Diagnosis and Treatment of Early Breast Cancer Frances Wright MD MEd FRCSC

Diagnosis and Treatment of Early Breast Cancer

Frances Wright MD MEd FRCSC

Objectives

• imaging & diagnosis• historical overview of surgical treatment• current practice

– breast surgery– axillary staging

Radiologic Work-up

• Common– Mammogram– Ultrasound

• Good for young women• Usually targeted

• Uncommon– Galactogram– MRI

Mammogram

Some cancers are not found until they reach this size

A mammogram can find cancer when it is only this size

www.obsp.on.ca

Benefits of Mammogram

Survival and Stage of Breast Cancer

Mammogram X-ray of the Breast

• No screening tool 100% effective

• 85-90% of all breast cancers in women > 50 can be identified on mammogram

Mammograms and Cancer

Ultrasound of Breast Cancer

Magnetic Resonance Imaging

MRI

• Advantage– Not affected by breast density– Can identify occult disease

• Disadvantage– Dependent on who does the imaging– Sensitive, not very specific– Need MRI biopsy capability

Breast MRI – Screening…

• Who should get ?– Screening - evidence

• BRCA mutation carriers• Untested 1st degree relatives of carriers• Family history of hereditary cancer syndrome;

risk > 25%– Screening – no good evidence

• Prior chest radiation before age 30 (Hodgkins)• Some women with LCIS/atypia

MRI for Surgeons

• Treatment Planning – 3% of contralateral breast cancers are occult to

physical exam/ mammo (Lehman 2007)– Occult primary with axillary mets– Paget’s disease of the nipple– Invasive lobular carcinoma – Extent of disease work up– Evaluation of residual disease

Breast Imaging Reporting & Data Systems = BIRADSInterpretation Risk Ca

0 Incomplete assessment

1 Negative 0.05%

2 Benign 0.05%

3 Probably benign 2%

4 Suspicious 15 - 50%

5 Highly suspicious 95 - 99%

6 Known cancer 100%

Imaging

• BIRADs classification

1

2

3 5

4

Needs biopsyNo action

The work-up: Pathology

• Core needle biopsy– Gives more information – – type of cells – invasive vs. non-invasive

• Fine needle biopsy – not done as much now– Malignant vs. not malignant– Rule out cyst

• Excisional biopsy - uncommon now

Ductal carcinoma in situ

Invasive ductal carcinoma

Pathology: Ductal Carcinoma in situ and Invasive ductal Carcinoma

No lymph node involvement

Potential lymph node involvement

• There must be clinical, radiologic and pathologic agreement (concordance) in diagnosis

• If one doesn’t fit – consider surgical excisional biopsy

The evolution of breast surgery

• Halsted 1852 - 1922 • tumour begins small• systematic progression

to surrounding tissues

• involvement of lymphatics leads to distant spread

• local control = cure


• Halstedian principles• radical mastectomy

– Breast, pectoralis major and minor and axillary tissue


• Bernard Fisher • breast cancer systemic

at onset• surgery impact is local• lumpectomy + RT =

mastectomy


• “Fisherian” theory• breast conservation


Halstedian principles

radical mastectomy

versus

“Fisherian” theory

breast conservation

Breast conservation

• Removal of tumour with a margin of normal tissue

• Suitable for clinical stage I-II tumours (< 5cm, mobile)

• Post-operative radiation to reduce local recurrence rates

• Acceptable cosmetic outcome• Equivalent survival to mastectomy

• higher local recurrence rate 7-8% vs. 5%

Importance of local control

• Local control is important• 42,000 women in 78 RCT meta-analysis• For every 4 local recurrences at 5 years, 1 life

lost at 15 years (Early breast cancer trialists collaborative

group meta-analysis 2005)

Mastectomy

• Large or multicentric tumours• Unacceptable cosmesis, small breast : tumour ratio• Persistent positive margins with conserving surgery• Contraindication to radiation• Patient preference

Surgical Treatment of Early Breast Cancer

Breast

Breast conservation

or

Mastectomy

Axilla

Sentinel Node Biopsy possible axillary dissection

or

Level I/II axillary dissection

Axillary Surgery

• Axillary status most significant prognostic indicator• Role in determining need for adjuvant therapy• Provides local control if nodes involved with tumour• Controversial survival benefit

Why Axillary Surgery?

