16/09/2015. ACOSOG Z011 changing practice. Presentation outline. Nodal mets #1 prognostic tool. Less surgery no change in oncologic outcomes

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1 ACOSOG Z011 changing practice The end of axillary US/FNA? Preoperative staging of the axilla in the era of Z011 Adena S Scheer MD MSc FRCSC Surgical Oncologist, St. Michael s Hospital Assistant Professor, University of Toronto February 2011, Giuliano A et al. JAMA Axillary dissection vs. no axillary dissection in women with invasive breast cancer and sentinel node metastasis In patients with limited axillary disease found on sentinel node biopsy observation=further surgery in recurrence and survival Since 2011 axillary dissection has nearly been abandoned Is it clinically important to identify limited axillary disease preoperatively? Is it detrimental to patients? Presentation outline The importance of the axilla in breast cancer Axillary staging with US, FNA/core The new era Axillary biopsy pre neoadjuvant therapy Future directions Nodal mets #1 prognostic tool N stage is the most significant independent prognosticator Positive nodes is an indication for systemic therapy and regional radiation therapy Anatomy of the axilla Less surgery no change in oncologic outcomes Clinically negative axilla Historically, axillary staging involved axillary node dissection (AxD) (levels 1/2) In clinically negative axilla only 25 30% of women have positive nodes Morbidity of AxD: Chronic lymphedema 15 20%, 30%+ with addition of radiation Chronic mobility impairment and pain in up to 75% Around 2000 the sentinel node biopsy (SNBx)was popularized On average 2 lymph nodes are removed Chronic lymphedema in 3 5% Mobility impairment is rare, sensory changes 3 5% No differences in local regional recurrence or survival between SNBx and AxD SNBx Negative, no further surgery Positive Completion AxD 1

2 How good is axillary ultrasound and FNA? Examination of level 1 (2 and 3 not routinely scanned) Borders: axillary vessels, pec minor anteromedially, latissimus dorsi and teres major posterolaterally Suspicious nodes: Cortical thickness >3mm in short axis diameter Architectural distortion/microlobulation Replaced/eccentric hilum Overall sensitivity 50 70% Specificity 100% Positive predictive value 100% Negative predictive value 64 75% Accuracy 75% Current guidelines are conflicting ESMO recommends routine axillary ultrasound to assess the lymph nodes ASCO/NCCN recommends ultrasound in the setting of clinically palpable nodes ACOSOG Z011 No difference in overall or disease free survival at 5 years Inclusion: T1/2 (<5cm) No palpable nodes Lumpectomy with negative margins Positive SNBx <3 nodes Whole breast radiation Exclusions: 3+ positive nodes Matted nodes Gross extranodal disease Neoadjuvant therapy 420 women underwent completion axillary dissection 436 women underwent observation JAMA. 2011;305(6): No difference in locoregional recurrence Locoregional recurrence free survival 96.7% for SNBx vs 95.7% AxD (p=0.28) Overall rate of complications (infection, seroma, lymphedema) was 70% for AxD vs 25% SNBx (p<0.001) In patients with <3 positive nodes, with tumours <5cm who undergo breast conservation and have adjuvant radiotherapy and systemic therapy (endocrine and/or chemo) axillary dissection is not required and is harmful AMAROS 744 women underwent completion axillary dissection Inclusion: T1/2 (<5cm) No palpable nodes Mastectomy or lumpectomy Positive sentinel node (95% had 2 or fewer) 681 women underwent axillary node radiation (3- field) Exclusions: Neoadjuvant therapy Lancet Oncol 2014; 15:

3 No difference in survival or recurrence And the evidence continues to build 5 year axillary recurrence 0.43% AxD vs 1.19% axillary radiation p=ns Clinically significant lymphedema rate at 5 years 23% AxD vs 11% radiation p< IBCSG (Lancet Oncol 2013; 14: 297) Randomized tumours <5cm and clinically N0 to completion ALND or none in the setting of micrometastases (<2mm deposits) 11% of patients had residual disease on further surgery No difference in regional recurrence (1.1% vs 0.2% no AxD vs AxD) Dutch BOOG randomizes clinically T1 2N0 breast cancer patients with macrometastatic SLNs treated with mastectomy, to completion axillary treatment or no further axillary treatment Meta analysis of 12 studies (130,575 patients) ALND had more paresthesia (RR 0.26, 95% CI] ; p < 0.01) More lymphedema (RR 0.28, 95% CI ; p < 0.01) No difference in OS(HR 0.95, 95% CI ; p = 0.35) No difference DFS (HR 1.00, 95% CI , p = 0.96) No difference in LRR (RR 0.92, 95% CI ; p = 0.73) Eur J Surg Onc 2015; 41:958 Should preoperative US be abandoned? In many patients with early stage tumours and clinically negative axillae a preoperative US may not be necessary as limited axillary disease does not need to be identified Avoid committing the patients to aggressive axillary surgery Yet some patients will have more than 2 nodes positive on their SNBx despite clinically negative axillae (~5%) Can preoperative ultrasound identify these patients? And many more patients will have zero nodes positive on SNBx (~75%) Can preoperative ultrasound identify these patients? Identifying patients who don t fit Z at MDACC Tumours <5cm clinically negative axillae Positive FNA N=190 (27%) T1 (<2 cm) 45% 60% Number of suspicious nodes Mean number of positive nodes 0 62% 17% 22% preoperative ultrasound axillary node dissection 4 2 Positive SNBx N= 518 (73%) 74% 17% 3% 6% Ann Surg Oncol (2014) 21: Identifying patients who don t fit Z011 Suspicious nodes on US is a poor prognostic sign Multiple other studies have been published since Z011 suggesting the same finding Patients with abnormal nodes on ultrasound with a positive FNA or core have a higher axillary node burden compared to patients with a positive SNBx Some studies suggest that an FNA is better than a core as the likelihood of picking up micrometastatic disease (clinically not significant) is lower thereby possibly minimizing unneccesary axillary dissection 3

