Treatment of the Axilla for Breast Cancer:

Treatment of the Axilla for Breast Cancer: V. Suzanne Klimberg, M.D., Ph.D. Courtney M Townsend, Jr. M.D. Distinguished Chair in General Surgery Chief of Surgical Oncology and Medical Director of the University of Texas Medical Branch Cancer Center

Objectives Debate Axillary Management in Breast Cancer Discuss What You Need to Know for Boards How Focusing on A Problem Can Make a Difference Residents & Fellows Can Make Big Contributions

What to Do with the Axilla?

Lymphedema

Incidence of Lymphedema ~400,000 Breast Cancer Survivors/Yr 3-5 Million with Lymphedema 1 in 5 women will Develop Varies with: Measurement Technique Length of Followup Time to Measurement Extent of Surgery Disipio Lancet Oncol 2013 Metaanalysis of 72 studies

SLN Concept

N Engl J Med. 1998 Oct 1;339(14):941-6. The sentinel node in breast cancer - a multicenter validation study. Krag D, Weaver D, Ashikaga T, Moffat F, Klimberg VS, Shriver C, Feldman S, Kusminsky R, Gadd M, Kuhn J, Harlow S, Beitsch P. Accuracy of SLNB was 97% (392 of 405) Sensitivity was 89 percent (101 of 114) Specificity of the method was 100 percent Positive predictive value was 100 percent Negative predictive value was 96 percent All of False Negatives Were in the UOQ

Subareolar SLN Injection Biopsy Intraoperative subareolar radioisotope injection for immediate SLNB Layeeque R, et al. Ann Surg. 2004 Subareolar versus peritumoral injection for location of the sentinel lymph node. Klimberg VS, Rubio IT, Henry R, Cowan C, Colvert M, Korourian S. Ann Surg. 1999 Jun;229(6):860-4;

Lymphedema Studies Study SLNB (#) ALND (#) Lymphedema SLNB (%) Lymphedema ALND (%) Schrenk 2000 35 35 0 17 Haid 2002 57 140 4 27 Swenson 2002 169 78 4 14 Blanchard 2003 683 91 6 34 Schijven 2003 180 213 1 7 Ronka 2005 43 40 13 77 Leidenius 2005 92 47 5 28 Mansel 2006 McLaughlin 2008 515 600 516 336 B32 2008 1975 8 14 5 5 13 16

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

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

Ann Surg. 2005 Jan;241(1):48-54. Prerandomization Surgical Training for the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial: a randomized phase III clinical trial to compare sentinel node resection to conventional axillary dissection in clinically nodenegative breast cancer. Harlow SP1, Krag DN, Julian TB, Ashikaga T, Weaver DL, Feldman SA, Klimberg VS, Kusminsky R, Moffat FL Jr, Noyes RD, Beitsch PD. 226 registered surgeons-site visit training by a core surgical trainer 187 completed training and approved to randomize patients 815 training (nontrial) cases demonstrated a technical success rate for ID SLN at 96.2% with a FNR of 6.7%. Protocol compliance of 98.6% for procedural fields, 95.5% for source documentation fields and 95.0% for data entry fields.

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

Ann Surg Oncol. 2016 Oct;23(11):3459-66. Troubleshooting Sentinel Lymph Node Biopsy in Breast Cancer Surgery James TA, Coffman AR, Chagpar AB, Boughey JC5, Klimberg VS, Morrow M, Giuliano AE, Harlow SP

What About a Micromet?

NCCN Guidelines Include Oncotype DX Testing in the Treatment-decision Pathway for Node-negative and Micrometastatic Disease Hormone receptor-positive, HER2-negative disease pt1, pt2, or pt3 and pn1mi > 0.5 cm, HR+, HER2 disease pt1, pt2, or pt3; pn0 and pn1mi ( 2 mm axillary node metastasis) Consider Oncotype DX No test Recurrence Score Result < 18 Recurrence Score Result 18-30 Recurrence Score Result 31 Adjuvant endocrine therapy ± adjuvant chemotherapy Adjuvant endocrine therapy Adjuvant endocrine therapy ± adjuvant chemotherapy Adjuvant endocrine therapy + adjuvant chemotherapy NCCN, National Comprehensive Cancer Network Adapted from NCCN Practice Guidelines in Oncology v.3.2013.

What About 1-2 Positive Nodes?

