Fellows Institute Cincinnati 2011

Sentinel lymph node controversies: is this the end for ALND?

Hiram S. Cody III MD Attending Surgeon The Breast Service, Department of Surgery Memorial Sloan-Kettering Cancer Center Professor of Clinical Surgery Weill Cornell Medical College No disclosures

SLN biopsy works

SLN 2010 69 validation studies in 8059 patients # pts SLN found SLN false-neg (SLN-/AX+) Accuracy (SLN correct/total) 8059 96% 7% 97% Kim T et.al. Cancer 2006;106:4-16

Trial SLN 2010 Results of 5 randomized trials # pts SLN found SLN false negative Accuracy EIO B-32 ALMANAC GIVOM SNAC 532 5611 836 749 1088 99% 97% 96% 95% 94% 61-73% had SLN-only disease 9% 10% 7% 17% 5% 97% 97% 98% 95% 98%

NSABP B-32

Clinically Negative Axillary Nodes (n=5,611) Randomization GROUP 1 SLNB



ALND

Will false-negative SLN procedures affect survival?

GROUP 2 SLNB Path. Pos.

SLN Path. Neg.

SLN ALND No ALND

Krag, DN et.al. Lancet Oncology 2010;11:927-33

0 NSABP B-32 OS: SLN negative (8 yr results) * 300 deaths triggered the definitive analysis * 309 reported as of 12/31/2009 84.6% received systemic therapy

Trt SNR+AD SNR

2

N 1975 2011 Deaths 140 169 HR=1.20 p=0.117

4

Years After Entry

6 Data as of December 31, 2009 8 Krag, DN et.al. Lancet Oncology 2010;11:927-33

NASBP B-32 DFS: SLN negative (8 yr results)

0

84.6% received systemic therapy

Trt SNR+AD SNR 2 N 1975 2011 Deaths 315 336 HR=1.05 p=0.542

4 Years After Entry 6

Data as of December 31, 2009

8

Krag, DN et.al. Lancet Oncology 2010;11:927-33z

Milan/EIO trial: 10 yr results 561 patients 1998-1999 95 mo f/u Veronesi U et.al. Ann Surg 2010;251:595-600

SLN 2010 False-negative = axillary LR

# pts # axillary LR (%) median f/u SLN-/no ALND 48 studies*

14,959

0.3%

34 mo

median time to axillary LR

20 mo

SLN-/no ALND IEO RCT SLN+/no ALND 6 studies

167 583

1.2% 0.5%

95 mo 31 mo 81 mo 22 mo *all with >3 yrs followup Van der Ploeg IMC et.al. EJSO 2008:34:1277-84

We’ve asked and answered the easiest questions

SLN 2010 Where have we come and what’s next?

• definition • case selection • technique – nuclear medicine – surgery – pathology • results – morbidity – local control – survival • non-axillary SLN?

• SLN and neoadjuvant?

• SLN micromets?

• SLN+ : ALND?

1) a blue node SLN 2010 What is the SLN?

2) a hot node 3) a palpable node

SLN 2010 Case selection • SLN biopsy is indicated in almost every patient with a cN0 invasive breast cancer • for DCIS?

– YES, selectively • for inflammatory/locally advanced CA?

– NO, outside of clinical trials

SLN 2010 Louisville (99 surgeons) method SLN found SLN false-negative single-agent (n=244) dual-agent (n=562) 86% 90% 11.8% 5.8% McMasters et.al.,JCO 2000;18:2560-2566

SLN 2010 Finding the positive SLN (n=255) Dye failure Dye success Isotope failure Isotope success -- 11% 11% 78% Cody HS et.al. Ann Surg Oncol 2001;8:13-19

SLN 2010 Declining marginal benefit of dye (finding the

positive

100%

SLN)

80% 60% 40% 20% 0% isotope success dye-only success 1-500 88% 12% 501-1000 90% 10% 1001-1500 96% 4% 1501-2000 98% 2%

Derossis et.al.JACS 2001;193:473-8

SLN 2010 Learning curve: ALMANAC 35 30 25

%

20 15 10 5 0 1 False negatives Failed localisations 2 to 10 11 to 20 21 to 30 31 to 40 Most failed and false-neg results occurred in the first procedure!

