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Implications of NSABP B-32 and Loco-Regional Therapy Considerations After Neoadjuvant Chemotherapy

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. NSABP B-04. Overall Survival. Operable Breast Cancer

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Implications of NSABP B-32 and Loco-Regional Therapy Considerations After Neoadjuvant Chemotherapy

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  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. NSABP B-04 Overall Survival Operable Breast Cancer N=1079 100 80 60 40 20 0 Global p=0.68 Clinically Node-Negative Radical Mast. Total Mast. + XRT Total Mast. Patients Deaths RM 362 259 TMR 352 274 TM 365 259 HR: 1.03 (95% CI 0.87-1.23; P=0.72) 0 5 10 15 20 25 • 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) Years Fisher B: NEJM, 2002

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

  4. NSABP B-32Technical 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 2007 4

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

  6. NSABP Protocol B-32 Overall Survival for SN Negative Patients 100 80 60 % Surviving 40 TrtNDeaths SNR+AD 1975 140 SNR 2011 169 HR=1.20 p=0.117 20 0 Data as of December 31, 2009 0 2 4 6 8 Years After Entry * 300 deaths triggered the definitive analysis *309 reported as of 12/31/2009 Krag D et al: Lancet Oncol 2010

  7. NSABP Protocol B-32 Disease-Free Survival for SN Negative Pts 100 80 60 % Disease-Free 40 TrtNEvents SNR+AD 1975 315 SNR 2011 336 HR=1.05 p=0.542 20 0 Data as of December 31, 2009 0 2 4 6 8 Years After Entry Krag D et al: Lancet Oncol 2010

  8. 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 Krag D et al: Lancet Oncol 2010

  9. NSABP B-32: Local and Regional Recurrences as First Events 9 2.7 3.0 2.4 2.5 SNR + ALND (n = 1975) SNR (n = 2011) 2.0 Patients (%) 1.5 1.0 0.3 0.3 0.5 0.25 0.1 0 Local Axillary Extra-axillary Recurrence Type Krag D et al: Lancet Oncol 2010

  10. NSABP B-32: Significantly Lower Morbidity Without vs. With ALND 10 P < .001 35 P < .001 SNR + ALND (n = 1975) 31 30 28 SNR (n = 2011) P < .001 25 19 20 P < .001 17 Patients (%) 15 13 13 10 8 7 5 0 Shoulder Abduction Deficit Arm Volume Difference > 5% Arm Numbness Arm Tingling Ashikaga T: J SurgOncol 2010

  11. 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 2010

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

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

  14. 14 NSABP B-32: Occult Metastases Clinically Negative Axillary Nodes Randomization GROUP 2 Sentinel Node Biopsy* GROUP 1 Sentinel Node Biopsy Axillary Dissection *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 2011

  15. NSABP B-32: Effect of Occult Metastases on Survival in Node-Negative Breast Cancer 15.9% 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 ChemotherapyAchievements • 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

  19. Individualizing Loco-Regional Therapy with Neoadjuvant ChemotherapyPromises • 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

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

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

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

  23. 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 Target Accrual: 550 pts

  25. SNB Before NC: Pros and Cons • Helpful if the SN is negative • 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 (-) • Requires two surgical procedures

  26. 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? • Breast XRT: Should be always given after lumpectomy • Chest 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 NC

  27. Combined Analysis of B-18/B-27Independent Predictors of LRF Mamounas et al: ASCO Breast 2010, Abstr. 90

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

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

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

  31. 10-Year Cum. Incidence of LRF Mastectomy Patients, > 5 cm n=128 Clin. Node (+) Clin. Node (-) n=179 n=95 n=33 n=16 n=11 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. Nomogram for Prediction of 10-Year Rate of LRF After NC Mastectomy 10-Year Probability of LRF Clinical Tumor Size at Entry (cm)

  34. 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

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