Assessment of the Axilla Post Neoadjuvant

Chemotherapy

ELENA PROVENZANO ADDENBROOKES HOSPITAL

CAMBRIDGE, U.K.

ACCME/Disclosures The USCAP requires that anyone in a position to influence or

control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their

spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and

creates a conflict of interest.

Dr. Elena Provenzano declares she has no conflict(s) of interest to disclose.

Pre Treatment Evaluation - Axilla • Routine axillary U/S with histological assessment of abnormal nodes by core biopsy or FNA

• Pre-treatment SLNB not advised unless positive result will influence decision to give chemotherapy

• Nodal response is an important prognostic factor independent of response in the breast

• Invalidates post treatment grading of response using RCB

Assessment of axillary lymph nodes • All nodes should be embedded in entirety

• Areas of myxoid change, fibrosis or collections of foamy macrophages suggestive of previous metastasis with response should be noted – intermediate prognosis compared with ‘true’ node negativity

• Low threshold for doing immunohistochemistry if suspicious of metastatic disease, especially if fibrosis

Lymph node changes - fibrosis

Lymph node changes

Lymph node changes

Lymph node changes – variable response

Complete response No response Partial response

Significance of nodal response • Nodal status post chemotherapy is a strong predictor of outcome

von Minckwitz G et al. JCO 2012;30:1796-1804

Significance of nodal response • Neo Tango – 44 patients (6%) residual disease in axilla despite pCR in the

breast • Residual nodal disease an independent predictor of poor prognosis, even in

presence of pCR in the breast

pCR No pCR

Lymph node changes

pCR breast Partial response LN

Significance of nodal response • 403 pts proven node positive • 22% axillary pCR (31% if ER neg) - 69% also pCR breast • 4% of breast pCR had residual axillary disease • Axillary node positive – 5 yr OS 72%, DFS 60% • Axillary pCR – 5 yr OS 93%, DFS 87%

Hennessy et al., J Clin Oncol 2005;23:9304-11

Significance of nodal response • Axillary conversion the MOST significant predictor of OS • Size of residual breast tumour NOT predictive if residual nodal

disease • No influence of size of metastasis – prognosis still worse if < 0.1 mm • Evidence of nodal response associated with improved DFS

Hennessy et al., J Clin Oncol 2005;23:9304-11

Significance of nodal response • 277 pts, tumours > 3 cm • 39% clinically node pos -> ypN0 • Number of positive nodes post chemo strongest predictor of survival • 122 pts, 52% node positive pre chemo • Worse DFS/ OS with increased number of nodes and increasing size of

metastasis • Size of largest metastasis the strongest predictor of survival on multivariate

analysis • ITC’s regarded as node positive

Cure et al., Breast Ca Res Treatment 2002;76(1):37-45

Klauber DeMore et al., Ann Surg Oncol 2006;13:685-91

ITC’s post chemotherapy • Presence of isolated tumour cells in lymph nodes • TNM – call ypN0(i+) BUT not pCR • WHO – call node positive i.e. NOT pCR • do NOT regard as pCR • often background fibrosis indicating previous macrometastatic disease with regression – nodal equivalent of minimal residual disease • measure size of entire deposit including intervening fibrosis

SLNB Timing: Pros and Cons

BEFORE Rx Pros: • Accurate staging before treatment – may guide decisions

regarding need for chemo/ radio Rx • More experience with SLN in this setting • Low axillary recurrence rates

SLNB Timing: Pros and Cons BEFORE Rx Cons: • Need for two operations • May delay commencement of therapy • Unnecessary ALND in patients who have axillary pCR (20-40%) • Loss of information regarding chemotherapy response in

axillary lymph nodes • Can’t calculate RCB if SLN +ve

Pre Rx SLN

• Pre treatment SLN positive in 30-80% of patients

• Up to 80% of patients have negative clearance – disease removed by SLN versus response to therapy