4 Hold on to your US probes In patients with early stage disease (tumours <5 cm) and clinically negative axillae Finding a suspicious node, and in particular, multiple suspicious nodes, may predict a nodal burden requiring axillary node dissection (i.e 3+ nodes, extranodal extension) Avoiding an extra operation in 5% of patients In patients with early stage disease and clincially negative axillae Can US detect the 75% of patients who do not have nodal metastases?...to be continued The positive node and neoadjuvant therapy Patients presenting with clinically resectable/no disease Pre Z011 a positive node on US/FNA committed a patient to a complete axillary dissection Post Z011 selective identification of patients with 3+ nodes Patients presenting with locally advanced disease A positive node is an indication for neoadjuvant therapy to promote tumour shrinkage with possibly breast conservation and an easier axillary dissection Patients presenting with HER2+ disease and a positive node on US/FNA Targeted therapies are enabling complete pathologic response in up to 60% of patients Do they still need an axillary dissection? Identifying complete path responses Following neoadjuvant chemotherapy (NA) with modern agents 30 40% of patients will have a complete pathologic response ER negative and HER2 +ve patients are more likely to respond Up to 60% of HER2+ve patients will have a pcr Can we identify and spare these patients axillary dissections? SNBx post neoadjuvant Traditionally a positive FNA pretreatment = axillary dissection The concern: Neoadjuvant chemotherapy may impair lymphatic drainage from the breast hampering detection of the SN Tumour regression in the axilla could follow a non uniform pattern leading to an unacceptable false negative (FN) rate SNBx post neoadjuvant cn0 Multiple studies have demonstrated the safety of SNBx postna equivalent identification rates satisfactory (<10%) false negative rate Current guidelines: Patients with a clinically/radiologically negative axilla pretreatment can proceed with a SNBx post NA therapy What about patients who present with CN+ disease? SNBx post neoadjuvant cn+ Patients who have clinically positive (matted, bulky) nodes Residual palpable disease AxD Clinically negative AxD Patients who have FNA positive or clinically positive N1 (not bulky or matted) nodes Residual palpable disease AxD Clinically negative Targeted AxD with removal of sentinel nodes AND the biopsied, clipped node 4

5 SNBx in clinically positive nodes post NA: The evidence The evidence: Alliance (JAMA 2013; 10:1455) Sentina (Lancet Oncology: 2013; 14:609) SNFNAC (J Clin Onc 2015; 33:258) The margin of error is too large Complete pathologic response in 41%, 52%, 34.5% Identification rates of 93%, 81.5% and 87.6% respectively Typically 97% Overall FN rates 12.6%, 15%, 8.4% Typically 5 7%, <10% is acceptable Improved identification and FN rate (acceptable range) Use of dual tracer radio colloid and blue dye Finding 3+ sentinel nodes Including micrometastases and isolated tumour cells as positive What if the initial biopsied node is removed? Targeted axillary surgery Alliance trial (JAMA Surg 2015; 150:137) Subgroup of patients had a clip placed at the time of FNA Clipped node removed with SNBx FN rate 7.4% Case presentation Ms. P 39 yo female with a self detected mass and erythema of the right breast Method: Clip placement at time of biopsy Localized via ultrasound and placement of radioactive iodine I 125 ( 125 I) labeled seeds or wire placement Case presentation Ms. P Case presentation Ms. P 5

6 Localization and resection of the clips Future Directions 3 trials actively recruiting SOUND Dutch trial INSEMA Conclusions Clinically negative axillae FNA of suspicious nodes may identify patients with 3+ nodes positive who do not fit Z011 criteria FNA of indeterminant nodes is likely not necessary and possibly harmful In the future a negative axillary US may be all that is required in these patients Clinically positive axillae 30 60% complete pathologic responses (higher with ER and HER2+) FNA/clip placement of positive node with targeted axillary surgery Dual tracer use Identification rates >90% and FN rate <10% 6