Accepted Manuscript

Controversies and recommendations regarding sentinel lymph node biopsy in primary

breast cancer: a comprehensive review of current data

Petros Charalampoudis, MD PhD FRCS FEBS, Christos Markopoulos, MD MPhil PhD

FEBS, Tibor Kovacs, PhD FRCS FEBS

PII: S0748-7983(17)30955-1
DOI: 10.1016/j.ejso.2017.10.215
Reference: YEJSO 4774

To appear in: European Journal of Surgical Oncology

Received Date: 1 September 2017

Revised Date: 21 September 2017
Accepted Date: 10 October 2017

Please cite this article as: Charalampoudis P, Markopoulos C, Kovacs T, Controversies and
recommendations regarding sentinel lymph node biopsy in primary breast cancer: a comprehensive
review of current data, European Journal of Surgical Oncology (2017), doi: 10.1016/j.ejso.2017.10.215.

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 ACCEPTED MANUSCRIPT

Controversies and recommendations regarding sentinel lymph node biopsy in primary

breast cancer: a comprehensive review of current data.

PT
Petros Charalampoudis MD PhD FRCS FEBS1,2, Christos Markopoulos MD MPhil PhD FEBS3

and Tibor Kovacs PhD FRCS FEBS1,2

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1
Breast Unit, Guy’s and Saint Thomas’ NHS Foundation Trust, London, UK

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2
Division of Cancer Studies, King’s College London, UK
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3
Breast Unit, Athens University School of Medicine, Greece
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For all correspondence: Petros Charalampoudis MD PhD FRCS FEBS, Consultant Oncoplastic
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Breast Surgeon and Clinical Lecturer

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Breast Unit, Guy’s and Saint Thomas’ NHS Foundation Trust, Great Maze Pond, London SE1
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9RT, United Kingdom

petros.charalampoudis@gmail.com
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Conflicts of interest: none

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Abstract

In primary breast cancer, sentinel lymph node biopsy has been established as the gold standard

for regional axillary staging. A robust body of randomized data support its accuracy and safety in

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patients with early, clinically node negative disease. However, the role of SLNB remains

debatable in various patient subgroups, and recent advances in histopathology, dedicated axillary

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ultrasound imaging and chemotherapy regimens, put its role under a new perspective. Herein, we

review the current literature data on the indications for SLNB and discuss the challenges in

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management germane to special patient subgroups and patterns of disease. We also present

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emerging data on the optimal management of the SLN+ patient, in light of recent trials
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challenging the dogma of completion axillary dissection after a positive sentinel node biopsy.
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Introduction
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Axillary nodal status in breast cancer patients is a paramount prognosticator, next to

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primary tumor size and grade. Hence, axillary staging remains the standard of care for all breast

cancers amenable to curative treatment(1,2). Sentinel lymph node biopsy (SLNB) has been
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established as the gold standard for axillary staging and has supplanted axillary lymph node

dissection (ALND) as a means of regional nodal staging in clinically and radiologically node-
C

negative breast cancer(3–7). SLNB provides adequate axillary nodal staging information to guide
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further regional and systemic treatment, whilst it spares the patient the increased risk of

complications associated with ALND, most importantly lymphedema, motor deficit and

dysesthesia of the operated arm(6,8–10). However, the appropriateness of SLNB in specific

patient subgroups, as well as the optimal further management of the positive sentinel lymph node

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(SLN) remain highly debatable. In fact, axillary nodal management in breast cancer still

represents one of the hottest topics of controversy across breast cancer multidisciplinary teams.

Herein, we assort the controversies and recommendations regarding SLNB in three

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groups. Firstly, we look at whether SLNB is always necessary in early, clinically node-negative

breast cancer and the role of preoperative axillary ultrasound during triple assessment (Group 1).

