This document discusses surgical management of the axilla after neoadjuvant treatment for breast cancer. It outlines the history of axillary procedures including axillary clearance and sentinel lymph node biopsy. It discusses accuracy of sentinel lymph node biopsy after neoadjuvant chemotherapy, particularly in patients who were node-positive before treatment. Techniques to minimize false negative rates are presented such as clip placement in biopsied nodes. Ongoing clinical trials are evaluating axillary management based on response to neoadjuvant therapy. The conclusion is that sentinel lymph node biopsy after chemotherapy can provide confident assessment of axillary response, especially with use of dual tracers and retrieving at least 3 nodes including a previously clipped node.

1. SURGICAL MANAGEMENT OF
THE AXILLA POST-
NEOADJUVANT TREATMENT
OF BREAST CANCER
Miss Leena Chagla, FRCS
Consultant Surgeon
St Helens and Knowsley Teaching Hospitals, UK
ABDA webinar, February 2023

2. AXILLARY PROCEDURES
• AXILLARY CLEARANCE
• AXILLARY 4 NODE SAMPLE
• SLNB
• MARI/TAD/RISAS

3. MORBIDITY ASSOCIATED WITH AXILLARY
CLEARANCE
Lymphoedema
(up to 20%)
Numbness due to
division of
Intercostobrachial
nerve
Pain and shoulder
stiffness
Cording
Recurrent
seromas
Lymphangitis
Nerve damage
(winging of the
scapula)

4. LYMPH NODAL ASSESSMENT ON USS
F. Maxwell e al. Diagnostic strategy for the assessment of axillary lymph node status in breast cancer. Diagnostic and
Interventional Imaging. 2015 Oct; 96(10):1089-1101

5. HISTORY OF MANAGEMENT OF THE AXILLA
• ANC was standard treatment for breast cancer up until 1990s
• SLNB - after Milan trial (1998-99), NASBP-B32 trial (1999-2004) and ALMANAC.
In the UK it was rolled out for clinically node negative pts after the New Start
programme using dual technique (2005-2006) Patients with positive SLN went
on to have ANC (Some units had OSNA and other intraoperative assessment
tools)
• Following ACOSOG Z0011(1999-2004) and AMAROS (2001-2010), ANC was not
being done for low burden positive SLNB and in UK we were recruiting into
POSNOC (1 or 2 positive nodes)
• Neoadjuvant chemotherapy caused chaos again – ANC, SLNB,TAD

6. SLNB IN THE NEOADJUVANT SETTING
• Until recently dichotomy of practice emerged in attempts to
define how sentinel lymph node (SLN) biopsy should be
incorporated into neoadjuvant setting:
SLN biopsy before initiation of chemotherapy
SLN biopsy +/- completion ALND after
chemotherapy*
*[prospective clinical trials assessed safety/accuracy]

7. SLN BIOPSY AND NEOADJUVANT THERAPY
• SLN biopsy prior to NACT can be helpful if
negative:
- no further axillary treatment necessary
- negative result reinforces decision to withhold
PMRT/nodal area irradiation
- clinicians feel more ‘comfortable’ with
definitive staging of axilla pre-chemotherapy
• Suggestion that knowledge of nodal response to
chemotherapy more relevant in terms of prognosis
and decision making for PMRT than initial nodal
status

8. • Rates of nodal pCR = 20 – 42% in patients with needle biopsy confirmed
positive nodes pre-chemotherapy [HENNESSY B et al. J Clin Oncol 2005; 23: 9304; BEATTY J et al. Am J Surg
2009; 197: 637 – 642; ALVARADO R et al. Ann Surg Oncol 2012; 19: 3177-84; BOUGHY J et al. JAMA 2013; 310 (14): 1455 - 61]
• Most metastases diagnosed on needle biopsy are macrometastases [>2mm]
and pCR may conceivably be higher for micrometastases
• Patients with pCR in breast and nodes appear to have better prognosis and
DFS [Klaube-Demore N et al. Ann Surg Oncol 2006; 13: 685 – 691]
• However, there are concerns about intrinsic accuracy SLN biopsy after
neoadjuvant therapy and possible increased false negative rates

