1. “Examining Advances in
Management of Breast Cancer
During the Last 30 Years”
LOCAL REGIONAL TREATMENT
7th Annual Breast Health Summit
Houston, TX
10/21/2011
A. Marilyn Leitch, MD
Professor of Surgery
UT Southwestern

2. OUTLINE
 Trends in breast cancer surgery
 Tension between BCS and total mastectomy
 Evolution to breast conserving surgery
 Increasing rate of bilateral mastectomies
 Adoption of Sentinel node biopsy of nodal
staging
 Abandonment of ALND for positive sentinel
node

3. Death rates decreased 31% between 1989 and 2007

4. 5 YEAR RELATIVE SURVIVAL RATES
BREAST CANCER: 1996 to 2005
SEER Data (CA Cancer J Clin 2010)
99
93 98
100
85 84
80
Percentage %
72
60
40 25 23
20 17
0
LOCAL REGIONAL DISTANT
WHITE AFRICAN AMERICAN ALL RACES

5. Trends in Breast
Cancer Surgery

6. Trends in Breast Cancer Surgery
BREAST CONSERVATION THERAPY:
LONG-TERM VALIDATION OF SAFETY

7. SURVIVAL IN RANDOMIZED TRIALS OF
BREAST CONSERVATION VS. MASTECTOMY
90%
80%
70%
60%
50%
MAST
40%
BCT
30%
20%
10%
0%
Gustave- Milan NSABP NCI EORTC Danish
Roussy

8. 20 YEAR FOLLOW-UP OF BREAST
CONSERVATION RANDOMIZED TRIALS:
OVERALL SURVIVAL
NEJM 2002; 347: 1227-32 & 1233-41 CANCER 2003;98 697-702

9. 20 YEAR FOLLOW-UP OF RANDOMIZED
BREAST CONSERVATION TRIALS:
LOCAL RECURRENCE
NEJM 2002; 347: 1227-32 & 1233-41 CANCER 2003;98 697-702

10. PATTERN OF LOCAL
RECURRENCE OVER TIME: B-06
TOTAL
LR < 5 YRS 5-10 YRS >10 YRS
78
EVENTS 40% 29% 31%
(14.3%)

11. LOCAL RECURRENCE IN
RECENT BCT TRIALS
 NSABP trials since B-06 show lower
rates of LR
 6% LR at 10 years in node negative
patients
 Attributed to use of adjuvant
systemic therapy
NEJM 2002;347:1233-41

12. NIH CONSENSUS CONFERENCE
ON EARLY STAGE BREAST
CANCER: 1990
 Outcomes of breast conserving
surgery similar to mastectomy in
randomized trials
 Breast conservation therapy is the
preferred treatment for most stage I
and II breast cancers

13. INCREASING UTILIZATION OF
BREAST CONSERVATION OVER TIME
68% 69%
70%
58%
60%
49%
50% 46%
40% 35% 36%
30%
19%
20%
10%
0%
1985-89 1995 2000 2007 Stage I
Stage II
Cancer 1999; 86: 628-37 / Cancer 1998;83:1262-73 / Commission on Cancer
Benchmark Reports 9/2003, 9/2010

14. WHY WOMEN DECLINE
BREAST CONSERVATION
 Fear of radiation
 Disbelief in radiation efficacy
 Inconvenience of prolonged and
daily radiation treatments
 Lack of radiation treatment facility
nearby
 Disbelief in equivalency to
mastectomy for survival
 Strong family history breast cancer

15. TREND TOWARD MORE AGGRESSIVE
SURGICAL TREATMENT
 SEER 1998-2003
• 152,755 patients with stage I-III
breast cancer
 3.3% (4969) had contralateral
Prophylactic Mastectomy (PM)
 contralateral PM increased from
1.8% to 4.5%

16. Contralateral Prophylactic Mastectomy (CPM):
Increased Use in U.S.
 CPM increased from 4% to 11 % of all
patients having mastectomy
 150% increase in opposite breast
mastectomy over 1998-2003 when
treated for Invasive breast cancer in
one breast

17. More likely to have contralateral
mastectomy if:
 Young
 White race
 More favorable tumors
 Women with previous history
of other cancer
 Infiltrating lobular cancer

18. Bilateral Mastectomy Rate INCREASED
FROM 0% TO 10% from 1997-2007
12%
10%
PERCENTAGE
8%
6%
4%
2%
0%
1996 1998 2000 2002 2004 2006 2008
YEAR
UT SOUTHWESTERN EXPERIENCE