Clarke DH. Ann Surg Oncol 2004;11:211S-15S

SLN 2010 Morbidity: early reports Lymphedema rates SLNB ALND 7 case series 2000-2005 (n=1903) 5% (0-13%) 29% (7-77%)

SLN 2010 Z0010 morbidity • prospective observational study of SLN biopsy • >5500 patients accrued 1999-2003 • at 6 months – 8.6% axillary paresthesias (>90% mild) – 3.8% decreased upper extremity ROM – 6.9% lymphedema (>2 cm over non-operated side) • lymphedema was predicted by – increased BMI (p=0.0005) – increased age (p=0.04) Wilke LG et.al. Ann Surg Oncol (suppl) 2005;12:S27

SLN 2010 MSKCC morbidity Lymphedema at 5 yrs SLNB alone n=600 SLNB/ALND n=336 Subjective Measured (>2 cm change) 3% 5% 27% p<0.0001

16% p<0.0001

McLaughlin SA et.al. JCO 2008:26:5213-26

SLN 2010 MKCC sensory morbidity p < 0.001

Temple LK, Ann Surg Oncol 2002;9:654-62

There are still some areas of debate

SLN 2010 Non-axillary SLN: what to do?

Author

SLN 2010 Internal mammary experience

IMN imaged

25%

IMN found

16%

IMN positive

4%

Van der Ent/2001

n=256

Estourgie/2003

n=691

Farrus/2004

n=120

Leidenius/2006

n=984

Madsen//2007

n=506 Heuts/2009 n=1008 22% 17% 14% 22% 20% 19% 12% 11% 17% 14% 3% 1.6% 1.8% 4% 3%

IMN-only positive

1.2% 1.3% 0 0.8% 1% 0.9%

SLN 2010 Reoperative SLN biopsy

“First time” SLN biopsy Reoperative SLN biopsy Non-axillary drainage on preoperative lymphoscintigram 6%

(313/5482)

30%

(19/63) p<0.0001

Port ER et.al. Ann Surg Onc 2007;8:2209-14

SLN 2010 SLN is better

after

neoadjuvant (my bias) • fewer operations • false-negative rate is probably not increased • avoidance of ALND for patients with pathologic CR • ACOSOG 1071 (PI J Boughey)

Sentinel node SLN before vs after chemo: cN0

MDACC 1994-2007 T1-3, cN0 n=3746 SLN found SLN false-negative

98.7% 4.2% (23/542)

SLN before chemo n=3171 SLN after chemo n=575

97.4% (p=0.017) 5.9% (5/84) (p=0.48) Hunt KK et.al. Ann Surg 2009 epub.

sensitivity: method+/SLN+ (%) 100 90 80 70 60 50 40 30 20 10 0

SLN 2010 Intraoperative assessment

frozen touch prep smear All cases <=2 mm Size of nodal metastasis >2 mm

Brogi E et.al. Ann Surg Oncol 2005;12:173-80

SLN 2010 EIO study (RT-PCR) • 293 SLN in 293 pts • frozen section of entire SLN – 50 m intervals – H&E (IHC selectively) – 118 sections (40-258)/SLN • intervening tissue – half for RT-PCR – half discarded Viale G et.al. Ann Surg 2008;247:136-42

SLN 2010 Frozen vs RT-PCR

sensitivity: method+/SLN+ (%) 100 90 80 70 60 50 40 30 20 10 0 frozen RT-PCR All cases <=2 mm Size of nodal metastasis >2 mm

Brogi E et.al. Ann Surg Oncol 2005;12:173-80 Viale G et.al. Ann Surg 2008;247:136-42

50

m SLN 2010 MSKCC pathology protocol

H&E and IHC H&E and IHC

1 H&E and 1 IHC (cytokeratin AE1:AE3) stained section from each of two levels 50 m apart Tan LK et.al. J Clin Oncol 2008; 26: 1803-9

MSKCC micromet study DFS by method of staining H&E-/IHC p<0.001

IHC+ H&E+ 0 - H& E , + I HC + H& E , + I HC - H& E , - I HC 5 1 01 52 02 5

MSKCC micromet study DFS by size of metastasis pN0 (negative) pN0i+ (<0.2 mm) pN1mi (0.3-2.0 mm) p<0.001

Tan LK et.al. JCO 2008;26:1803

Netherlands micromet study DFS by size of metastasis N0 vs N0i+ or N1mi N0 vs N0i+, N0 vs N1mi p<0.001

p<0.002

p<0.001

de Boer M et.al. NEJM 2009;361:653-63

www.mskcc.org/nomograms Van Zee KJ. Ann Surg Oncol 2003;10:1140-51

Predicting non-SLN metastases SLN+ (mets <2 mm) SLN+ (all pts) A comparison of 9 models by AUC curves Coutant C et.al. JCO 2009;27:2800-08

SLN 2010 Selective ALND for SLN+

1960 patients with positive SLN Nomogram score

(median predicted likelihood of residual axillary disease)

SLN+/no ALND

(n=315)

15% of SLN+ SLN+/ALND

(n=1645)

85% of SLN+

10% 37%

Axillary local recurrence

( at 26 mo) 1.9% 0.36% p=0.004

Park J et.al. Ann Surg 2007;245:462-8

SLN 2010 Selective ALND for IHC+ SLN

171 patients with IHC+ SLN Nomogram score

(predicted odds of non-SLN disease)