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Secondly, we review the issues related to the technique, feasibility and indications of SLNB in

modern breast cancer care (Group 2). Finally, we look at the current evidence and

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recommendations with regards to the appropriate management of the axilla following a positive

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SLNB finding (Group 3). AN
Group 1
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Is SLNB always necessary in early invasive breast cancer? The role of preoperative axillary
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ultrasound.
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Since its conception, sentinel lymph node biopsy (SLNB) has achieved a ground-

breaking shift of practice in primary breast cancer management and has been established as the
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gold standard of care for upfront axillary staging in early, clinically node-negative disease. The
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clinical value, feasibility and safety of the SLNB have been validated in a robust body of
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randomized controlled trials, which enrolled patients with early breast cancers and no clinically

palpable lymph nodes(3,5,7,9–11). Currently, SLNB has supplanted axillary lymph node

dissection (ALND) as the modality for primary axillary staging in early, clinically node negative

breast cancer(11). Following a negative SLNB, completion of ALND is unnecessary as it does

not add any clinical benefit (3,12,13). SLNB provides non-inferior prognostic information, is less

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invasive and confers less complications to the affected arm (lymphedema, motor deficit,

dysesthesia), as compared to ALND(14,15). Importantly, omission of ALND in SLNB-negative

patients does not increase the risk of axillary recurrence, nor it impacts negatively on

survival(4,6,16–18).

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Next to clinical palpation of the axilla, regional nodal evaluation with axillary ultrasound

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(AUS) has recently emerged as a useful adjunct modality to stage the axilla during triple

assessment of patients with symptoms and signs suspicious for breast cancer(19). AUS is

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implemented in the clinical practice guidelines across dedicated breast units as a tool of

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significant clinical utility(20). Patients who have abnormal or suspicious nodes on AUS, i.e.
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nodes demonstrating loss of their fatty hilum, notable enlargement, cortical thickening or a

combination thereof, undergo AUS-guided fine needle aspiration cytology (FNAC) or core
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biopsy (ultrasound needle biopsy - UNB). Following an AUS-guided biopsy-proven regional

spread by the primary breast cancer, the axilla is considered clinically positive and the patient is
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routinely committed to ALND, without the need for SLNB as a staging procedure. It has been
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suggested that AUS and UNB represent an efficient, feasible and cost-effective staging strategy

in preoperative axillary staging(21). In an updated meta-analysis, preoperative AUS with UNB in

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early breast cancer had a positive predictive value (PPV) of 100%, a sensitivity of 50% and a
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false negative rate (FNR) of 25%(22). Notably, AUS findings may be less accurate in the setting
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of lymphovascular invasion (LVI), and it has been suggested that a negative AUS in patients

with LVI should be interpreted with caution. SLNB remains standard of care if AUS does not

establish axillary nodal involvement (23,24).

Although the ACOSOG Z11 trial(25) preceded the AUS staging studies, it unavoidably

called into question the clinical value of AUS and UNB in preoperative axillary staging. In the

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‘post-Z11’ era (25,26), not all patients with a positive macrometastatic sentinel lymph node

(SLN) require a completion ALND. Can AUS and UNB reliably identify cases that fall outside

the Z11-eligibility group? Breast cancer care teams who have adopted Z11 may find preoperative

AUS and UNB of uncertain utility. The ability of AUS and UNB to quantify the axillary nodal

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burden and consequently identify Z11-(in)eligible patients has been challenged(21). On one

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hand, AUS-guided biopsy-proven node-positive patients have been found to carry significantly

higher positive axillary nodal burden in the axilla, compared with SLNB-positive patients. Farrel

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and colleagues showed that a single nodal metastasis detected by UNB correlated with a mean of

5.2 nodes on final histopathology after ALND(26). Furthermore, Hieken and colleagues

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demonstrated that up to 66% of T1 and T2 UNB-positive patients with multiple suspicious
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lymph nodes on AUS had >2 positive lymph nodes after axillary surgery, suggesting that a

UNB-positive axillary nodal basin falls outside the Z11 criteria(27). Similarly, Boland and
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colleagues showed that AUS and UNB can reliably identify Z11-ineligible patients(28).
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Conversely, in a recent meta-analysis of six studies reporting on the axillary nodal burden of
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ultrasound-positive versus ultrasound-negative patients, it was suggested that nearly half of the

ultrasound-positive patients could carry axillary nodal burden low enough to be considered for
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omission of ALND (‘Z11 eligible’)(29). Recent data suggest that streamlining axillary US

guided FNA+ patients to ALND may be overtreatment.(30,31). A safe and accurate approach to
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direct ultrasound node-positive patients towards the appropriate further axillary surgical
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management (ALND versus no ALND) is yet to be defined.

