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You
r Patie
nt h
as a Po
sitive Se
ntin
el N
od
e!
Disse
ct, Irradiate
or Le
ave th
e re
st?
UK
BC
M N
ove
mb
er 2
01
3
Re-thinking the axilla
Early and locally advanced breast cancer
Implementing NICE guidance
2009
NICE clinical guideline 80
– Pretreatment ultrasound evaluation of the axilla should be performed for all patients being investigated for early invasive breast cancer
– If morphologically abnormal lymph nodes are identified, ultrasound-guided needle sampling should be offered
Staging of the axilla
LNODE TACTICS SCENARIO I (ONE STOP)
• LNode + pre-operative
Clinical +
Ultrasound +
FNA/Core +
• Perform Definitive Axillary Surgery with breast surgery at first operation
– Minimal surgery, rather than lymph node clearance, should be performed to stage the axilla for patients with early invasive breast cancer and no evidence of lymph node involvement on ultrasound or a negative ultrasound-guided needle biopsy
– Sentinel lymph node biopsy is the preferred technique
Surgery to the axilla
LNODE TACTICS SCENARIO II (2 STOP)
• LNode - pre-operative
Clinical - Ultrasound - FNA/Core -
• Perform Sentinel Node Biopsy
• If SNB + do definitive axillary surgery as second operation
The Impact of Sentinel Node Biopsy
Impact on the Patient
• Anxiety for 2-3 weeks for result
• 25% need second operation
• Biggest delays for worst patients
Impact on the Oncologist
• Slower referrals
• Prognostic information may change
IMPACT on the SURGEON
DO NOTHING
Z11
Z0011 Giuliano et al JAMA 2011; 305; 569-575
• ‘Lymph node study shakes Pillar of Breast Cancer Care’
• Conclusion: ‘Among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival.’
Z0011 Giuliano et al JAMA 2011; 305; 569-575
ALND
• 5 yr OS 92%
• 5 yr DFS 82%
• 5 yr LR 3%
SNB
• 5 yr OS 93%
• 5 yr DFS 84%
• 5 yr LR 2%
Seroma , infection, parasthesiae 70% v 25%, clinical oedema P< 0.001
• No difference in OS or DFS
• OS & DFS much better than anticipated
• AXR ‘early’ event in EBCTCG
• Z0011 shows NO BENEFIT for more surgery
• Only additional information is the no of + LN, ? unlikely to change therapy
Z0011 Giuliano et al JAMA 2011; 305; 569-575
• 5 yr accrual 856 patients from 115 centres
• 103 ineligible included
• 32 ALND had SNB, 11 SNB had ALND
• 1% of ALND were N -, 7% of SNB were N –
• Missing data: Age 2%, Size 2%, Receptors 9%, VI 25%, Grade 25%, Type 2%, Nodes 11%.
• Median Follow up 6.3 yrs
• 94 deaths
Z0011 Giuliano et al JAMA 2011; 305; 569-575
DO NOTHING SOMETIMES....but SOMETIMES DO SOMETHING
SURGICAL
IBCSG 23-01 Lancet Oncology 2013 Galimberti et al
• Non-inferiority trial
• 27 centres, recruitment 9 years
• Sentinel Node Positive micromets or ITC
• Randomised between Clearance or Observe
• Accrual 1960 – stopped at 931
• 62% from one institution
• Mastectomy and WLE
• Step sectioning, scintigraphy
CLEARANCE OBSERVATION
Randomised 464 467
Median no of SN 2 1
Median no of NSN 21
Positive NSN 13%
No of breast events 47 48
Overall Survival at 5 years 450 445
Axillary recurrence 1 5
Oedema 13% 3%
Sensory loss 18% 12%
Motor impairment 8% 3%
IBCSG 23-01 Lancet Oncology 2013 Galimberti et al
• No detriment of omitting dissection providing the patient received radiotherapy and appropriate systemic therapy
• Similar to Z-11
• St Gallen 2011 : No dissection if micromet and systemic therapy
IBCSG 23-01 Lancet Oncology 2013 Galimberti et al
DO SOMETHING SURGICAL SOMETIMES BECAUSE ITS IMPORTANT
Micrometastases & ITC: Relevant & Robust or Rubbish – The MIRROR study
de Boer et al N Engl J Med 2009; 361; 653-663.
