1. 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

2. Operable Breast Cancer N=1079 ClinicallyNode-Negative RadicalMast. NSABP B-04 TotalMast. TotalMast.+XRT 100 80 80 60 60 40 40 20 20 0 Years 0 5 10 15 20 25 Patients Deaths Patients Deaths RM 362 259 TMR 352 274 TM 365 259 Global p=0.68 Overall Survival Fisher B: NEJM, 2002 40% of pts in the RM group had + nodes 40% of pts in the RM group had + nodes Thus, only about 290 pts contribute to the comparison of RM with TM (about 145/group) Thus, only about 290 pts contribute to the comparison of RM with TM (about 145/group) HR: 1.03 (95% CI 0.87-1.23; P=0.72)

3. Clinically Negative Axillary Nodes N=5611 GROUP 1 Sentinel Node Biopsy Axillary Dissection GROUP 2 Sentinel Node Biopsy* Randomization Stratification Stratification AgeAge Clinical Tumor SizeClinical Tumor Size Type of SurgeryType of Surgery *Axillary node dissection only if the SN is positive NSABP B-32 Schema

4. NSABP B-32 Technical Results Krag D, et al: Lancet Oncol 2007 Identification Rate: 97%Identification Rate: 97% False Negative Rate:9.7%False Negative Rate:9.7% Average number of SNs: 2.9Average number of SNs: 2.9 Factors significantly affecting ID rate:Factors significantly affecting ID rate: –Age, Tumor Size and Tumor Location Factors significantly affecting FN rate:Factors significantly affecting FN rate: –Type of Biopsy and Number of Removed SNs 4

5. Clinically Negative Axillary Nodes GROUP 1 SN +AD SN Neg (SN only) Stratification Stratification AgeAge Clinical Tumor SizeClinical Tumor Size Type of SurgeryType of Surgery B-32 SN pos + AD SN Pos SN Neg (SN+AD) Intraop cytology & postop HE FU FU 1,975 pts 2,011 pts Randomization Krag D et al: ASCO 2010 Abstr. LBA 505 829 pts 793 pts GROUP 2 SN

6. * 300 deaths triggered the definitive analysis * 309 reported as of 12/31/2009 NSABP Protocol B-32 Years After Entry % Surviving 02468 0 20 40 60 80 100 Trt N Deaths Trt N Deaths SNR+AD1975 140 SNR 2011 169 HR=1.20 p=0.117 SNR 2011 169 HR=1.20 p=0.117 Overall Survival for SN Negative Patients Data as of December 31, 2009 Krag D et al: Lancet Oncol 2010

7. Years After Entry % Disease-Free 02468 0 20 40 60 80 100 NSABP Protocol B-32 Disease-Free Survival for SN Negative Pts Trt N Events Trt N Events SNR+AD1975315 SNR 2011 336 HR=1.05 p=0.542 SNR 2011 336 HR=1.05 p=0.542 Data as of December 31, 2009 Krag D et al: Lancet Oncol 2010

8. B-32 Hazard Ratios Between Groups According to Site of Treatment Failure Hazard Ratio 0.20.40.60.81.01.21.41.6 All events HR= 1.05 Local Regional Recurrences Distant Recurrences Opposite Breast Cancers 2nd cancers Dead, NED SNR+AD better SNR better Krag D et al: Lancet Oncol 2010

9. NSABP B-32: Local and Regional Recurrences as First Events 0 0.5 1.0 1.5 2.0 2.5 3.0 LocalAxillaryExtra-axillary Patients (%) Recurrence Type 2.72.4 0.10.3 0.250.3 SNR + ALND (n = 1975) SNR (n = 2011) 9 Krag D et al: Lancet Oncol 2010

10. NSABP B-32: Significantly Lower Morbidity Without vs. With ALND 0 5 10 15 25 30 35 Patients (%) SNR + ALND (n = 1975) SNR (n = 2011) ShoulderAbductionDeficit1913 Arm Volume Difference > 5% 2817 137 ArmTinglingArmNumbness318 20 P <.001 10 Ashikaga T: J Surg Oncol 2010

11. B-32: Conclusion No significant differences were observedNo significant differences were observed OS, DFS, or Regional Control Morbidity decreasedMorbidity 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 2010