Sabel MS. Surg Onc Clin N Am 2010;19:519-38

Chung A, Ann Surg Onc 2010;17:2401-10

SLNB Timing: Pros and Cons AFTER Rx Pros: • Large series suggest comparable accuracy to SLN in adjuvant

setting • No delays to commencement of therapy • Single procedure • Information regarding nodal response – may be better predictor of

survival • Avoid unnecessary ALND in patients who have pCR in axilla

SLNB Timing: Pros and Cons AFTER Rx Cons: • Limited data regarding axillary recurrence rates • Variable false negative rate if node positive before Rx

– up to 30% in some series • Learning curve for procedure

Literature review • Overview 27 studies including 4 large multicentre studies (2148 pts) • IR 91% (71-100%) • False negative 10.5% (0-39%) • Accuracy 94% (77-100%) • SLN involvement 49%, 40% only positive node (0-67%) • Clinically N0 (266 pts) - IR 93%, accuracy 94.4% • Clinically N1 (342 pts) – IR 88%, accuracy 94.5%

Van Deurzen et al. EJC 2009;45(18):3124-30

Node negative patients • 3746 pts, 575 neoadjuvant chemoRx • T1-3, clinically node negative (exam & U/S) • NAC group younger, more T3 tumours • IR – 99% adjuvant, 97% NAC • False negative rate – 4% adjuvant, 6% NAC • Fewer positive nodes in NAC group T1 – 13% v 19% T2 – 21% v 37% T3 – 30% v 51% • 55 months follow up – LRR 2.1% (1.2%), regional RR 1.2% (0.9%) and distant

7.5% (2.7%)

Hunt et al. Ann Surg 2009;250(4):558-66

Literature review • LN +ve patients • Overview 19 studies including 793 pts • IR 85% (68-100%) • False negative 11% (0-33%) • Axillary pCR rate 35% • Authors own data - Axillary pCR rate 20%

ER+/HER2- 4% triple –ve 33% ER-/HER2+ 38% Straver et al. EJC 2009;45(13):2284-92.

NSABP-B27 • 2365 pts, 428 with SLN followed by ALND • 76% clinically N0, smaller tumours = select group • Identification rate 85% - improved to 90% in 2000 but trend N/S • 67% 1-2 nodes sampled (1-12) • 36% node positive; 56% SLN only positive node • False negative rate 7% - N0 = 7%, N1-2 = 12% (N/S) • pCR in breast, false negative 1.7%

Mamounas et al. JClin Onc 2005;23(12):2694-702

SENTINA study cN0 → Pre NAC SLN

(IR 99%) cN+ → NAC

SLN -ve SLN +ve

Repeat SLN post NAC

No further axillary

intervention IR 61%

FNR 52%

Post NAC cN+

SLN

Post NAC cN0

ALND

IR 80% FNR 14.2% Kuehn et al. Lancet Oncol

2013;14(7):609-18

ACOSOG Z1071 • Eligibility – invasive breast cancer T0-4 N1-2 M0, proven axillary metastasis (Bx/

FNA), no prior axillary surgery

• Axillary US pre and post Rx – clip biopsied node

• 701 women – 687 underwent SLNB post chemotherapy

• Detection rate 92.9% cN1 and 89.5% cN2

• Only significant factor in detection rate is use of dual agent mapping – blue dye only 77%, dye and radioisotope 94%

Boughey et al., JAMA 2013;310(14):1455-61.

ACOSOG Z1071

• 585 women cN1 with at least 2 SLNs and completion axillary clearance • Nodal pCR rate 41% - 21% ER+/ HER2-, 49% TN, 65% HER2+ • 20.6% residual nodal disease confined to SLN • Overall FNR 12.6% (10.8% if dual mapping vs 20.8% single mapping only) • FNR 9.1% if 3 or more SLNs examined compared with 21% if 2 nodes

examined and 31% if only a single node examined

Boughey et al., JAMA 2013;310(14):1455-61.