The findings of the ACOSOG Z11 randomized controlled trial suggested that completion

ALND in select patients who undergo breast conserving surgery, whole breast radiotherapy and

tailored adjuvant systemic treatment, found to have one or two sentinel macrometastases, does

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not improve survival or the risk of axillary failure during a median follow-up of 9.25

years(25,32). The concept that axillary nodal extirpation by means of ALND may not

significantly impact on patient outcomes is not new. In the NSABAP-04 study, clinically node-

negative patients proceeded to either total mastectomy alone with delayed ALND in case of later

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nodal recurrence or total mastectomy with concurrent ALND. Interestingly, the subsequent

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failure rate in the total mastectomy-alone group was only about half (19%) that predicted from

the proportion of patients with axillary metastases that underwent ALND (40%) (27,28).

SC
Furthermore, in contemporary multidisciplinary breast cancer care, prognostic information

derived from the number of involved axillary lymph nodes is less likely to impact on systemic

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treatment decision-making, as opposed to patient characteristics and tumor molecular profiling.
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Isolated axillary relapse, even in cases of previously SLNB-positive disease is remarkably low

(around 1%)(16). In this direction, the very necessity of axillary nodal staging in early breast
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cancer has been challenged, particularly for small, low grade, favorable breast cancers, which are
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less likely to metastasize regionally. Looking at this challenging hypothesis, the SOUND trial
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has been designed to investigate whether omission of primary axillary staging with SLNB in

early, clinically and radiologically node-negative breast cancer will have an impact on patient
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outcomes, as compared with standard SLNB. The trial closed accrual in January 2017 and its

results are awaited with great interest(33).

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Summary of recommendations and controversies (Group 1)

• In primary operable breast cancer, SLNB is standard of care in patients with a clinically

and radiologically negative axilla. ALND is no longer recommended in these patients, as

it only adds to arm morbidity without conferring any prognostic or staging benefit(11).

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• During triage of patients with newly diagnosed breast cancer, axillary ultrasound with

biopsy of the abnormal lymph node(s) can fast-track patients to ALND without upfront

SLNB, in cases where nodal biopsy is positive for regional metastasis. Although several

studies have correlated a US-guided biopsy-proven positive axilla with a higher nodal

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burden at completion ALND, as compared with the US-negative axilla, a significant

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subgroup of patients with UNB+ axillary node(s) may have only one or two involved

nodes in the ALND specimen (‘Z11 eligible’). Therefore, there is a need for establishing

SC
an approach to properly identify UNB+ patients in which ALND would be

overtreatment(20,22,29).

•
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Complete omission of SLNB in early, small, favorable breast cancers is under
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investigation, provided that a clinical and ultrasound axillary follow-up proves non-
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inferior in patients with clinically node negative breast cancers at presentation(33).

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Group 2

SLNB in various clinical scenarios

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Repeat SLNB after previous SLNB

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Data on repeat SLNB after previous SLNB are scarce, however they suggest that SLNB
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may be feasible after previous limited axillary staging. Albeit, repeat SLNB is likely to yield

lower identification rates, compared to standard primary SLNB in the previously non-operated

axilla. Kothari and colleagues reviewed a total of 6 studies encompassing 327 patients

undergoing SLNB, of which 60% had previous SLNB or limited axillary staging. The median

overall repeat sentinel identification rate was 70%. No axillary recurrences were observed in

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patients who had a negative repeat SLNB at a follow-up of maximum 46 months(34). In a

systematic review and meta-analysis, Maaskant-Brant and colleagues looked at patients who

underwent repeat SLNB for ipsilateral breast cancer local recurrence. The authors reviewed 692

patients who either had previous SLNB (301/692), or previous ALND (361/692), or no previous

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axillary surgery (30/692). The medial overall identification rate was 65% across all 692 cases,

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but repeat SLNB had a higher identification rate in patients who had previous SLNB, as opposed

to those who had previous ALND(35). At present, repeat SLNB can be considered in patients

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who had previous SLNB or limited axillary sampling, but patients must be informed of the

higher rate of SLNB identification failure and therefore should be consented to proceed to

ALND in case an SLN cannot be retrieved(36).

