeratin is tumours and positive axillary nodes [20]. In a population-
not used routinely for pathological examination but can be based cohort study by Thorsen et al. [33], the irradiation of
useful for cases of invasive lobular carcinoma (where tumour internal mammary lymph nodes increased the OS in patients
cells closely resemble lymphoid cells). It should be used to with early-stage node-positive breast cancer. One of the most
diagnose a suspicious area on hematoxylin and eosin defini- important arguments against this approach is the potential
tively (i.e., antibodies can uncover a small number of tumour for cardiopulmonary toxicity [33]. Thus, when considering
cells that are not easily visible) [8, 25]. investigating internal mammary nodes, a diagnostic proce-
dure with a complication rate of approximately 2%–6%, the
6. Molecular SN study surgeon should consider how the results will affect adjuvant
The One-Step Nucleic Acid Amplification (OSNA) test is chemotherapy or radiotherapy [34].
a molecular method for detecting metastatic SNs. It relies on Intra-mammary lymph nodes may be detected in 1%–28%
detecting mRNA expression of epithelial marker cytokeratin of breast cancers [35]. Positive intra-mammary nodes can
19 (CK19), which is highly expressed in most breast cancer modify disease staging but do not necessarily imply axillary
cells but is absent in normal lymph nodes. The sensitivity and lymph node involvement. In this setting, biopsy of both the
specificity of the OSNA test has been reported for the detec- axillary and intra-mammary nodes is recommended, with the
tion of metastases, with a low rate of false positives [29, 30]. completion of axillary surgery detailing the status of the ax-
Therefore, OSNA is considered a reliable tool for intraoper- illa [36, 37]. If the intra-mammary nodes are the only drain-
ative diagnosis of whole SNs and can minimise the need for ing sites detected on lymphoscintigraphy, an uncommon sce-
secondary surgery [29]. nario, care should be individualised to the needs of the patient
[36] but management of the axilla should be governed by ax-
7. SN mapping: lymphoscintigraphy and illary SN status.
extra-axillary drainage
8. Staging the axilla after a negative SLNB
In many centres, lymphoscintigraphy is performed as part
of the SLNB to obtain images from a gamma camera. This The role of axillary surgery as a staging and prognostic
technique provides individual mapping for each patient and procedure, rather than only as a therapeutic intervention, has
offers the possibility to visualise the SN of unexpected lo- been widely accepted over recent years. Several factors have
cations. However, controversy surrounds the technique’s contributed to the progressive decrease in the extent of axil-
use, with arguments for and against. Those who defend it lary surgery, such as screening mammography, adjuvant and
argue that it gives the option to mark the skin during the systemic therapies, radiotherapy, and the relevance of biolog-
gamma camera imaging, making SN detection easier with a ical markers [38, 39].
gamma probe during surgery. Although sometimes not pre- Axillary recurrence after SLNB is considered a rare event
cise enough to distinguish between SNs that are very close, it [40]. In a systematic literature review by Van der Ploeg et al.
can indicate the number of nodes present. Moreover, it pro- [41], the axillary recurrence rate in SLNB-negative cases was
vides information about the extra-axillary drainage of radio- just 0.3%. According to other studies, this recurrence rate
colloid to the internal mammary, intra-mammary, contralat- could increase to 1.5% after 5 years [7]. Of note, neither the
eral axillary and supraclavicular nodes. Arguments against ALMANAC [42] nor the NSABPB-32 [9] study found statis-
lymphoscintigraphy include the added cost, that the hand- tically significant differences in OS, DFS or regional control
held gamma probe may be more accurate in identifying the between SLNB alone and ALND following a negative SLNB.
best side for skin incision, and that most lymph nodes drain- Given an identification rate of 98% and a predictive value
ing breast cancer are in the axilla, meaning that nodes in other for SN of 97.5%, we are confident that it is not necessary
locations may not alter management [8, 11]. to perform ALND in patients without SN involvement [43].
Today, SLNB is considered standard care for axillary staging
According to the literature, lymphoscintigraphy may be
in cN0 breast cancer [1] because axillary local recurrence is
used in patients with breast cancer recurrence who have pre-
extremely rare after a negative SLNB (0.3%), adding ALND
viously undergone any type of axillary procedure [25]. As de-
to SLNB does not affect the DFS or OS, and the morbidity of
tection techniques have improved, however, there has been
SLNB is less than that of ALND [44, 45].
an increase in the detection of extra-axillary lymph nodes in
breast cancer. The clinical importance of these nodes de-
tected remains unclear [31].
Concerning the internal mammary nodes, we must con-
sider that the SN technique has limitations due to radioac-

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 Table 2. Axillary local recurrence and relative survival in tases and 33% had micrometastases (neither group under-
SN micrometastases, macrometastases with or without went ALND). Compared with the rest of the patients who
ALND. Patients: National Cancer Database (1998–2006). underwent ALND, there were no significant differences in
Adapted from Bilimoria et al. [46]. OS over a 50-month follow-up period. Thus, compared with
Surgery and micro/ Axillary local recurrence Relative survival SLNB alone, it was shown that ALND does not improve
macrometatasis (5 years) (5 years) survival for breast cancer patients with micrometastasis at
SN micrometastases SLNB.
