Definitive Analysis of the Primary Outcomes ASCO Abstract LBA505 NSABP PROTOCOL B-32 A Randomized, Phase III Clinical Trial to Compare Sentinel Node Resection to Axillary Dissection in Clinically Node-Negative Breast Cancer Patients Definitive Analysis of the Primary Outcomes DN Krag, SJ Anderson, TB Julian, A Brown, SP Harlow, JP Costantino, T Ashikaga, D Weaver, EP Mamounas, N Wolmark

All trials reported higher survival in the AD group AD vs. no AD Randomized Trials Survival All trials reported higher survival in the AD group Orr RK. Ann Surg Oncol 1999;6(1):109-16

Few vs. Some vs. Many Survival >15 nodes 1-5 nodes All nodes negative Nodes Examined 1-5 6-10 11-15 16+  Krag et al. Ann Surg Oncol, 2003. 10 (10): p. 1-8.

Anatomy

Clinically Negative Axillary Nodes Intraop cytology & postop HE * 07/16/96 B-32 Stratification Age Clinical Tumor Size Type of Surgery Clinically Negative Axillary Nodes Randomization GROUP 1 SN +AD GROUP 2 SN Intraop cytology & postop HE SN Neg (SN+AD) SN Neg (SN only) SN Pos SN pos + AD FU FU 1,975 patients 2,011 patients * ##

SN Detection Methods Technetium sulfur colloid Blue dye B-32 Surgery Technetium sulfur colloid Blue dye Palpation (~2% cases)

Standardized Path Protocol B-32 Pathology Standardized Path Protocol Intraop- Cytology Postop- HE

Core Trainers Travel Map B-32 Training Seth Harlow Thomas Julian David Krag Fred Moffat Roberto Kusminsky Sheldon Feldman Suzanne Klimberg Peter Beitsch R. Dirk Noyes

Surgeon Performance 224 surgeons audited 94 items per case B-32 QC SN Surgery is complex - expect variation Surgeon Performance 224 surgeons audited 94 items per case averaged below one error per patient. Sets a standard for surgical trials Supports accuracy and conclusions of the B-32 trial.

B-32 Analysis Plan 3,989 - SN neg (71% of 5611) 99.9% - follow-up information 95 months - average time on study Primary endpoints OS, DFS, Regional Control Study powered to detect 2% difference OS

Evenly Balanced Entry Characteristics Associated Treatments Age Race Tumor size Surgical treatment plan Associated Treatments Radiation Therapy 85% & 84% Systemic Therapy 82%

B-32 OS NSABP Protocol B-32 Overall Survival for Sentinel Node Negative Patients 100 80 60 % Surviving 40 Trt N Deaths SNR+AD 1975 140 SNR 2011 169 HR=1.20 p=0.117 20 Data as of December 31, 2009 2 4 6 8 Years After Entry * 300 deaths triggered the definitive analysis * 309 reported as of 12/31/2009 12

Protocol B-32: Sentinel Negative Patients B-32 OS Protocol B-32: Sentinel Negative Patients Smoothed Hazard Ratio Plots for Mortality 10.0 5.0 2.0 HR 1.0 0.5 0.2 Data as of December 31, 2009 0.1 2 4 6 8 Time after Randomization (Year) 13

B-32 SN Negative Patients: Hazard Ratios of OS B-32 OS B-32 SN Negative Patients: Hazard Ratios of OS According to Stratification Variables Planned Mastectomy Planned Lumpectomy Tumor size >2 cm Tumor size ≤ 2 cm Patients 50 + at entry Patients < 50 at entry All patients with follow-up HR= 1.2 SNR better SNR+AD better 0.2 0.6 1.0 1.4 1.8 2.2 2.6 Hazard Ratio

B-32 DFS NSABP Protocol B-32 Disease-Free Survival for Sentinel Node Negative Patients 100 80 60 % Disease-Free 40 Trt N Deaths SNR+AD 1975 315 SNR 2011 336 HR=1.05 p=0.542 20 Data as of December 31, 2009 2 4 6 8 Years After Entry

B-32 SN Negative Patients: Hazard Ratios of DFS B-32 DFS B-32 SN Negative Patients: Hazard Ratios of DFS According to Stratification Variables Planned Mastectomy Planned Lumpectomy Tumor size >2 cm Tumor size ≤ 2 cm Patients 50 + at entry Patients < 50 at entry All patients with follow-up HR= 1.05 SNR better SNR+AD better 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Hazard Ratio

B-32 Hazard Ratios Between Groups B-32 DFS B-32 Hazard Ratios Between Groups According to Site of Treatment Failure Dead, NED 2nd cancers Opposite Breast Cancers Distant Recurrences Local Regional Recurrences All events HR= 1.05 SNR better SNR+AD better 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Hazard Ratio

Local and Regional Recurrences B-32 RR Local and Regional Recurrences as First Events Group 1 Group 2 Local 54 (2.7%) 49 (2.4%) Axillary 2 (0.1%) 8 (0.3%) Extra-axillary 5 (0.25% 6 (0.3%)

Residual Morbidity at End of Follow-up B-32 Morbidity Residual Morbidity at End of Follow-up Lower in SN group Not nonexistent Group 1 SN + AD Group 2 SN Shoulder abduction deficit 19% 13% Arm volume difference >5% 28% 17% Arm numbness 31% 8% Arm tingling 7% Ashikaga et al JSO in press All differences p<0.001

Quality of Life Sub-Study 789 SN-negative patients Questionnaires: Weeks 1 & 2-3. q6 months through 3 years. AD > SN Ipsilateral arm and breast symptoms p≤0.002 all Restricted work and social activity Impaired QOL From 1 – 3 years <15% of either group reported moderate or greater severity Arm morbidity was greater with AD than SN, but lower than expected even for AD. Land et al, JCO, in press

NSABP B-32 Conclusion No significant differences were observed OS, DFS, or Regional Control Morbidity decreased When the SN is negative, SN surgery alone with no further AD is appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes.