Sentinel Lymph Node Dissection (SLND) for Breast Cancer

1. ACOSOG Z0011: A Randomized Trial of Axillary Node Dissection in Women with Clinical T1-2 N0 M0 Breast Cancer who have a Positive Sentinel Node Giuliano AE, McCall L, Beitsch PD, Whitworth PW, Blumencranz PW, Leitch AM, Saha S, Hunt K, Morrow M, Ballman KV

2. Sentinel Lymph Node Dissection (SLND) for Breast Cancer • SLND has replaced axillary lymph node dissection (ALND) for histopathologically node-negative women • Numerous studies have demonstrated its staging efficacy and safety • ALND remains the gold standard for node-positive women • ALND more morbidity than SLND

3. Contemporary Breast Cancer • Tumors are smaller than in past • Fewer node-positive patients • Sentinel node (SN) often only node involved (40-70%) • BCT common – tangential field irradiation treats much of axilla • Adjuvant systemic therapy usually given for node-positive women

4. Modern Randomized Trials of Axillary Treatment with BCT Ax RT vs. Obs ALND vs. Obs ALND vs. Ax RT Author Martelli Veronesi Louis-Sylvestre N 219 435 658 Median F/U 5 5.3 15 Axillary Recurrence 0 vs 1.8% 0.5% vs 1.5% 1% vs 3% No significant differences in survival Martelli G, Ann Surg 2005, 242:1; Louis-Sylvestre C, JCO 2004, 22:97; Veronesi U, Ann Oncol 2005, 16:383.

5. Hypothesis: SLND alone achieves similar locoregional control and survival as Level I and II ALND for H&E SN node-positive women.

6. ACOSOG Z0011 A randomized trial of axillary node dissection in women with clinical T1-2 N0 M0 breast cancer who have a positive SN 165 Investigators / 177 Institutions 50 investigators with 5 or more patients Target accrual 1900 patients (non-inferiority) Closed early

7. Eligibility Clinical T1 T2 N0 breast cancer H&E-detected metastases in SN (AJCC 5th edition) Lumpectomy with whole breast irradiation Adjuvant systemic therapy by choice Ineligibility Third field (nodal irradiation) or APBI Metastases in SN detected by IHC Matted nodes 3 or more involved SN Inclusion/Exclusion Criteria

8. Z0011 Study Design Schema

9. Study Population Schema 5/99–12/04

10. All analyses performed on both intent-to-treat and actual treatment received. No meaningful differences in findings. Intent-to-treat analysis reported.

11. Patient and Tumor Characteristics ALND (420 pts) SLND (436 pts) Age (median range) 56 (24-92) 54 (25-90) Clinical Stage T1 T2 67.9% 70.6% 32.1% 29.4% ER (+) (-) 83.0% 83.0% 17.0% 17.0% PR (+) (-) 67.7% 69.9.% 32.3% 30.1% LVI Yes No 40.6% 35.2% 59.4% 64.8%

12. Patientand Tumor Characteristics ALND (420 pts) SLND (436 pts) Modified Bloom-Richardson I 22.0% 25.6% II 48.9% 46.8% III 29.1% 27.5% Clinical Tumor Size (median cm.) 1.7 (0.4-7.0) 1.6 (0.0-5.0)

13. Adjuvant Systemic Therapy ALND SLND Chemotherapy 57.9% 58.0% Hormonal therapy 46.4% 46.6% Either/Both 96.0% 97.0% P = N.S.

14. Median Number of Lymph Nodes Removed

15. Size of SN Metastasis

16. Number of Positive Lymph Nodes

17. 106 (27.4%) patients treated with ALND had additional positive nodes removed beyond SN.

18. Locoregional Recurrences ALND (420 pts) SLND (436 pts) Recurrence Local (Breast) 15 (3.6%) 8 (1.8%) Regional (Axilla, Supraclavicular) 2 (0.5%) 4 (0.9%) Total Locoregional 17 (4.1%) 12 (2.8%) P = 0.11 Median follow-up = 6.3 years Regional recurrence seen in only 0.7% of the entire population

19. It is highly improbable that the 0.9% regional or 2.8% locoregional recurrence with SLND would significantly impact survival.

20. Locoregional Recurrence-Free Survival

21. Associations of Prognostic Variables with Locoregional Recurrence Univariable Analysis P value Multivariable Analysis P value Treatment Arm NS NS Age (< 50, > 50) 0.0421 0.0260 ER status 0.0002 NS PR status 0.0207 NS # Positive Total LN NS NS LVI present vs. absent NS NS Histologic Type NS NS SN Metastasis Size NS NS Tumor Size 0.0012 NS Adjuvant Systemic Therapy NS NS Modified Bloom-Richardson 0.0002 0.0258

22. ER/PR Status and 5-Year Locoregional Recurrence-Free Survival

23. Disease-Free Survival

24. Associations of Prognostic Variables with Disease-FreeSurvival Univariable Analysis P value Multivariable Analysis P value Treatment Arm NS NS Age (< 50, > 50) NS NS ER status 0.0003 0.007 PR status 0.031 NS # Positive Total LN 0.005 NS LVI present vs. absent NS NS Histologic Type NS NS SN Metastasis Size NS NS Tumor Size 0.002 NS Adjuvant Systemic Therapy 0.016 0.006 Modified Bloom Richardson NS NS

25. ER/PR Status and 5-Year Disease-Free Survival

26. Overall Survival

27. Associations of Prognostic Variables with Overall Survival Univariable Analysis P value Multivariable Analysis P value Treatment Arm NS NS Age (< 50, > 50) 0.002 0.006 ER status 0.012 0.013 PR status NS NS # Positive Total LN 0.044 NS LVI present vs. absent NS NS Histologic Type NS NS SN Metastasis Size NS NS Tumor Size 0.042 NS Adjuvant Systemic Therapy 0.020 0.025 Modified Bloom Richardson NS NS

28. ER/PR Status and 5-Year Overall Survival

29. Summary LocoregionalRecurrence-Free Survival • Locoregional recurrence in only 2.8% of SLND and 4.1% of ALND patients. • Only age (< 50) and higher Bloom-Richardson score were associated with locoregional recurrence by multivariable analysis. • Neither number of positive SN, size of SN metastasis, nor number of lymph nodes removed was associated with locoregional recurrence.

30. Summary Disease-Free and Overall Survival • No significant difference in DFS between patients treated with SLND (83.9%) or ALND (82.2%) • No significant difference in OS between patients treated with SLND (92.5%) or ALND (91.8%) • Only older age, ER-, and lack of adjuvant systemic therapy - not operation - were associated with worse OS by multivariable analysis.

31. Conclusion In this prospective randomized studySLND alone provided excellent locoregional control and survival comparable to completion ALND.

32. This study does not support the routine use of ALND in early nodal metastatic breast cancer. The role of this operation should be reconsidered.

33. Acknowledgments The authors thank our courageous patients as well as the ACOSOG staff and investigators for their contributions to this study.