• Retrospective
• Consecutive SNB patients with favourable Ca
• 113 Centres
• 2707 patients
• Missing data: grade 2%, receptors 3%
• 5.1 yrs follow up (4% lost)
• 84% disease free
2705
Micrometastases & ITC: Relevant & Robust or Rubbish – The MIRROR study
de Boer et al N Engl J Med 2009; 361; 653-663.
SNB + 1851
995
995 Adjuvant given
83% 5yr DFS ITC+
88% 5yr DFS mic+
SNB - 856 No treatment
86% 5yr DFS
856 No treatment
77% 5yr DFS ITC+
76% 5yr DFS mic+
• If micrometastases or ITC present 5yr DFS reduced by about 10%
• If adjuvant therapy given about 10% absolute benefit in DFS
• No big differences between micrometastases and ITC
• Omission of ALND for micrometastases increases 5 yr axillary recurrence from 1% to 6%
Micrometastases & ITC: Relevant & Robust or Rubbish – The MIRROR study
de Boer et al N Engl J Med 2009; 361; 653-663.
DO DOMETHING SURGICAL...but in a NEW WAY
LNODE TACTICS SCENARIO III (1 or 2 STOP)
• LNode - pre-operative
Clinical - Ultrasound - FNA/Core -
• Do Sentinel Node Biopsy to STAGE and perform PER-OPERATIVE assessment
• If SNB + perform definitive axillary surgery at first operation with breast surgery
Why examine SN intraoperatively?
• Advantages
– One axillary procedure
– One admission
– One anaesthetic
– Save money
– ?Easier operation
– Less delay in adjuvant therapy
• Disadvantages
– Planning of operating list
– Time waiting
– Prolonged anaesthetic
– Resources
– ?pre-op counselling
– Cost of tests
– Loss of income
OSNA® ‘One Step Nucleic Acid Amplification’
Rapid molecular diagnosis of lymph nodes
Detection of CK19 mRNA
expressed by breast cancer cells in lymph nodes indicative of metastatic disease
Identifies metastatic
disease (>0.2mm) according to a threshold level of mRNA expression.
30-40 mins for 2 nodes
• No more second operations
• If one stop surgery, quicker oncology
• ? More anxiety...NO!
One Step Nucleic Amplification: The role of micrometastases
Babar et al EJSO In Press
• Prospective data 2008-2010 one institution • 471 patients with clinically and ultrasound
negative axillae • 161 were SN positive (34%) • Macrometastases (>5000 copy numbers of CK19)
present in 48% • Micrometastases (250-5000 copy numbers of
CK19) present in 37% • Inhibited positive present in 15%
OSNA results protocol dependent on copy numbers CK-19 mRNA
• OSNA negative:
– 0-250 copy numbers/ul
– no further surgery
• OSNA positive:
– >5000 copy numbers/ul
– ++ macro-metastasis
– level 3 AND
• OSNA positive:
– 250-5000 copy numbers/ul
– + micro-metastasis
– level 1 AND
• OSNA positive:
– + inhibited
– pragmatic level 1
UK OSNA Implementation Meeting 33
Nodal positivity
0
10
20
30
40
50
60
70
+ Inhibited + ++ -
5
12.5 16.5
66
%
% cases
MACROMETASTASES MICROMETASTASES INHIBITED +
NUMBER
78 (48%)
59 (37%)
24 (15%)
NON-SENTINEL NODE POSITIVE
39%
17%
8%
NON-SENTINEL NODE POSITIVE >4
40%
20%
0%
NUMBER OF POSITIVE NON-SENTINEL NODES
137/1234 (11%)
24/743 (3%)
5/315 (3%)
One Step Nucleic Amplification: The role of micrometastases
Babar et al EJSO In Press
Breast cancer metastases burden in sentinel node biopsies using
