Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York, NY 10065 10th International Congress on the Future of Breast Cancer Coronado, CA 6 August 2011 Implications of ACOSOG Z11 for Clinical Practice: Surgical Perspective Monica Morrow MD Chief, Breast Surgery Service Anne Burnett Windfohr Chair of Clinical Oncology Memorial Sloan-Kettering Cancer Center
Why Do Axillary Dissection? Staging Local Control Survival
Relapse-free Survival (%) Nodal Treatment and Survival NSABP B04 100 80 60 Women with Negative Nodes 40 Women with Positive Nodes 20 0 0 5 10 15 20 25 Fisher B, NEJM 2002;347:567 Years of Follow-up
Revisiting Axillary Dissection for SN Positive Patients Pro Smaller cancers, lower nodal disease burden # nodes NOT deciding factor for systemic Rx. Most patients get RT and systemic Rx. Molecular determinants of prognosis, predictors of treatment benefit available Con Local therapy does influence survival.
ACOSOG Z0011 A randomized trial of axillary node dissection in women with clinical T1-2 N0 M0 breast cancer who have a positive SN Principal Investigator: Armando E. Giuliano, MD 165 Investigators / 177 Institutions Giuliano A, JAMA 2011;305:589
Inclusion/Exclusion Criteria Eligibility Clinical T1 T2 N0 breast cancer H&E-detected metastases in SN (AJCC 5 th edition) Lumpectomy with whole breast irradiation Adjuvant systemic therapy by choice Ineligibility Third field (nodal), irradiation Metastases in SN detected by IHC only Matted nodes 3 or more involved SN
Z0011 Study Design Schema
Patient and Tumor Characteristics ALND n = 420 Intent-to-treat SLND n = 436 Median age 56 (24-92) 54 (25-90) Clinical T1 68% 71% ER+ 83% 83% PR+ 68% 70% LVI present 41% 36%
Patient and Tumor Characteristics Grade ALND n = 420 Intent-to-treat SLND n = 436 1 22% 26% 2 49% 47% 3 29% 28% Histology Ductal 83% 84% Lobular 7% 9% Other 11% 8% Giuliano A, Ann Surg 2010;252:426
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.
Median Number of Lymph Nodes Removed Giuliano ASA Z0011 040810 11
106 (27.4%) of patients treated with ALND had additional positive nodes removed beyond SN.
Number of Positive Lymph Nodes Intent-to-Treat Analysis Giuliano ASA Z0011 040810 13
Locoregional Recurrence Z11 Median F/u 6.3 yrs ALND n = 420 SN n = 436 Local 15 (3.6%) 8 (1.8%) Regional 2 (0.5%) 4 (0.9%) Total 17 (4.1%) 12 (2.8%) p = 0.11 Giuliano A, Ann Surg 2010;252:426
Survival Outcomes Z11 Median F/u 6.3 yrs % DFS % OS SN 83.9 (80.2-87.9%) 92.5 (90-95.1%) ALND 82.2 (78.3-86.3%) 91.8 (89.1-94.5%) HR 0.82 (0.58-1.17) 0.79 (.56-1.1) Adjusted HR* 0.88 (0.62-1.25) 0.87 (.62-1.2) Adjusted for age, adjuvant rx Giuliano A, JAMA 2011;305:589
Z11: Is it Practice Changing? Yes, but not for: Clinically N+ LABC Mastectomy PBI Neoadjuvant Therapy
Top 5 Things Critics Don t Like About Z11 5. Follow-up isn t long enough 4. Not enough ER negatives 3. Not enough young women 2. Failed Study didn t reach accrual goal
Time to Nodal Relapse Author Local Rx % ER+ Axillary Recurrence Median Time Fisher, B04 Mastectomy? 14.8 mo Greco BCT 75 30.6 mo Martelli BCT 92 33 mo Fisher B, NEJM 2002;347:567 Greco M, Ann Surg 2000;232:1 Martelli G, Ann Surg Oncol 2011;18:125-33
Multivariate Analysis of Regional Nodal Failure Nodal Factors Tumor Factors Rx Factors # Excised T size Nodal RT # Positive LVI Chemotherapy % Positive ER status ECE Margin status Patient Factors Metastasis size Grills IS, IJROBP 2003;56:658 n = 1500 Median F/u 8.1 yrs Rx: BCT, Axillary Dissection ± Nodal RT Age Maximum size nodal mets only significant predictor of regional recurrence.