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AN
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SLNB in large tumors and locally advanced or inflammatory breast cancer

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The main body of high-level evidence studies regarding the feasibility of SLNB, looked
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at patients with T1 and T2 cancers with a clinically node-negative axilla. The updated ASCO

guidelines in 2016 recommend against SLNB in T3 breast cancers (level of recommendation:

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weak, type: informal consensus)(37). However, data from non-randomized studies suggest that

SLNB is accurate in patients with T3 cancers and a clinically negative axilla(38,39). In most
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breast cancer centers, SLNB is considered acceptable in cT3N0 patients. In locally advanced
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(LABC) or inflammatory breast cancer (IBC), upfront SLNB is not routinely recommended,

based on the hypothesis that locally advanced or inflammatory changes may lead to partial

obstruction of dermal or parenchymal lymphatics and hence yield unacceptable FNRs of sentinel

node retrieval(37,40). In patients with non-inflammatory LABC who have excellent clinical and

radiological response to neoadjuvant chemotherapy (NACT), SLNB instead of ALND may be

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considered and is moderately recommended by the most recent edition of the NCCN

guidelines(41). However, in order to increase sensitivity and accuracy of the procedure, at least 3

SLNs should be retrieved and complete ALND is advised even if only one SLN is found to be

positive(56-60).

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SLNB in pregnancy

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The ASCO updated guideline in 2016 remained unchanged regarding SLNB in pregnant

SC
patients. High-level evidence is lacking and therefore, the panel weakly recommended against

SLNB in this setting(37). However, data from non-randomized studies suggest that SLNB with

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radioisotope only (no blue dye) is safe in pregnant breast cancer patients(42–44). Sentinel lymph
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node biopsy involves a technetium colloid injection, which demonstrates low radioactivity and

limited local uptake with a rapid wash-out, as well as negligible systemic diffusion(45).
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Furthermore, radioisotope doses absorbed by the fetus have been shown to be less than 20
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micrograys (µGy) for injections up to 20 megabequerels (Mbq). Conversely, blue dye injection is

not recommended in pregnancy, as it carries a low (1%) but potentially harmful risk of
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anaphylactic maternal reaction(46,47). In conclusion, SLNB with omission of blue dye injection
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may be considered in pregnant patients.

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SLNB after neoadjuvant chemotherapy (cN0 patients at diagnosis)

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Neoadjuvant chemotherapy (NACT) is being increasingly recommended in patients with

breast cancer(48). Frequent indications for NACT include tumor downsizing to optimize breast

conservation, conversion of large unifocal breast cancers needing a mastectomy to cancers

amenable to breast conserving surgery (BCS) and conversion of large inoperable, locally

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advanced or inflammatory cancers to operable tumors(49). It has been suggested that

pathological complete response to NACT may serve as a good surrogate for disease-free

survival. Also, NACT provides useful information on responses to different chemotherapy

regiments. However, a survival benefit between patients receiving neoadjuvant compared to

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adjuvant chemotherapy has not been demonstrated to date(50).

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SLNB has been established as a valid modality of axillary staging in trials enrolling

patients who were receiving upfront surgery, followed by tailored adjuvant systemic treatment.

SC
The concept of SLNB instead of ALND to stage patients receiving neoadjuvant chemotherapy

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was initially met with reluctance(51). There was concern that lymphatic tumor emboli and
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chemotherapy-induced fibrosis may cause a non-uniform response across the axillary nodal basin

and potentially lead to unacceptably high SLNB false negative rates. Indeed, early studies on
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SLNB after NACT for node-negative patients (cN0) reported on identification rates ranging from

63% to 100%, and FNRs ranging from 0% to 33%(52,53). However, these studies included
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various clinical stages and cases with bulky nodal disease at presentation, which persisted after
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completion of NACT. Subsequent studies showed that SLNB after NACT in node-negative

patients is feasible and FNR is comparable to pre-chemotherapy SLNB. The GANEA study
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looked at 130 clinically node-negative patients to assess the feasibility of SLNB following
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NACT. Among the 130 patients with cN0 disease, the SLN identification rate was 95% with an
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FNR of 9%(54). A study from MD Anderson Cancer Center looked at 3171 cN0 patients

undergoing upfront SLNB and 575 cN0 patients who underwent SLNB following NACT.

