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

Benefits of Mammogram www.obsp.on.ca 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

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 Disadvantage 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 = BIRADS Interpretation Risk Ca Incomplete assessment 1 Negative 0.05% 2 Benign 3 Probably benign 2% 4 Suspicious 15 - 50% 5 Highly suspicious 95 - 99% 6 Known cancer 100%

Imaging BIRADs classification 1 2 3 4 5 No action Needs biopsy

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

Pathology: Ductal Carcinoma in situ and Invasive ductal Carcinoma No lymph node involvement Ductal carcinoma in situ Potential lymph node involvement Invasive ductal carcinoma

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

The evolution of breast surgery Halstedian principles radical mastectomy Breast, pectoralis major and minor and axillary tissue

The evolution of breast surgery Bernard Fisher breast cancer systemic at onset surgery impact is local lumpectomy + RT = mastectomy

The evolution of breast surgery “Fisherian” theory breast conservation

The evolution of breast surgery 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 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 Prognosis 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

Why Axillary Surgery? 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)

Why Axillary Surgery? 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

Effect of additional sections on identification of LN metastases Weaver 2005 43

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 44

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) Cancer Care Ontario 2009

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) Cancer Care Ontario 2009

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

Women with invasive breast cancer (n=5611) 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 positive Group 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 tracer Krag 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 2010 No difference in overall survival Group I SLNB + ALND Group II SLNB 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 Exclusion 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) 0.88% (3) 6.9% (28) 1 58.1% (198) 71.8% (290) 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 pN1 mi Micro metastases > 0.2 mm - 2mm ALND* pN1 > 2mm * Discuss at Tumor board/ with patient/ Nomogram

Options…. Memorial Sloan Kettering Nomogram Looks at tumour factors 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 Overtreatment Extended Radical Mastectomy Radical Mastectomy Modified Radical Mastectomy BCT + RT Sentinel Node Biopsy BC + RT Ax LND I D E A L T H E R A P Y 1900 1950 2000 Radiation Lumpectomy

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%