Sentinel Node Biopsy and Clinical Decision Making

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1 Sentinel Node Biopsy and Clinical Decision Making Monica Morrow, M.D. Chairman, Department of Surgical Oncology G. Willing Pepper Chair in Cancer Research

2 The Evolving Role of Axillary Dissection Therapy Prognosis Need for Adjuvant Rx Local Control 1900 s 1970 s 1980 s 1990 s

3 Re-Examining Axillary Dissection Increased frequency of small mammographically detected tumors Systemic therapy of N+ and N0 Cancers Neoadjuvant Chemotherapy

5 Results of SN Biopsy: Single Institution Trials Author n % SN identified % False negative Giuliano Borgstein Veronesi DeCicco Zervos Cox

6 Is SN Biopsy the Standard of Care? Can the results of single institution studies be generalized? What is an acceptable false negative rate? Long-term outcomes Local control Morbidity

7 NSABP B32 Clinical NO RANDOMIZE SN Biopsy SN Biopsy + Axillary Dissection SN - SN + No Further Surgery Axillary Dissection

8 ACOSOG Sentinel Node Study T 1 -T 2 Candidate for BCT SN Biopsy N+ N - Axillary Dissection No Axillary Dissection RT to Breast IHC + Adjuvant Rx SN + Marrow RT to Breast Adjuvant Rx

9 Comparison of NSABP B32 and ACOSOG Z10 ACOSOG Z10 NSABP B32 # Cases # Surgeons Technique Any combined Training cases +ALND Proctor, 5 cases + ALND Patients T 1 T 2, N 0 + BCT T 1 T 2 N 0, any surgery

10 Comparison of NSABP B32 and ACOSOG Z10 ACOSOG Z10 NSABP B32 SN ID 98.6% 97% SN positive 24% 26%

11 Factors Associated with SN Identification BMI p Age p Cases accrued p Not Significant Nodal status T size Tumor location Histology Biopsy Type

12 Results of SN Biopsy: Collaborative Studies No. of Technique (%) SN False - Author Patients Localization Identification Rate(%) Krag 443 R McMasters 806 Any Shivers 560 B&R Tafra 535 B&R Bergkvist 498 B&R NSABP 5210 B&R R - radioactivity B - blue dye

13 SN Biopsy Reliably Stages the Axilla % Nodal Metastases Mansel N = 1031 Veronesi N = 516 SN Biopsy 24.8% 35.5% Axillary Dissection 23.8% 32.3%

14 Local Control After SN Biopsy Alone * median Author n Mean Follow-up (months) no. Axillary Failures Roumen Shivers Dessureault Chung Hansen Loza Badgwell Veronesi Cody , * 31* Total 4,551 5 (0.001%)

15 Initial Results: ACOSOG Z10 n= axillary LRs (0.3%) at a median of 31 mo follow-up 3/16 1+SN, no ALND 1/16 3+ SN, ALND done 12/16 SN negative, no ALND Median to recurrence 16 mo ( mo)

16 Is SN Biopsy the standard of care? SN biopsy reliably identifies axillary nodal metastases with low morbidity. Long term local control rates after SN biopsy are excellent. SN biopsy is the procedure of choice for managing the clinically node negative axilla today.

17 Rationale for Axillary Surgery in DCIS Incomplete sampling Diagnosis by core bx DCIS has the ability to metastasize

18 How Common is Undiagnosed Invasive Cancer? Cause specific survival rates of 97% - 100% NOT compatible with high rates of invasive cancer Smaller mammographic DCIS seen today less likely to have undiagnosed invasion Pathologic sampling more extensive

19 DCIS Diagnosed by Core Biopsy: How Common is Sampling Error? Author # Patients % Invasive Kestin Rosenfeld Darling Cox Cox Morrow

20 Does DCIS Have The Capacity To Metastasize? Pendas Klauber-DeMore n=87 n=76 SN+ 5 (6%) 9 (12%) IHC only 3 7 Addl. + nodes 0 1/6 Invasion in primary 1 18 suspicious

21 What do IHC Positive Cells in DCIS Mean? Retrospective review 79 DCIS patients F/U > 10 years Axillary Dissection performed Nodes recut, IHC performed 4 IHC positive patients (5.1%) Outcome: 8/79 patients recurred, NONE with IHC+ Cox, Moffit