Axillary local recurrence

( at 6.4 yrs)

SLN+/no ALND

(n=76)

44% of SLN+ SLN+/ALND

(n=95)

56% of SLN+

4.2% 8.1% 0% (63% chemo, 5% ax RT) 0% (88% chemo, 2% ax RT) Pugliese MS. Ann Surg Oncol 2010;17:1063-68

80 75 % ALND for SLN+ 70 65 60 55 50 1997

SLN 2010 Fewer ALND for SLN+ (FS negative or not done)

1998 1999 2000 Year 2001 2002 2003

p<0.001

2004

Park J et.al. Ann Surg 2007;245:462-8

SLN 2010 Patterns of ALND (NCDB) 23% no ALND 55% no ALND Bilomoria KY et.al. JCO 2009;27:2946-53

SLN 2010 Trends in ALND for SLN+ (NCDB) SLN+ and no ALND % Bilomoria KY et.al. JCO 2009;27:2946-53

SLN 2010 Outcome +/- ALND (NCDB)

Axillary local recurrence SLN only (n=802) SLN micrometastases (<2 mm)

0.4%

SLN/ALND (n=2357)

0.2%

5 yr relative survival

99% 98%

SLN only (n=5596) SLN/ALND (n=22591) SLN macrometastases (>2 mm)

1.0% 1.1% 90% 89% Bilomoria KY et.al. JCO 2009;27:2946-53

2010 annus mirabilis!

1) micromets on IHC?

2) micromets on H&E?

3) ALND for SLN+?

ACOSOG Z0010-Z0011

Z0010

cN0 and BCT SLN biopsy Bone marrow aspiration clinician/patient blinded to IHC and bone marrow SLN+

Z0011

randomize to ALND Observe suspended 12/04 at n=889 due to slow accrual and too few events SLN Observe www.acosog.org

Z0010 trial Survival by staining method Method H&E negative H&E positive (3945/5184) (1239/5184) IHC negative (3595) IHC positive (350) 5 year survival (95% CI) 95.6% 92.8% 95.8% 95.1% (95.0-96.3) (91.3-94.3) p=0.0002

(95.0-96.5) (92.7-97.5) p=0.53

Cote R et.al. ASCO 2010

NSABP B-32

Clinically Negative Axillary Nodes (n=5,611) Randomization GROUP 1 SLNB*



ALND A combined 1390 pts had H&E+ SLNs with f/u in 1389 pts GROUP 2 SLNB * Path. Pos.

SLN Path. Neg.

SLN ALND No ALND

Julian TB et.al. SABCS 2010

NSABP Protocol B-32 1390 pts with H&E+ SLN

Variable Category # pts size of metastasis micro (0.2-2 mm) macro (>2 mm) Unknown 312 422 626

Julian TB et.al. SABCS 2010

NSABP B-32

DFS by SLN status on

H&E

100 80 60 40 20 Patients Neg SN Pos SN (Micromets) Pos SN (Macromets) HR* (95% CI) 0.998 (0.765-1.302) 1.783 (1.480-2.150) P-value* 0.99

<0.001

0 0 1 2 3 4 5 Years after Randomization

* HR (95% CI) & p-value comparison with Neg SN

6 7

Julian TB et.al. SABCS 2010

8

NSABP B-32 OS by SLN status on H&E

100 80 60 40 20 Patients Neg SN Pos SN (Micromets) Pos SN (Macromets) HR* (95% CI) 0.788 (0.518-1.199) 2.387 (1.891-3.013) P-value* 0.27 <0.001

0 0 1 2 3 4 5 Years after Randomization

* HR (95% CI) & p-value comparison with Neg SN

6 7

Julian TB et.al. SABCS 2010

8

NSABP B-32 IHC study • 5611 accrued • 3989 (71%) pN0 by H&E – 2 mm slices – routine IHC prohibited • 3887 (97%) path • 3884 (99.9%) follow up • 95 mo median f/u • IHC sections at UVM – 0.5 and 1.0 mm deeper • 15.9% IHC+ – 11.1% ITC (N0i+) – 4.4% micromets (N1mi) – 0.4% macromets (N1) Weaver DL et.al. NEJM 2011; epub 1/19/11