ACOSOG Z0011: A Randomized Trial of Axillary Node Dissection in Women with Clinical T1-2 N0 M0 Breast Cancer Who Have a Positive Sentinel Node. A. E. Giuliano, L. M. McCall, P. D. Beitsch, P. W. Whitworth, M. Morrow, P. W. Blumencranz, A. M. Leitch, S. Saha, K. Hunt, K. V. Ballman Clinically Node-Negative Pts who Had 1 or 2 Positive Nodes on SLNB by H&E Were Randomized to ALND or No Further Axillary Specific Treatment All Patients Had Lumpectomy and Intended XRT Adjuvant Systemic Therapy Was at Discretion 446 Pts Were Randomized to SNB Alone 445 to SNB + ALND J Clin Oncol 28:18s, 2010

Results of Randomized Trials: ALND Vs SLNB with SLNB+ ACOSOG Z11 Trial Closed to Accrual 12/04 with 900 of 1900 Accrued Poor Accrual Few Cancer Events

ACOSOG Z0011: A Randomized Trial of Axillary Node Dissection in Women with Clinical T1-2 N0 M0 Breast Cancer Who Have a Positive Sentinel Node. A. E. Giuliano, L. M. McCall, P. D. Beitsch, P. W. Whitworth, M. Morrow, P. W. Blumencranz, A. M. Leitch, S. Saha, K. Hunt, K. V. Ballman SLNB alone Had a Median of 2 LNs Removed Versus ALND With a Median of 17 LNs Removed 17.6% of ALND Had >3 + Nodes 5.0% of SLNB Pts had Negative Nodes (p < 0.001) Median F/U is 6.2 years. 5-year IBR after ALND was 3.7% Vs 2.1% for SLNB (p = 0.16) 5-year Nodal Recurrence after ALND was 0.6% Vs 1.3% (p = 0.44) 5-year OS SLNB + ALND - 91.9% SNB alone - 92.5% (p = 0.24) DFS 82.2% compared to 83.8% respectively (p = 0.13). J Clin Oncol 28:18s, 2010

ACOSOG Z-0011 Giuliano, A. E. et al. JAMA 2011;305:569-575 Copyright restrictions may apply.

Ann Surg. 2016 Sep;264(3):413-20. Locoregional Recurrence After SLN Dissection With or Without Axillary Dissection in Patients With SLN Metastases: Long-term Follow-up From the ACOSOG Z0011 Randomized Trial. Giuliano AE, Ballman K, McCall L, Beitsch P, Whitworth PW, Blumencranz P, Leitch AM, Saha S, Morrow M, Hunt KK. Median follow-up of 9.25 years No Difference in LR-free survival (P = 0.13). The Cumulative Incidence of Nodal Recurrences was 0.5% in the ALND arm and 1.5% in the SLNB alone arm (P = 0.28). 10-year cumulative LRR was 6.2% with ALND and 5.3% with SLNB alone (P = 0.36).

Controversies Completion ALND for Positive SLN Results in Increased Morbidity 40-50% of Pts Have No additional Mets ~8% Have 4 + Positive Nodes ALND May Provide Additional Prognostic Information Effect of Radiation Instead of Surgery Impact on Local Recurrence & Survival? Use Outside Confines of Existing Trials

Journal of the American College of Surgeons Available online 26 March 2015 Impact of the American College of Surgeons Oncology Group Z0011 Randomized Trial on the Number of Axillary Nodes Removed for Patients with Early-Stage Breast Cancer Presented at the Western Surgical Association 122nd Scientific Session, Indian Wells, CA, November 2014. Katharine Yao, MD, FACS Erik Liederbach, BS, Catherine Pesce, MD, Chi-Hsiung Wang, PhD, David J. Winchester, MD, FACS

Methods Using the National Cancer Data Base, Yao et al examined use of SNB alone in patients who did and did not fulfill Z0011 eligibility criteria from 1998 to 2011. Because the National Cancer Data Base does not specifically identify SNB vs ALND, categorized removal of 4 nodes as SNB only and 10 nodes as ALND

Results Of 74,309 lumpectomy patients who fulfilled Z0011 criteria; 17,630 (23.7%) had a 4 nodes removed, 15,619 (21.0%) had 5 to 9 nodes removed, 41,060 (55.3%) had 10 nodes removed.

Results Patients outside of Z0011 criteria also underwent SNB alone: 54% of patients with tumors >5 cm, 52.5% who received no radiation therapy or accelerated partial breast irradiation, 35.9% with clinically positive nodes, 22.3% who underwent mastectomy, 12.9% who had >3 tumor-positive nodes.

