1. 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 Fellows Institute Cincinnati 2011 No disclosures

2. SLN biopsy works

3. Kim T et.al. Cancer 2006;106:4-16 SLN 2010 69 validation studies in 8059 patients # ptsSLN foundSLN false-neg (SLN-/AX+) Accuracy (SLN correct/total) 805996%7%97%

4. SLN 2010 Results of 5 randomized trials Trial# ptsSLN foundSLN false- negative Accuracy EIO53299%9%97% B-32561197%10%97% ALMANAC83696%7%98% GIVOM74995%17%95% SNAC108894%5%98% 61-73% had SLN-only disease

5. No ALND Clinically Negative Axillary Nodes (n=5,611) NSABP B-32 GROUP 1 SLNB  ALND ALND Path. Neg. SLN GROUP 2 SLNB Randomization Path. Pos. SLN Krag, DN et.al. Lancet Oncology 2010;11:927-33 Will false-negative SLN procedures affect survival?

6. * 300 deaths triggered the definitive analysis * 309 reported as of 12/31/2009 Years After Entry % Surviving 02468 0 20 40 60 80 100 Trt N Deaths SNR+AD 1975 140 SNR 2011 169 HR=1.20 p=0.117 Data as of December 31, 2009 84.6% received systemic therapy NSABP B-32 OS: SLN negative (8 yr results) Krag, DN et.al. Lancet Oncology 2010;11:927-33

7. Years After Entry % Disease-Free 02468 0 20 40 60 80 100 TrtNDeaths SNR+AD1975315 SNR 2011336 HR=1.05 p=0.542 Data as of December 31, 2009 84.6% received systemic therapy NASBP B-32 DFS: SLN negative (8 yr results) Krag, DN et.al. Lancet Oncology 2010;11:927-33z

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

9. Van der Ploeg IMC et.al. EJSO 2008:34:1277-84 SLN 2010 False-negative = axillary LR # pts# axillary LR (%) median f/umedian time to axillary LR SLN-/no ALND 48 studies* 14,959 0.3% 34 mo20 mo SLN-/no ALND IEO RCT 167 1.2% 95 mo81 mo SLN+/no ALND 6 studies 583 0.5% 31 mo22 mo *all with >3 yrs followup

10. We’ve asked and answered the easiest questions

11. 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?

12. SLN 2010 What is the SLN? 1) a blue node 2) a hot node 3) a palpable node

13. 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

14. McMasters et.al.,JCO 2000;18:2560-2566 SLN 2010 Louisville (99 surgeons)

15. Cody HS et.al. Ann Surg Oncol 2001;8:13-19 SLN 2010 Finding the positive SLN (n=255)

16. Derossis et.al.JACS 2001;193:473-8 SLN 2010 Declining marginal benefit of dye (finding the positive SLN)

17. Clarke DH. Ann Surg Oncol 2004;11:211S-15S SLN 2010 Learning curve: ALMANAC Most failed and false-neg results occurred in the first procedure!

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

19. Wilke LG et.al. Ann Surg Oncol (suppl) 2005;12:S27 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)

20. SLN 2010 MSKCC morbidity Lymphedema at 5 yrs SLNB alone n=600 SLNB/ALND n=336 Subjective3%27% p<0.0001 Measured (>2 cm change) 5%16% p<0.0001 McLaughlin SA et.al. JCO 2008:26:5213-26

21. Temple LK, Ann Surg Oncol 2002;9:654-62 SLN 2010 MKCC sensory morbidity p < 0.001

22. There are still some areas of debate

23. SLN 2010 Non-axillary SLN: what to do?

24. SLN 2010 Internal mammary experience AuthorIMN imaged IMN found IMN positive IMN-only positive Van der Ent/2001 n=256 25%16%4%1.2% Estourgie/2003 n=691 22%19%3%1.3% Farrus/2004 n=120 17%12%1.6%0 Leidenius/2006 n=984 14%11%1.8%0.8% Madsen//2007 n=506 22%17%4%1% Heuts/2009 n=1008 20%14%3%0.9%

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

26. 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)

27. Sentinel node SLN before vs after chemo: cN0 MDACC 1994-2007 T1-3, cN0 n=3746 SLN foundSLN false-negative SLN before chemo n=3171 98.7%4.2% (23/542) 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.

28. Brogi E et.al. Ann Surg Oncol 2005;12:173-80 SLN 2010 Intraoperative assessment

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

30. Brogi E et.al. Ann Surg Oncol 2005;12:173-80 SLN 2010 Frozen vs RT-PCR Viale G et.al. Ann Surg 2008;247:136-42

31. Tan LK et.al. J Clin Oncol 2008; 26: 1803-9 SLN 2010 MSKCC pathology protocol 50  H&E and IHC 1 H&E and 1 IHC (cytokeratin AE1:AE3) stained section from each of two levels 50  apart

32. H&E-/IHC- IHC+ H&E+ p<0.001 Tan LK et.al. JCO 2008; 26: 1803-9 MSKCC micromet study DFS by method of staining

33. 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

34. Netherlands micromet study DFS by size of metastasis de Boer M et.al. NEJM 2009;361:653-63 N0 vs N0i+ or N1miN0 vs N0i+, N0 vs N1mi p<0.001 p<0.002

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

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

37. Park J et.al. Ann Surg 2007;245:462-8 SLN 2010 Selective ALND for SLN+ 1960 patients with positive SLN Nomogram score (median predicted likelihood of residual axillary disease) Axillary local recurrence ( at 26 mo) SLN+/no ALND (n=315) 15% of SLN+ 10%1.9% SLN+/ALND (n=1645) 85% of SLN+ 37%0.36% p=0.004

38. Pugliese MS. Ann Surg Oncol 2010;17:1063-68 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+ 4.2%0% (63% chemo, 5% ax RT) SLN+/ALND (n=95) 56% of SLN+ 8.1%0% (88% chemo, 2% ax RT)

39. Park J et.al. Ann Surg 2007;245:462-8 SLN 2010 Fewer ALND for SLN+ (FS negative or not done) p<0.001

40. SLN 2010 Patterns of ALND (NCDB) Bilomoria KY et.al. JCO 2009;27:2946-53 23% no ALND55% no ALND

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

42. SLN 2010 Outcome +/- ALND (NCDB) Axillary local recurrence 5 yr relative survival SLN micrometastases (<2 mm) SLN only (n=802) 0.4%99% SLN/ALND (n=2357) 0.2%98% SLN macrometastases (>2 mm) SLN only (n=5596) 1.0%90% SLN/ALND (n=22591) 1.1%89% Bilomoria KY et.al. JCO 2009;27:2946-53

43. 2010 annus mirabilis! 1) micromets on IHC? 2) micromets on H&E? 3) ALND for SLN+?

44. www.acosog.org ACOSOG Z0010-Z0011 clinician/patient blinded to IHC and bone marrow suspended 12/04 at n=889 due to slow accrual and too few events

45. Z0010 trial Survival by staining method MethodH&E negative (3945/5184) H&E positive (1239/5184) IHC negative (3595) IHC positive (350) 5 year survival (95% CI) 95.6% (95.0-96.3) 92.8% (91.3-94.3) p=0.0002 95.8% (95.0-96.5) 95.1% (92.7-97.5) p=0.53 Cote R et.al. ASCO 2010

46. No ALND Clinically Negative Axillary Nodes (n=5,611) NSABP B-32 GROUP 1 SLNB*  ALND ALND Path. Neg. SLN GROUP 2 SLNB * Randomization Path. Pos. SLN A combined 1390 pts had H&E+ SLNs with f/u in 1389 pts Julian TB et.al. SABCS 2010

47. NSABP Protocol B-32 1390 pts with H&E+ SLN VariableCategory# pts size of metastasis micro (0.2-2 mm)312 macro (>2 mm)422 Unknown626 Julian TB et.al. SABCS 2010