SLNB 0.4% 99% Another retrospective study comprising 276 SN-positive
SLNB + ALND 0.2% 97.8% patients, treated both with and without ALND, also con-
SN macrometastases cluded that the omission of ALND in women with SN-
SLNB 1.0% 89.9%
positive disease did not significantly affect breast, nodal or
SLNB + ALND 1.1% 89.1%
distant recurrence, or mortality. This study also reported low
rates of axillary recurrence at 28–82 months (typically, 0%–
9. Overview of management after a positive 2%) [48].
SLNB The ACOSOG Z0011 study tried to answer if ALND af-
9.1 Introduction fects the survival of patients with SN involvement [49, 50].
This prospective, non-inferiority, randomised trial closed
The presence of axillary lymph metastases is still one of
prematurely due to poor enrolment and a low number of
the most important prognostic factors in breast cancer. As
events. ACOSOG Z0011 included 891 SN-positive cases with
outlined above, ALND has been the preferred method for as-
clinical stage T1–T2/N0 breast cancer randomly assigned to
sessing axillary involvement for years, allowing us to know
complete ALND. These were compared with a group that
the state of the axilla and when clinically relevant disease
received no further surgery. All patients underwent breast
was present. Although this could affect axillary recurrence
conserving surgery (BCS) and whole-breast radiation ther-
and local disease control, removing all axillary nodes causes
apy, with most women also receiving systemic treatments.
anatomic disruption that may result in interstitial fibrosis and
Patients were excluded if they had ≥3 positive SNs or mat-
lymphedema. This is one of the most uncomfortable com-
ted nodes, and SLNB was studied by routine hematoxylin and
plications of axillary surgery, compromising quality of life.
eosin staining. Additional positive nodes were described in
SLNB therefore aims to avoid the morbidity of ALND while
27.3% of cases that underwent ALND, but at a median follow-
preserving its prognostic utility. In the studies of validation
up of 6.3 years, there were no differences between the ALND
of sentinel node biopsy, concordance between SN involve-
and non-ALND arms in local (3.6% vs. 1.9%), regional (0.5%
ment and axillary involvement was reported in 97.5% of cases
vs. 0.9%), or overall locoregional (4.1% vs. 2.8%) recurrence
and in 95% of case of non-metastatic involvement of the ax-
[51]. Consequently, they concluded that SN alone did not re-
illa.
sult in statistically inferior survival compared to ALND. The
9.2 Axillary surgery after a positive SLNB 5-year OS rate was 92.5% in the SN group and 91.8% in the
Patients with a positive SN had historically undergone ALND group (p = 0.25); the corresponding rates for the 5-
ALND to assess nodal involvement. Today, however, some year DFS were 83.9% and 82.2%, respectively (p = 0.14).
clinical trials have concluded that performing an ALND does Unfortunately, several criticisms were levelled at the
not provide any survival benefits for patients with limited ax- ACOSOG Z0011 study. If we consider the entire population
illary disease. of the study, 69% of the patients were stage T1, more than
First, we must consider that 30%–50% of patients with a 80% were had hormone receptor-positive disease and 61%
positive SN have disease limited to this SN, without other had no intravascular invasion. Moreover, the patients were
involved nodes [1]. Moreover, axillary recurrence is un- not stratified by important prognostic factors, such as HER2
common, reported in less than 2% of cases in most stud- overexpression or proliferation markers, and the follow-up
ies. In a retrospective study, Bilimoria et al. [46] reported was too short. The groups were also unbalanced by the size
on 97,314 SN-positive cases, among which 23% with SN of metastasis (micrometastases: 37.5% in the ALND group
macrometastases (pN1) and 55% with SN micrometastases and 44.8% in the SN group; p < 0.05). Of even greater im-
(pN1mi) did not undergo ALND and the remaining 22% un- portance was the use of poorly defined radiotherapy proto-
derwent ALND. After adjusting for differences in patholog- cols. It was concluded that BCS followed by whole-breast ir-
ical characteristics and adjuvant treatment between partic- radiation could include treatment of the lower axilla, but the
ipating clinics, axillary local recurrence and 5-year relative lack of clearly described protocols means that the results of
survival for both pN1 and pN1mi SN disease, were the same ACOSOG Z0011 cannot be readily translated to all patients
with or without ALND (Table 2, Ref. [46]). with early-stage breast cancer.
Similar results were reported by Yi et al. [47] in a ret- Although the Z0011 protocol required only whole-breast
rospective study of 26,986 SN-positive cases from the SEER radiotherapy using standard tangential fields, the extent of ra-
Database (1998–2004). Of these, 11% had SN macrometas- diotherapy coverage of axillary or upper nodes had not pre-

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 Table 3. Studies of SLNB after neoadjuvant treatment.
Year of N Identification False Mapping Method Mapping Method Number of SN
Study name Period Patients
publication Axila rate negative rate Identification rate False negative rate False negative rate
N0–N1
2005 NSABP B27 [85] 1997–2000 428 88.9% 10.7% Dual mapping 9.3%
palpation
11.5%
2008 French study [21] 2003–2007 195 N0–N1 90% N0 9.4% Dual mapping
N1 15 %
2013 SENTINA TRIAL 2009–2012 900 N1–N2 80% 14% I: 77% I 16% 1 SN 24%
(Arm C) [101] Ultrasound I + Blue: 87% I + Blue 8.6% 2 SN 18%
3 SN 7%
2013 ACOSOG Z1071 2009–2011 649 N1–N2 92.9% 12.6% I: 20.3% 2 SN 21.1%
Alliance trial [102] Cytology, I + Blue 10.8% ≥3 SN 9.1 %
Core biopsy Multiple injection 7.1%
Simple injection 13.3%
2015 FNAC [103] 2009–2012 153 N1–N2 87.6% IHQ I ± Blue
i+ Mic
8.4%
If ypNo (i+) – 13.3%
2018 GANEA2 [89] 2010–2014 957 N0–N1 N0 97.6% 11.5% Number of nodes not
N1 79.5% predictors of
complementary
involvement ALNDo
related
IHQ, Immunohistochemistry; I, Radiolabeled colloid mapping.

