Implications of NSABP B-32 and Loco-Regional Therapy Considerations After Neoadjuvant Chemotherapy Terry Mamounas, M.D., M.P.H, F.A.C.S. Professor of Surgery Northeastern Ohio Medical University Medical Director Aultman Cancer Center Radical Mast. Operable Breast Cancer N=179 Clinically Node-Negative Negative Total Mast. HR: 1.3 (9% CI.87-1.23; P=.72) NSABP B-4 Total Mast. + XRT 1 8 6 4 2 Overall Survival Global p=.68 Patients Deaths RM 362 29 TMR 32 274 TM 36 29 4% of pts in the RM group had + nodes Thus, only about 29 pts contribute to the comparison of RM with TM (about 14/group) 1 1 2 2 Years Fisher B: NEJM, 22 NSABP B-32 Schema NSABP B-32 Clinically Negative Axillary Nodes N=611 GROUP 1 Biopsy Axillary Dissection Stratification Age Clinical Tumor Size Type of Surgery Randomization GROUP 2 Biopsy* *Axillary node dissection only if the SN is positive Technical Results Identification Rate: 97% False Negative Rate: 9.7% Average number of SNs: 2.9 Factors significantly affecting ID rate: Age, Tumor Size and Tumor Location Factors significantly affecting FN rate: Type of Biopsy and Number of Removed SNs Krag D, et al: Lancet Oncol 27 4 B-32 SN Pos Clinically Negative Axillary Nodes GROUP 1 SN +AD SN Neg (SN+AD) Randomization Intraop cytology & postop HE SN pos + AD 829 pts FU 793 pts GROUP 2 SN Stratification Age Clinical Tumor Size Type of Surgery SN Neg (SN only) FU 1,97 pts 2,11 pts Krag D et al: ASCO 21 Abstr. LBA % Surviving 2 4 6 8 1 NSABP Protocol B-32 Overall Survival for SN Negative Patients Trt N Deaths SNR+AD 197 14 SNR 211 169 HR=1.2 p=.117 Data as of December 31, 29 2 4 6 8 Years After Entry * 3 deaths triggered the definitive analysis * 39 reported as of 12/31/29 Krag D et al: Lancet Oncol 21 Page 1 1
% Disease-Free 2 4 6 8 1 NSABP Protocol B-32 Disease-Free Survival for SN Negative Pts Trt N Events SNR+AD 197 31 SNR 211 336 HR=1. p=.42 Data as of December 31, 29 2 4 6 8 Years After Entry Krag D et al: Lancet Oncol 21 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. SNR better.2.4.6.8 1. 1.2 1.4 1.6 Hazard Ratio SNR+AD better Krag D et al: Lancet Oncol 21 NSABP B-32: Local and Regional Recurrences as First Events 9 NSABP B-32: Significantly Lower Morbidity Without vs. With ALND 1 Patients (%) 3. 2. 2. 1. 1.. 2.7 2.4 Local.3.2.3.1 Axillary Recurrence Type SNR + ALND (n = 197) SNR (n = 211) Extra-axillary axillary Patients (%) 3 3 2 2 1 1 P <.1 19 13 Shoulder Abduction Deficit 28 P <.1 17 Arm Volume Difference > % P <.1 31 8 Arm Numbness 13 SNR + ALND (n = 197) SNR (n = 211) P <.1 7 Arm Tingling Krag D et al: Lancet Oncol 21 Ashikaga T: J Surg Oncol 21 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. Krag D et al: Lancet Oncol 21 B-32 In Perspective Could the B-32 trial ever show more than 2% difference in overall survival? SNB + AND 287 pts 1,97 pts* 7 Pts Had Negative SN and Positive NSNs on AND *3 pts had no F/U ID Rate 97% 17 pts had no SNB 829 pts 793 pts Node-Positive SND + AND 2.6% Reg. Nodal Recurrence 8 vs. 14 SNB Alone 284 pts 2,11 pts About 7 Pts Positive NSNs and did not have AND Page 2 2
