1. Management of the Axilla in Patients Receiving Neoadjuvant Chemotherapy (neoCTX) for Breast Cancer Lisa A. Newman, M.D., M.P.H., F.A.C.S. Professor of Surgery Director, Breast Care Center University of Michigan Ann Arbor, MI

2. CTX Effect on Primary Tumor Expanding BCS Eligibility: Neoadjuvant Systemic Therapy

3. Preop vs Postop CTX: Randomized Trials StudyStgF/U BCSLR after BCS Overall Survival PrePostPrePostPrePost Institut Curie 2-366 m82%77%24%18%86%78% Royal Mars 1-348 m89%78%3%4%80% NSABP B18 1-3108 m68%60%10.7%7.6%69%70%

4. Surgical Staging of the Axilla Axillary Lymph Node Dissection Morbidity: Lymphedema, Numbness, Shoulder dysfunction Lymphatic Mapping & SLN Bx Alternative surgical staging strategy; minimizes risks of axillary surgery without compromising staging/treatment Goal: Replicate pathway of cancer cells from primary tumor to initial draining axillary lymph node(s)

5. Is SLN Bx Compatible with Neoadjuvant CTX Protocols? Should it be performed pre-; post-; or pre- and post-CTX? What happens to intramammary lymphatics as the primary breast tumor enlarges? Does chemotherapy have a uniform effect on all axillary nodal metastases? Does chemotherapy alter lymphatic drainage patterns?

6. SLN A CCURACY IN T2/T3 T UMORS What happens to intramammary lymphatics as the primary breast tumor enlarges? Are SLN non-identification and false negative rates higher in cases of bulky breast tumors?

7. CTX E FFECT ON A XILLARY M ETASTASES Inferential Evidence: Decreased rates of node-positive disease in pts treated with neoadjuvant CTX NSABP B-18 Direct Evidence: Studies of pts with node-pos disease (documented by sono-guided FNA Bx) treated with neoadjuvant CTX:  23-33% converted to node-negative status on post-CTX axillary lymph node dissection Newman et al, Ann Surg Onc 2002 Rouzier et al, JCO 2002 Kuerer et al, Ann Surg 1999

8. SLN B X A FTER N EOADJUVANT CTX StudyNIDFNMets Limited to SLN Breslin 20005185%12%40% Nason 20001587%33%NR Haid 20013388%0%50% Tafra 20012993%0%NR Julian 20023491%0%42% Miller 20023586%0%44% Brady 20021493%0%60% Piato 20034298%17%0% Balch 20033297%5%56% Schwartz 200321100%9%64% Reitsamer 20033087%7%53% Mamounas 200542885%11%50% Tanaka 20067090%5%42%

9. SLN B X P RIOR TO N EOADJUVANT CTX StudyN Pre-CTXPost-CTX SLN ID SLN + ALND performed ALND neg (%) Zirngibl 2002 1593%43%Only SLN+100% Sabel 2003 24100%42%Only SLN+30% Olilla 2003 22100%45%All pts 12 SLN-neg pts: 100% 10 SLN-pos pts: 60%

10. A DVANTAGES OF P RE -neoCTX VS. P OST -neoCTX SLN B X Following neoCTXBefore neoCTX Pro More data on results of SLN Bx performed after neoadjuvant CTX delivered Surgical sequence consistent with conventional neoadjuvant regimen Significance of nodal status better understood when axillary staging performed at diagnosis Preferred by many medical and radiation oncologists More surgical experience with SLN Bx in the pre-CTX setting Con False negative rates not yet optimized -range, 0-40% Significant learning curve ? Unnecessary ALND’s -metastatic disease limited to the excised SLN in 30-50% -CTX sterilizes 25-30% node- pos pts Requires additional surgery

11. U NIVERSITY OF M ICHIGAN N EO CTX P ROGRAM Comprehensive pre- and post- Neoadjuvant CTX axillary evaluation Baseline axillary ultrasound –With sono-guided FNA-Bx of any suspicious nodes Baseline SLN Bx in sono-neg pts After completion of neoCTX: –Pre-CTX node-neg pts → → No further axillary surgery –Pre-CTX node-pos pts → → SLN Bx + cALND