viously been described in these patients. This fact led to con- group (p = 0.28). The 10-year cumulative locoregional recur-
siderable speculation that high tangent fields, a third field rence rate was 6.2% with ALND and 5.3% with SLNB alone (p
of directed nodal treatment, could have explained the re- = 0.36). Despite the potential for residual axillary disease after
sults in the SN group. For this reason, Jagsi et al. [52] re- SLNB alone, not performing axillary clearance still produces
viewed the radiotherapy protocols to determine if there were excellent regional control in appropriately selected patients.
differences between the two groups. Studying 605 patients Another important change that has come with the thor-
with completed case report forms, they found that only 89% ough assessment of SNs is the more frequent identification
received whole-breast radiotherapy, and that, of these, 89 of micrometastatic foci (≤2 mm in diameter) and isolated
(15%) also received treatment to the supraclavicular region. tumour cells. Currently, the significance of these findings
Detailed radiotherapy protocols were obtained for 228 pa- is still unknown. The International Breast Cancer Study
tients, of whom 185 (81.1%) received tangent-only treatment Group (IBCSG) 23-01 [26] is a multicentre, phase 3, ran-
and 43 (18.9%) received nodal radiotherapy using three fields domised, non-inferiority trial designed to identify whether
(ALND group = 22; SN group = 21). They noted that pa- ALND represents overtreatment for patients who have SN
tients who received direct nodal irradiation had statistically micrometastases. The eligibility criteria were tumour ≤5 cm,
significant greater nodal involvement. To assess the tangent non-palpable axillary lymph nodes, and one or more SN mi-
height, they then reviewed 142 patients. High tangents (cra- crometastases with no extracapsular extension, resulting in
nial tangent border ≤2 cm from the humeral head) were used 931 patients being randomly assigned to ALND or no fur-
in 50% of patients (33 of 66) randomly assigned to ALND and ther surgery. It should be noted that the study included pa-
in 52.6% (40 of 76) randomly assigned to SLNB alone. It was tients with isolated tumour cells and that 70% of the patients
concluded that most patients in the ACOSOG Z0011 trial re- had metastases smaller than 1 mm. Most patients underwent
ceived tangential radiotherapy and that there were no signif- BCS, but mastectomies were performed in 9% of cases. After
icant differences in the use of prohibited nodal fields between a median follow-up of 5.0 years, the 5-year DFS was 87.8%
the study groups. in the SLNB group and 84.4% in the ALND group (p = 0.16).
Recently, Giuliano et al. [53], the authors of the ACOSOG In addition, axillary recurrence was 1% in the SN group de-
Z0011 report, published their results for long-term locore- spite 13% of non-sentinel positive nodes being found in the
gional recurrence. At a median follow-up of 9.25 years, there ALND group [26]. These findings were corroborated after
was no statistically significant difference in local recurrence- a median follow-up of 9.7 years [28]. The considerable pro-
free survival (p = 0.13). The incidence of nodal recurrence at portion of non-sentinel metastatic nodes was also reported
10 years was 0.5% in the ALND group and 1.5% in the SLNB in a meta-analysis [54], non-sentinel involvement in 20%–

986 Volume 42, Number 5, 2021

40% of cases. Therefore, we can conclude that ALND may factors, such as hormone receptor status, HER2 overexpres-
be avoided in cases with micrometastasis. This is why the St sion and proliferations markers are of far greater value when
Gallen Consensus Statement, since 2013, has recommended determining systemic treatment than the number of nodes
avoiding axillary node clearance for metastases measuring <2 involved.
mm at SLNB in patients with early breast cancer, without this
9.4 Locoregional recurrence: related factors and the relationship
affecting survival [55]. with systemic treatment
Despite the negative and controversial opinions arising
Based on several large randomised controlled trials [58,
from the ACOSOG trial, its conclusions mean that 38% of
59], BCS with whole-breast irradiation has equivalent DFS
SN-positive patients older than 50 years are spared complete
and OS to mastectomy for early breast cancer. Locore-
axillary dissection [10]. What is more, the 2014 American
gional relapses have been correlated with conventional clin-
Society of Clinical Oncology (ASCO) guidelines recommend
icopathological parameters, such as tumour size, grade and
not performing ALND in patients with one or two SN metas-
lymph node involvement. However, if we consider the bi-
tases who will be treated by BCS with whole-breast radio-
ology of breast cancer, traditional prognostic factors provide
therapy, and if needed, systemic therapy [16].
limited information. A molecular taxonomy for breast cancer
9.3 The prognostic value of ALND may therefore improve the prediction of locoregional recur-
Axillary dissection has historically been used to guide ad- rence. Breast cancer subtypes are associated with different
juvant treatment rather than as a treatment. In the IBCSG 23- risks of locoregional recurrence after breast cancer surgery.