12. B-32 In Perspective Could the B-32 trial ever show more than 2% difference in overall survival?Could the B-32 trial ever show more than 2% difference in overall survival? SNB + AND 2807 pts SNB Alone 2804 pts 2,011 pts Neg SN 1,975 pts* Neg SN *3 pts had no F/U 829 pts 793 pts Node-Positive SND + AND ID Rate 97% 157 pts had no SNB 75 Pts Had Negative SN and Positive NSNs on AND About 75 Pts Positive NSNs and did not have AND 2.6% Reg. Nodal Recurrence 8 vs. 14

13. B-32 In Perspective Could the B-32 trial ever show more than 2% difference in overall survival?Could the B-32 trial ever show more than 2% difference in overall survival? SNB + AND 2807 pts SNB Alone 2804 pts 2,011 pts Neg SN 1,975 pts* Neg SN *3 pts had no F/U 829 pts 793 pts Node-Positive SND + AND ID Rate 97% 157 pts had no SNB 75 Pts Had Negative SN and Positive NSNs on AND About 75 Pts Positive NSNs and did not have AND 2.6% Reg. Nodal Recurrence 8 vs. 14 1:40 Dilution of Any Real Benefit from ALND!

14. Clinically Negative Axillary Nodes GROUP 1 Sentinel Node Biopsy Axillary Dissection GROUP 2 Sentinel Node Biopsy* Randomization *Axillary node dissection only if the SN is positive NSABP B-32: Occult Metastases IHC and detailed pathologic examination of the SNs performed centrally and results were not disclosed 14 Weaver D et al: N Engl J Med 2011

15. 15.9% NSABP B-32: Effect of Occult Metastases on Survival in Node-Negative Breast Cancer Weaver D et al: N Engl J Med 2011

16. NSABP B-32: Effect of Occult Metastases on Survival in Node-Negative Breast Cancer Weaver D et al: N Engl J Med 2011

17. Loco-Regional Therapy Considerations After Neoadjuvant Chemotherapy

18. Individualizing Loco-Regional Therapy with Neoadjuvant Chemotherapy Achievements Conversion of patients with inoperable tumors to operable candidatesConversion of patients with inoperable tumors to operable candidates Conversion of mastectomy candidates to candidates for BCSConversion of mastectomy candidates to candidates for BCS Improvement in cosmesis by reducing the size of lumpectomy in BCS candidates with large tumorsImprovement in cosmesis by reducing the size of lumpectomy in BCS candidates with large tumors

19. 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 axillary surgery by down-staging involved axillary nodes (SNB) Reduction in the extent of L-R XRT by down- staging primary tumors and axillary nodesReduction 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 biomarkersPotential 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

20. Surgical Management of Axillary Nodes After NC NC down-stages axillary nodes in 20-40% of the patientsNC down-stages axillary nodes in 20-40% of the patients Potential for decreasing the extent of axillary surgery with SNBPotential for decreasing the extent of axillary surgery with SNB AC NSABP B-18 40 40 30 30 20 20 10 10 0 % Conversion From Node (+) To Node (-) AT  CMF ECTO 30 37 FECEORTC 19 AC  TXT NSABP B-27* 43 *Assuming 30% nodal down- staging with neoadjuvant AC with neoadjuvant AC

21. Identification Rate: 85%Identification Rate: 85% With blue dye: 78%With blue dye: 78% With isotope + blue dye: 88-89%With isotope + blue dye: 88-89% False Negative Rate: 11%False Negative Rate: 11% With blue dye: 14%With blue dye: 14% With isotope + blue dye: 8.4%With isotope + blue dye: 8.4% SNB After NC Multi-Center Studies: NSABP B-27 (n=428) Mamounas EP: J Clin Oncol, 2005 Clinically Node (-): 12.4% Clinically Node (+): 7.0% P=0.51

22. SNB After NC Meta-Analysis of Single-Institution and Multi-Center Studies 24 studies24 studies 1779 patients1779 patients Identification Rates: 63-100%Identification Rates: 63-100% –Pooled estimate: 89.6% False Negative Rates: 0-33%False Negative Rates: 0-33% –Pooled estimate: 8.4% Conclusion: SNB is a reliable tool for planning treatment after NC Kelly A et al: Acad Radiol 2009