B-32 In Perspective Could the B-32 trial ever show more than 2% difference in overall survival? SNB + AND 287 pts 1,97 pts* 7 Pts Had Negative SN and Positive NSNs on AND *3 pts had no F/U ID Rate 97% 17 pts had no SNB 829 pts 793 pts Node-Positive SND + AND 2.6% Reg. Nodal Recurrence 8 vs. 14 SNB Alone 284 pts 1:4 Dilution of Any Real Benefit from ALND! 2,11 pts About 7 Pts Positive NSNs and did not have AND NSABP B-32: Occult Metastases Clinically Negative Axillary Nodes GROUP 1 Biopsy Axillary Dissection Randomization GROUP 2 Biopsy* *Axillary node dissection only if the SN is positive IHC and detailed pathologic examination of the SNs performed centrally and results were not disclosed Weaver D et al: N Engl J Med 211 14 NSABP B-32: Effect of Occult Metastases on Survival in Node-Negative Negative Breast Cancer NSABP B-32: Effect of Occult Metastases on Survival in Node-Negative Negative Breast Cancer 1.9% Weaver D et al: N Engl J Med 211 Weaver D et al: N Engl J Med 211 Individualizing Loco-Regional Therapy with Neoadjuvant Chemotherapy Achievements Loco-Regional Therapy Considerations After Neoadjuvant Chemotherapy Conversion of patients with inoperable tumors to operable candidates Conversion of mastectomy candidates to candidates for BCS Improvement in cosmesis by reducing the size of lumpectomy in BCS candidates with large tumors Page 3 3
Individualizing Loco-Regional Therapy with Neoadjuvant Chemotherapy Promises Reduction in the extent of axillary surgery by down-staging involved axillary nodes (SNB) Reduction in the extent of L-R XRT by down- staging primary tumors and axillary nodes Potential for eliminating some loco-regional therapy altogether (surgery or XRT) with the use of more active regimens and/or with appropriate patient selection with biomarkers Surgical Management of Axillary Nodes After NC NC down-stages axillary nodes in 2-4% of the patients Potential for decreasing the extent of axillary surgery with SNB 4 3 2 1 3 AC NSABP B-18 % Conversion From To 19 FEC EORTC 37 43 AT CMF AC TXT ECTO NSABP B-27 27* *Assuming 3% nodal down- staging with neoadjuvant AC SNB After NC Multi-Center Studies: NSABP B-27 (n=428) Identification Rate: 8% With blue dye: 78% With isotope + blue dye: 88-89% 89% False Negative Rate: 11% With blue dye: 14% With isotope + blue dye: 8.4% Clinically : 12.4% Clinically : 7.% P=.1 Mamounas EP: J Clin Oncol, 2 SNB After NC Meta-Analysis of Single-Institution and Multi-Center Studies 24 studies 1779 patients Identification Conclusion: Rates: 63-1% Pooled SNB is estimate: a reliable 89.6% tool for False planning Negative treatment Rates: -33% after NC Pooled estimate: 8.4% Kelly A et al: Acad Radiol 29 Author Shen, 26 Lee, 26 Newman, 27 SNB After NC: Single Institution Series Positive Axillary Nodes Before NC Stage # Pts (Node +) Success Rate ( %) FN Rate (%) Accurate T1-T4, T4, N1-N3N3 69(4) 93 2 No T1-T4, T4, N1 (Palpable and FNA (+) or > 1cm thick with loss of fat hilum on US and SUV > 2. Resectable T1-3, N1 (FNA (+) under US) 219 (124) 78 6 Yes 4 (28) 98 11 Yes All 328 (172) 84 11.6 Z171: SLNB + AND After NC T1-4 N1-2 invasive breast cancer (pretreatment axillary ultrasound with FNA or core biopsy documenting axillary metastases) REGISTER* Patients receive neoadjuvant chemotherapy (stratify patients by age, stage and number of cycles and type of chemotherapy) Target REGISTER* Accrual: pts SLN and ALND Page 4 4