22 When Should Sentinel Node Biopsy Be Performed in DCIS Microinvasive carcinoma Metastases in 3% - 20% of cases DCIS treated by mastectomy opportunity lost if invasion found Done as a second procedure if invasion found after lumpectomy Prior biopsy does not interfere with mapping

23 Contraindications to SN Biopsy Locally advanced breast cancer Pregnancy and Lactation Prior axillary surgery

24 Is a Repeat SN Biopsy Feasible? Intra, et al n=18 100% SN identification 2/18 positive No axillary recurrence at 12.7 mo median Ann Surg Oncol 2005

25 Controversies Multicentricity Internal Mammary Nodes Neoadjuvant Therapy

26 SN Biopsy for Multicentric Cancer Original hypothesis: Unique drainage pathway for each cancer. Concordance studies indicate the majority of breast tumors drain via central collecting system. Reasonable to do a subareolar injection or separate peritumoral injections.

27 SN Biopsy for Multicentric Cancer Author Number of Cases % SLN identified % Sensitivity Kumar, et al Tousimis, et al Kumar, et al Ozmen, et al Fernandez, et al Jin Kim, et al Schrenk, et al Total

28 Internal Mammary Node Metastases 7070 Patients 22.4% I.M. node positive 4.9% I.M. node were only site of metastases Morrow and Foster, Arch Surg 1981

29 How Common are Isolated IM Metastases? Dupont, et al Vander Ent, et al ALMANAC 3/1273 3/256 5/ % 1.2% 0.4%

31 Nodal Response to Neoadjuvant Therapy? Tumor SN Non-SN

32 SN Biopsy After Neoadjuvant RX Studies Since 2002 % SN % False Author n Identified Negative Stearns Brady Miller Reitsamer Balch Vigario Piato Schwartz Kang Patel Shimazu

33 SN Biopsy After Neoadjuvant RX HIGHLY VARIABLE RESULTS DUE TO: SMALL NUMBERS 2/17 STUDIES > 50 PTS DIVERSE POPULATIONS T1 T4 N0, N+? CLASSIFICATION PALPABLE, ABNORMAL NODES

34 NSABP B27 T1C - T3, N0 or N1 Randomize AC x 4 Surgery AC x 4 Surgery Docetaxol x 4 AC x 4 Docetaxol x 4 Surgery

35 Accuracy of SN Biopsy NEOADJUVANT RX PRIMARY SURGERY NSABP B27 Metaanalysis, Studies n=428/2365 n=10,000 SN identified 85% 90% False negative 11% 8.4%

36 Relationship Between SN False Negative Rate and Response RESPONSE % FALSE NEGATIVE Clinical CR 8.7 Other 11.6 p=ns

37 Accuracy of SN Biopsy by Pathologic Response RESPONSE % ACCURACY CR 98.4 CCR, Residual tumor 96.0 PR/Stable 94.9 p=ns

38 Unresolved Problems Is Completion Axillary Dissection Necessary After a Positive SN Biopsy? Significance of Micrometastases

39 Management of the Positive SN Is Axillary Dissection Indicated? Small primary tumors Small metastatic deposits not seen intraop

40 Risk of Additional Metastases: T1b Cancer Author n % Cases Chu - 13 Wong Nos Viale* Van Zee *T1a+b

41 Risk of Additional Metastases by Size of Metastatic Deposit Author n Size % Cases Viale 116 <0.2 mm mm 16.9 Leidenius 39 <0.2 mm mm 34.3

42 Risk of Additional Metastases by Size/Detection Method: Micrometastases Author n Method % Cases Mignotte 44 IHC H&E 33.2 Kamath 26 IHC H&E 25.0

43 Multivariate Analyses of Factors Predictive of Involvement of Non-Sentinel Nodes n=4017 Patients, 10 Studies Tumor Size : 5/10 Tumor Grade : 0 Metastases Size: 7/10 # SN involved : 6/9 LVI : 4/10 # SN removed : 3/4

44 Axillary Dissection? Pros: Significant risk of additional nodal disease Small survival benefit for dissection cannot be excluded Information on the status of remaining nodes may help clarify decisions about adjuvant rx

45 Unresolved Questions Significance of micrometastases

46 Pathologic Analysis of Lymph Nodes Pre-SLND Bivalve lymph nodes Half of lymph node discarded Section from 1/2 lymph node evaluated with H&E Post-SLND Serial sections of sentinel node Evaluation with H&E and IHC

47 IHC Detected Micrometastasis

48 Micrometastases Present in 7% - 32% H & E negative nodes Heterogeneous - ranging from missed tumors greater than 2mm to single cells in subcapsular sinus Prognostic significance uncertain no benefit important in postmenopausal women DFS differences 2% - 14%

49 Significance of Micrometastases: Ludwig Trial Method: Retrospective analysis of a prospective trial 736 of 921 patients included Serial sections Single section from first level of node stained for AE-1 and CAM5-2 Median follow-up 12 yrs Cote, Lancet 1999

50 Detection of Micrometastases: Ludwig Trial H&E Serial Selection IHC 7% 20% Cote, Lancet 1999

51 Prognostic Significance of Micrometastases Immunohistochemistry Hematoxylin and eosin Disease Free Survival (%) P=.09 Occult node negative Occult node positive Disease Free Survival (%) P= Time Since Randomization (years) Time Since Randomization (years) Cote, Lancet 1999

52 John Wayne Prospective Study of Micrometastases n = 683 Stage I and II cancer 1/92-4/99 SN Step Sectioned, H & E stained If H & E IHC Stratified by SN met size Hansen et al

53 Results Group n Mean Age Definition Neg SN (-)( ) H&E & IHC IHC Micro Macro SN (+) IHC SN (+) H&E Mets < 2 mm SN (+) H&E Mets > 2 mm

54 Disease Free Survival Survival (%) yr DFS (%) Neg IHC Micro Macro Median F/U: 44 mos Time (mos) P=0.0001

55 IHC Should NOT be used routinely Decisions regarding Stage and the need for adjuvant therapy should be made on the basis of H & E staining CAP Consensus Phila Concensus

56 Conclusions SN Biopsy is the procedure of choice for managing the clinically node negative axilla Axillary dissection remains standard management for the SN+ patient Routine use of IHC awaits results of prospective trials

57 Sentinel Node Biopsy and Clinical Decision Making Monica Morrow, M.D. USCAP, February 12, 2005 References Kim T, Giuliano AE, Lyman GH. Lymphatic mapping and sentinel lymph node biopsy in early-stage breast carcinoma. Cancer 2005 [Epub ahead of print] Lyman GH, Giuliano AE, Somerfield MR, Benson AB 3 rd, Bodurka DC, Burnstein HJ, Cochran AJ, Cody HS 3 rd, Edge SB, Galper S, Hayman JA, Kim TY, Perkins CL, Podoloff DA, Sivasubramaniam VH, Turner RR, Wahl R, Weaver DL, Wolff AC, Winer EP; American Society of Clinical Oncology. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol 2005;23(30): Calhoun KE, Hansen NM, Turner RR, Giuliano AE. Nonsentinel node metastases in breast cancer patients with isolated tumor cells in the sentinel node: implications for completion axillary node dissection. Am J Surg 2005;190(4): Posther KE. McCall LM, Blumencranz PW, Burak WE Jr, Beitsch PD, Hansen NM, Morrow M, Wilke LG, Herndon JE 2 nd, Hunt KK, Giuliano AE. Sentinel node skills verification and surgeon performance: data from a multicenter clinical trial for earlystage breast cancer. Ann Surg 2005;242(4): Mamounas EP, Brown A, Anderson S, Smith R, Julian T, Miller B, Bear HD, Caldwell CB, Walker AP, Mikkelson WM, Stauffer JS, Robidoux A, Theoret H, Soran A, Fisher B, Wickerham DL, Wolmark N. Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2005;23(21):4808. Davidson NE, Morrow M, Kopan DB, Koerner FC. A 56-year old woman with breast cancer and isolated tumor cells in a sentinel node. N Eng J Med 2005;353: Cote RJ, Peterson HF, Chaiwun B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Gusterson B, Neville AM, for the International Breast Cancer Study Group. Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. The Lancet 1999;354:

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