01 study [26], the SN and ALND groups did not differ in ad- In a systematic review of 12,592 patients with breast can-
juvant therapy, suggesting that more extensive surgery in the cer who underwent conservative or radical surgery, those
axilla did not influence systemic treatment. The AMAROS with luminal subtype tumours had a lower risk of locore-
randomised, multicentre, phase 3 non-inferiority trial [56], gional recurrence than those with triple-negative and HER2-
randomised patients with T1–T2 breast cancer and non- overexpressing tumours. Consequently, breast cancer sub-
palpable axillary nodes to receive either ALDN or axillary type should be taken into account when considering local
radiotherapy following a positive SLNB. This study aimed control and may help to identify patients at increased risk of
to assess whether axillary radiotherapy provided comparable locoregional recurrence [60].
regional control, with fewer side-effects, to that offered by Another consideration for not performing ALND after
ALND. After a median follow-up of 6.1 months (IQR 4.1– a positive SLNB in breast cancer is that personalised sys-
8.0) the study reported that there were no significant differ- temic therapy can reduce locoregional relapse. The NSABP
ences in 5-year axillary recurrence, DFS or OS between the B-13 study [61] compared surgery alone with the use of se-
two groups. Given the percentages of patients receiving any quential chemotherapy plus surgery in patients with oestro-
systemic treatment (90%), hormone therapy (ALND 79%, SN gen receptor-negative tumours and negative axillary nodes.
77%) and chemotherapy (61%) in this trial, we can conclude At 8 years’ follow-up, there was locoregional recurrence in
that the extent of axillary surgery had no influence on sys- 12.7% and 5.8% of patients in the surgery and surgery plus
temic treatment. However, there was a significant difference chemotherapy groups, respectively (p = 0.0003). The NS-
in ipsilateral arm lymphedema between the two groups at 5 ABP B-14 study [62] then examined the benefit of adjuvant
years, with this affecting 23% in the ALND group and 11% tamoxifen in women with clinically node-negative, oestro-
in the radiotherapy group (p < 0.0001). Axillary radiother- gen receptor-positive breast cancer. After 10 years, the ad-
apy after a positive SN was thus shown to provide comparable dition of tamoxifen had resulted in lower rates of ipsilat-
axillary control to ALND with significantly less morbidity for eral recurrence (placebo = 10.3%, tamoxifen = 3.4%; p <
patients with early-stage breast cancer. 0.001) and regional recurrence (placebo = 2.4%, tamoxifen =
The ACOSG Z0010 [57] study enrolled 5210 patients with 1.4%; p = 0.02). Furthermore, the NSABP B-31 and NCCTG
T1–T2 disease who underwent BCS with whole-breast irra- N9831 [63] trials reported that the addition of trastuzumab
diation and SLNB. The researchers aimed to determine the to chemotherapy in patients overexpressing HER2 reduced
prevalence and significance of occult metastases in SNs and locoregional relapse by 40% compared with chemotherapy
bone marrow. Immunohistochemistry was used to analyse alone.
cases with an SN-negative hematoxylin-eosin stain, which For these reasons, we can conclude that appropriate tar-
revealed occult metastases in 10.5% of patients; however, geted multimodal therapy not only increases DFS and OS but
these metastases were not associated with inferior survival. also contributes to achieving locoregional control.
By contrast, occult bone marrow metastases were present in
3%, were associated with decreased OS and were unrelated 9.5 Macrometastasis in patients with mastectomy
to SN involvement. This trial indicated that the prognostic The NSABP B-04 trial [58] compared radical mastectomy,
value of SLNB is limited, but that it sometimes cannot be im- total mastectomy, and total mastectomy followed by irradia-
proved by extending axillary surgery and adding ALND. tion that included the axilla. Patients were classified as hav-
These data indicate that the information provided by ing palpable or non-palpable axillary lymph nodes. Patients
ALND is no longer considered useful. Biological prognostic with clinically positive axillary nodes underwent radical mas-

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tectomy or total mastectomy with postoperative irradiation, proves distant DFS (78% versus 75%, p = 0.02) without im-
while those with clinically negative nodes underwent one proving the OS at 10 years follow-up [66]. The NCIC Clinical
of three procedures: radical mastectomy; total mastectomy Trials Group MA.20 trial reported by Whelan et al. [67] pro-
without ALND but with postoperative irradiation; or total duced similar results. Distant DFS at 10 years (nodal irradia-
mastectomy plus axillary dissection, only if their nodes be- tion = 86.3%, control = 82.4%; p = 0.03), but no improvement
came positives. None of the women received adjuvant sys- was seen in the OS. These debated results reflect that care-
temic therapy. After 25 years of follow-up, no significant ful treatment selection is needed for some individuals, with
differences in regional recurrence were found between the postmastectomy radiotherapy potentially indicated for some
radical mastectomy (8%) and mastectomy plus radiotherapy patients with 1–3 positive nodes.
