Surgical Issues in Neoadjuvant Chemotherapy

14 th Bossche Mamma Congress Ruwenbergstraat 7 5271 AG Sint Michielsgestel June 14, 2016 Surgical Issues in Neoadjuvant Chemotherapy Tari A. King MD FACS Chief, Breast Surgery Dana Farber/Brigham and Women s Cancer Center Associate Division Chief for Breast Surgery Brigham and Women s Hospital Associate Professor of Surgery Harvard Medical School

Accepted Facts Neoadjuvant Therapy No survival advantage or disadvantage In breast pathologic response rate correlates with both DFS and OS Allows down-staging of disease large tumors and BCT in select patients reduces need for axillary node dissection Requires a multi-disciplinary approach.

Neoadjuvant Therapy and Survival ~1500pts, AC ~2300 pts, AC/T Rastogi P et al. J Clin Oncol 2008;26:778-785

OS by response to neoadjuvant tx TNBC vs non-tnbc Adapted from Liedtke C et al. JCO 2008

Neoadjuvant Therapy and BCT Trial %BCT Chemo first % BCT Surgery first Royal Marsden 89 78 Institut Curie 82 77 NSABP B18 67 60 EORTC 37 21 Tumor shrinkage 79% pts (36% ccr and 43% cpr)

Neoadjuvant Chemotherapy and BCT Fisher B et al. J Clin Oncol 1997;15:2483-2493

LRR after Neoadjuvant therapy LRR not different in patients downstaged to BCT No differences in LRR after NAC by surgery type Mieog J et al. Br J Surg 2007;94:1189-1200 Mamounas E et al. J Clin Oncol 2012;30:3960-3966

Where are we now? King T and Morrow M. Nat Rev Clin Oncol 2015;12:335-343

CALGB 40603 Randomized phase II trial, addition of carboplatin and/or bevacizumab to paclitaxel in TNBC In breast pcr: 60% with addition of carbo 219 (54%) BCS candidates 59% with addition of bev increased to 68% 185 (46%) not BCS candidates 78 (42%) converted to BCS eligible 31% chose mastectomy 53 (68%) chose BCS 48 (91%) completed BCS Sikov W et al. J Clin Oncol 2015;33:13-21 Golshan M et al. Ann Surg 2015;262:434-439

Where do we go from here? pcr BCS

Surgical Challenges Neoadjuvant Therapy Need accurate imaging tools for quantifying response Need a standard method for monitoring response Consider differences in response by subtype

How Do We Know What to Resect? THIS? OR THIS?

Residual Imaging Tumor Size Compared to Path Tumor Size Imaging Modality Sensitivity Specificity Accuracy Clinical breast exam 49-50% 49-50% 54% Mammography 79-81% 79-81% 32% Ultrasound 89-90% 30-33% 60% MRI* 86-92% 60-86% 90% * Varies by tumor subtype and definition of pcr Adapted from Dialani et al. Ann Surg Oncol March 2015

MRI as a predictor of pcr TBCRC 017 Multicenter, retrospective study, pooled data 8 NCI centers 746pts, 2002-2011 Overall, pcr rates 24% (defined as no invasive ca or DCIS) TN: 37% Her2 positive: 38% (78% received trastuzamab) De Los Santos JF et al, Cancer, 2013

Breast Imaging in Neoadjuvant Patients A Practical Approach CLINICAL T1,T2 N0 Mammogram /US pre- and post-treatment MRI pre- and posttreatment ONLY if downstaging to BCT Clip placed in breast tumor No routine axillary US CLINICAL T3,T4 N0 Mammogram/US pre- and post-treatment MRI pre- and posttreatment ONLY if downstaging to BCT Clip placed in breast tumor Routine axillary US No metastatic work-up Metastatic workup pretreatment

Approach to Lumpectomy After Neoadjuvant Chemotherapy Remove any suspicious clinical or radiologic findings Generous sample of normal breast tissue It is NOT necessary to remove the entire volume of tissue initially occupied by tumor

Challenges with Neoadjuvant Therapy Pattern of Response negative margins?

Guidelines for Re-excision after Neoadjuvant Chemotherapy In the setting of BCT and neoadjuvant chemotherapy, if viable tumor is present throughout the specimen even if it does not extend to the margin, a further re-excision should be considered. American College of Radiology, the American College of Surgeons, the College of American Pathology, and the Society of Surgical Oncology

Margins After Neoadjuvant Therapy Consensus Statement Does Not Apply! When margins are negative surgeons need to use the description of the response/residual disease both qualitatively and quantitatively to determine need for re-excision negative margins?

Neoadjuvant Chemotherapy Surgical Management of the Breast Evaluating the extent of residual disease remains a problem Resection and detailed pathology review are often the only way to determine suitability for BCT Persistent finding of scattered, viable tumor in resection specimens should prompt consideration of re-excision vs mastectomy

Axillary Management Neoadjuvant Chemotherapy NAC downstages axilla ~ 40% of patients (tumor subtype specific) Potential to consider SLNB after NAC avoid ALND Should management dependent on pretreatment clinical nodal stage? Clinically node negative Clinically node positive

Axillary Node Downstaging Neoadjuvant Chemotherapy NSABP B18 Surgery first (n = 743) Chemo first (n = 735) Overall node + 57% 41% 1-3 nodes + 30% 24% 4-9 nodes + 17% 12% > 10 nodes + 10% 4% p < 0.001 Can we do SLN biopsy after NAC and avoid ALND? Fisher B, J Clin Oncol 1997;15:2483

SNB Before Neoadjuvant Therapy Arguments in Favor Information on the status of SLN can be obtained without the confounding effects of neoadjuvant therapy This may provide an advantage regarding: Further surgical management of the axilla Selection of optimal local-regional XRT Limited information on axillary recurrence rates with SLN after NAC

SNB Before Neoadjuvant Therapy Disadvantages Requires two surgical procedures Does not take advantage of the potential downstaging effects of neoadjuvant therapy on lymph nodes Commits all patients with pre-treatment positive nodes to ALND Uncertain prognostic value of negative nodes after NAC if the SLN was the only positive node and was removed

Sentinel Lymph Node Biopsy Neoadjuvant Therapy Clinically node negative; before or after? + + + + + + + After treatment + + Identification rate? + False neg rate?

SLN Biopsy Before or After NAC clinically node negative SLN Identification rate False-negative rate BEFORE McMasters et al (2000) 86% and 90% 5.8 and11.8% ALMANAC trial (2006) 96.1% 6.7% NSABP B32 (2007) 97.2% 9.8% Kim et al* (2006) 96% (41-100%) 7.3% (0-29%) AFTER NSABP B27 (2005) 85% 10.7% Hunt et al (2009) 97.4% 5.9% Xing et al**(2006) 90% (72-100%) 12% (0-33%) Kelly et al***(2009) 89.6% (95%CI 86.0-92.3) 8.4 (95%CI 6.4-10.9) single agent vs dual agent *Metanalysis 69 trials, 8059 pts; ** metaanalysis 21 trials, 1273 pts; ***metaanalysis 24 trials, 1799 pts

SLN Biopsy After Neoadjuvant Chemotherapy MDACC 1994-2007, T1-3, cn0, n = 3746pts SLN found SLN false negative SLN before chemo n = 3171 98.7% 4.2% (23/542) SLN after chemo n = 575 97.4% (p = 0.02) 5.9% (5/84) (p = 0.48) No difference in LRR (median f/u 47 mos) Hunt KK, Ann Surg 2009;250:558

Neoadjuvant Chemotherapy Decreases Axillary Dissection MDACC 1994-2007, T1-3, cn0, n = 3746pts % Node Positive SN first Chemo first P T1 19.0 12.7 0.2 T2 36.5 20.5 <.0001 T3 51.4 30.4 0.04 No difference in LRR (median f/u 47 mos) Hunt KK, Ann Surg 2009;250:558

Predictors of LRR after NAC pre- vs post-treatment nodal status NSABP B-18 (AC)/B-27 (AC-T) MVA: Predictors of LRR combined dataset at 10yrs Variable HR p Age 50 yrs vs < 50yrs 0.78 (0.63-0.98) 0.03 Clin. Tumor Size > 5 cm vs 5cm 1.51 (1.19-1.91) <0.001 Clin. Node (+) vs. Clin. Node (-) 1.61 (1.28-2.02) <0.001 ypnode(-)/no breast pcr vs. ypnode(-)/breast pcr ypnode(+) vs. ypnode(-)/breast pcr 1.55 (1.01-2.39) 2.71 (1.79-4.09) <0.0001 Mamounas E et al JCO 2012

LRF by Path Nodal Status and pcr B-18/B-27 : cn0 Lumpectomy pts >= 50yrs < 50yrs Low rates of regional recurrence all patients irrespective of path nodal and pcr status Mamounas E et al JCO 2012

LRF by Path Nodal Status and pcr B-18/B-27 : cn0 Mastectomy pts No PMRT Allowed T< 5cm T > 5cm Low rates regional recurrence all groups; increased CW recurrence node + after tx Mamounas E et al JCO 2012

Sentinel Lymph Node Biopsy Neoadjuvant Therapy A Practical Approach Clinically node negative SLN biopsy after NAC Intraoperative Frozen Section of SLN calnd for failed mapping calnd for any positive LN including micrometastatic disease Radiation tx decisions made on final node status and pcr status

Sentinel Lymph Node Biopsy Neoadjuvant Therapy Clinically node positive pt that converts to cn0? + + + + + + + After treatment + + + Identification rate? False neg rate?

