1. THE ROLE OF SENTINEL LYMPH NODE BIOPSY in breast cancer AFTER NEoADJUVANT CHEMOTHERAPY
Joint Hospital Surgical Grand Round
Dr. Robin Lok Man Sheung
Kwong Wah Hospital

2. introduction Breast cancer is a chemo-sensitive disease
Chemotherapy is widely used in breast cancer management
In selected groups of patients, neoadjuvant chemotherapy (NAC) is beneficial
Sentinel lymph node biopsy (SLN Bx) is a well recognized procedure1 for:
Staging
Treatment for clinically node -ve (cN0) disease
In this presentation, I would like to clarify the use of SLNB in breast cancer patient with NAC
*NSABP = National Surgical Adjuvant Breast and Bowel Project

3. Sentinel lymph node biopsy
Definition of SLN
The first lymph node draining the tumour–bearing area of the breast2
Advantage
To avoid axillary dissection (AD) and associated morbidities in patients with -ve SLN Bx results
Disadvantage
False negative (FN) results of SLN Bx ~5-10%3,4 which may ↑ the potential of axillary recurrence
FN results in frozen section, which may lead to a 2nd stage operation for AD
radioisotope-labelled albumin (colloid)
Morbidities of AD:
Lymphedema
Nerve injury leading to pain and numbness
ROM restriction in upper limb
* The use of combination (blue dye + radiocolloid agents) will significantly ↓false –ve rate! 5,6

4. NEOADJUVANT CHEMOTHERAPY7
Goal
To improve disease-free and overall survival while enable more limited surgery
Indication
Downstage locally advanced tumour and hence increase operability
↑ breast conserving rate
- ↑ breast conserving rate ( for stage 1 & 2 disease)
- For NAC, we hope to get a response in :
Tumour
Axilla
In KWH, <10% patient will undergo NAC
How is the selection?
Locally advance tumour
Significant LN disease, esp matted LN
Locally advanced tumour = >= T3
Patient very eager for BCT

5. Systemic review of post-NAC SLN Bx8
AD and its associated morbidities
There is clearly over-treatment in a significant % of patients
NAC results in nodal conversion (from cN1 to ycN0) in ~40% patients
AD - the standard-of-care in this group of patients
Over-treatment !!!!!!
*cyN0 = clinically node-ve after NAC

6. Local-regional control
treatment principle2,9
Local-regional control
Systemic control
Breast
Breast conservative treatment + radiotherapy
Chemotherapy
Adriamycin + cyclophosphamide (AC)
Mastectomy
Hormonal control
Tamoxifen
Aromatase inhibitor (anastrozole, letrozole)
Axilla
Sentinel lymph node biopsy
Targeted therapy
Trastuzumab (Herceptin)
Bevacizumab (Avastin)
Axillary dissection
All nodal +ve patient should receive adjuvant chemotherapy
Patient with ER+ PR+ tumour should receive adjuvant hormonal therapy for 5 years
Patient with HER2/c-erb2 status +ve tumour should receive targeted therapy

7. SLN BX IN PATIENT WITH NEOADJUVANT CHEMOTHERAPY
Local-regional control
Systemic control
Breast
Breast conservative treatment + radiotherapy
Chemotherapy
Adriamycin + cyclophosphamide (AC)
Mastectomy
Hormonal control
Tamoxifen
Aromatase inhibitor (anastrozole, letrozole)
Axilla
Sentinel lymph node biopsy ???
Targeted therapy
Trastuzumab (Herceptin)
Bevacizumab (Avastin)
Axillary dissection
*Main controversy*
Feasibility
Reliability (FN rate)
Timing
Before
After
Before and after
Technical consideration
Back to treatment principle
Conventionally, SLN Bx is done in patients clinically node–ve, then adjuvant treatment will be given according to histological results.
For SLNB in patient with NAC
What is the difficulty?
What is the problem we are facing?
Can AD be avoided?

8. SLN Bx with neoadjuvant chemotherapy
SENTINA10
2. ACOSOG Z107111
SLN Bx with neoadjuvant chemotherapy

10. SENTINA (Sentinel neoadjuvant)
Published in Lancet Oncology in 2013
Prospective, multicenter cohort study
Total of 2234 patients included from 103 centers in Germany and Austria
Women with breast cancer scheduled for NAC were enrolled
Objective
To evaluate a specific algorithm for timing of a standardized SLN Bx in patients who undergone NAC
- SENTINA is a four-arm, prospective, multicentre cohort study undertaken at 103 institutions in Germany
and Austria.
- Women with breast cancer who were scheduled for neoadjuvant chemotherapy were enrolled into the
study.