(11%) groups for patients with palpable axillary lymph nodes To answer if it is time to apply the Z0011 criteria to pos-
(p = 0.67); there were also no significant differences in dis- itive SN mastectomy patients, we need to wait for new ran-
tant recurrence (41% and 43%, respectively; p = 0.44). In domised trials. The UK POSNOC trial (“POsitive Sentinel
the group with non-palpable nodes, the comparison between NOde: adjuvant therapy alone versus adjuvant therapy plus
axillary clearance, axillary radiotherapy and no treatment at Clearance or axillary radiotherapy”), which includes Z0011
all, revealed no differences in distant metastasis. However, mastectomy patients [28], and the Dutch BOOG 2013-07
there were statistically significant differences in regional re- trial, which was designed for patients with 1–3 positive SNs
currence between patients with no axillary treatment (6%) [68] should be interesting.
and those who underwent ALND or axillary radiotherapy The SINODAR ONE trial is an ongoing prospective non-
(4%) (p = 0.002). inferiority randomized study designed to assess the therapeu-
Given these results and those of the ACOSOG Z0011 tic role of ALND in patients with one or two positive sentinel
study, we must evaluate if ALND can be avoided after a pos- nodes, who are candidates for breast-conserving surgery or
itive SLNB that is outside the Z0011 criteria, treated by mas- mastectomy [69].
tectomy without radiotherapy. In a retrospective study, Mil- Another very interesting ongoing study is the SENO-
grom et al. [64] compare outcomes in patients with SN- MAC trial. This prospective and non-inferiority study in-
positive breast cancer treated by mastectomy or BCS with- cludes breast cancer patients undergoing mastectomy and tu-
out axillary-specific treatment. Most patients had hormonal mors larger than 5 cm. Specifically, the study includes clin-
receptor-positive, HER2-negative invasive ductal carcinoma ically node-negative breast cancer patients with up to two
and minimal nodal disease. However, compared with pa- macrometastases in their sentinel lymph node biopsy. Pa-
tients treated by BCS, those treated by mastectomy were tients with T1–T3 as well as patients prior to systemic neoad-
younger, had larger tumours, had higher nomogram scores juvant therapy are included. Both breast-conserving surgery
(predicting additional axillary disease) and were more likely and mastectomy are eligible interventions. Patients are ran-
to receive chemotherapy. Radiotherapy was used in 95% domised 1:1 to undergo or not undergo ALND. The primary
treated by BCS and 5% treated by mastectomy. At a median endpoint is breast cancer-specific survival at 5 years and the
follow-up of 5 years, there were no significant differences in secondary endpoints are arm morbidity and health-related
local (1.7% vs. 1.4%) or regional (1.2% vs. 1.0%) node recur- quality of life measured by questionnaires at 1, 3 and 5 years
rence between the mastectomy and BCS cohorts. The study [70].
concluded that patients with breast cancer who have minimal While we wait for these results to be published, we must
SN disease have excellent outcomes without ALND when un- not forget that systemic therapy reduces locoregional recur-
dergoing either BCS or mastectomy. rence and that most patients with breast cancer receive sys-
These data and others from the MD Anderson Center temic treatment. Moreover, local control is closely related to
[65] suggest that avoiding ALND could be reasonable for a both the biologic subtype and the gene expression profile.
low-risk subset of patients with SN-positive disease who will
not receive postmastectomy radiotherapy. What is more, ac- 10. The SN in other scenarios
cording to the AMAROS trial [56], we know that axillary ra- 10.1 Elderly women
diotherapy and ALND are equally effective. This trial ran- In women older than 65 years, performing ALND after
domised 1425 patients with clinical T1–T2 disease and a pos- a positive SLNB does not improve either breast-specific or
itive SN to either ALND or axillary radiotherapy. Although all-cause survival. In the retrospective SEER study (Surveil-
33% of the ALND group had additional positive nodes, after lance, Epidemiology and End Results), there were no signif-
5 years, local recurrence was rare in the axilla (ALND: 0.4%, icant differences in 5-year all-cause survival for women who
Radiotherapy: 1.2%), DFS and OS were similar, and the mor- underwent ALND (n = 4586; 84% survival) compared with
bidity of axillary radiotherapy was significantly lower. those who did not (n = 629; 83% survival). Similar results
Radiotherapy in patients treated with mastectomy im- were found for 5-year breast cancer specific survival (94.6 vs.
proves survival in cases with >3 positive nodes, but some 91.6%) [71].
trials have reported benefit from regional node irradiation in A randomised trial in 2006 also demonstrated that ALND
cases with 1–3 positive nodes. Regional node irradiation im- can be avoided in elderly women (age ≥60 years) with clini-

988 Volume 42, Number 5, 2021

cal lymph nodes and receptor-positive tumours when treated tice guideline update from ASCO concluded that pregnant
with adjuvant tamoxifen [72]. In a retrospective study eval- women should not undergo SLNB [79]. However, limited
uating axillary treatment in 671 elderly patients (≥70 years data suggests that SLNB can be performed with radioactive
old) with operable breast cancer and clinically clear axillas colloid, which is not teratogenic at the dose administered for
who were treated with tamoxifen, there was no significant biopsy. Indeed, a study has shown that the radioactive col-
difference in breast cancer mortality between the ALND and loid administered results in a minimal dose of radiation to the
non-ALND groups after a median follow-up of 15 years [73]. foetus. They concluded that SLNB with radiolabelled tracers
Older women do not require axillary lymph node surgery was safe during pregnancy [23]. Other authors have consid-
if it will not modify adjuvant treatment choice or outcome. ered both methylene blue and radiocolloid to be safe in preg-
The NCCN 2016 guidelines affirms that “in the absence of nant women. In a study of 25 pregnant women with node-
definitive data indicating superior survival, the performance negative breast cancer who received methylene blue or 99 Tc,
of axillary staging may be considered optional in patients who no fetal adverse outcomes were observed at 2.5 years’ follow-
have particularly favourable tumours, patients in whom the up (one cleft lip was observed, but this was not attributable
selection of adjuvant systemic and/or radiation therapy is un- to the injection) [80].
