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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

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UK

BC

M N

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mb

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I am still Re-thinking the axilla