5 year survival

NSABP B-32 Survival by IHC status

IHC negative n=3268 IHC positive n=616 OS DFS

95.8% 89.2% 94.6% 86.4%

p

0.03

0.02

DDFS

92.5

89.7% 0.04

Weaver DL et.al. NEJM 2011; epub 1/19/11

NSABP B-32 Multivariate hazard ratios

Variable IHC (+ vs -) Hormonal rx (+ vs -) T size (T2-3 vs T1) Death

1.40

p=0.02

0.53

p<0.001

1.32 p=0.06

Any event Distant disease

1.31

p=0.009

0.60

p<0.001

1.30

p=0.03

0.68

p=0.001

1.41

p<0.001

1.42

p=0.01

Weaver DL et.al. NEJM 2011; epub 1/19/11

First treatment Failure Local

NSABP B-32 Site of first treatment failure

IHC-negative

All patients n=3268 2.6% no ALND n=1660 2.6%

IHC-positive

All patients n=616 2.6% no ALND n=300 1.3%

Regional Distant

0.4% 2.9% 0.5% 3.2% 1.1% 3.7% 1.7% 3.3% Weaver DL et.al. NEJM 2011; epub 1/19/11

SLN 2010 Are we asking the wrong question?

We’ve been asking We should be asking • “which SLN+ patients don’t need ALND?” • “do

any

SLN+ patients need ALND?”

SLN 2010 Z0010-Z0011 trials (ACOSOG)

Z0010

cN0 and BCT SLN biopsy Bone marrow aspiration clinician/patient blinded to IHC and bone marrow SLN+

Z0011

randomize to ALND Observe suspended 12/04 at n=889 due to slow accrual and too few events SLN Observe www.acosog.org

SLN 2010 Z0011 schema Giuliano AE et.al. Ann Surg 2010;252:439

SLN 2010 Z0011 eligibility

Eligible

• clinical T1-2N0 breast cancer •

Nodal RT

Ineligible

• H&E-detected SLN metastases •

IHC-detected SLN metastases

• lumpectomy + whole breast RT •

Matted nodes

• adjuvant systemic therapy by choice •

3 or more involved SN

Giuliano AE et.al. Ann Surg 2010;252:439

SLN 2010 Z0011 systemic therapy Systemic therapy chemo hormonal chemo and/or hormonal SLN+/ALND 58% 46% 96% SLN+/no ALND 58% 47% 97% Giuliano AE et.al. Ann Surg 2010;252:439

SLN 2010 Z0011 locoregional recurrence

Recurrence @ 6.3 yrs median follow-up SLN+ ALND (n=388) SLN+ no ALND (n=425) local

3.6% 1.9%

regional node

0.5% 0.9%

local+regional

4.1% Additional positive nodes in 27% of ALND’s 2.8% p=0.47

Giuliano AE et.al. Ann Surg 2010;252:439

SLN 2010 Z0011 overall survival Giuliano AE et.al. JAMA 2011;305:569-75

SLN 2010 Z0011 survival

Survival @ 6.3 yrs median follow-up DFS SLN+ ALND (n=388)

82.2%

SLN+ no ALND (n=425)

83.8%

OS

91.9% 92.5% Giuliano AE et.al. ASCO 2010

SLN 2010 Z0011 overall survival • HR boundary for non inferiority = 1.3 • unadjusted HR 0.79

– 0.56-1.10

• adjusted HR 0.87

– 0.62-1.23 – adjusted for age, ER Giuliano AE et.al. JAMA 2011;305:569-75

SLN 2010 AMAROS trial: first 2000 patients Straver ME et.al. JCO 2010; 28:731-7

SLN 2010 AMAROS adjuvant rx SLN+ ALND n=300 SLN+ Axillary RT n=266 endocrine rx chemo rx 32% 35% 30% 39% chemo+endocrine rx breast/chest wall RT 47% 86% 46% 89% Straver ME et.al. JCO 2010; 28:731-7

SLN 2010 Conclusions • SLN metastases detected only by IHC are of marginal significance • this has significant implications for – pathologists – surgeons – medical oncologists – patients!

• should IHC staining of SLN be abandoned?

SLN 2010 Conclusions • in the absence of extensive axillary disease, SLN+ patients having BCT/ RT may not need ALND • this has significant implications for • • • • preop axillary staging by ultrasound and FNA: unnecessary?

intraoperative SLN assessment by pathology: irrelevant?

prediction of non-SLN status by nomograms: obsolete?

return to OR for ALND: historical interest only?

SLN 2010 ALND: the end of an era?

• IF ALND for SLN+ patients – does not change systemic therapy – does not reduce local recurrence – does not improve survival • THEN ALND for SLN+ patients should be done – to salvage local recurrence (a rare event) – not to prevent it

Low/Low risk

hormonal RCT SLN 2008 MINDACT trial EORTC 10041 (BIG 3-04) T1-3N0 breast cancer n = 6000 1) 70 gene profile 2) Adjuvant! Online

Discordant risk

(low/high or high/low)

High/High risk

chemo RCT +/- hormonal RCT Rx based on 70 gene profile Rx based on Adjuvant! Online www.mindact.org