• Clinical Examination – not accurate– 35-40% of non-palpable nodes have histological

evidence of metastases (Luini 2005)

• Prognosis – The most important prognosticator– Presence, size and number of metastases in LNs


• Aids in determining best adjuvant therapy– 50% of adjuvant systemic therapy decisions need

axillary staging (Olivotto 1998)

– 30% of breast cancer patients might be considered for post mastectomy radiation (Manitoba data)


• Local control issues– 5% survival benefit (Orr 1999)

Likelihood of having lymph node involvement

Diameter of primary tumour

Percent with positive axillary nodes

0.5 - 0.9 cm 21 %

1.0 - 1.9 cm 33 %

2.0 – 2.9 cm 45 %

3.0 – 3.9 cm 55 %

4.0 – 4.9 cm 60 %

> 5.0cm 70 %

Carter 1989

The sentinel node for breast cancer

• Cabanas 1977 - penile cancer and inguinal nodes• Morton 1992 - melanoma• Krag 1994 - isotope in breast cancer• Guiliano - blue dye in breast cancer• Albertini - blue dye and isotope

Sentinel node concept

• First node or nodes in the draining nodal basin most likely to harbour metastases

• Status of the sentinel node reflects the status of the entire nodal basin

• If found to be negative, no further axillary nodes removed

• Enables staging with less morbidity

tumour

Radioisotope +/-Blue Dye

radioactivity

blue dye

Identifying the Sentinel Lymph Node

• Gamma Probe used intra-operatively to identify “hot” node

Identifying the Sentinel Lymph Node

• Blue dye is injected under the areola by the surgeon intra-operatively to aid SN identification

Pathological evaluation

• Axillary dissection - bi-valve of 10 - 20 nodes • retrieval of fewer nodes (1-3) allows more extensive

evaluation– H & E multiple sections every 2-3mm– immunohistochemical staining (IHC)

– No accepted standard

Weaver 2005

Effect of additional sections on identification of LN metastases

Do LN micromets indicate a worse survival?

• LN micromets (< 0.2 mm or 0.2-2mm) indicate that the patient has a worse overall survival

Noguchi 2002, ASCO 2005

Who should get a Sentinel Lymph Node Biopsy?

• T1, T2 breast cancer with clinically negative nodes– ASCO guidelines (2005) also support SLN in T2

cancers (non-randomized data) • Multicentric breast cancer• DCIS with mastectomy

Cancer Care Ontario 2009

DCIS – a few caveats

• *If doing a mastectomy• *Mastectomy and immediate reconstruction• * Large area > 5cm

– 27% will have an invasive foci

• *Core biopsy with suspected or proven micro-invasion – 10% risk of axillary mets with micro-invasion

• +/- Palpable

Adamovich 2003, ASCO 2005*, Cancer Care Ontario 2009

Who should NOT get a SLNB?

• Inflammatory breast cancer (T4)


Inconclusive or inadequate evidence

• Pregnancy – case reports only (blue dye concerns)• Before pre-operative therapy• T3 or T4 tumors• DCIS (without mastectomy)• Suspicious palpable axillary nodes• Prior breast surgery• After pre-operative systemic therapy (ongoing

study)


Why Sentinel Lymph Node biopsy?

• Assessment of randomized patients (SLN vs ALND) @ 6, 24 months

• Less pain• Less numbness• Less arm swelling• Better arm mobility

Veronesi 2003

Sentinel node biopsy by whom?

• Specialized multidisciplinary technique involving surgeon, nuclear medicine and

pathology• Surgeons should be familiar with risks/benefits and

perform breast surgery routinely• Recommended surgeons have performed at least 20

cases with “back up” axillary dissection first• Should have a localization rate > 90%• Should have false negative rate < 5%

What’s the early evidence for sentinel lymph node biopsy?