MSKCC Neoadjuvant Therapy N = 245 cn0 and N1 Surgical Database Clinical Stage I-III breast cancer, enrollment 11/2013-7/2015 245/440 pts had completed surgical therapy % pcr breast and axilla* N =133 cn1 % pcr axilla ALL 74 30 65 (133) 49 ER+/HER 2-7 (80) 9 12 (52) 23 ER+/HER2+ 33 (66) 50 20 (27) 74 ER-/HER2+ 17 (27) 63 16 (18) 89 ER-/HER2-17 (72) 24 17 (36) 47 *No residual invasive or in situ disease in breast and axilla; includes patients that were initially cn0

ACOSOG Z1071 Eligible T0-T4, N1-2, M0 Biopsy Proven Nodal disease n = 663 cn1 SN ID rate 95% 649 SN ALND 2 SN identified n = 525, 79% Failed to meet primary endpoint FNR 10% FNR 12.6% (9.9, 16.1) Boughey JC, JAMA 2013

ACOSOG Z1071 cn1 patients How do we translate these findings in clinical practice??? FNR by Number of SN # SN Removed 1 2 3 % of Cases 12% 24% 47% False Negative Rate 32% 21.1% 9.1% p=.007 Boughey JC, JAMA 2013

SLN Biopsy After Neoadjuvant Therapy cn1 convert cn0 ACOSOG Z1071 SENTINA SN FNAC N 649 592(cN+)* 153 Mapping Dual recommended (79%) Technetium required Pre-op biopsy? Yes Not required (biopsy =25%) Nodal pcr 41% 52% ypn0 (?) 35% IR 92.7% 80.1% 87.6% FNR (Overall) 12.6% 14.2% 8.4% 1 SLN 31.5% 24.3% 18.2% 2 SLN 21.1% 18.5% 4.9% 3SLN 9.1% 7.3% Technetium required, IHC *1737 patients enrolled in 4 arm multicenter trial. 592 ARM C were cn+ to cn0 Yes

SLN After Neoadjuvant Chemotherapy # of SN ACOSOG Z1071 N=649 cn+ convert to cn0 False Negative Rate (%) SENTINA N=592 SN-FNAC N=153 GANEA 2 N=270 1 32 24 18.2 23 2 21 19 4.9-3 9 7-12 Consistent unacceptable FNR unless 3 SN removed Residual disease resistant to treatment? No data on LRR in this setting Do know importance of path node status in predicting LRF in patients that start out cn+ implications for RT

Pre- vs post-treatment nodal status impact on LRR cn+ ypn+ LLR >25% cn+ ypn- no breast pcr cn- ypn- no breast pcr cn+ ypn- breast pcr cn- ypn- breast pcr Updated Analysis NSABP B-18 (AC)/B-27 (AC-T) Mamounas E et al JCO 2012

SLN biopsy after NAC cn1 convert to cn0 suggestions to minimize the FNR Dual agent mapping Normal exam after chemotherapy Remove 3 SN Include IHC detected disease as node positive Leave a clip at time of biopsy and localize for SLN

Inclusion of micromets (<0.2mm) in the definition of residual nodal dz after neoadj tx reduces the pcr rate and improves the accuracy of SLN 2014 SABC

Placement of a clip + identification of the clip during SLN and removal at least 2 SLN reduces FNR

Targeted Axillary Dissection Calculated the ability of the clipped node +/- SLN to reflect the status of the nodal basin in all-comers undergoing NAC Clipped node n=191 pts; 120 path node +, pcr 37% FNR 4.2% (95%CI 1.4-9.5) SLN n=118; 74 path node+, pcr 37% FNR 10.1% (95%CI 4.2-19.8) SLN + clipped node n=118, 74 path node+, pcr 37% FNR 1.4% (95%CI 0.03-7.3) Not a study restricted to cn1 pts that converted to cn0 after therapy Median number SLN removed 2.7 (<3 SLN) so the FNR of the SLN procedure alone not optimized in this analysis.

