THE AXILLARY SWAMP INNOVATIVE TREATMENTS IN CANCER MEDICINE ROME MAY 18-19 2016   Isabel T. Rubio Breast Surgical Unit, Breast Cancer Center Hospital Universitario Vall d´Hebron Barcelona, Spain

19th century (an area of) very wet, soft land or it can be a situation fraught with difficulties and imponderables and along the history of breast cancer we have been struggling to know more about the role of lymph nodes that

Halstedian Era Halsted proved beyond any doubts that 76 patients treated with radical mastectomy 40 had survived > 3 years 36 had died within 3 years The halstedian theory was based on the asume stepwise progresion of cancer cells from the local primary to the regional nodes acting as filters and only later to systemic therapy but the results were not as expected as many women still die from the disease, even though…. Halsted proved beyond any doubts that meticulous surgeries were technically possibly in breast cancer

Controversy Statistical relationship between lymph node metastases and survival Lymph node resections are related to survival The meaning of micrometastasis and ITC In most cancers With or without lymph node metastases

“ Lymph node metastasis are predictors, Fisherian theory “ Lymph node metastasis are predictors, not governors, of overall survival since they do not control survival” Blake Cady, Arch Surg 1984

The believe that Removing more negative nodes is the result of a Will Rogers effect on stage migration that occurs on more extensive tissue removal one of the most important biases limiting the use of historical controls groups in experimental treatment trialsIf you harvest 20 nodes rather than 10 nodes you probably end up finding an unexpected positive node or mode, an example of stage shifting

Axillary Lymph Node Dissection Goals - Survival Advantage - Accurate Staging - Regional Control

Regional Treatment and Survival NSABP B04 Regional Treatment and Survival

Survival Advantage with Axillary Dissection Orr: Ann Surg Onc 1999 5.4% average survival advantage in axillary dissection group Before screening mammography Before development of effective systemic therapies Before the introduction of margin control Now, if we knew for sure that we could increase the survival of patients by an average of 5% or so with axillary therapy, then many would in fact agree that this should be recommended. Is there really a survival advantage? Which are the patients who will have a survival advantage? The 15 year of the Institut Curie shows no differences in survival, nor the 25 year follow up on NSABP

Veronesi U et al. Eur J Cancer 1999 The involvement of internal mammary was predictor of poor prognosis but there was no survival benefit from resecting those nodes Veronesi U et al. Eur J Cancer 1999

Local Control Survival Sabemos desde hace unos años que el control local y la supervivencia están relacionados y esto ha sido un cambio importante en el cáncer de mama. Pero hay un mensaje importante y es que hay que reducir la recidiva local en + 10% para obterenr beneficios en la supervivencia EBCTCG. Lancet 2005

Sentinel Lymph Node Biopsy Works Trial N Patients SLN SLN-FN Accuracy EIO 532 99% 9% 97% B-32 5611 10% ALMANAC 836 96% 7% 98% GIVOM 749 95% 17% SNAC 1088 94% 5%

RANDOMIZED STUDIES

Unfavourable events (Follow up 78 month ) EVENT ALND SLN Risk ratio (95%CI) Breast cancer related events Axillary metastases Supraclavicular metastases Tumour reappearanc/breast Distant metastases Total 2 3 13 18 1 4 11 16 1,26 (0,8-5,65) 0,8 (0,36-1,79) 0,84 (0,43-1,6) Contralateral and other primary tumour Contralateral breast cancer Other primary tumour 6 12 36 5 27 0,79 ( 0,24-2,59) 0,47 (0,18-1,27) 0,71(0,43-1,18) Deaths Deaths from breast cancer Deaths from other causes Deaths of unknown cause 5 year overall survival 96,4% 98,4% 1,44(0,24-8,63) 0,19 (0,02-1,65) 0,24(0,03-2,15) 0,44(0,15-1,26)

False negative = Axillary recurrence Will SLN False Negative Rates Predict Nodal Recurrence Rates? False negative = Axillary recurrence SLN - /no ALND N Axillary Recurrence F/U years 48 STUDIES 14.959 0.3% > 3 NSABP B-32 2011 0.7% 8 SLN +/no ALND (6 studies) 583 0.5% 3 Most of the axillary recurrences appear between 18 and 36 months after surgery Van der Ploeg et al. EJSO 2008 Krag DN et al. Lancet Oncology 2010

The greatest accomplishment of the SLN is to achieve the goal of avoiding removal of regional and nodal lymphatic basins that do not harbour metastastic disease A decided break in the surgical tradictional conception of lymph nodes as effective filters blocking dissemination of cancer cells.