Can We Avoid Axilla after Neoadjuvant Chemotherapy?

What About After CTX? Neoadjuvant CTX Often Used in N+ Pts 40-70% Convert to pln- with CTX Use of SLNB is Limited by High FN Rate Kuerer Ann Surg 1999; Hennessy J Clin Oncol 2005;Dominici Cancer, 2010

ACOSOG Z1071 Hypothesized that SLNB is Accurate for Staging After NeoCTX SLNB Followed by ALND 40% Nodal pcr FNR 12.6% FNR 6.8% In Pts with Clip Retrieved in SLN Boughey JC JAMA 2013 and SABCS 2014 Poster P2-01-02

J Clin Oncol. 2016 Apr 1;34(10):1072-8 Improved Axillary Evaluation Following Neoadjuvant Therapy for Patients With Node- Positive Breast Cancer Using Selective Evaluation of Clipped Nodes: Implementation of Targeted Axillary Dissection Caudle AS, Yang WT, Krishnamurthy S, Mittendorf EA, Black DM, Gilcrease MZ, Bedrosian I, Hobbs BP, DeSnyder SM, Hwang RF, Adrada BE, Shaitelman SF, Chavez-MacGregor M, Smith BD, Candelaria RP, Babiera GV, Dogan BE, Santiago L, Hunt KK, Kuerer HM. Determine Whether Selective Localization and Removal of the Clipped Node Plus the SLNB Improves Accuracy of Axillary Evaluation

Eligibility Prospective MDACC Registry Biopsy Proven Nodal Metastases Clip Place in the Sampled Node Received NeoAdjuvant CTX

Staging US shows abnormal lymph nodes Prospective Registry of Breast Cancer Patients with Axillary Nodal Metastases Identified During Ultrasound Courtesy Caudle et al Needle Biopsy confirms metastases 1 Clip placed in sampled node 2 Surgery Axillary LNs removed with X-ray to identify the clipped node Clipped node pathology reported separately Enrollment Patient receives neoadjuvant therapy 1 Krishnamurthy et al. Cancer, 2002 2 NCCN Guidelines Version 3.2014

How does the evaluation of the clipped node compare to SLNB?

Evaluation of Patients Undergoing SLNB SLNB N= 123 Neoadjuvant therapy No ALND N= 16 Path Node Negative N= 41 (38%) Path Node Positive N= 66 (62%) SLN negative = 7/61 SLN not identified = 5 Clipped node and SLN negative N= 1/66 False Negative Rate SLNB Alone = 11.5% (95% CI 4.7-22 ) SLNB + Evaluation of Clipped Node = 1.5% (95% CI 0.04-8.2 )

Targeted Axillary Dissection Clipped node was NOT a SLN in 24% (30/123) Not influenced by the presence of residual nodal disease % Clipped node not SLN Residual nodal disease 24.3% No residual nodal disease 24.5% Must Remove Clipped Node & SLN

Prospective Targeted Axillary Dissection (TAD) 1-5 Days Before Surgery Day of Surgery Breast Imaging I 125 seed placed in marked node I 125 Seed Node containing I 125 seed selectively removed I 125 Seed Clip Clip Nuclear Medicine Radioisotope injection for SLND SLNs removed Remaining axillary nodes removed Caudle et al. JAMA-Surg. 2015. 150(2): 137-43

Fluoroscopic Intraoperative Node or Neoplasia Detection (FIND) Fiona Denham, MD & V. Suzanne Klimberg, MD, PhD Uses Fluoro to Find the Clip in the Node Quarter Dose of that Used for Line Placement

Can We Avoid SLNB?

34 Pts No SLNB 32 Pts SLNB No Significant Clinical or Pathologic Differences 17 Month (1-32) Follow Up No RR Negative Predictive Value of AUS for ID of Axillary Disease >2mm was 96.9%.

SOUND Trial: Sentinel Node Vs Observation After Axillary Ultra-souND Hypothesis Avoiding ALND Does Not Worsen Outcome of Pts with Small Breast Cancer Pre-Op Imaging of the Axilla Can Identify Pts with Clinically Relevant Nodal Burden Aims To Verify Whether SLNB Can Be Spared in the Presence of a Negative Preop Axillary Assessment The Decision on Adjuvant Medical Tx Can be Made on the Biology of the Tumor No AND Can Improve Pt s QOL