9. RIOGI B ET AL., MANAGEMENT OF THE AXILLA FOLLOWING NEOADJUVANT CHEMOTHERAPY FOR BREAST
CANCER – A CHANGE IN PRACTICE, THE SURGEON, HTTPS://DOI.ORG/10.1016/J.SURGE.2020.01.009
Pre and Post NACT

10. SENTINEL LYMPH NODE BIOPSY AFTER NEOADJUVANT
CHEMOTHERAPY – ACCURACY CLINICALLY N0/N1 PATIENTS
STUDY/AUTHOR IDENTIFICATION FALSE NEGATIVE
RATE RATE
NSAPB B-27 85% 11%
[J Clin Oncol 2005;23: 2694-702] (8% [dye + RI]; 14% [dye alone])
(428 patients)
GANEA (French) 90% 11%
[J Clin Oncol 2009;27: 726-32] (9.4% [node -ve]; 11.6% [node +ve])
(195 patients)
MDACC 97.4% 5.9%
[Hunt K, et al.Ann Surg 2009; 250: 558-66] (4.1% [pre-chemotherapy];p=0.39)
(575 patients)

11. SENTINEL LYMPH NODE BIOPSY AFTER NEOADJUVANT
CHEMOTHERAPY – ACCURACY IN BIOPSY PROVEN NODE POSITIVE PATIENTS
• Mixed reports on false negative rates for biopsy proven [core
biopsy/FNAC] node positive cases pre-chemotherapy
• Limited number of studies relating specifically to this patient group:
AUTHOR No. PATIENTS FALSE NEGATIVE RATE
Shen et al. (2007) 69 25%
Newman et al. (2007) 54 10.7%
Alvarado et al. (2012) 150 16.1%
Boughey et al. (2013) 649 12.6%
van Nijnatten et al. (2015) SR (8 studies) 15.1%

12. SENTINEL LYMPH NODE BIOPSY AFTER NEOADJUVANT
CHEMOTHERAPY – ACCURACY IN BIOPSY PROVEN NODE POSITIVE PATIENTS
• Meta-analysis (19 articles) examined accuracy of SLN biopsy after
NACT in biopsy-proven clinically node positive patients (n = 3,398):
POOLED IDENTIFICATION RATE = 91%
FALSE NEGATIVE RATE = 13%
[EL HAGE H, et al. Am J Surg 2016; 212(5):969-981]
• More refined patient selection and optimization of techniques

13. SENTINEL LYMPH NODE BIOPSY AFTER NEOADJUVANT
CHEMOTHERAPY – ACCURACY IN BIOPSY PROVEN NODE POSITIVE PATIENTS
• American College of Surgeons Oncology Group Z1071 trial examined false negative rates
for patients with core biopsy proven node positive breast cancer [BOUGHEY J et al. 2013;
JAMA 310 (14) 1455 – 61]
- enrolled ~700 clinically node positive patients (T0 – T4, N1[663],N2 [38],M0)
- SLN biopsy (dual/single tracer) and concomitant ALND after primary chemotherapy
• Primary endpoint = false negative rate when ≥ 2 nodes removed
• False negative rate 12.6% when ≥2 nodes harvested (reduced to 10.8% with dual tracers but
lowest when at least 3 nodes [9.8%])

14. SENTINA TRIAL

15. SENTINEL LYMPH NODE BIOPSY AFTER NEOADJUVANT
CHEMOTHERAPY – MINIMIZING FALSE NEGATIVE RATES
• Placement of titanium clip in axillary node at time of biopsy
- retrieval with SLN biopsy after chemotherapy
• Ensures false negative rate
lies below 10% threshold
• Problems with surgical identification
[radioactive seed localization/MARI?]
• False negative rate only 1.4% when clipped node examined
pathologically compared to 10.1% without [p=0.03] [CAUDLE AS et al. J Clin
Oncol 2016; 34(18): doi:10.1200/JCO.2015.64.0094 ]

16. • Problem of clipped node not identified within SLN biopsy
specimen
• Subgroup analysis of American College of Surgeons
Oncology Group Z1071 trial examined impact of clip
placement and retrieval:
• False negative rate related to location of clipped node:
- 107 cases (75.9%) within SLN biopsy specimen = 6.8%
- 34 cases (24.1%) within ALND specimen = 19.0%

17. SENTINEL LYMPH NODE BIOPSY AFTER
NEOADJUVANT CHEMOTHERAPY – TARGETED
ALND
• Targeted forms of ALND biopsy post-NACT relies on strategies for primary marking
biopsied node [CORE NEEDLE BIOPSY or FNAC]:
- CLIP (localization with wire or radioactive iodine seed)
- MAGNETIC SEEDS (Magseed/ Pintuition)
- CHARCOAL
- INKING (STERILE BLACK CARBON SUSPENSION - SpotTM)
- RADIOFREQUENCY DEVICES (Saviscout)

18. SENTINEL LYMPH NODE BIOPSY AFTER
NEOADJUVANT CHEMOTHERAPY – RISAS
• Prospective multicentre RISAS [NCT02800317] trial – radioactive seed placement
in axillary node before NACT with combined SLN biopsy and retrieval of
radioactive seed post-NACT [SIMONS J, et al. SABCS 2020]
• Approximately one-third patients (35.4%) pCR axilla after NACT
• Determine treatment response without removing nodes (ALND) using method with
low false negative rate and high negative predictive value
IR FNR NPV
SLNB 89% 17% 57.86%
MARI 97% 7% 83%
RISAS 98% 3.47% 93.59%

19. SO HOW DO WE ACCESS THE AXILLA?
• Consider RISAS and TAD to be most suitable axillary
staging procedure after NACT in node positive patients
• No maximum number of nodes that can be clipped (most patients
have ≤4 suspicious nodes). Consider cost and feasibility
• Recommend dual tracer technique but each institution will have
their own protocols

20. HOW DO WE NOW TREAT THE AXILLA AND
DOES IT MATTER?
Patients that
were clinically
node negative
pre NACT
Patients that
were node
positive pre
NACT

21. OUR JOURNEY WITH NEOADJUVANT
TREATMENT AND THE AXILLA
• 1998: At the time all patients had ANCs following NAC even if they were down-
staged to have WLE
• Introduction of SLNB in 2005. Initially oncologist felt more comfortable if patients
having NAC had an ANC regardless of pre NAC nodal status.
• After a while we agreed to upfront SLNB with no further surgery if SLNB negative
but for ANC following NAC if SLNB was positive at the outset
• Following Monica Morrow’s paper on SLNB post NAC we started doing dual
technique at least 3 nodes SLNB post NAC. If they were positive then patients had
clearance
• From 2013 all pts had assessment of axilla with USS +/- repeat FNA post NAC and
only patients with normalised LNs had SLNB

22. Riogi B et al.,Management of the axilla following neoadjuvant chemotherapy for breast cancer – A change in practice,The Surgeon,
https://doi.org/10.1016/j.surge.2020.01.009
ERA 1
cN0/cN+
ALND
ERA 2
Upfront SLNB
+ SLNB
Post NAC ALND
-Ve SLNB
No further
treatment
ERA 3
cN0
SLNB post NAC
cN+
Axilla imaging post NAC
Normal axilla
SLNB
+ve SLNB
ALND/RT
-ve SLNB
RT
abnormal Nodes
ALND
RT breast chest
wall and SCF

23. DATA ON MANAGEMENT OF AXILLA IN NAC
2007-2016
165 pts NAC
abnormal
axilla (123)
SLNB(40) ALND( 83)
Normal axilla
(42)
ALND(7) SLNB(35)
5 upfront
30 post NAC

24. WHAT HAPPENED TO THOSE NODES THAT
WERE POSITIVE PRE NAC?
Pre chemo
abnormal nodes
(123)
Post chemo SLNB
Era 3 (40)
Tumour free
nodes (29)
Positive nodes
(11)
Post chemo ANC
Eras 1 & 3 (83)
Tumour free
nodes(27)
Positive nodes
(56)

25. CANCER OUTCOMES
• Median Follow up 67 months (range 24-138 months)
• 34/165 patients died (20.6% mortality).
• 6 had local recurrence in the breast or mastectomy scar (3.6%)
• NO RECURRENCE IN THE AXILLA (0/165)
Riogi B et al., Management of the axilla following neoadjuvant chemotherapy for breast
cancer – A change in practice,The Surgeon, https://doi.org/10.1016/j.surge.2020.01.009