• ALMANAC trial 2006, Veronesi 2003 – no difference in staging, survival

• Veronesi 2003 - prospective randomized trial – 516 patients (T1) ages 40-75, randomized to either– SLNB + automatic ALND– SLNB and ALND only if SNB positive

• Outcomes variables– Breast cancer events (axillary mets, Supraclav mets,

recurrence in ipsilateral breast, or contra lateral breast, distant mets), morbidity

What’s the evidence for Sentinel Node Biopsy?

• Results– 32.3% LN positive in ALND– 35.5% LN positive in SLNB

• Accuracy of SLNB (from automatic ALND group) 97%

• No cases of axillary metastases in group that underwent SLN alone

• No difference in breast cancer events between 2 groups

NSABP 32 Sentinel lymph node biopsy compared with conventional ALND in clinically node negative

patients with breast cancer

Women with invasive breast cancer (n=5611)

Randomized

SLNB + ALND

Group I

SLNB and ALND Only if SLNB positiveGroup II

Technical Issues with the SLNB

• NSABP 32 – Stratification

• Age (≤ 49, > 50) • Surgical treatment plan (lumpectomy vs. mastectomy)• Clinical tumor size (≤ 2cm, 2.1-4cm, ≥4.1cm)

– All surgeons did 1-5 pre-qualifying cases of SLNB• SLNB identified with both blue dye,

radioactive tracerKrag 2007

Technical Issues with the SLNB

• Demographics and Results– 97% were T1/ T2– Technical success 97%, median number of

SLNs removed was 2– SLN positivity rate 26% and 25.7%– Location

• 98.6% located in axillary level I, II• 0.5% located in level III• 1% elsewhere (internal mammary, supraclavicular)

Krag 2007

Technical aspects of the Sentinel node biopsy

• Overall positive rate 29.2%• 1.4% SLN outside of axillary levels I, II• 24.3% labeled with radioactivity only (no blue

dye)• 9.8% False negative

– Need to palpate axilla for very firm suspicious nodes

– Lateral breast cancers, previous excisional biopsy, fewer nodes (i.e. 1 node 17.7%, 2 nodes 10%, 3 nodes 6.9%) higher FN

Krag et al. Lancet 2007. 8: 881-888

Update from B-32 2010No difference in overall survival

Group I SLNB + ALND

Group IISLNB and ALND

only if SLNB positive

Deaths 140/1975 169/2011

Overall survival (8 year KM estimate)

91.8% 90.3%

Number of regional node recurrences

8 14

Update for Z0010

• Data from ASCO update only (no paper)• Study design – prospective, multicentre

– 5210 women who had lumpectomy, SNLB and bilateral iliac crest bone marrow aspiration

– Negative sentinel nodes and the bone marrow aspirates were examined by IHC

Update for Z0010

• Results– Median patient age 56– 85% of tumors < 2cm– 80% invasive ductal and 80% ER positive– 76% (n=3995) sentinel nodes were

negative• 349 patients (10%) had IHC positive nodes

– Bone marrow micromets found in 104/ 3413 (3%) of patients examined

Update for Z0010

• Results– IHC positive bone marrow not related to tumor size – 5 year survival

• 93% histologically identified positive SNB• 96% with IHC positive SNB or nodes with no metastases• Bone marrow mets not associated with overall worse survival

– Predictors of survival: histologically positive SNB, younger age, tumor size (not IHC positive node, not bone marrow mets)

• Conclusion: routine examination of sentinel node with IHC not warranted

Update for Z0011• Inclusion criteria

– T1, T2– Lumpectomy (negative margins) and positive SLNB– All patients received radiation– All patients received adjuvant therapy

• Exclusion– Implants, multicentric disease, bilateral breast cancer, neo-adjuvant

chemotherapy or hormonal therapy, history of ipsilateral axillary surgery, pregnant/ lactating, mastectomy

– IHC only positive SLN– Distant mets– ***Matted nodes, gross extranodal disease at time of SLNB and

three or more involved SLNs

Update for Z0011

• Study schema • Sentinel node positive• Randomized to ALND

or no further axillary treatment– ALND – had to have at

least 10 nodes and be performed within 42 days of positive SLNB

• Both groups got whole breast radiation and adjuvant systemic therapy

Annals of Surgery 2010

Update for Z0011

• Planned accrual of 1900 patients– 891 patients randomized (35 then excluded

as withdrew consent) ****• Intention to treat analysis

Z0011 study sample Remember accrual meant To be 1900 (46%)