likely to be affected, the elderly or those with serious condi- The NCCN breast cancer 2016 guideline also states that
tions” [74]. The 2008 NCCN Task Force Report on breast blue dye is contraindicated for SLNB during pregnancy, but
cancer in older women underlined the possibility of omitting that radiolabelled sulfur colloid may be safe [74]. In addition,
biopsies in cases of oestrogen receptor-positive early breast a group of specialists has reviewed the guidelines and pro-
cancer [75]. However, because of the lack of high quality ev- vided guidance on the management of pregnant women with
idence, this remains controversial [76]. breast cancer considering recent advances. They concluded
In elderly patients (age >70 years) with small opera- that SLNB can be safely performed during pregnancy if the
ble breast tumours that are hormone receptor-positive and risk-benefit assessment is favourable [81].
HER2/neu-negative with clinically and ultrasonographically 10.4 Neoadjuvant chemotherapy
negative nodes, axillary surgery (including SLNB) can be Initially used for patients with advanced or inoperable
avoided. The decision should be made in a multidisciplinary breast cancer, the use of neoadjuvant chemotherapy (NAC)
setting. By contrast, it is advisable to perform a SLNB has been extended to women with early breast cancer. Some
in patients with histological high-risk types, such as triple- trials report comparable DFS and OS between patients who
negative or HER2/neu-positive tumours. If SLNB is positive, receive NAC and adjuvant chemotherapy [82], but the neoad-
the indications for ALND are the same as for young women. juvant approach benefits from tumour size reduction to fa-
10.2 Male breast cancer cilitate more conservative surgery, the in vivo assessment of
Breast cancer is uncommon in men [77]. Although primary tumour sensitivity, and if pathological complete re-
it shares similarities with breast cancer in women, it also sponse is achieved, this becoming a new favourable prognos-
presents crucial differences. As in women, it is important tic factor. The increasing use of NAC has raised questions
to assess the status of the axillary nodes. The ASCO consid- about what is the optimal local therapy for the axilla because
ers that SLNB is “acceptable” in males with clinically node- this approach downstages axillary lymph nodes in 30%–40%
negative early-stage breast cancer. The role of SLNB in such of patients [83]. As an extension of how NAC may facilitate
cases has been established in women, but there is a lack of less extensive surgery, a proportion of patients who are ini-
large clinical trials to determine its sensitivity and specificity tially node-positive may be spared ALND if the involved SNs
in men. Small reports do indicate that is feasible and accu- become free of tumour (ycN0) after NAC. For this, we must
rate [8], with one literature review concluding a detection consider two different situations: clinically node-negative
rate of 100% with no false-negatives among included stud- (cN0) and clinically node-positive (cN1) disease.
ies [78]. However, the 2005 ASCO panel considered that the
10.4.1 Clinically node-negative disease
existing limited data precluded making any firm recommen-
dations about SLNB for men with breast cancer. Despite the When considering the timing of SLNB, the identification
data limitations, it seems that the principles guiding SLNB in rate before NAC was 98% and 95% after NAC in a population-
women apply to male cancer and that it is acceptable to pro- based study (p = 0.032). The proportion of patients under-
ceed with care in the same manner [8, 25]. going ALND was 45% in patients with SLNB before NAC
and 33% for those with SLNB after NAC (p = 0.006) [84].
10.3 Pregnancy Performing SLNB after chemotherapy does require a simul-
In pregnant women, the concern about possible terato- taneous operation (breast and axilla), but it does have the
genic effects of dyes has limited the use of SLNB. Isosulfan benefit of possible nodal downstaging by achieving complete
blue, for example, is best avoided in pregnant women due pathological response in the axilla, avoiding the morbidity of
to its potential teratogenicity when absorbed systemically af- ALND. The feasibility and accuracy of SLNB after NAC has
ter subcutaneous injection. Coupled with the lack of safety also been reported in multiple studies. In the NSABP B-27
data on this and other tracers [16], the 2016 clinical prac- study [85], the identification rate was 84.8% with SLNB and

Volume 42, Number 5, 2021 989

the false-negative rate was just 10.7%. The study concluded eosin and immunohistochemistry rather than hematoxylin-
that performing an SLNB after NAC provides comparable eosin alone. In another meta-analysis of eight studies [93],
results to those obtained from SLNB before systemic ther- the pooled identification rate was 92.3%, with a false-negative
apy. The false-negative rate observed after NAC was similar rate of 15.1%, and 36.8% showed axillary complete response.
to that for other multicentre trials of SLNB before systemic The false-negative rate was significantly higher when only
therapy, in which the false-negative rates were between 7% one SN was removed (23.4%) compared with two or more
and 13% [51, 86, 87]. (10.4%) (p = 0.026).
