Surgical management in the setting of neo-adjuvant therapy

Frances Wright MD MEd FRCSCAssociate Professor of Surgery

Outline of Talk

• Locally advanced breast cancer and NAT

• Smaller high risk tumors and NAT

• Operations on the breast

• Operations on the axilla

Who gets neo-adjuvant therapy?

• Locally advanced breast cancer– Tumor > 5cm– Skin involvement, chest wall involvement– Fixed, matted axillary nodes– Supraclavicular nodes– Inflammatory breast cancer

• Inoperable and operable– Can I get clear margins?

Locally Advanced Breast Cancer

Locally Advanced Breast Cancer

Inoperable Breast Cancer

• Neo-adjuvant therapy (NAT)– Assess response

• Successful - surgery - then radiation post op• If fails - change chemotherapy regime• If that fails – radiation

– Then possibly surgery (some success with triple negative patients with twice daily rads)

Shenkier 2004

Inoperable Breast Cancer: Inflammatory Breast Cancer

• Success story of multi-modal treatment

Treatment Approach 5 year survivalMastectomy 0

Radiation 0

Mastectomy & Radiation 0

Pre-op chemo, surgery, rads 46%

Lopez 1996

Who gets neo-adjuvant therapy?

• Smaller high risk tumors (2-5cm)– Her 2 neu positive, triple negative– Node positive– Often younger patients (<50)

Pre-operative work up

2-5cm Node neg

2-5cm Node pos

LABC

Mammo, U/S

MRI

Core biopsy and receptors

Clip if considering BCS

Metastatic work upBone scan, CT chest, abd pelvis

Maybe

Pre-operative work up LABC

• Imaging work up– 7% contralateral breast cancer

• Metastatic work-up– ~10% will have mets at presentation

NAT and Survival

• Overall, no demonstrated overall survival benefit with pre-op vs. post-op chemotherapy (NSABP 18, 27)– Subset analysis for women < 50 – Pre-op chemo trend toward improved overall

survival vs. post op chemo– At 16 years OS 61% (NAT) vs

55% (post op chemo)

Rastogi 2008

NAT provides in vivo tumour assessment

• Assess response to chemo (Chawla 2012)

• 91% respond• 6% stable• 3% progress

– Does the chemo need to be changed?– Does the patient need to get to the OR for

salvage mastectomy?

NAT and Prognostication

• Good prognosticator

• Aim of neo-adjuvant chemotherapy is complete pathological response (pCR)

Better response = Improved survival

Estevez 2004

Complete Pathological Response and Improved OS in NSABP 18, 27

Rastogi 2008 JCO

Chemo RegimeDoxorubicin/ cyclophosphamide (AC) x 4 cyclesAll women > 50 received tamoxifen post op x 5 years

pCR 6.7%

pCR

pCR

Pathological Complete Response and Breast Cancer Subtype

Tumor Subtype Percentage of type of

breast cancer

Complete pathological

response

ER/PR pos, her2 neg 40-55% 8%

ER/PR pos, her 2 pos“Triple positive”

15-20% 19%

ER/PR neg, her 2 pos 7-12% 39%

Triple Negative 13-25% 31%

Houssami 2012 EJC

NAT and Impact on Surgery

• Increased rate of breast conserving surgery (BCS)– Improves cosmesis and patient satisfaction

• ~ 25% reduction in mastectomy rate to BCS with pre-op chemo

Chawla 2012

Breast Cancer Subtype and Impact on Breast Surgery

Patient Info Rate of Breast Conserving Treatment

Re-operation rate

Overall 694 patients 40% 7.2%

Triple Negative 25% (170) 47% 3.5%

Her 2 neu positive 30% (207) 43% 6.8%

ER/PR+/ her 2 neu neg 46% (317) 35% 9.8%

Data from ACOSOG Z1071 – sentinel node biopsy after NACPatient age, stage did not differ across subgroups

Boughey 2014 Annals of Surgery

Is the recurrence rate higher if we downstage patients?