11. method
Arm A = Patients with clinically LN -ve disease (cN0) underwent SLN Bx before neoadjuvant chemotherapy
Arm B = SLN +ve (pN1), a second SLN Bx was done after neoadjuvant chemotherapy
Arm C = patient with clinically node +ve disease (cN+) received neoadjuvant chemotherapy. Those who converted to clinically node -ve disease after chemotherapy (ycN0) were treated with SLN Bx and AD
Arm D = Only patients whose clinical nodal status remained +ve (ycN1) underwent AD WITHOUT SLN Bx

12. Primary endpoint = arm C
Method (cont’d)
Primary endpoint = arm C
Secondary endpoint
Accuracy (FN rate) of SLN Bx after NAC for patients who converted from cN1 to ycN0
Comparison of the detection rate of SLN Bx before and after NAC
2. FN rate and detection rate of SLN Bx after removal of the SLN

13. results SLNB before NAC (Arm A & B) NAC SLN Bx, then NAC
Detection rate = 99.1%
NAC
SLN Bx, then NAC
*pN0sn at presentation
*pN1sn at presentation
*cN1 at presentation
*Conversion to ycN0
*Persistent ycN1
In arm B, if so high FN rate and low detection rate  means ALL patients from Arm B shoulder undergo AD directly after NAC
2nd SLNB (Arm B)
Detection rate= 60.8%
FN rate = 51.6%
SLNB (Arm C)
Detection rate= 80.1%
FN rate = 14.2%

14. ↑ detection rate Result (cont’d) *dual tracer*
Table 2 – some variations in SLNB procedure evident in table 2
Table 3 – presents detection rates of SLN
When sentinel-lymph-node biopsy was done after neoadjuvant chemotherapy, in arms B and C, the additional use of blue dye was associated with
a significant increase in the detection rate and a higher number of nodes were detected in arm C (median three vs two in arm B; p=0・0059).
↑ detection rate
*↑ no. of SLN harvested*

15. Result (cont’d) 2nd SLN Bx is not a useful option!
FN rate ↓ with ↑ no. of SLN removed
↓FN rate with dual tracer in Arm C

16. Conclusion of sentina
After systemic treatment or early SLN biopsy, the procedure has a lower detection rate and a higher FN rate
SLN biopsy accuracy is especially unfavourable with < 3 harvested SLN after NAC
Use of dual tracer might improve the detection and FN rate
A 2nd SLN Bx after NAC is not a good clinical option

17. *The American College of Surgeons Oncology Group = ACOSOG

18. ACOSOG z1071 (alliance) clinical trial
Published in The Journal of the American Medical Association (JAMA) in Oct 2013
Background
Application of SLN Bx for axilla staging after NAC (initially cN1) is unclear
Due to high FN results reported in previous studies
Objective
To determine the FN rate for SLN Bx post-NAC in women initially presents with bx-proven cN1 breast cancer

19. METHOD
Enrolled female 756 patients from 136 institutions in USA, from July 2009 to June 2011
Breast cancer, T0-4, N1-2, M0
Received NAC
Patient re-evaluation with (1) physical exam (2) USG axilla
Proceed BOTH (1) SLN Bx and (2) AD
Dual tracer for SLN Bx (isosulfan blue/ methylene blue + radiolabeled colloid) was encouraged
Primary endpoints
FN rate of SLN Bx post-NAC
*Rate expected of FN rate with ≥ 2 SLNs harvested was set to be ≥ 10% 6,7
(according to the FN rate in SLNB with cN0 disease)

20. Result SLN non-detected rate = 7.1% FN rate = 39/310 = 12.6%

21. ↓ FN rate Result (cont’d)
Bivariable analyses found that the likelihood of a false negative SLN finding was significantly decreased when the mapping was performed with the combination of blue
dye and radiolabeled colloid and by examination of at least 3 SLNs (Table 3).
↓ FN rate

22. Conclusion of ACOSOG z1071(alliance) clinical trial
SLN bx is a useful tool for detection of residual nodal disease in women with node +ve breast cancer receiving NAC
Although FN rate = 12.6% in ACOSOG Z1071 (not ≤ 10%)
FN rate can be minimized by:
Resection of ≥ 3 SLNs
Use of dual tracer

23. *Currently, no long term data to observe for axilla recurrence*
Take home message
SLN Bx after NAC is feasible
Lower detection rate
Higher FN rate
For patient from cN1 to cN0 after NAC, SLN Bx:
can be a useful diagnostic tool
enable avoid axillary dissection and associated morbidities
To increase success of SLN bx (i.e. lower FN rate) after neoadjuvant chemotherapy
Liberal use of axillary imaging and biopsy before SLN surgery
Use of dual-tracer
Resection of ≥ 3 SLNs
Repeated SLN Bx is not advised
*Currently, no long term data to observe for axilla recurrence*
- SLN Bx after neoadjuvant chemotherapy is still controversial
 Need larger scale study with more unified standards (particularly factors of performing SLN Bx), to minimize the variability among each case and the studies
- can be a useful diagnostic tool in selected patients (good response to neoadjuvant chemo and converted to ycN0 disease)
Many confounding factors, a large one = RT to the axilla (which will affect the result)
RT axilla vs AD: LONG TERM results showed that they are equal or RT even better (because better morbidity)

24. reference
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25. Reference (CONT’D)
El Hage Chehade H, Headon H, Kasem A, et al. Refining the Performance of Sentinel Lymph Node Biopsy Post-neoadjuvant Chemotherapy in Patients with Pathologically Proven Pre-treatment Node-positive Breast Cancer: An Update for Clinical Practice. Anticancer Research. 2016 Apr;36(4):
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27. Thank you