Importantly, both identification rates and false negative rates were similar between pre-

chemotherapy and post-chemotherapy SLNB (identification rate 99% and 97%, FNR 4% and

6%, respectively)(55). Furthermore, data from meta-analyses including more than 5000 patients

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treated with SLNB after NACT have reported on SLN identification rates ranging from 90% to

94% and FNRs ranging from 7% to 12%(56,57). At present, SLNB in clinically node-negative

breast cancer at diagnosis is recommended after NACT, provided that the end-of-chemotherapy

clinical palpation and imaging suggest no evidence of overall progression and the nodes remain

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clinically normal. Trials such as Alliance A011202 are ongoing to further address the need for

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ALND in SLN+ patients after NACT(58).

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SLNB after neoadjuvant chemotherapy (cN+ patients at diagnosis)

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Interestingly, studies on SLNB after NACT in cN0 patients demonstrated that post-
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NACT axillary staging yielded less nodal burden as compared to pre-chemotherapy axillary

staging (54). Moreover, increasing rates of pathological complete response have been observed
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in patients treated with NACT(59). These findings led investigators to design studies looking at
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the feasibility of SLNB after NACT in patients who presented with cN+ disease at diagnosis.
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The GANEA study looked at 65 patients with cN+ patients who underwent SLNB and back-up

ALND after NACT. The SLNB identification rate was 81.5% and the FNR was 15%(54). In the
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SENTINA trial, 592 patients converting from cN+ to cN0 following NACT had an SLN

identification rate of 80%, with an overall FNR of 14%. However, the FNR in the subgroup
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where 3 or more sentinel nodes were harvested dropped to 7%, compared with 19% with 2 nodes
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harvested and 24% with only 1 SLN harvested(60). The ACOSOG Z1071 trial also looked at

patients with cN+ breast cancers at diagnosis who underwent SLNB after NACT. In this trial, a

pre-defined acceptable FNR was set to 10%. Unlike the SENTINA trial, conversion from cN+ to

cN0 was not mandatory and only patients where more than 2 harvested SLNs were included in

the analysis to calculate the FNR of the procedure. The overall FNR for patients who had at least

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2 SLNs retrieved was 13%, but an unplanned exploratory analysis showed that the FNR

significantly dropped to 9% when 3 or more SLNs were harvested(61). Similarly, the SN-FNAC

study looked at biopsy proven cN+ patients who received SLNB after NACT. Unlikely the

SENTINA and ACOSOG Z1071 trials, immunohistochemistry (IHC) to detect nodal disease

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down to isolated tumor cells (ITCs) was mandatory in the SN-FNAC trial. In their results, the

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investigators report on an FNR of 8% provided that patients with ITC post-NACT were

considered node-positive, whereas the FNR was 13% when these patients were considered node-

SC
negative(62). Lastly, a Swedish group reported on 195 biopsy-proven node positive breast cancer

patients who underwent SLNB after NACT. The overall FNR in the study was 14% but dropped

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to 4% when 2 or more SLNs were harvested (58).
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In summary, four studies have reported on SLNB after NACT in cN+ patients at
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diagnosis. They all demonstrate that SLNB is technically feasible provided a good clinical and

radiological response is achieved after NACT. A very important common finding of these studies
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is that FNRs are unacceptably high unless at least 3 SLNs are identified(60–63). The questions
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which remain unanswered are what would be the long-term outcome of cN+ patients having a

negative SLNB (with more than 3 nodes harvested) after NACT, if a completion ALND was
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omitted, and whether postmastectomy radiotherapy adds any benefit to cN+ patients who revert
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to ypN0 after NACT(64). All four studies required a back-up ALND to calculate the FNR of the
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SLNB and therefore cannot address this question. At present, SLNB after NACT for cN+

patients is being considered across dedicated breast units and is implemented in the last edition

of the NCCN guidelines as a Level 2b recommendation(41). Pre-NACT clipping or radioactive

seed marking of the biopsy-proven nodes, which are harvested during post-NACT axillary

staging along with the sentinel nodes, is currently under investigation, aiming to provide more

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robust evidence of nodal response to chemotherapy and improve the false negative rates of the

procedure(65–67).