Z0011 Results

• Median patient age 56 (67% > 50)– 83% invasive ductal, 83% ER positive, 40% LVI, 30%

Grade III, – 96% had adjuvant systemic therapy (either chemo

{46%} or hormones {58%} p=NS)

• Median total number of positive nodes with ALND = 1

• Median number of positive nodes with SLNB = 1

Treatment received Results ALND n=388 SNLB n=425

Median number of nodes removed

17 2

Positive nodes, % (n)

0 0.88% (3) 6.9% (28)

1 58.1% (198) 71.8% (290)

2 19.9% (68) 18.3% (74)

>3 21.1% (72) 3% (12) )

Unknown 47 21

Regional recurrence in ipsilateral axilla

0.5% (2) 0.9% (4)

Local recurrence (median 6.3 year)

3.6%(15) 1.8% (8)

Receipt of adjuvant therapy

403 (96%) 423 (97%)

Z0011 data

• 27% (n=97) in ALND arm had additional nodal mets removed by ALND

• At a median of 6.3 years – authors suggest that not all non SN metastases develop into clinically detectable disease

Z0011 Caveats

• Study is significantly underpowered (meant to accrue 1900, accrued < 900)

• Most patients were post menopausal • All the patients had a lumpectomy and

whole breast radiation– Likely irradiating lower axilla

• 96% of patients had systemic therapy– Which lowers rate of loco-regional

recurrence

Caveats with Z0011

• Patients with extranodal disease, three or more involved SLNs and matted nodes were excluded

• Median f/u is 6.3 years– Is this too short for breast cancer?

Z0011 Conclusions

• In a certain subset of patients with minimal disease in axilla, having a lumpectomy, radiation and systemic therapy– Is it ok to omit the ALND?– Maybe – discuss with the patient risks and

benefits– Talk with your tumor board

What to do in the meantime?

Pathology Definition What to do

pN0 (i-) No regional node mets, IHC negative

Nothing

pN0 (i+) < 0.2mm Nothing

pN1 mi Micro metastases > 0.2 mm - 2mm

ALND*

pN1> 2mm

ALND*

* Discuss at Tumor board/ with patient/ Nomogram

Options….

• Memorial Sloan Kettering Nomogram – predict the likelihood of non sentinel lymph

node metastases after a positive SLN biopsy

• Looks at tumour factors – Nuclear grade, LVI, multifocal, ER status,

number of negative LN, Number of positive LN, pathological size of tumour, method of detecting sentinel LN.

http://www.mskcc.org/nomograms Van Zee 2003

Breast Cancer Treatment in the 20th Century:Quest for the Ideal Local-regional Therapy

1900 2000

Radical Mastectomy

Extended Radical Mastectomy

Modified Radical Mastectomy

Lumpectomy

BC + RT

Ax LND

BCT + RT

Sentinel Node BiopsyI D E A L T H E R A P Y

1950 Radiation

Overtreatment

Summary

• Evolution of breast cancer surgery from more to less

• More and more specialized • Less morbidity for patient

Update from B-32 2010

• Patient Reported Morbidity Data – Arm symptoms (tenderness, swelling, pain, tightness,

numbness, weakness)– Arm avoidance– Social and occupational activity limitations

• More arm symptoms for ALND vs SLNB at 6 mos and 12 mos

• From 12-36 mos < 15% of either ALND, SLNB patients reported moderate or greater severity of any given symptom or activity limitation

JCO 2010

Update from B-32 2010

• Shoulder range of motion, arm volumes and numbness/ tingling

• Shoulder abduction– Peaked at 1 week for ALND (75%), SLNB (41%)

• Numbness and tingling – peaked at 6 months– ALND (49%, 23%), SLNB (15%, 10%)

• Arm volume ≥ 10% at 36 months – ALND 14%, SLNB 8%

Documents

Diagnosis and Treatment of Early Breast Cancer Frances Wright MD MEd FRCSC