12. Rationale for SLN Bx after Negative Axillary Ultrasound: Risk of False Negative Imaging University of Michigan Growney et al, SSO 2009 –121 node-positive cases –Nodal mets documented by sono FNA in 88 (73%) and by SLN biopsy in 33 (27%) –Follow-up SLN necessary for accurate staging in ultrasound-negative cases

13. UM Approach to NeoCTX and Axillary Staging –Pts presenting with node-neg disease –Pts presenting with node-pos disease, downstaged to pN-0 –Pts presenting with node-pos disease that is chemoresistant Pre- and post-CTX staging allows stratification of pts into 3 distinct categories

14. Is it necessary to document the pathologic axillary status prior to delivery of neoadjuvant chemotherapy?

15. Operable Breast Cancer Stratification Age Age Clinical Tumor Size Clinical Tumor Size Clinical Nodal Status Clinical Nodal Status Surgery AC x 4 Surgery NSABP B-18: Patterns of Locoregional Failure AC x 4 Tamoxifen X 5 years for pts > 50 after completion of chemo Fisher B. et al: JCO 1997, JCO 1998; Wolmark N. et al: JNCI 2001 Neoadjuvant vs. Adjuvant AC –Stages I-III –Lumpectomy patients received breast XRT –Mastectomy patients received no chest wall or regional XRT

16. NSABP B-18: P REDICTORS OF LRF B-18 Data suggest that post-CTX nodal status is reliable indicator of pts likely to benefit from locoregional or postmastectomy XRT However: -Small sample size of post-CTX node-negative cases -Unknown: LRF rates among pts that started out pathologically node-negative compared to those that were downstaged to node-negativity

17. UM Neoadjuvant CTX Experience N= 161 neoadjuvant chemotherapy cases Median age at diagnosis49 years Mean tumor size at presentation 45.0 mm Median follow-up 38.1 months Relapse rate at median follow-up 21.7% –35 patients –17 Local Recurrences –28 Distant Recurrences Kilbride et al, Ann Surg Onc 2008

18. Outcome by Axillary Lymph Node Response Lymph Node Response n Any Relapse LocoReg Recurrence Distant Recurrence Node-Negative at Presentation 37 (23%) 13.5%8.1% Downstaged to Node-Negative 36 (23%) 19.4% 5.6%13.9% Persistently Positive 86 (54%) 25.6% 14.0%22.1% P value 0.13 0.210.05

19. Use of regional radiation (PMRT or breast + nodal fields) in downstaged group 12.5% 3.6% p=0.33

20. UM Approach to NeoCTX and Axillary Staging Pre- and post-CTX staging allows stratification of pts into 3 distinct categories –Pts presenting with node-neg disease –Pts presenting as node-pos, downstaged to pN-0 –Pts presenting as node-pos disease, chemoresistant Sequential use of lymphatic mapping offers promise of minimizing number of cases subjected to ALND

21. UM: 54 Cases of Node-Pos Breast Cancer Undergoing SLN Bx & Completion ALND after Neoadjuvant CTX Newman E et al Ann Surg Onc 2007 Non- identification of post-CTX SLN in 1/54 cases (2%) The Future: Abandon completion ALND in cases with a neg post-CTX SLN

22. ACOSOG Z1071 Study Schema Phase II Study Evaluating the Role of Sentinel Lymph Node Surgery and Axillary Lymph Node Dissection Following Preoperative Chemotherapy in Women with Node Positive Breast Cancer Accrual Target: 550 patients

23. Summary Neoadjuvant chemotherapy (neoCTX) improves eligibility for breast-conserving surgery Optimal strategy for integrating lymphatic mapping and neoadjuvant CTX remains undefined –Accuracy of sentinel lymph node biopsy not yet optimally-defined when performed after neoCTX –SLN biopsy prior to neoCTX requires additional surgical procedure and anesthetic exposure Combination of pre- and post- neoCTX axillary staging provides maximal information regarding CTX response and is important for planning XRT

24. University of Michigan Health Center MUCHAS GRACIAS POR SU ATENCION!!!!