48. NSABP B-32 DFS by SLN status on H&E Patients HR* (95% CI)P-value* Neg SN Pos SN (Micromets)0.998 (0.765-1.302) 0.99 Pos SN (Macromets)1.783 (1.480-2.150)<0.001 * HR (95% CI) & p-value comparison with Neg SN Julian TB et.al. SABCS 2010

49. NSABP B-32 OS by SLN status on H&E Patients HR* (95% CI)P-value* Neg SN Pos SN (Micromets)0.788 (0.518-1.199) 0.27 Pos SN (Macromets)2.387 (1.891-3.013)<0.001 * HR (95% CI) & p-value comparison with Neg SN Julian TB et.al. SABCS 2010

50. 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

51. NSABP B-32 Survival by IHC status 5 year survival IHC negative n=3268 IHC positive n=616 p OS95.8%94.6%0.03 DFS89.2%86.4%0.02 DDFS92.589.7%0.04 Weaver DL et.al. NEJM 2011; epub 1/19/11

52. NSABP B-32 Multivariate hazard ratios VariableDeathAny eventDistant disease IHC (+ vs -) 1.40 p=0.02 1.31 p=0.009 1.30 p=0.03 Hormonal rx (+ vs -) 0.53 p<0.001 0.60 p<0.001 0.68 p=0.001 T size (T2-3 vs T1) 1.32 p=0.06 1.41 p<0.001 1.42 p=0.01 Weaver DL et.al. NEJM 2011; epub 1/19/11

53. NSABP B-32 Site of first treatment failure First treatment Failure IHC-negativeIHC-positive All patients n=3268 no ALND n=1660 All patients n=616 no ALND n=300 Local2.6% 1.3% Regional0.4%0.5%1.1%1.7% Distant2.9%3.2%3.7%3.3% Weaver DL et.al. NEJM 2011; epub 1/19/11

54. SLN 2010 Are we asking the wrong question? We’ve been asking “which SLN+ patients don’t need ALND?” We should be asking “do any SLN+ patients need ALND?”

55. www.acosog.org SLN 2010 Z0010-Z0011 trials (ACOSOG) clinician/patient blinded to IHC and bone marrow suspended 12/04 at n=889 due to slow accrual and too few events

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

57. SLN 2010 Z0011 eligibility Eligible clinical T1-2N0 breast cancer H&E-detected SLN metastases lumpectomy + whole breast RT adjuvant systemic therapy by choice Ineligible Nodal RT IHC-detected SLN metastases Matted nodes 3 or more involved SN Giuliano AE et.al. Ann Surg 2010;252:439

58. SLN 2010 Z0011 systemic therapy Systemic therapySLN+/ALNDSLN+/no ALND chemo58% hormonal46%47% chemo and/or hormonal 96%97% Giuliano AE et.al. Ann Surg 2010;252:439

59. SLN 2010 Z0011 locoregional recurrence Recurrence @ 6.3 yrs median follow-up SLN+ ALND (n=388) SLN+ no ALND (n=425) local3.6%1.9% regional node0.5%0.9% local+regional4.1%2.8% p=0.47 Giuliano AE et.al. Ann Surg 2010;252:439 Additional positive nodes in 27% of ALND’s

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

61. SLN 2010 Z0011 survival Survival @ 6.3 yrs median follow-up SLN+ ALND (n=388) SLN+ no ALND (n=425) DFS82.2%83.8% OS91.9%92.5% Giuliano AE et.al. ASCO 2010

62. 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

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

64. SLN 2010 AMAROS adjuvant rx SLN+ ALND n=300 SLN+ Axillary RT n=266 endocrine rx32%30% chemo rx35%39% chemo+endocrine rx47%46% breast/chest wall RT86%89% Straver ME et.al. JCO 2010; 28:731-7

65. 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?

66. 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?

67. 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

68. www.mindact.org SLN 2008 MINDACT trial EORTC 10041 (BIG 3-04) 1) 70 gene profile 2) Adjuvant! Online