Amit Goyal

Consultant Oncoplastic Breast Surgeon & Associate Professor

Royal Derby Hospital, Derby, United Kingdom

Neoadjuvant Chemotherapy and the search for optimum management of lymph node

positive breast cancer

Axillary Node Down-Staging with NAC

AC

NSABP B-18

50

40

30

20

10

0

%

Conversion

From

Node (+)

To

Node (-)

AT→CMF

ECTO

3037

FEC

EORTC

19

AC→TXT

NSABP B-27*

43

*Assuming 30% nodal down-staging with neoadjuvant AC

More than 40% of initially node-positive

women could potentially avoid ALND!

cN1 converts to N0 post NACT

Question

• Axillary lymph node dissection

• Axillary radiotherapy

• Sentinel node biopsy

cN1 convert to N0 (ATNEC EOI survey)

Axillary surgery after NACT

ACOSOG Z1071

n = 663 cN1

SN ID rate 95%

649 SN ALND

≥ 2 SN identified

n = 525, 79%

FNR

12.6% (9.9, 16.1)

EligibleT0-T4, N1-2, M0Biopsy Proven Nodal disease

Failed to meetprimary endpointFNR ≤ 10%

Boughey JC, JAMA 2013

ACOSOG Z1071FN rate by number of nodes removed

Boughey JC, JAMA 2013

SLN biopsy after NACTcN1 convert to N0

ACOSOG Z1071 SENTINA SN FNAC

N 649 592(cN+)* 153

Mapping Dual tracer

recommended (79%)

Technetium required Technetium required,

IHC

Pre-op biopsy? Yes Not required (biopsy

=25%)

Yes

Nodal pCR 41% 52% ypN0 (?) 35%

IR 92.7% 80.1% 87.6%

FNR (Overall) 12.6% 14.2% 8.4%

1 SLN 31.5% 24.3% 18.2%

2 SLN 21.1% 18.5% 4.9%

≥3SLN 9.1% 7.3%

*1737 patients enrolled in 4 arm multicenter trial. 592 ARM C were cN+ to cN0

Kuehn T et al. Lancet Oncol 2013; 14: 609–18 Boileau JF et al. JCO 2015; 33: 258–264

Pre vs. Post treatment nodal statusimpact on LRR

NSABP B-18 (AC)/B-27 (AC-T) Mamounas E et al JCO 2012

• Post NACT - SLN biopsy has higher FN rate

• Residual disease potentially resistant to treatment

• Do know importance of path node status in

predicting LRR … implications for RT

• cN1 to N0 post NACT - No data on LRR if ALND is

omitted

ALND remains standard of care outside clinical

trials

cN1 after neoadjuvant chemotherapy

Summary (1)

cN1 convert to N0 after NACT

Suggestions to minimise FNR

• Dual agent mapping

• Normal USS after chemotherapy

• Remove ≥ 3 SLN

• Include IHC detected disease as node positive

• Leave a clip at time of biopsy and localize for SLN

ACOSOG Z1071: 57% SENTINA: 34%

cN1 convert to N0 after NACT

Suggestions to minimise FNR

• Dual agent mapping

• Normal USS after chemotherapy

• Remove ≥ 3 SLN

• Include IHC detected disease as node positive

• Leave a clip at time of biopsy and localize for SLN

SLN biopsy AFTER NACT

cN1 convert to N0 after NACTACOSOG Z1071 SENTINA SN FNAC

N 649 592(cN+)* 153

Mapping Dual tracer

recommended (79%)

Technetium required Technetium required,

IHC

Pre-op biopsy? Yes Not required (biopsy

=25%)

Yes

Nodal pCR 41% 52% ypN0 (?) 35%

IR 92.7% 80.1% 87.6%

FNR (Overall) 12.6% 14.2% 8.4%

1 SLN 31.5% 24.3% 18.2%

2 SLN 21.1% 18.5% 4.9%

≥3SLN 9.1% 7.3%

*1737 patients enrolled in 4 arm multicentre trial. 592 ARM C were cN+ to cN0

Inclusion of mets <0.2mm in the definition of residual nodal

disease after NACT reduces the pCR rate and improves the

accuracy of SLN

2014 SABC, Boughey et al.

Evaluation of SLN after NACT

• Significance of residual ITC’s or disease <0.2mm (ypN0i+) after NACT

unclear

• 2012 WHO classification: small nodal mets and ITCs are evidence of

an incomplete response

• 7th (and 8th) edition AJCC TNM Staging Manual

ypN0i+ or ypN1mi residual nodal disease ALND remains

standard of care

cN1 convert to N0 after NACT

Suggestions to minimise FNR

• Dual agent mapping

• Normal USS after chemotherapy

• Remove ≥ 3 SLN

• Include IHC detected disease as node positive

• Leave a clip at time of biopsy and localize for SLN

Placement of a clip + identification of the clip during SLN and removal at least 2 SLN reduces FNR