Elsewhere, the systematic review and meta-analysis by In the nodal involvement group of the GANEA 2 study
Geng et al. [88], which included 1456 patients from 16 stud- [89], the overall false-negative rate was 11.2%, increasing to
ies, revealed a pooled identification rate of 96% for SLNB 19.3% for cases with one resected SN and 7.8% for cases with
after NAC in cN0 disease, with a false-negative rate of 6%. two or more SNs. In this work, combining blue dye and
Moreover, no significant differences were found in the iden- radiocolloid was recommended for SLNB, but patients with
tification rate by the mapping method used. The large two or fewer SNs were not excluded from the trial. The mul-
prospective multicentre GANEA 2 study [89], designed to tivariate logistic regression analysis of 103 patients with no
evaluate the accuracy and safety of SLNB after NAC in 419 SN involvement showed that lymphovascular invasion and a
women with early breast cancer, also revealed that SLNB residual breast tumour size ≥5 mm after NAC remained in-
was accurate (only one axillary relapse among after a median dependent predictors of complementary node involvement at
follow-up of 3 years) in the cN0 group. Given these findings ALND.
and the assertions of other authors [90], we can conclude that The pooled estimate for the identification rate in a system-
SLNB after chemotherapy in patients with cN0 disease has atic review of 13 studies with 1921 patients was 90% with a
similar accuracy to SLNB performed before treatment but has false-negative rate of 14% (11%–17%) [94]. Subgroup analysis
the added benefit of reducing the need for ALND. revealed false-negative rates of 11% (6%–15%) with dual map-
ping and 19% (11%–27%) with single mapping. Considering
10.4.2 Clinically node-positive disease (cN1) the number of SNs, the false-negative rate was 20% (13%–
The main question concerning SLNB after NAC is not 27%) when one node was removed, 12% (5%–19%) when two
its feasibility but its accuracy and safety. NAC causes fibro- nodes were removed, and 4% (0 to 9) when three or more
sis and disruption of lymphatic channels and can modify the nodes were removed.
lymphatic drainage. A false-negative SLNB is drug resis- Omitting further ALND in patients with clinically posi-
tant and associated with a high risk of relapse. Some studies tive nodes and negative SLNB after NAC is not a reliable ap-
have shown nodal pathological complete response depend- proach in the absence of an improved technique and better
ing reaching 49% in triple-negative breast cancer and 74% in patient selection. The rate of identification is lower in cN1
HER2-positive disease [91]. Performing ALND in this con- disease than in cN0 disease, probably due to altered lymphatic
text seems to be an overtreatment. drainage. However, this is not a reason to exclude SLNB in
The application of SLNB for staging the axilla in the these patients, because we can improve the identification rate
neoadjuvant setting is unclear for women who initially had by dual-agent mapping. The main problem with SLNB in
node-positive breast cancer because of the high false-negative patients with axillary involvement is the high false-negative
rates reported in some studies. The ACOSOG Z1071 (Al- rate, which must be improved before this approach can be
liance) trial [19] enrolled 663 women with N1–N2 breast can- advocated.
cer who received NAC, SLNB (blue dye and radiolabelled col-
loid), and ALND. The false-negative rate was 12.6% in pa- 10.4.3 Measures for reducing false-negative rates in cN1 disease
tients with at least two SNs at the time of surgery, which One approach that could reduce the false-negative rate
was higher than the prespecified threshold of 10%. The false- in cN1 disease is to consider micrometastasis (ypN1mi) or
negative rate was influenced by the use of dual- or single- isolated tumour cells (ypN0+) at SLNB to indicate positive
agent mapping (10.8% versus 20.3%, p = 0.05). The presence lymph nodes. According to the seventh edition of the AJCC
of fibrosis after chemotherapy makes the evaluation of lym- cancer staging system, these patients are considered to have
phatic drainage more difficult, and using two mapping agents residual disease, necessitating ALND [95]. For this reason,
with different molecular features, the false-negative rate is SLNB should include hematoxylin-eosin and keratin stain-
lower. Another factor influencing the false-negative rate was ing. Another measure to improve accuracy could be to ex-
the number of SNs evaluated, it being lower when more than cise the greatest number of SNs possible. The false-negative
two SNs were evaluated (9.2%) compared with two (21.1%). rate changed from 31.5% when one SN was removed to 21.1%
In a meta-analysis [92] of 15 studies including 2471 when two were removed and 9.1% when three or more SNs
patients with node-positive breast cancer who underwent were removed [46]. However, we know that it is not always
chemotherapy, SLNB, and then ALND, the pooled identifi- possible to identify three or more SNs, and data do not sup-
cation rate was 89%. The false-negative rate was 14% and port random sampling to identify more than two SNs. Other
fell lower when the SN was staged using both hematoxylin- methods to reduce false-negative rates include the use of dual

990 Volume 42, Number 5, 2021

mapping, nomograms to predict axillary response, or optimal NAC with SLNB [104]. Persistent nodal disease could re-
imaging techniques to re-stage the axilla [95]. flect chemoresistant disease, but in the neoadjuvant setting,
Clip placement in the involved nodes at diagnosis and re- patients have already received chemotherapy appropriate to
moval of the clipped nodes and the SN can also reduce the the molecular subtype of their tumour. These patients with
false-negative rate. In the ACOSG Z1071 trial, a clip was residual disease after NAC are candidates for new drug tri-
placed in 203 patients. In 75.9%, the clip was placed in the als and additional systemic therapy (adjuvant after neoadju-
SN and gave a false-negative rate of 6.8% [96]. A prospective vant). Knowing the pathological complete response in the
study with 208 cN1 patients was performed in which a clip axilla is a surrogate marker of a favourable outcome in these
was placed on involved nodes [97]. After neoadjuvant treat- patients. Thus, SLNB after NAC could be an option in pa-
ment, patients underwent ALND and the pathologic evalua- tients with node-positive breast cancer if we carefully se-
tion of clipped nodes was compared with that of the SNs and lect patients with the highest possibility of complete nodal
the other nodes from the ALND. The authors describe a new response (triple-negative and HER2-overexpressed) and im-
surgical technique, targeted axillary dissection (TAD), which prove the techniques used. Future prospective trials should
involves removing the SN and the clipped nodes by locali- seek to provide more complete scientific evidence of the re-
sation with iodine-125 radioactive seeds. The false-negative liability of this technique.