OSNA predicts non-sentinel node involvement: a prospective cohort study
Milner et al BJS In Press
• 845 patients with cT1-3 ultrasound node negative
tumours who had SLNB • Completion Clearance in 290 with + SN (34%) • Categorised into Solitary +SN, Multiple
incomplete +SN, Multiple all +SN • Non-SLN positive in 74(26%) • Factors predicting Non-SLN positive : > 5000 copy
numbers of CK19, Multiple all positive, mastectomy
MULTIPLE ALL POSITIVE
SOLITARY POSITIVE
MULTIPLE INCOMPLETE POSITIVE
MULTIPLE INCOMPLETE POSITIVE MICROMETS ONLY
RISK OF NON-SLN POSITIVE 51% 30% 18% 9%
Breast cancer metastases burden in sentinel node biopsies using OSNA predicts non-sentinel node involvement: a prospective
cohort study
Milner et al BJS In Press
Site Protocol Total SLN Total Patients
SLN/ Patient +/++ ratio Policy for micromets
Positive Patients %
Guildford WN 1882 914 2.1 0.49 : 0.51 Level 1 33.0%
High Wycombe WN 1105 711 1.6 0.45 : 0.55 Nothing 40.8%
Royal Marsden Sutton WN 796 372 2.1 0.48 : 0.52 36.8%
Bristol WN 694 339 2.0 0.53: 0.47 31.3%
Orpington WN 558 302 1.8 0.42 : 0.58 36.1%
Royal Marsden London WN 456 257 1.8 0.48 : 0.52 36.6%
Chichester WN 366 257 1.4 0.41 : 0.59 32.3%
Warwick WN 359 253 1.4 0.42 : 0.58 30.0%
Winchester WN 421 252 1.7 0.36 : 0.64 32.5%
Royal Cornwall WN 463 218 2.1 0.56 : 0.44 33.0%
Royal Free HN 313 193 1.6 0.44 : 0.56 23.3%
Salisbury WN 124 79 1.6 0.39 : 0.61 36.7%
Reading WN 106 56 1.9 0.43 : 0.57 33.9%
Basingstoke WN 107 52 2.1 0.73 : 0.27 36.5%
Liverpool WN 65 33 2.0 0.73 : 0.27 27.3%
Solihull WN 57 26 2.2 0.40 : 0.60 26.9%
N. Staffs HN 29 15 1.9 0.13 : 0.88 46.7%
Sheffield WN 6 3 2.0 1.00 : 0.00 33.3%
Frimley Park WN 3 2 1.5 0.00 : 1.00 50.0%
Totals 7910 4334 1.8 0.47 : 0.53 34.3%
UK OSNA GROUP questionnaire (n=17)
MICROMET In 1/1
MICROMET In 1/2
MICROMET In >2
MACROMET
NO CLEARANCE
36%
30%
12%
O%
CLEARANCE
48%
24%
66%
100%
MDT
12%
6%
6%
0%
OTHER
6%
12%
6%
0%
DONT KNOW
0%
30%
12%
0%
LET SOMEONE ELSE DO SOMETHING
AMAROS : Rutgers et al 2013
• 1425 patients with positive SN
• Randomised to more surgery or radiotherapy
• 33% Positive Non-SLN (8% > 4+)
• DFS 87% v 83%
• Axillary recurrence 0.5% v 1%
• Oedema 28% v 14%
NSABP B-04 Louis-Sylvestre et al JCO 2002
• 1982-1987, 658 patients
• Randomised to clearance or radiotherapy
• Clinically node negative (no ultrasound)
• 21% of those assigned clearance were N+
• 15 year follow-up
• No difference in survival (73.8% v 75.5%)
• Axillary recurrence 1% v 3%
EVOLUTION ?
SAMPLING
SENTINEL NODE OSNA
AMAROS
GENE PROFILING
OBSERVATION
BUBBLES
CLEARANCE
ALMANAC NEW START NTAC
DO WE NEED TO REMOVE NON SENTINEL NODES?
Z-11
CONCLUSION
• Fry, Slash or Leave – whatever works for you!!!
• Deploy technology to help decide
• Personal preference is to slash if risk>10%
• Slash if patient having immediate reconstruction
• Record what you have done
• Clip the level
• Micromets in whole node are important
• Do metastases metastasize ??
You
r Patie
nt h
as a Po
sitive Se
ntin
el N
od
e!
Disse
ct, Irradiate
or Le
ave th
e re
st?
UK
BC
M N
ove
mb
er 2
01
3
I am still Re-thinking the axilla