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SLNB in DCIS

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Ductal breast cancer in situ (DCIS) makes up 20% of all newly diagnosed breast cancers,

and by definition, does not have the potential to spread(68). Axillary failure in patients with

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DCIS is rare, as demonstrated in early trials. In the NSABP-B17 trial, only 3/620 of patients with

DCIS recurred in the axilla at 15 years(69). Similarly, in the NSABP-B24 trial, axillary failure

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events were very infrequent (6/1799 at 12 years)(69). It has been suggested that approximately
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20% of DCIS diagnosed on preoperative core biopsy will upgrade to invasive disease on final

histopathology after surgery (70,71). The frequency of axillary metastasis in patients who
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undergo mastectomy for DCIS has been reported as high as 20%(72). In a meta-analysis by
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Ansari and colleagues, the incidence of sentinel node metastases in patients with a preoperative
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diagnosis of DCIS was 7.4%, compared with 3.7% in patients with a definitive postoperative

diagnosis of pure DCIS(73). In patients with DCIS amenable to breast conserving surgery,
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SLNB is not recommended, unless DCIS presents with features suggestive of higher risk of

invasion (palpable mass, suspicious imaging features, large size)(74,75). Conversely, in patients
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needing mastectomy for extensive DCIS, the risk of non-sampled invasive breast cancer is more
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substantive. Additionally, following a mastectomy, the parenchymal lymphatics will have been

extirpated and hence, SLNB as a subsequent procedure carries a higher risk of failure to identify

the sentinel nodes(76). The clinical significance of nodal involvement in pure DCIS remains

unclear(77,78). In summary, although randomized data are not available, SLNB for DCIS should

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be considered in breast-conserving surgery for high-risk DCIS and in patients undergoing

mastectomy for extensive DCIS.

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SLNB in multisite BC (multifocal or multicentric)

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In multisite breast cancer, it has been suggested that the accuracy of SLNB may be

compromised, as drainage from different primaries in the same breast may complicate the

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sentinel node identification and thus result in suboptimal axillary staging. Data on SLNB in

multisite breast cancer are only available from observational studies. Interestingly, no difference

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in axillary recurrence or survival are noted across these cohorts, when compared with patients
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with unifocal disease(79,80). In an unplanned subgroup analysis of the ALMANAC trial, SLNB

in cases of multisite breast cancer did not result in lower FNR or lower identification rates,
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compared to SLNB performed for unifocal lesions(3). In the AMAROS trial, a SLN was
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identified successfully in 96% of patients with multisite breast cancer as compared with a 98%
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rate in patients with unifocal breast cancer. This difference was not statistically

significant(81,82). At present, SLNB is considered feasible and safe in patients with early,
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multisite breast cancer.

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Summary of recommendations and controversies (Group 2)

• Repeat SLNB after previous SLNB for locally recurrent breast cancer may be considered,

although the false negative rate of repeat axillary staging may be higher than upfront

SLNB in the non-operated axilla. ALND may be needed in these patients in cases where

a sentinel node is not identified(35,36).

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• SLNB with single tracer (radioisotope) is considered safe in pregnant patients. Blue dye

is not recommended due to the small but clinically important risk of maternal

anaphylactic reaction(43,44,46)

• Upfront SLNB in locally advanced or inflammatory breast cancer is not recommended.

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SLNB after neoadjuvant chemotherapy in non-inflammatory LABC may be considered,

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on the basis of overall and axillary response to neoadjuvant treatment(37,41).

• SLNB is safe and accurate in patients with cN0 breast cancers after neoadjuvant

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chemotherapy. In patients with cN+ disease at diagnosis, SLNB may be considered

(Level of evidence 2a) when radiological and clinical complete response is achieved after

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NACT. There are now four studies supporting this practice, but the long-term outcome of
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these patients is yet undefined(60–63).

•
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SLNB in multifocal and multicentric breast cancer is deemed safe and accurate, although

randomized data are lacking(80).

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• SLNB in DCIS patients undergoing breast conservation may be considered for large,
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high-risk DCIS, as well as in patients treated by mastectomy on the basis of extensive

DCIS, which portends a higher risk of non-sampled invasive disease(73).

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Group 3
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Management of the SLN-positive axilla

Robust evidence suggests that following a negative SLNB, completion ALND is not

necessary, as it only adds on regional morbidity without conferring any clinical benefit in terms

of recurrence risk, disease-free survival or overall survival(11). Axillary local recurrence after a

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negative SLNB is rare (16,25). With the advent of modern histopathology and improvements in

staining and immunohistochemistry techniques (IHC), even small metastatic clusters of regional

nodal spread can be identified, leading to coining of the terms ‘isolated tumor cells, ITCs’ (nodal

foci <0.2mm), ‘micrometastases’ (foci 0.2mm-2mm) and ‘macrometastases’ (foci >2mm).