Study Number of patients

Local Recurrence

Median Follow up

Comments

NSABP 18 Pre-op Chemo

Downstaged BCS (11/69) vs mastectomy (43/434)

15.9% vs 9.9% 9 years When controlled for age, initial tumor size, no difference in LRR

NSABP 18 – pre operative vs post operative chemoHigher local recurrence in women < 50 (p=0.00003) (13.1% vs 5.2%)Tumor size did not correlate with local recurrenceBiology more important

Updated MD Anderson data

• 652 patients received NAT • At 5 years

– 93% LRR free survival rates for NAT – 97% LRR for surgery first – Patients receiving NAT had more advanced disease

Mittendorf 2013

Updated MD Anderson data

• Multivariate analysis for local regional recurrence • age < 50• clinical stage III, • grade 3• ER neg disease • ER positive (but not take treatment) • LVI• multifocal disease on pathology• close/ positive margins (wanted at least 2 mm)

• LRR driven predominantly by disease stage/ tumor biology

Mittendorf 2013

BCS margins after NAT

• MD Anderson wants 2mm margin with BCS after pre-op chemo

• They do not remove entire pre-chemo tumor volume (Mittendorf 2013)

• There is no data from prospective trials regarding margin width and oncologic safety (Kummel 2014)

Surgical Complications after NAT

• NSQIP study (2005-11)

– Compared outcomes in patients who had NAT and those who did not

– NAT was independently associated with a lower overall morbidity for patients who did and did not have breast reconstruction

– Unclear why NAT protective

Abt 2014 JAMA

Choosing who should get BCS after NAT

• Difficult to judge clinically, amount of disease present – Not all tumours are discrete masses

Imaging Accuracy after NATStudy No. of

patientsCorrelation of residual disease after NAT

with pathology as the gold standard

Clinical MRM US MRI

Yeh 2005 31 IIB, IIIA 19% 26% 35% 71%

Akazawa 2006 30 R=0.55 R=0.49 R=0.9

Balu-Maestro 2002 60 52% 38% 43% 63%

Partridge 2002 52 R=0.6 R=0.89

Rosen 2003 21 LABC R=0.61 R= 0.75

Londero 2004 15 LABC R=0.67 R=0.57 R=0.70

Cheung 2003 33 LABC R=0.98

Weatherall 2001 20 R=0.72 R=0.63 R=0.94

Segara 2007 68 I, II, III R=0.44 R= 0.61 R=0.75

Belli 2006 45 R= 0.97

Range 0.44 – 0.72 26% - 0.67 35%-0.61 63%-0.97

Meta-analysis of accuracy of MRI after NAT

• MRI – slightly overestimate pathologic size– Measurement errors can be large enough to be clinical significant– Chemotherapy effect – decrease in contrast enhancement parameters – Loss of tumour continuity – to non-continuous small foci– Decrease tumour cellularity

(Rieber 2002, Warren 2004, Schott 2005, Thibault 2004, Rosen 2003, Rajan 2004)

• MRI more accurate than mammogram

• Need studies comparing MRI to ultrasound

Marinovich 2013

Pre-TreatmentCircumscribed masswith rim enhancement

After NATTumour shrank toSmaller mass, resectable

Pre-TreatmentMRI of Breast Cancer

After NATTumour shrunk to lesser volume along septa

BCS decisions based on breast cancer histology

• Lobular carcinoma– Very difficult to assess extent of disease

clinically, mammogram and MRI– Not respond as well to pre-op chemo

• Inflammatory carcinoma– High rate of recurrence (39%) if no surgery

and just radiation after chemotherapy (Danforth 1998 – did if post chemo biopsy was negative)

Lymph Node Staging and LABC

Likelihood of having lymph node involvement

Diameter of primary tumour

Percent with positive axillary nodes

0.5 - 0.9 cm 20.6%

1.0 - 1.9 cm 33.2%

2.0 – 2.9 cm 44.9%

3.0 – 3.9 cm 55.2%

4.0 – 4.9 cm 60.0 %

> 5.0cm 70.0%

Carter 1989

Node Negative before NAT

• Clinically and radiologically node negative prior to NAT SNB– We have asked our radiologists not to

biopsy indeterminate lymph nodes

• Allows for patient to get benefit from NAT if nodes were positive

• 40% downstaging

Node positive before NAT

• Is sentinel node biopsy accurate when nodes are positive and the patient then receives NAT?