SNB Before NC: Pros and Cons Helpful if the SN is negative Patients with large operable breast cancer have high likelihood of positive nodes (-7%) Does not take advantage of the downstaging effects of NC on nodes: 3-4% conversion from (+) to (-) Requires two surgical procedures SNB Before NC: Selection of Loco-Regional XRT? Breast XRT: Should be always given after lumpectomy Can We Use Tumor and Nodal Chest Wall and Regional XRT: Consider factors predicting local-regional failure after NC Response to NC in Order to Individualize the Use of L-R XRT? These factors may predict LR failure more accurately than the original pathologic nodal status before NC Combined Analysis of B-18/B-27 Independent Predictors of LRF Lumpectomy + XRT (189 Pts, 19 Events) Age (> years vs. < years) Clinical Nodal Status (+) vs. (-) Breast/Nodal Path Status Node(-)/No vs. Node(-)/ Node(+) vs. Node(-) / Mastectomy (17 Pts, 128 Events) Clinical Tumor Size (> cm vs. < cm) Clinical Nodal Status (+) vs. (-) Breast/Nodal Path Status Node(-)/No vs. Node(-)/ Node(+) vs. Node(-) / Mamounas et al: ASCO Breast 21, Abstr. 9 2 1 1 n=9 1. 1. 2 1-Year Cum. Incidence of LRF Lumpectomy Patients, > years n=348 1. 6. 8 No I B TR n=212. 6. 7 Clin. Clin. n=31 6. n=8 8. 7 No n=122 7. 7. 2 Mamounas et al: ASCO Breast 21, Abstr. 9 2 2 1 1. 7 6. 9 1-Year Cum. Incidence of LRF Lumpectomy Patients, < years n=13 n=376. 8. 3 No I B TR n=223 2. 3 1. Clin. Clin. n=7 1. 8 1 1. 4. 3 n=84 2. 4 No n=14 8. 7 1 3. 6 Mamounas et al: ASCO Breast 21, Abstr. 9 2 1 1 n=46 4. 3 2. 2 1-Year Cum. Incidence of LRF Mastectomy Patients, < cm Che st Wa l l 2. 3 4 No 2. 8 7. 3 n=21 Clin. Clin. n=178 n=183 n=37 8. 1 2. 7 No n=143 6. 4 1. 6 Mamounas et al: ASCO Breast 21, Abstr. 9 Page
2 2 1 1 6. 2 1-Year Cum. Incidence of LRF Mastectomy Patients, > cm C he st Wa l l 3. 2 8. 6 No 1. 7 1 2. 3 Clin. Clin. n=179 n=16 n=9 n=11 n=33 9. 2 n=128 4. 8 1 7. 6 No Mamounas et al: ASCO Breast 21, Abstr. 9 1-year probability (%) of being Local Failure Free 1-Year Probability of LRF 1 1 2 2 3 Nomogram for Prediction of 1-Year Rate of LRF After NC Lumpectomy + XRT 4 4 6 6 7 Age at Entry (Years) Age at Entry (Years) CNS pos, CNS pos,, No CNS pos,, CNS neg, CNS neg,, No CNS neg,, 1-Year 1-year probability Probability (%) of being Local Failure of LRF Free 1 1 2 2 3 Nomogram for Prediction of 1-Year Rate of LRF After NC Mastectomy CNS pos, CNS pos,, No CNS pos,, CNS neg, CNS neg,, No CNS neg,, 1 2 3 4 Clinical Tumor Size at Entry (cm) Clinical Tumor Size (cm) Summary/Conclusions SNB alone is the standard of care for staging the axilla in patients with negative SNB SNB alone appears reasonable for patients with occult mets, micromets or macromets (not identified intraoperatively or by routine H & E assessment) Following neoadjuvant chemotherapy loco-regional therapy can be tailored based on clinico-pathologic tumor response in the breast and axillary nodes This approach holds great promise as NC regimens (+ targeted biologics) become considerably more effective and as genomic and imaging technology allows for more accurate prediction and identification of pathologic complete responders 34 Page 6 6