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Consequently, the clinical significance of axillary nodal burden on the basis of size of nodal foci

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has been evaluated.

Although isolated tumor cells (ITCs) can be detected on routine hematoxylin and eosin

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(H&E) stains, they are usually found on deeper, serial H&E levels or typically during IHC

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staining. However, routine use of IHC to look for ITCs in the SLNs is not supported(83,84). In
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the presence of ITCs in the SLNs, only a small percentage of non-SLNs are involved by residual

disease and the risk of axillary recurrence in cN0(i+) patients who forgo ALND is very
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low(85,86). According to the updated AJCC-TNM edition for breast cancer, patients with

pN0(i+) only disease (ITCs only) are considered clinically node-negative(41). In patients with
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ITCs only in the SLNs, completion ALND may be omitted without negatively impacting on their
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outcome(85,87). Albeit, the presence of ITCs carries less favorable prognosis than pN0 disease

and tailored systemic treatment may be appropriate(88–90). At present, omission of ALND in

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N0(i+) patients is considered when upfront surgery is recommended. The presence of residual
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ITCs in post-NACT SLNB in patients with clinically positive nodes who have received
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neoadjuvant chemotherapy may be of higher clinical significance, compared with ITCs found on

upfront SLNB, as the latter could reflect residual, chemoresistant disease. Interestingly, a recent

study from the Netherlands showed that baseline cN1 patients who had ITCs only found on post-

NACT ALND carried similar prognosis compared with ypN0 patients (where no residual disease

was identified in the ALND specimen)(91).

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Nodal foci with size from 0.2mm to 2mm are termed ‘micrometastases’. The randomized

controlled trial by Galimberti and colleagues challenged the dogma of standard completion

ALND in patients with micrometastatic senitinel involvement. This trial randomized patients

undergoing breast surgery and found to have micrometastases only in the SLN, to undergo either

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completion ALND or no further surgical axillary treatment(77). Axillary radiotherapy was not an

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alternative to ALND in this study and most patients in both groups received adjuvant systemic

therapy at the discretion of the treating clinician. Completion ALND in patients with sentinel

SC
micrometastases was not found to confer statistically significant benefit in disease-free or overall

survival, compared to no further axillary surgery. Although patients with micrometastases are

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considered lymph node-positive (as opposed to ITC only+ patients), this trial provided high-level
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evidence that surgical extirpation of the axillary nodal basin following micrometastatic SLNB

does not confer clinical benefit. Sola and colleagues independently confirmed the findings by
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Galimberti and colleagues, albeit recruiting less patients.(92)

D

After a SLNB positive for macrometastases, the standard of care has long been a
TE

completion ALND. However, three randomized controlled trials (ACOSOG Z11, EORTC-

AMAROS, OTOASOR) challenged the dogma of completion ALND in select patients with SLN
EP

macrometastases(25,81,93). In the Z11 trial, patients with T1 and T2 breast cancers and one or
C

two sentinel macrometastases, who underwent breast conserving surgery without completion
AC

ALND, followed by whole breast radiotherapy and appropriate adjuvant systemic treatment, had

similar axillary failure event rates and survival outcomes up to 9.25 years of follow-up, as

compared with patients who underwent completion ALND. The cumulative incidence of axillary

recurrence at 10 years was 0.5% in the ALND arm and 1.5% in the SLND alone arm (p = 0.28).

Ten-year cumulative locoregional recurrence was 6.2% with ALND and 5.3% with SLND alone

17
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(p = 0.36)(25,32). Importantly, in the SLNB+ALND arm of the trial, only about one out of four

SLN-positive patients were found to have residual disease in the completion ALND specimen.

This finding suggested that SLNB provides adequate local control next to its staging role, whilst

it spares the patient the long-term sequelae of ALND (lymphedema, sensory loss and motor

PT
deficit of the affected arm), without impacting negatively on survival or regional axillary

RI
recurrence. Although the Z11 trial was criticized (lack of homogeneity in the whole breast

radiotherapy tangents, early accrual closure, too many ER-positive patients), it remains a very

SC
well-designed trial and is largely considered as practice-changing. The AMAROS trial enrolled a

patient population similar to the Z11 (T1-2 breast cancers, clinically node negative, undergoing

U
breast conservation with whole breast radiotherapy). In the test arm of the study, axillary
AN
radiotherapy (as opposed to no further regional treatment in the Z11) was offered to patients after

one or two positive (macrometastatic) nodes found during the SLNB. Axillary radiotherapy with
M

omission of ALND conferred similar survival and recurrence outcomes as compared with
D

standard completion ALND. Also, lymphedema rates in the axillary radiotherapy arm were
TE

significantly reduced compared to the ALND arm(81). Similar in design, the OTOASOR trial

independently confirmed the AMAROS findings. Amongst patients with early breast cancer and
EP

low SLNB burden, axillary nodal irradiation was non inferior to completion ALND in terms of

survival and regional recurrence(93).

C
AC

The Z11 trial enrolled patients undergoing breast conserving surgery with whole breast

radiotherapy(25). In the trial by Galimberti and colleages, some 9% of patients in each arm

underwent mastectomy. An unplanned subgroup analysis suggested that omission of ALND may

be acceptable in patients with small invasive primary tumors treated by mastectomy(94).

Notably, in the same trial, 19% of patients in the non-ALND arm underwent breast conserving

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surgery with partial breast irradiation as opposed to whole breast tangents(94). However, there

was no subgroup analysis to look at whether patients who received partial breast irradiation

exhibited any outcome detriment compared with those who received standard whole breast

radiotherapy.. Clinicians should be cautious when extrapolating outcomes from the Z11 trial to

PT
patients who undergo mastectomy or receive partial breast irradiation. In the Z11 trial, one

RI
interpretation of the similarity in outcomes between the ALND and non-ALND groups may be

that in (at least) a proportion of patients, a low axillary tangent (as part of the whole breast

SC
irradiation field) treated partially the axilla. However, a dedicated axillary irradiation field was

not offered in the Z11, as opposed to the AMAROS trial where targeted axillary irradiation was

U
part of the treatment protocol in the test arm. The randomized controlled POSNOC trial is
AN
currently recruiting patients with up to two positive sentinel macrometastases who undergo either

breast conservation or mastectomy, looking at whether omission of ALND in the test group
M

confers similar survival and axillary recurrence outcomes compared with the standard ALND
D

group. The POSNOC trial will therefore attempt to partially resolve the question whether the
TE

Z11 outcomes are reproducible to patients undergoing mastectomy(95).

EP

Summary of recommendations (Group 3)

C

• Completion ALND in patients with sentinel node isolated tumor cells is no longer
AC

recommended. However, pN0(i+) disease confers inferior outcomes compared with pN0

disease and therefore adjuvant chemotherapy may be considered in these patients(88).

• Data from two randomized controlled trials support that ALND is not of clinical benefit

in patients with sentinel micrometastases(92,94).

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• In patients with one or two sentinel macrometastases, completion ALND is non-inferior

to no further axillary treatment, in cases where breast conserving surgery with whole

breast irradiation and appropriate adjuvant systemic therapy is planned. Dedicated

axillary radiotherapy is considered equivalent to completion ALND in these patients, and

PT
axillary radiotherapy confers lower risk of lymphoedema compared to ALND(25,81,93).

RI
• In patients with one or two sentinel node macrometastases undergoing mastectomy, the

findings of the Z11 trial should be extrapolated with caution. The POSNOC trial aims to

SC
address the question of whether ALND is non-inferior to no further axillary surgery in

patients with limited SLN burden undergoing mastectomy(95).

U
AN
Conclusion
M

SLNB has well established indications and remains an operation with minimal morbidity, high
D

accuracy, and clinically valid prognostic significance. Recent advances in multimodality therapy
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and dedicated axillary imaging highlight the potential for de-escalating axillary surgery and

SLNB has a cardinal role in such an approach. Furthermore, non-randomized data suggest that
EP

the indication for SLNB may be expanded in patients where standard treatment would include a

complete axillary node dissection (locally advanced and multisite tumors). Clinicians need to be
C

well aware on the recent data supporting the use of SLNB in controversial settings, such as node-
AC

positive patients who respond excellently after neoadjuvant chemotherapy and patients who have

minimal sentinel node involvement.

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