26. POINTS TO CONSIDER
• Post-Z0011 reasoning for omission of completion ALND would not
apply to SLN biopsy positive patients after NACT. These patients have
not responded well to chemotherapy and have residual disease
• Significance of micrometastases [ypN1mi] and/or isolated tumor
cells [ypN0i+] in post-chemotherapy SLN unclear, treat as positive

27. SENTINEL LYMPH NODE BIOPSY AFTER NEOADJUVANT
CHEMOTHERAPY – RECURRENCE RATES
• Analysis of non-metastatic (clinically T1-3, N1, M0) breast cancer
patients (n=1617) from NCDB and treated between 2006 and 2014
examined outcomes for NACT with residual nodal disease (ypN1)
[ALMAHARIQ M et al. Annals Surg Oncol 2021; 28: 930 – 940]
• Compared survival after NACT amongst matched ypN1 cohorts
receiving either SLN biopsy + RNI (n=304) or ALND + RNI (n=1313)
• Most patients ALND but proportion of patients undergoing SLN
biopsy increased over period of study (especially after 2011 [Z0011] )
• Inferior 5 year overall survival on both univariate and MVA for SLN
biopsy compared with ALND cohorts (71% versus 77%) [p = 0.01]

28. AXILLARY MANAGEMENT FOLLOWING
NACT AND SLN BIOPSY
CLINICAL NODE NEGATIVE PATIENTS (cN0)
1) ypN0 no further local treatment to axilla required
2) residual tumor axillary lymph node dissection*
3) ypN0 with fibrosis (1 or 2 nodes) consider axillary RT
* NB - consider axillary RT for micrometastases or ITCs only (St Gallen 2021)?

29. AXILLARY MANAGEMENT FOLLOWING NACT
AND SLN BIOPSY* (TAD)
CLINICAL NODE POSITIVE (BIOPSY PROVEN) PATIENTS (cN1)
1) ypN0 axillary RT or no further treatment (ATNEC, B-51 trials)
2) ypN1 axillary lymph node dissection ( or ALND vs RT axilla
A11202 trial)
3) cN1 axillary lymph node dissection (without SLN biopsy)
*NB - dual tracer agents, ≥3 nodes and marked node retrieved (targeted ALND)

30. CLINICAL TRIALS OF AXILLARY MANAGEMENT IN CN1 PATIENTS
CONVERTING TO CN0 POST-NACT (WITH SLN BIOPSY)
PATIENTS WITH NO RESIDUAL NODAL DISEASE (ypN0)
ATNEC [T1-T3] no further axillary treatment v ALND/ RT axilla
NSABP B-51 [T1-T3] no further axillary treatment v regional RT*
PATIENTS WITH RESIDUAL NODAL DISEASE (ypN1; not ITCs)
A11202 [T1-T3] randomize ALND v RT axilla
* NB - if BCS breast RT with RNI; if mastectomy chest wall RT with RNI

31. CONCLUSIONS
• Advantages and limitations with SLN biopsy before or after NACT but
shift towards SLN biopsy following chemotherapy (node positive and
negative)
• Greater confidence in declaration of a ‘negative’ SLN biopsy
after NACT for node positive disease (cN1) if
- normal nodes on ultrasound post NACT
- remove preferably 3 sentinel nodes
- use dual localization with blue dye and radioisotope
- clip placement at node biopsy and localize at time of SLN biopsy

32. FINALLY
• Enter registration study or consider trial of no further
surgery versus ALND/RT [e.g. ATNEC]
• Ongoing NSABP-51/ALLIANCE (A11202) trials aim to
determine :
1) Whether PMRT is based on axillary status before or after
NACT [B51]
2) Whether PMRT + RNI or addition of RNI to breast RT post
BCS increases invasive breast cancer recurrence-free
interval in cN1 patients converting to ypN0 after NACT
[B51]
3) Whether axillary RT (+RNI) is non-inferior to cALND +
RNI for pN1 disease after NACT and SLN biopsy
[ALLIANCE]

33. AXILLARY MANAGEMENT – NOT LESS, NOT
MORE, BUT JUST RIGHT

34. THANK YOU FOR YOUR ATTENTION
Acknowlegements: Prof John Benson
Bahaty Riogi
Staff and patients at STHK