23. AuthorStage # Pts (Node +) Success Rate ( %) Rate ( %) FN Rate (%)Accurate Shen, 2006 T1-T4, N1-N3 69(40)9325 No No Lee, 2006 Lee, 2006 T1-T4, N1 (Palpable and FNA (+) or > 1cm thick with loss of fat hilum on US and SUV > 2.5 219 (124) 786 Yes Yes Newman, 2007 Newman, 2007Resectable T1-3, N1 (FNA (+) under US) 40 (28) 9811 Yes Yes All 328 (172) 8411.6 SNB After NC: Single Institution Series Positive Axillary Nodes Before NC

24. Z1071: 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 ) ↓ REGISTER * ↓ SLN and ALND TargetAccrual: 550 pts

25. Helpful if the SN is negativeHelpful if the SN is negative Patients with large operable breast cancer have high likelihood of positive nodes (50-70%)Patients with large operable breast cancer have high likelihood of positive nodes (50-70%) Does not take advantage of the downstaging effects of NC on nodes: 30-40% conversion from (+) to (-)Does not take advantage of the downstaging effects of NC on nodes: 30-40% conversion from (+) to (-) Requires two surgical proceduresRequires two surgical procedures SNB Before NC : Pros and Cons

26. Breast XRT: Should be always given after lumpectomyBreast XRT: Should be always given after lumpectomy Chest Wall and Regional XRT: Consider factors predicting local-regional failure after NCChest Wall and Regional XRT: Consider factors predicting local-regional failure after NC These factors may predict LR failure more accurately than the original pathologic nodal status before NCThese factors may predict LR failure more accurately than the original pathologic nodal status before NC Can We Use Tumor and Nodal Response to NC in Order to Individualize the Use of L-R XRT? SNB Before NC: Selection of Loco-Regional XRT?

27. Combined Analysis of B-18/B-27 Independent Predictors of LRF Lumpectomy + XRT (1890 Pts, 190 Events) Mastectomy (1070 Pts, 128 Events) Age (>50 years vs. 50 years vs. <50 years) Clinical Tumor Size (>5 cm vs. 5 cm vs. <5 cm) Clinical Nodal Status (+) vs. (-) Clinical Nodal Status (+) vs. (-) Breast/Nodal Path Status Node(-)/No pCR vs. Node(-)/pCR Node(+) vs. Node(-) /pCR Breast/Nodal Path Status Node(-)/No pCR vs. Node(-)/pCR Node(+) vs. Node(-) /pCR Mamounas et al: ASCO Breast 2010, Abstr. 90

28. 10-Year Cum. Incidence of LRF Lumpectomy Patients, >50 years n=31 n=212 n=58 n=122 n=348 n=90 Clin. Node (-) Clin. Node (+) Mamounas et al: ASCO Breast 2010, Abstr. 90

29. 10-Year Cum. Incidence of LRF Lumpectomy Patients, <50 years n=57 n=223 n=84 n=154 n=376 n=135 Clin. Node (-) Clin. Node (+) Mamounas et al: ASCO Breast 2010, Abstr. 90

30. 10-Year Cum. Incidence of LRF Mastectomy Patients, < 5 cm n=21 n=183 n=37 n=143 n=178 n=46 Clin. Node (-) Clin. Node (+) Mamounas et al: ASCO Breast 2010, Abstr. 90

31. 10-Year Cum. Incidence of LRF Mastectomy Patients, > 5 cm n=11 n=179 n=33 n=128 n=95 n=16 Clin. Node (-) Clin. Node (+) Mamounas et al: ASCO Breast 2010, Abstr. 90

32. Nomogram for Prediction of 10-Year Rate of LRF After NC Lumpectomy + XRT 10-Year Probability of LRF Age at Entry (Years)

33. Mastectomy Clinical Tumor Size at Entry (cm) Nomogram for Prediction of 10-Year Rate of LRF After NC 10-Year Probability of LRF

34. SNB alone is the standard of care for staging the axilla in patients with negative SNBSNB 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)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 nodesFollowing 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 respondersThis 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 Summary/Conclusions 34