19. ASSISTING WOMEN IN DECISION MAKING
FOR MASTECTOMY OR NOT?
 Inform in unbiased way about options- data
driven
 Discuss alternatives that make lumpectomy
without opposite mastectomy less worrisome
 Adjuvant therapy taken after surgery
 Enhanced surveillance with MRI
 Lifestyle risk reduction strategies
 ONCOPLASTIC ALTERNATIVES for
making saved breast more attractive and
matching opposite breast
 Insurance covers these procedures

20. AXILLARY STAGING:
SENTINEL NODE BIOPSY
MINIMIZING NODAL SURGERY
Has replaced ALND as standard for nodal staging

21. HISTORY OF AXILLARY STAGING
FOR BREAST CANCER
 Formal axillary node dissection levels
2-3 standard of care for decades
 NSABP B04 trial showed ALND not
associated with improved survival
 With smaller tumors detected in
mammography screening, less node
positive
 Thus nodes removed unnecessarily

22. RATIONALE FOR LYMPHATIC MAPPING
AND SENTINEL NODE BIOPSY
 Axillary dissection carries morbidity of
lymphedema, decreased ROM and
decreased sensation of upper inner arm
 The status of the axillary nodes is the
most important prognostic feature for
breast cancer
 If axilla accurately staged with a sentinel
node biopsy which removes few nodes,
then less morbidity of staging procedure

23. SUMMARY OF SENTINEL NODE
BIOPSY SERIES DATA
 False negative rate 0-12%
 Success in identification of sentinel
node 70-100%, with most series better
than 90% success
 Higher success in SLN identification
and lower false negative rates (<5%) in
series with more experience

24. WHAT WE HAVE LEARNED
FROM CLINICAL TRIALS
 ACOSOG Z0010- ? significance of IHC
occult mets
 NSABP B32- ? Safety of SLND
compared to ALND
 ACOSOG Z0011- role of ALND for
positive sentinel node

25. ACOSOG Z10 TRIAL
Giuliano, A. E. et al. JAMA 2011;306:385-393
To identify:
 Prevalence and prognostic significance of sentinel
lymph node (SLN) micrometastases and bone
marrow (BM) micrometastases detected by
immunohistochemistry (IHC)
• Assess risk of regional recurrence for SLN negative
by H&E
• Assess operative morbidity
 Women with clinical T1-T2N0M0 breast cancer

26. ACOSOG Z10 METHODS
 5,539 patients (4/1999 - 5/2003)
 Breast conserving surgery, Bone marrow aspiration and
sentinel node biopsy
 Bone marrow specimens examined with IHC (investigators
blinded to results)
 SLNs processed by standard pathology with H&E staining
 SLNs negative by H&E examined with IHC for cytokeratin
(investigators blinded to results)
 H&E node positive patients-
 Axillary node dissection (ALND) or
 Randomized on ACOSOG Z0011 study to no further
surgery or ALND

27. SURGICAL TECHNICAL OUTCOMES: Z0010
Using a standard skill requirement surgeons
achieved a low SLN failure rate
 98.7% SLN identification rate
Posther KE et al: Annals of Surgery 2005
Low complication rate for SLN dissection with
defined incidence of lymphedema
 1-7% rate of various axillary complications
 7% rate of lymphedema
Wilke LG et al: Annals of Surg Oncology 2006

28. ACOSOG Z10: FINDINGS
 Sentinel Lymph node data
 H&E: 24% positive for metastases
 IHC: 10% of cases with micrometastases
 Increasing breast tumor size is associated
with positive SLN
 Bone marrow data – n= 3,413
 ICC:3% micrometastases
 NO relationship to breast tumor size

29. Bone Marrow Specimen Results and Cumulative Incidence of Death
Median follow-up 6.3 yrs
Giuliano, A. E. et al. JAMA 2011;306:385-393
Copyright restrictions may apply.

30. Sentinel Lymph Node Results and Cumulative Incidence of Death
NO DIFFERENCE
Giuliano, A. E. et al. JAMA 2011;306:385-393
Copyright restrictions may apply.