Rationale to Avoid ALND in SLN+ Patients 1. Impact on Lymphedema 2. SLN is Often the Only + LN 3. Adjuvant Therapy May Treat Subclinical Nodal Metastases 4. Most Data Indicate the ALND Does Not Improve Survival 5. ALND is for Staging

Bilomoria KY et.al. JCO 2009;27:2946-53 SLN + and no ALND SLN+ and no ALND % Bilomoria KY et.al. JCO 2009;27:2946-53

Outcome +/- ALND Axillary local recurrence 5 yr relative survival SLN micrometastases (<2 mm) SLN only (n=802) 0.4% 99% SLN/ALND (n=2357) 0.2% 98% SLN macrometastases (>2 mm) (n=5596) 1.0% 90% SLN/ALND (n=22591) 1.1% 89% Bilomoria KY et.al. JCO 2009

Management of the axilla when the SLN is positive

ACOSOG Z0011 ALND n = 420 SN n = 436 Local 15 (3.6%) 8 (1.8%) Regional 2 (0.5%) 4 (0.9%) Total 17 (4.1%) 12 (2.8%) p = 0.11 ACOSOG Z0011 ALND n = 420 SN n = 436 Local 19 (5.6%) 12 (3.8%) Regional 2 (0.5%) 5 (1.5%) Total 21 (6.2%) 17 (5.3%) p = 0.36 Giuliano A, Ann Surg 2010;252:426

Mastectomy and +SLN Mastectomy w/o XRT or ALND (n=58) Mastectomy (n=210) BCS (n=325) LR 1.7% 1.4% RR 1.2 (2.5%) 1% (1.5%) Milgrom S. Ann Surg Oncol 2012 Mastectomy w/o XRT or ALND (n=58) Fitzsullivan. Ann Surg Oncol 2017 without any axillary-specific treatment Entre parétesis si se excluyen pN0(ITC

Removal of Positive Nodes Lymph nodes metastases may or may not precede the distant metastasis Presence of positive nodes is a predictor Small volume of tumor burden in the axilla can be taken care of with systemic therapy In the abscence of extensive axillary disease , removing positive nodes do not improve survival or increase locoregional control Rather than an instigator of distant disease

Controversy Statistical relationship between lymph node metastases and survival Lymph node resections are related to survival The meaning of micrometastasis and ITC In most cancers With or without lymph node metastases

Z0010 trial Survival by staining method H&E negative (3945/5184) positive (1239/5184) IHC (3595) (350) 5 year survival (95% CI) 95.6% (95.0-96.3) 92.8% (91.3-94.3) p=0.0002 95.8% (95.0-96.5) 95.1% (92.7-97.5) p=0.53 Cote R et.al. ASCO 2010

Important issues already proven 1. Sentinel Lymph Node Biopsy Works 2. Improvements in systemic therapy have increased rates of pCR Let´s start by mentioning that there are two issues already proven: Improvements in systemic therapy have increased rates of pCR in the breast and in the axilla and it is time for us as surgeons to reevalute the local treatment in our patients

PROGNOSIS Cortazar P et al. Lancet 2014 Patients with no invasive tumor in the breast and the axilla p complete response that correlates best with long-term outcome, The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0.24, 95% CI 0.18–0.33; OS: 0.16, 0.11–0.25) and in those with HER2-positive, hormone-receptornegative tumours who received trastuzumab (EFS: 0.15, 0.09–0.27; OS: 0.08, 0.03, 0.22). Attaining pCR reduced the risk of death by 92% in cancers that were HER2 positive and hormone receptor–negative cancers and by 84% in (TNBCs). Cortazar P et al. Lancet 2014

pCR rates vary by subtype pCR rates vary depending on biologic subtype and therapy used TNBC has higher pCR rates that HR+ disease - 22% vs 11% in a study of 1118 patients Her2 3+ - Rates up to 65% in pactients with Trastuzumab - Rates higher in dual blockage Sstudies further demonstrate that in subgroups considered to have slowly proliferating tumors, pCR is not associated with prognosis, whereas in subgroups with highly proliferating tumors, pCR increases in this subgroups up to 65%. And how all this achievemt has impact on the surgical management? Baselga . Lancet 2012 Gianni, Lancet Oncology 2012 Buzdar, JCO 2012

Can axillary node dissection be spared in patients after neoadjuvant treatments ?

Conversion of Axillary Metastases: FNA Positive to Pathologic Negative 109 patients Pathologic NEGATIVE 81 patients Trastuzumab + A or T HER2+ 74% Median # LNs Removed = 19 CANCER, 2010

Mamtani A. Ann Surg Oncol 2016 cT4 or cN2/N3 ineligible para SLN regardless of response 48% no ALND Mamtani A. Ann Surg Oncol 2016

# patients with residual nodal disease 310 83 226 619 ACOSOG Z1071 FN SNAC SENTINA TOTAL STUDIES N PATIENTS 756 153 592 1501 # patients with residual nodal disease 310 83 226 619 FNR with single SLN 31.5% 17/54 18.2% 4/22 24.3% 17/70 26% 36/146 FNR if >2 SLNs 12.6% 39/310 4.9% 3/61 9.6% 15/156 10.8% 57/527 FNR with dual tracer 27/251 5.2% 3/58 8.6% 6/70 9.5% 36/379 FNR inclusion of N0(i+) 8.7% 27/311 8.4% 7/83 - 34/394 , and further studies are necessary to help determine optimal axillary management.