Sentinel Lymph Node Biopsy Neoadjuvant Therapy A Practical Approach Clinically node positive converts to node neg SLN biopsy after NAC w/ dual mapping agents Remove at least 3 SLN, Intraoperative Frozen Section of all SLN calnd for failed mapping fewer than 3 SLN any positive LN including micrometastatic disease/itcs (unless on trial)

69 th Annual Society of Surgical Oncology Cancer Symposium Boston, MA March 3 rd, 2016 How Often Does Neoadjuvant Chemotherapy Avoid Axillary Dissection in Patients with Histologically Confirmed Nodal Metastases: Results of a Prospective Study Anita Mamtani, MD, Andrea V. Barrio, MD, Tari A. King, MD, George Plitas, MD, Kimberly J. Van Zee, MD, Melissa Pilewskie, MD, Mahmoud B. El-Tamer, MD, Mary L. Gemignani, MD, Alexandra S. Heerdt, MD, Lisa M. Sclafani, MD, Virgilio Sacchini, MD, Hiram S. Cody III, MD, Sujata Patil, PhD, and Monica Morrow, MD Breast Service, Department of Surgery Memorial Sloan Kettering Cancer Center New York, NY

Objectives Determine the frequency with which ALND is avoided after NAC in biopsy-proven N+ patients Identify patient populations likely to benefit from this approach

Patient Population Clinical stage II III breast cancer Receiving NAC 11/2013 11/2015 n = 534 Biopsy-proven N+ n = 195

Results Stage II-III, biopsy-proven N+ n = 195 ct4 or cn2/n3 n = 40 (21%) Downstaging to SLNB possible n = 155 (79%) ALND n = 40

Results Stage II-III, biopsy-proven N+ n = 195 Pre-neoadjuvant ct4 or cn2/n3 n = 40 Downstaging to SLNB possible n = 155 Post-neoadjuvant ALND n = 40 cn+: Not eligible for SLNB n = 23 (15%) cn0: Eligible for SLNB n = 132 (85%) SLNB deferred intraoperatively n = 4 SLNB n = 128

SLNB: Technical Details n = 128 Technical Factors n (%) SLN identified 125 (98%) # SLN removed 0 (failed mapping) 1 or 2 3 3 (2%) 15 (12%) 110 (86%) Median # SLN removed 4.0

SLNB: Outcomes n = 128 SLNB attempted n = 128 3 SLN retrieved underwent n = 110 SLNB ALND avoided in 62 of 128 (48%) of patients who ypn+ n = 48 ypn0 n = 62 ALND n = 48 No ALND n = 62

Nodal pcr by Receptor Status Receptor Status n % All 96 / 195 49% ER+/HER2-15 / 73 21% ER-/HER2-26 / 55 47% ER+/HER2+ 26 / 37 70% ER-/HER2+ 29 / 30 97% p < 0.0001

Summary Of 195 biopsy-proven N+ patients, 132 (68%) were eligible for SLNB after NAC 3 SLN retrieved in 86% of cases Study # SLN retrieved, median 3 SLN, % SENTINA (Arm C, n = 592) 2 34% Z1071 (N1 arm, n = 651) 3 57% SN FNAC (n = 153) 2.7* Not reported * Mean reported

Conclusions This study supports the feasibility of identifying 3 SLN after NAC in the majority of patients presenting with nodal metastases Avoidance of ALND is an additional indication for NAC in patients with operable breast cancer Long-term follow-up will determine rates of regional failure in this cohort

Post NAC Trials of Axillary Management cn1 to cn0 ALLIANCE A11202 Schema Clinical T1-3 N1 M0 BC Neoadjuvant Chemotherapy BCT or Mastectomy Sentinel Lymph Node Surgery SLN Negative Randomization SLN Positive NSABP B-51/RTOG 1304 (NRG 9353) Schema Clinical T1-3 N1 M0 BC Axillary nodal involvement (FNA or core needle biopsy) Neoadjuvant chemo (+ Anti-HER-2 therapy for HER-2 neu pts) Definitive surgery with histologic documentation of negative axillary nodes (by axillary dissection or by SLNB axillary dissection Stratification Type of surgery (mastectomy vs lumpectomy) ER status (+ vs -), HER-2 status (+ vs -) pcr in breast (yes vs no) ALND Breast/chest wall and nodal XRT (no Axillary RT) No further axillary surgery. Breast/chest wall and nodal XRT (incl. Axilla) No Regional Nodal XRT with breast XRT if BCS & No chest wall XRT if mastectomy Randomization Regional Nodal XRT with breast XRT if BCS and chest wall XRT if mastectomy

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