20% pts clip not

in SLN

Clip placed 170 pts

2014 SABC, Boughey et al.

MD Anderson

Clipping the node for SLN after NACT

• Clipped node +/- SLN to reflect the status of the nodal basin in all-comers undergoing NAC

Also noted clipped node was not a SLN in ~ 20% pts

“Targeted Axillary Dissection”

Caudle AS et al JCO 2016;34(10):1072-8

Post NACT trials of axillary Management

Amit Goyal (Chief Investigator)

ATNEC trialAxillary management in T1-3N1M0 breast cancer patients with FNA or core

biopsy proven nodal metastases at presentation who convert to node negative after NEoadjuvant Chemotherapy

T1-3,N1,M0 breast cancer

FNA/core biopsy documented axillary metastasis

NEOADJUVANT CHEMOTHERAPY (NACT)

Breast conserving surgery or mastectomy + Targeted

(dual agent) sampling + at least 3 nodes removed + removal of clipped/tattooed node

Axillary ultrasound and FNA or core biopsy of abnormal nodes

Not malignant

No nodal metastasis

RANDOMISATION 1:1

Axillary treatment

ALND or ART

No Axillary

treatment

nodes positive

(micro or macrometastases)

Failed localisation of

clipped/tattooed node

Axillary lymph node

dissection(ALND)

malignant

Marking the positive node

• Clip placed• SPOT dye tattoo – anterior surface and perinodal tissue

cN1 convert to N0 (ATNEC EOI survey)

Axillary surgery – ATNEC Trial

Clipped/tattooed node + 2 more nodes

At least 3 nodes removed (clipped/tattooed node not mandatory)

Clipped/tattooed node + 1 more node

cN1 convert to N0 (ATNEC EOI survey)

Patient selection – ATNEC Trial

Marking and identifying positive node after NACT

• Clip

o Wire

• Radioactive seed

o Regulations

o Availability

o Cost

• Magseed

o Licensing issues

o Equipment –

o Cost - £200 per seed, probe >£10,000

• Tattooing

o £10 per syringe

o Feasibility

o No audio signal

Women undergoing axillary ultrasound and FNA or core biopsy of abnormal nodes

OUTCOMES

• Identification rate of tattooed node

• Concordance of tattooed node and

sentinel node (tattooed node

removed as part of sentinel node

biopsy)

• Migration of SPOT dye into other nodes

Not malignant

Mark the node with SPOT dye tattoo at the time of FNA or core biopsy

• cortex and perinodal tissue

Axillary lymph node

dissection(ALND)

malignant

OUTCOMES

• Identification rate of tattooed node in the

ALND specimen

• False negative rate of tattooed node (in

women undergoing ALND after NACT)

• Migration of SPOT dye into other nodes

(number of black nodes in ALND specimen)

Breast cancer treatment as per local MDT

(Neoadjuvant chemotherapy or No neoadjuvant chemotherapy)

Sentinel Node Biopsy• Sentinel node biopsy and

removal of tattooed node

PRE-ATNEC

• Carbon black tattooing ink

• Pre-loaded syringe

• Used routinely in GI tract

• £10 per syringe

• Removal of needle biopsy proven positive node

after NACT reduces FN rate

• Marking and visualizing the needle biopsy positive

node needs to be standardized

• Pre ATNEC – simple, low cost solution!

cN1 convert to N0 after NACT

Summary (2)

POSNOC Achievements

30

✓ Largest UK breast cancer surgical trial

✓ 1st UK led international breast cancer surgical trial

TOP 10 recruiting sitesSite Numbers

randomised

Derby 61

Oxford 28

Lincoln 27

Bristol 26

Aberdeen 26

Manchester 26

Belfast 24

Marsden 21

Melbourne (Australia) 21

Hull, Wycombe, Gillingham, Cambridge

20

Amendments• Sentinel node biopsy BEFORE Neoadjuvant Chemotherapy allowed

• Sentinel node biopsy tracer technique – as per local guidelines o Sentimag allowed

o Blue dye only allowed

Z11 POSNOC

Size of metastases micrometastasis or

macrometastasis

macrometastasis

Macrometastases 430 1020*

Extranodal invasion x √

Mastectomy x √

Radiotherapy quality

assurancex √

Mandatory pre-op

axillary ultrasoundx √

Sentinel node biopsy

before NACx √

*POSNOC recruitment ongoing (sample size 1900)

POSNOC vs. Z11

Recruitment end date Aug 2021