Targeted Axillary Dissection (TAD) 1-5 Days Before Surgery Day of Surgery Breast Imaging I125 seed placed in marked node Node containing I125 seed selectively removed I125 Seed I125 Seed Clip The localize the clipped node, patients go to breast imaging 1-5 days before surgery. Similar to our approach for localizing breast tumors with I125 seeds, the radiologist places an I125 seed in the clipped node under US guidance. If SLN is planned, they either go to Nuclear Medicine for radioisotope injection the day before surgery or the surgeon injects the isotope in the OR. During their axillary surgery, the surgeon uses a neoprobe to identify the node containing the I-125 seed and clip. The SLNs are also removed. At this time, patients also undergo completion ALND. Clip SLNs removed Remaining axillary nodes removed Nuclear Medicine Radioisotope injection for SLND Courtesy Dr. Kuerer Caudle et al. JAMA-Surg. 2015. 150(2): 137-43

Diaz-Botero, S et al. Ann Surg Oncol 2016

Residual Disease After Neoadjuvant Treatment Diaz-Botero, S et al. Ann Surg Oncol 2016

IMPORTANT POINTS TO CONSIDER Refine the SLN technique after NACT Improving SLN IR and reducing the chance of false negativity: - Marking the + nodes - Dual mapping techniques - Resection of >2 SLN when possible - Following proper pathological evaluation - Broadening the definition of SLN positivity to include micrometastases and isolated tumor cells Encouraging patients and junior doctors to enroll patients in future research programs

Follow up of patients with cN0 or cN1-2 before NAC The European Institute of Oncology group reported that SLN among 147 patients initially node positive who converted to node negative after NACT had a 5 year axillary recurrence rate of only 0.7% Patients with N1 disease who had a pCR, SN negativity was a significant predictor of good outcome, suggesting that SN status accurately reflect axillary status. Galimberti V et al. EJSO 2016

Regional Failure Rates in other trials: After mastectomy alone, fewer than 50% of N+ patients developed axillary first failure. Conventional radiation tangents treat approx. 80% of Level 1, 50% Level 2 + 3 Adjuvant systemic rx reduces LRR by > 50% NSABP B04: RM 40% N+, TM: 18.5% delayed ALND NSABP B13: No Rx 13.4%, CTX 2.6% NSABP B14: Placebo 14.7%, Tam 4.3% Fisher B, NEJM 1985;312:674 Reznik J, IJROBP 2005;61:163 Fisher B, JCO 1996;14:1982 Fisher B, JNCI 1996;88:1529

TRIAL OPTIONS ALLIANCE - cT1-3 N1 - NACT then +SLN - ALND + Nodal irradiation vs. Nodal Irradiation - Z11 after NACT NSABP B-51 - NACT then – axillary nodes (SLN or ALND) - No nodal Irradiation vs. Nodal Irradiation - Omit nodal radiation in pCR patients Our deliberation is the role and impact of RDT use or nonuse in the residual undissected axilla in patients were only the SLN is performed. These two trials are designed to investigate the role of RDT and surgery among patients with initial biopsy proven disease and residual or non residual disease after NACT.

AUTHOR Thompson, 2007 Nos, 2007 Boneti,2008 Ponzone, 2009 Boneti,2009 No. Patients Blue Node Identification % %Crossover No. Patients Neoadjuvant Tx %Blue node positivity Thompson, 2007 40 61 Nos, 2007 21 71 - 7 Boneti,2008 131 3.9 Ponzone, 2009 49 55 11 Boneti,2009 220 2.8 Casabona, 2009 72 45 Bedrosian, 2010 30 50 22 13 Noguchi, 2010 20 88 14 43 Rubio, 2011 36 83 29

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Local Regional Recurrence Among Patients with pCR Breast conserving therapy, n = 751 2005-2012, with trastuzumab Five-year local-regional recurrence HER2+ pCR vs not 2.6% vs 13.3% TN pCR vs not P =0.007 1.4% vs 10.1% LRR rates among pts w pCR are extremely low. On multivariate analysis, the HR-/HER2- subtype, clinical stage III disease, and failure to experience a pCR were associated with LRR. Swisher et al, Ann Surg Onc 2015

2016 Forward How will we safely select patients for avoidance of breast surgery after neoadjuvant therapy? While trying to increase BCS rates in some subgroups, historically driven to mastectomy, on the other hand we are moving forward to avoid surgery in other subgroups

Eliminating Breast Cancer Surgery in Exceptional Responders with Neoadjuvant Therapy Eligibility Desires BCT T1/T2 unicentric TN and HER2+ Clinical (ultrasound) N0 at presentation Neoadjuvant chemotherapy w anti-HER2 Imaging complete or near complete Question re size remaining calcs absolute or plan to sample 90% (THEREFORE without extensive microcalcifications)

2018

2018- THE END OF AN ERA FOR ALND? Inflammatory and extensive LABC w/o major response Axillary Recurrence Clinically node negative axilla with positive SLN: in mastectomy patients w/o PMRT- not all!!! In BCT patients not meeting Z11 criteria Does ALND for SLN + patients change systemic treatment, reduce local recurrence or improve survival? It is clear that ALND plays a role in breast cancer for prognosis, for adiding or not RDT and for local control although there no therapeutic role for ALND in many situations where it was useful a decade ago. So the question remains….