ACOSOG Z1071 • Conclusion – ‘changes in approach and patient selection

that result in greater sensitivity would be necessary to support use of SLN as an alternative to ALND in this population’ -> avoid SLN if clinically evident residual nodal disease or poor response to therapy

Boughey et al., JAMA 2013;310(14):1455-61.

Post treatment axillary US • ACOSOG Z1071 - subsequent paper looking at results in relation to

post treatment axillary US • 30% of patients had an Abnormal AUS – 72% node positive, FNR

8.1% • Abnormal AUS correlated with larger size of metastasis and more

involved nodes • 70% of patients had a Normal AUS – 56% node positive, FNR 15% • If use AUS to triage patients for SLN, FNR = 9.8%

•Boughey JClin Oncol 2015;33(30):3386-93

Post treatment axillary US • 150 node positive patients • 53% complete clinical response in the axilla 88% palpation, 50% normalised U/S • 26% pCR in the breast, 42% pCR in the axilla • IR 93%, overall FNR 21% • Normalised US – 50% pCR, FNR 16% • Suspicious /indeterminate US – 33% pCR, FNR 28%

Alvarado et al., Ann Surg Onc 2012;19(10):3177-84

Targeted Axillary Dissection • ACOSOG Z1071 • Follow up paper looking at patients with clip in biopsied node (n=170) • 29 patients clip not located at time of axillary surgery • 107 (76%) clip in SLN – FNR 6.8% • 34 (24%) clip in non-SLN – FNR 19% • 41% of cases clipped node was only positive node • Correlation with overall LN status 93%

Boughey et al. Ann Surg 2015; Epub Nov 26.

Targeted Axillary Dissection • 12 patients with placement of clip in LN sampled by pre treatment

FNA • Removal of clipped node by wire localisation or placement of

radioactive I125 labelled seeds • All 12 nodes successfully removed • 5 patients had concomitant SLN biopsy – in 4 clipped node was

SLN • 4/9 patients had residual nodal disease post NAC – clipped node

positive in all Caudle AS et al., JAMA Surg 2015;150(2):137-43

Abnormal LN on AUS Normal LN on AUS

Axillary core biopsy

NEOADJUVANT CHEMOTHERAPY

+ve LN -ve LN

SLN

cCR on AUS non-cCR on AUS

+ve LN -ve LN

Axillary clearance No further axillary surgery

SN FNAC study • 153 pts, T0-3, N1-2 with biopsy proven metastasis • SLN cut at 2mm intervals, IHC on all negative nodes • Axillary pCR rate 34.5% • FNR 13.3% • If ypN0(i+) included as node positive, FNR 8.4% • ≥ 2 SLN FNR 4.9% • Recommend ypN0(i+) be regarded as node positive • Similar analysis on Z1071 – FNR becomes 8.7%

•Boileau et al., JClin Oncol 2015;33(3):258-64

SN FNAC • HOWEVER no change in prognosis with occult metastasis identified by

IHC alone • 51 patients with axillary pCR • Slide review with additional H&E level and cytokeratin

immunohistochemistry • Occult metastases identified by IHC in 8 patients • 6 in 1 node only, 2 in 1 and 2 nodes respectively • No difference in DFS or OS (100% DSS at 10 years)

Loya et al., Cancer, 2009;115:1605-12

von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012;30:1796-804.

Provenzano E, Vallier AL, Champ R, et al. A central review of histopathology reports after breast cancer neoadjuvant chemotherapy in the neo-tango trial. Br J Cancer 2013;108:866-72.

Hennessy BT, Hortobagyi GN, Rouzier R, et al. Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol 2005;23:9304-11.

Curé H, Amat S, Penault-Llorca F, et al. Prognostic value of residual node involvement in operable breast cancer after induction chemotherapy. Breast Cancer Res Treat. 2002 Nov;76(1):37-45.