Age and Z11 Regional Recurrence Age < 50 yrs Ax Diss SN n = 2 n = 1
Is Z11 a Failed Study? Planned accrual 1900, closed at 891 Slow accrual and low event rate Pre-defined analysis plan carried out Non-inferiority of SN by p =.008 Total LRR, DFS, OS all numerically favor SN group No suggestion of a power problem To reach the 10% LRR threshold suggested by EBCTCG, LRR in the remaining patients in the SN group would need to increase 12x.
Survival and Local Control EBCTCG Group 5yr LR 15yr Survival N-, BCS ± RT 16.1% 5.1% N+, BCS ± RT 30.1% 7.1% N+, M ± RT 17.1% 5.4% N-, M ± RT 4.0% -3.6% Z11 ± Ax Diss 0.4% NO CHANCE! Lancet 2005;366:2087 Giuliano A, JAMA 2011;305:589
Understanding Z11 Accepting the results of Z11 means recognizing that some patients will have positive nodes which are not removed. There is NO role for nomograms to predict the likelihood of additional positive nodes.
Lessons Learned from NSABP B04 Radical Mastectomy n = 362 Total Mastectomy n = 365 Median nodes removed 16 40% positive axillary nodes 18.5% delayed axillary dissection After mastectomy alone, only ½ of patients with involved nodes develop axillary first failure. Fisher B, NEJM 1985;312:674
Standard Breast Tangents Treat Some of the Axilla Axillary Level Treated to 95% Prescribed Dose I 79% II 51% III 49% Reznik J, IJROBP 2005;61:163-8
Effective Systemic Therapy Contributes to Local Control NSABP B13 ER neg NSABP B14 ER pos No Rx/Placebo 13.4% 14.7% CTX/Tam 2.6% 4.3% NSABP B31 HER2 + N9831 HER2+ CTX 2.8% 2.7% CTX + H 1.7% 1.5% Fisher B, JCO 1996;14:1982 Romand, NEJM 2005;353:1673 Fisher B, JNCI 1996;88:1529
Axillary Failure After No Surgery, Tangent RT + Systemic Rx Author n Median f/u (yrs) % Ax Recurrence Martelli 499 15 3.7* IBCSG 473 6.6 3.0** Veronesi 435 5.3 1.5 * T1 only ** RT 33% Martelli G, Ann Surg Oncol 2011;18:125 Rudenstam CM, JCO 2006;24:337 Veronesi U, Ann Oncol 2005;16:383
ACOSOG Z11 SN only positive node in 70% of cases. 0.9% regional recurrence at 6.3 years completely consistent with other published studies.
Why NOT do Axillary Dissection? Morbidity of Axillary Surgery n = 821 SN% ALND % p-value Wound Infection 3 8.0016 Axillary Paresthesia, 12 mo 9 39 <.0001 Lymphedema, 12 mo Patient Perceived 6 19 <.0001 Measured 6 11.0786 Lucci A, JCO 2007;25:3657
Clinical Implications In clinically node-negative patients undergoing BCT with macrometastases in the SN: - Systemic Rx decision made - ALND not necessary for local control - ALND does not contribute to survival
Implementing a Policy of Individualized Axillary Management T3 or N1 Any T,N + mastectomy Receiving neoadjuvant rx Preop documentation of nodal disease with US+FNA avoids SN biopsy. Frozen section to minimize reoperation No IHC for H+E negative nodes.
Implementing a Policy of Individualized Axillary Management T1 T2 N0 Undergoing BCT Identification of single abnormal axillary nodes with US + FNA does NOT change management. Cost effectiveness of US to identify extensive axillary disease in cn0 patients requires study. Frozen section of SN no longer routine. Patients 3 involved SN on final pathology returned to OR for axillary dissection.
# 1 Thing Critics Don t Like About Z11 Doesn t seem right To cut is to cure (and I get paid for doing it) I m all for progress, it s just change I don t like. Samuel Clemens