rates when removing the SN was 10.1%, falling to 4.2% when
removing the clipped nodes and 2.0% when removing the SN 10.4.4 Axillary surgery in N2–N3 patients
and the clipped nodes (TAD). The clipped node was different Although this patient group have a high axillary tumour
from the SN in 23% of the patients, including six with metas- burden, several studies have reported that we should consider
tasis to the clipped nodes who had a negative SN. Straver et evaluating SLNB and avoiding ALND when there is patho-
al. [98] also described a ‘marking the axilla with radioactive logical complete response. In a study of 100 patients with
iodine seeds’ (MARI) procedure for evaluating the axillary re- breast cancer who received NAC (N2 = 59, N3 = 41), 79.3%
sponse to neoadjuvant treatment. This involved removing had residual disease. However, 60% when of patients with
the marked lymph node (I125 -labelled) after chemotherapy clinical complete response also showed pathological complete
with a gamma probe and performing ALND. The identifica- response [105]. In a retrospective study of 221 patients [106]
tion rate was shown to be 97%, with a false-negative rate of (N2 and N1 with ≥3 suspicions lymph nodes) ypN0 was
7% [99]. achieved in 40% of patients: 68% in HER2-positive cases and
The Radioactive Iodine Seed localisation in the axilla with 45% in triple-negative cases. These data indicate that it is nec-
the sentinel node procedure (RISAS) trial assessed a combi- essary to evaluate if we can reliably perform SLNB in this set
nation of MARI and SLNB. This single-arm multicenter vali- of patients by selecting those with clinical complete response
dation study sought to evaluate the accuracy of the procedure, and subtypes with high pathological complete response rates.
the identification rate, false-negative rate, negative predictive Prospective studies are needed.
value. Even though the definitive results have not been pub- Recent studies, such as CREATE-X [107] and Katherine
lished, a high negative predictive value has been reported for [108], have shown that adjuvant treatment for patients with
the procedure [100]. residual cancer after NAC reduces the risk of recurrence for
Due to the lack of sufficient evidence and because of triple-negative breast cancer or HER2-amplified cancers, re-
discrepancies between different countries, the EUBREAST spectively. Similarly, the conversion of nodes from positive
study group has started a prospective cohort trial (AXANA to negative may allow for regional nodal irradiation to be
Protocol- NCT 04373655). This international project com- omitted, depending on the results of trials such as NSABP B-
pares data on axillary staging after neoadjuvant chemother- 51 [109].
apy in cN+ patients who underwent ycN0, treated with dif- Residual disease is very important because it reflects the
ferent axillary staging techniques. The primary study end- patient prognosis and the need for adjuvant treatment after
points are: the evaluation of 5-year invasive disease-free sur- neoadjuvant treatment [110].
vival, the 3-year axillary recurrence rate and quality of life
and arm morbidity in patients treated with different axillary 11. Conclusions
staging techniques. In conclusion, SLNB is currently the best method for ax-
Some of the most relevant studies regarding SLNB after illary staging in breast cancer, allowing patients to be treated
neoadjuvant treatment are summarised in Table 3 (Ref. [21, according to risk of recurrence, and with good evidence that
85, 89, 101–103]). morbidity is less than with other more radical techniques.
In conclusion, the clinical relevance of leaving residual dis- The following statements summarise the key elements of our
ease in the axilla after NAC is unclear, but there is robust knowledge.
evidence that axillary surgery has changed considerably over • The presence of axillary lymph metastases is still a key
time. In patients with cN0 disease, there has been a substan- prognostic factor in breast cancer.
tial decrease in ALND and increase in SLNB after NAC, while • In early-stage breast cancer with clinically negative axil-
in cN+ disease, ALND has increasingly been omitted after lary lymph nodes, SLNB is the standard method for assessing

Volume 42, Number 5, 2021 991

involvement of the axilla. OS, DFS and regional control are Barcelona for editing the manuscript. We thank the CERCA
statistically equivalent in SLNB and ALND. programme/Generalitat de Catalunya and IDIBELL for insti-
• SLNB predicts the axillary state in 95% of patients, giving tutional support. We also thank the Gynaecologyc Depart-
a false-negative rate of 5%. ment at our institution and the multidisciplinary breast can-
• Only inflammatory breast cancer and known node in- cer team.
volvement are contraindications to the use of SLNB to stage
the axilla. Funding
• Axillary recurrence after SLNB is a rare event, occurring This research received no external funding.
at rates between 0.3% and 1.5% at 5 years.
• ALND can be avoided in patients with early breast can- Conflict of interest
cer and micrometastasis on SLNB. The authors declare no conflict of interest.
• In patients with limited positive nodal disease (<3 in-
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