Lymphedema Studies Study SLNB (#) ALND (#) Lymphedema SLNB (%) Lymphedema ALND (%) Schrenk 2000 35 35 0 17 Haid 2002 57 140 4 27 JUST DO BETTER SURGERY Swenson 2002 169 78 4 14 Blanchard 2003 683 91 6 34 Schijven 2003 180 213 1 7 Ronka 2005 43 40 13 77 Leidenius 2005 92 47 5 28 Mansel 2006 McLaughlin 2008 515 600 516 336 B32 2008 1975 8 14 5 5 13 16

Intraoperative SLN Injection Biopsy Subareolar versus peritumoral injection for location of the sentinel lymph node. Klimberg VS, Rubio IT, Henry R, Cowan C, Colvert M, Korourian S. Ann Surg. 1999 Jun;229(6):860-4; Johnson CB, Boneti C, Korourian S, Adkins L, Klimberg VS. Ann Surg. 2011 Oct;254(4):612-8.

ARM: Axillary Reverse Mapping

ARM Concept

Axillary Vein ARM 2 Variations SLN

Axillary Vein Blue Arm Lymphatics

Axillary Vein Blue Node

Axillary Vein ARM Variations 3 SLN

Axillary Vein ARM Variations 4 SLN

Axillary Vein

Axillary Vein ARM 5 Variations SLN

Blue Arm Lymphatics

Axillary Vein 1 ARM 4 2 5 Variations 3 SLN

Split Mapping: Radionuclide in Breast and Blue Dye in Arm

Measured Outcomes Presence of Axillary Malignancy Identification of Blue ARM Lymphatics Relationship to SLN Safety of Leaving Blue Node Behind Axillary Recurrences Incidence of Postop Lymphedema

Lymphedema Evaluation Water volume displacement: Volumeter filled with water 10 cm Above the Elbow Displaced Volume Preoperatively 6 Month Intervals Asymmetrical Increase in Volume >20% from Baseline

Patients 654 patients; 57y.o. (+/-13) T1-64.1% T2-27% T3 8.9% In-Situ 9.4% Node (+) 28.7% N1-71.8% N2-20.2% N3-8% Died 27 pts LTF 21 pts Radiation 31.5%

Feasibility ARM Blue Lymphatic in Axilla SLNB 29.2% (138/472) ALND 71.8% (153/213)

Feasibility ARM Juxtaposed to SLN SLNB 7.8% (37/472)

Feasibility ARM Node Hot & Blue SLNB 3.8% (18/472) ALND 5.6% (12/213)

SAFETY Resected Crossover Node Malignancy (Hot + Blue) SLNB Blue Node 22% (4/18)

SAFETY Leaving Blue Nodes (Non-Concordant) Blue Node Not SLN ALND Blue Node 4.5% (2/44)

SAFETY Axillary Recurrence SLNB ALND RR (20m) 0.4% (2/429) 0.9% (2/213)

EFFECTIVE Lymphedema SLNB 0.8% (3/350) ALND 6.5% (10/154) TOTAL 2.5% (13/504)

ALND 33% LE @ 20 Mo. (n=127) ALND+ARM 6%LE @ 20 Mo. (n=129)

Reanastomose Afferent & Efferent Lymphatics

Anastomosis/Reapproximation BLUE ARM Transections Lymphedema Not Reanastomosed 54.2% (39/72) 12.8% (5/39) Reanastomosed 45.8% (33/72) 0% (0/33)

Simple Reapproximation of Surgically Disrupted Lymphatics Reestablishes Lymphatic Flow Via Lymphangiogenesis Juan Camilo Barreto-Andrade, YiHong Kaufmann, Chun- Yang Fan, Eric Siegel, Julia Aronson, V. Suzanne Klimberg 44 lymphatics in 22 animals were studied. At 5 weeks showed inconsistent recanalization in only 50% of cases. At 6 weeks & 9 weeks, lymphatic flow assessment and immunohistochemistry showed a successful rate of lymphatic recanalization in 90%. There was upregulated expression of D2-40 at the anastomotic site in the recanalized lymphatic tissue a marker of lymphogenesis.

Alliance Protocol A221702 : Axillary Reverse Mapping (ARM) A Prospective Trial to Study Rates of Lymphedema and Regional Recurrence after SLNB & SLNB Followed by ALND with and without ARM

Conclusions For Novice Dual Dye Gives Lowest False Negative Rate Subareolar Injection Avoids Shine Through and Overlap of the Axilla ARM Added to SLNB or ALND Results in Lowest Lymphedema Rates Reconnect any Lymphatics Residents & Students Can Do Research Put Pts on Clinical Trials!