Klauber-DeMore N, Ollila DW, Moore DT, et al. Size of residual lymph node metastasis after neoadjuvant chemotherapy in locally advanced breast cancer patients is prognostic. Ann Surg Oncol 2006;13:685-91.

Sabel MS. Sentinel Lymph Node Biopsy Before or After Neoadjuvant Chemotherapy: Pros and Cons. Surg Onc Clin N Am 2010;19:519-38.

Chung A and Giuliano A. Axillary Staging in the Neoadjuvant Setting. Ann Surg Oncol 2010;17:2401-10.

Edge SB, Byrd DR, Compton CC, et al. (eds). American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 7th ed. Springer-Verlag: New York; 2009.

Lakhani SR, Ellis I.O., Schnitt SJ, Tan PH, van de Vijver MJ. WHO Classification of Tumours of the Breast. 4th ed. World Health Organization; 2012.

van Deurzen CH1, Vriens BE, Tjan-Heijnen VC, et al. Accuracy of sentinel node biopsy after neoadjuvant chemotherapy in breast cancer patients: a systematic review. Eur J Cancer. 2009 Dec;45(18):3124-30.

Hunt KK, Yi M, Mittendorf EA, Guerrero C, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients. Ann Surg. 2009 Oct;250(4):558-66.

Straver ME, Rutgers EJ, Russell NS, et al. Towards rational axillary treatment in relation to neoadjuvant therapy in breast cancer. Eur J Cancer. 2009 Sep;45(13):2284-92.

Mamounas EP, Brown A, Anderson S, et al. Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2005 Apr 20;23(12):2694-702.

Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol 2013;14:609-18.

Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013 Oct 9;310(14):1455-61.

Boughey JC, Ballman KV, Hunt KK, et al. Axillary Ultrasound After Neoadjuvant Chemotherapy and Its Impact on Sentinel Lymph Node Surgery: Results From the American College of Surgeons Oncology Group Z1071 Trial (Alliance). J Clin Oncol. 2015 Oct 20;33(30):3386-93.

Alvarado R, Yi M, Le-Petross H, et al. The role for sentinel lymph node dissection after neoadjuvant chemotherapy in patients who present with node-positive breast cancer. Ann Surg Oncol. 2012 Oct;19(10):3177-84.

Boughey JC, Ballman KV, Le-Petross HT, et al. Identification and Resection of Clipped Node Decreases the False-negative Rate of Sentinel Lymph Node Surgery in Patients Presenting With Node-positive Breast Cancer (T0-T4, N1-N2) Who Receive Neoadjuvant Chemotherapy: Results From ACOSOG Z1071 (Alliance). Ann Surg. 2015 Nov 26. [Epub ahead of print]

Caudle AS, Yang WT, Mittendorf EA, et al. Selective surgical localization of axillary lymph nodes containing metastases in patients with breast cancer: a prospective feasibility trial. JAMA Surg. 2015 Feb;150(2):137-43.

Boileau JF, Poirier B, Basik M, et al. Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: the SN FNAC study. J Clin Oncol. 2015 Jan 20;33(3):258-64.

Loya A, Guray M, Hennessy BT, et al. Prognostic significance of occult axillary lymph node metastases after chemotherapy-induced pathologic complete response of cytologically proven axillary lymph node metastases from breast cancer. Cancer 2009;115:1605-12.

Provenzano E, Bossuyt V, Viale G, et al.; Residual Disease Characterization Working Group of the Breast International Group-North American Breast Cancer Group Collaboration. Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group. Mod Pathol. 2015 Sep;28(9):1185-201.

Rabban JT, Glidden D, Kwan ML, Chen YY. Pure and predominantly pure intralymphatic breast carcinoma after neoadjuvant chemotherapy: an unusual and adverse pattern of residual disease. Am J Surg Pathol 2009;33:256-63.