ACOSOG Z1071

• 663 evaluable patients with positive axillary nodes (biopsy proven)– 649 had chemo followed by SNB + ALND– 7.1% (46) could not identify SNB– 12% (78 patients) had only 1 SNB– No cancer in 41% (215) = pCR 41%– 39 no cancer in SNB but cancer found on

ALND • False negative 12.6%

Boughey 2013 JAMA

ACOSOG Z1071

• What decreased the false negative ?– Mapping performed with two agents (blue dye

and radiocolloid 89% of time) vs one agent • FNR = 10.8% vs 20.8%

– Examination of at least 3 sentinel nodes• FNR = 9.1% vs 21.1%

Boughey 2013 JAMA

Similar Trials – Assessing accuracy of SNB in node positive patients post chemo

• Sentina – 1737 patients had NAT

• For clinically node positive group • All got SNB and ALND• Detection rate overall 80%• When > 3 sentinel nodes removed after chemo,

FNR < 10%• Double mapping , FNR 8.6%

Kuehn 2013 Lancet Oncology

Similar Trials – Assessing accuracy of SNB in node positive patients post chemo

• SN FNAC (Canadian)– FNR 8.4% overall– FNR 4.9% when >2 nodes removed

Boileau 2014 in press

A (complicated) way forward ?

• MD Anderson– TAD (targeted axillary dissection)– Placing a clip at time of the lymph node biopsy– At time of surgery (after neo-adjuvant chemo),

lymph node is localized – During the SNB – all SLNs and the clipped nodes

are removed and doing ALND (to see accuracy)• Undergoing study now

Mittendorf 2014

New frontiers

• Sentinel node positive after NAT– ALND?– Radiation? (would it deal with chemo

resistant disease?)

Lymph Nodes as prognosticators after NAT

Post NAT nodal status 5 year survival

Negative nodes 75%

1-4 nodes 40-50%

5-10 nodes 30%

> 10 nodes 20%

McCready 1989

Future directions

• Further chemotherapy post operatively for patients who do NOT have pCR

• Especially high risk patients– Young patients– Triple neg– Her 2 neu positive (KATHERINE TRIAL)

Summary

• NAT – standard for patients < 50, triple negative, Her2 neu positive, LABC

• Pathological complete response affected by subtype (triple neg, Her 2 neu pos) which in turn can affect surgery

• Need to do pre and post imaging including MRI to assess extent and pattern of disease to decide if BCS appropriate

Summary

• Who not to offer BCS– Inflammatory– Multifocal on initial MRI or post chemo MRI– Diffuse pre-op malignant calcifications on

pre chemo mammogram

Summary

• Nodes– Node negative prior to NAT

• It is safe to offer sentinel node biopsy if lymph nodes clinically/ radiologically node negative prior to NAT

– Node positive prior to NAT • Likely sentinel node safe if use dual tracer and

take out at least 3 nodes • Jury out at the moment

New Chemotherapeutic Agents – better response for LABC

• Better response in subsets of breast cancers– Triple negative, Her 2 neu positive

• Her2 Positive patients (15-20% of all cancers)– NOAH study (Giani 2010) – chemo (doxorubicin, paclitaxel,

cyclophosphamide, methotrexate and 5 fluorouracil) + herceptin vs chemo alone – 38% vs 19% pCR

– GeparQuinto study (2012) – chemo + herceptin vs chemo alone – 30% vs. 23%

– Neosphere trial – Her2 positive/ER/PR positive pCR 26% and Her2neu positive/ER/PR-negative patients 63% pCR

New Chemotherapeutic Agents – better response for LABC

• Triple negative (15% of all breast cancers)– 22% pCR (MD Anderson Liedke 2010)– Now using cisplatin especially for BRCA patients

Considerations based on Receptor Status

• Higher pCR with triple negative (25%), her 2 neu positive patients (40%)

• If good clinical and imaging response then I will consider lumpectomy post treatment even if large tumor to begin with

• Can always go back if margins positive or diffuse disease across lumpectomy specimen to do mastectomy

Personal Practice

• We use NAT in young patients < 50 who are Her 2 neu positive and triple negative

• I will consider BCS if one quadrant of disease or larger if patient is triple negative or her 2 neu positive and has had good response

• Nodes – moving toward SNB if node positive prior to NAT– Difficulty what to do if sentinel node positive

– ? Will radiation deal with chemo-resistant disease

– ? Does patient need ALND