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

2. Objectives imaging & diagnosis
historical overview of surgical treatment
current practice
breast surgery
axillary staging

3. Radiologic Work-up Common Mammogram Ultrasound Good for young women
Usually targeted
Uncommon
Galactogram
MRI

4. Mammogram

5. 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   

6. Survival and Stage of Breast Cancer

7. 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

8. Mammograms and Cancer

9. Ultrasound of Breast Cancer

10. Magnetic Resonance Imaging

11. 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

12. 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

13. 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

14. Breast Imaging Reporting & Data Systems = BIRADS
Interpretation
Risk Ca
Incomplete assessment 1
Negative
0.05% 2
Benign 3
Probably benign 2% 4
Suspicious % 5
Highly suspicious % 6
Known cancer
100%

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

16. 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

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

18. There must be clinical, radiologic and pathologic agreement (concordance) in diagnosis
If one doesn’t fit – consider surgical excisional biopsy

19. The evolution of breast surgery
Halsted
tumour begins small
systematic progression to surrounding tissues
involvement of lymphatics leads to distant spread
local control = cure

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

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

23. The evolution of breast surgery
“Fisherian” theory
breast conservation

24. The evolution of breast surgery
Halstedian principles
radical mastectomy
versus
“Fisherian” theory
breast conservation

25. 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%

26. 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)

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

28. Surgical Treatment of Early Breast Cancer
Breast conservation or
Mastectomy
Axilla
Sentinel Node Biopsy possible axillary dissection or
Level I/II axillary dissection

29. 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

30. 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

31. 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)

32. Why Axillary Surgery? Local control issues
5% survival benefit (Orr 1999)

33. Likelihood of having lymph node involvement
Diameter of primary tumour
Percent with positive axillary nodes cm
21 % 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

34. The sentinel node for breast cancer
Cabanas penile cancer and inguinal nodes
Morton melanoma
Krag isotope in breast cancer
Guiliano - blue dye in breast cancer
Albertini - blue dye and isotope

35. 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

36. tumour

37. Radioisotope +/-Blue Dye

38. radioactivity
blue dye

39. Identifying the Sentinel Lymph Node
Gamma Probe used intra-operatively to identify “hot” node

40. Identifying the Sentinel Lymph Node
Blue dye is injected under the areola by the surgeon intra-operatively to aid SN identification

41. Pathological evaluation
Axillary dissection - bi-valve of nodes
retrieval of fewer nodes (1-3) allows more extensive evaluation
H & E multiple sections every 2-3mm
immunohistochemical staining (IHC)
No accepted standard

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

44. 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

45. 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

46. 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

47. Who should NOT get a SLNB?
Inflammatory breast cancer (T4)
Cancer Care Ontario 2009

48. 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

49. Why Sentinel Lymph Node biopsy?
Assessment of randomized patients (SLN vs 6, 24 months
Less pain
Less numbness
Less arm swelling
Better arm mobility
Veronesi 2003

50. 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%

51. What’s the early evidence for sentinel lymph node biopsy?
ALMANAC trial 2006, Veronesi 2003
no difference in staging, survival
Veronesi 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

52. 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

53. 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

54. 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

55. 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

56. 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 :

57. 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

58. 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

59. 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

60. 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

61. 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

62. 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

63. Update for Z0011 Planned accrual of 1900 patients
891 patients randomized (35 then excluded as withdrew consent) ****
Intention to treat analysis

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

65. 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

66. 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%)

67. 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

68. 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

69. 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?

70. 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

71. 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

72. 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.
Van Zee 2003

73. 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

74. Summary Evolution of breast cancer surgery from more to less
More and more specialized
Less morbidity for patient

75. 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 mos < 15% of either ALND, SLNB patients reported moderate or greater severity of any given symptom or activity limitation
JCO 2010

76. Update from B
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%