31. Conclusions from ACOSOG Z10
 Outcome in this population was EXCELLENT- 5 year
overall survival of 93% in patients with H&E+ SLN
 Occult SLN metastases detected by IHC not associated with
overall survival differences (95.7% IHC negative and 95.1%
for IHC positive)
 Occult bone marrow metastases were significantly
associated with increased mortality
 Routine IHC examination of H&E–negative SLNs and bone
marrow is not clinically warranted for early-stage (clinical
T1-T2N0) breast cancer.
 Incidence BMA+ was too low to recommend incorporating
bone marrow aspiration biopsy into routine practice for
patients with clinical T1,2 N0M0 breast cancer

32. NSABP B-32:
 Largest prospective randomized phase III
trial of SLND alone vs SLND +ALND for
sentinel node negative
 5,611 women with operable, clinically N0
 Median follow-up 95 mos

33. Kaplan-Meier Survival Estimates According to the Presence or Absence of Occult Metastases
Detected in Initially Negative Sentinel Lymph Nodes.
Weaver DL et al. N Engl J Med
2011;364:412-421

34. NSABP B32 Conclusions
• Significant difference overall survival between patients
with IHC occult metastases and those in whom no
occult metastases were detected (94.6% and 95.8%)
• Occult metastases were an independent prognostic
variable in patients with sentinel nodes that were
negative on initial examination; however, the
magnitude of the difference in outcome at 5 years was
small (1.2 percentage points)
• Data do not indicate a clinical benefit of additional
evaluation with IHC for initially negative sentinel nodes
in patients with breast cancer.

35. COMPARISON ACOSOG Z10
AND NSABP B32
ACOSOG Z10 NSABP B32
Tumor size 1.4cm
T1 83% 80%
H&E pos SLNS 24% 26%
IHC pos SLNS 10.5% 15.9%
BMA positive 3% NA
Systemic Adjuvant 86% 78%

36. MANAGEMENT OF THE POSITIVE
SENTINEL NODE
 Standard of care :
 Axillary Lymph Node Dissection
 Is ALND necessary?

37. RATIONALE TO AVOID ALND IN
SLN POSITIVE PATIENTS
 SLN often the only positive node
 Adjuvant therapy may treat
subclinical nodal metastases
 Most data indicate that ALND
does not improve survival
 ALND is for staging

38. ACOSOG Z0011
A randomized trial of axillary node dissection
VS no axillary dissection in women with
clinical T1-2 N0 M0 breast cancer who have
a positive SN
Target accrual 1900 patients (non-inferiority)
• 4/1999 - 12/2004
• Closed early with 891 pts
38

39. ACOSOG Z11 RESULTS:
REPORTED ASCO 6/2010
 106 (27.4%) patients undergoing ALND had
additional positive nodes removed beyond SN
 Median follow-up = 6.3 years
 Regional NODAL recurrence seen in only
0.7% of the entire population

40. Locoregional Recurrence-Free Survival
40

41. Summary
Locoregional Recurrence-Free Survival
 Locoregional recurrence in only 2.8% of
SLND and 4.1% of ALND patients
 Only age (< 50) and higher Bloom-
Richardson score were associated with
locoregional recurrence by multivariable
analysis
 Locoregional recurrence not related to
number of positive SNs, size of SN
metastasis, or number of lymph nodes
removed 41

42. Overall Survival
100
90
80
70
60
% Alive
50
40
30
20 ALND
No ALND
P-value = 0.25
10
0
0 1 2 3 4 5 6 7 8
42
Time (Years)

43. Summary
Disease-Free and Overall Survival
 No significant difference in DFS between
patients treated with SLND (83.9%) or ALND
(82.2%)
 No significant difference in OS between
patients treated with SLND (92.5%) or ALND
(91.8%)
 Only older age, ER-, and lack of adjuvant
systemic therapy - NOT OPERATION -
were associated with worse OS by
multivariable analysis.
43

44. Z11 Conclusion
In this prospective
randomized study - SLND
alone provided excellent
locoregional control and
survival comparable to
completion ALND for SLN
node positive patients

45. REMEMBER: APPLIES TO
SELECTED PATIENTS
• Initially clinically node negative
• Patients having breast conserving
surgery + radiation
• MASTECTOMY PATIENTS
EXCLUDED
• < 2 positive SLNs and no gross
extranodal extension

46. ACOSOG Z10 AND Z11/ NSABP B32
PRACTICE CHANGING
• Abandon use of IHC to evaluate
sentinel nodes
• Abandon ALND for positive
sentinel node

47. THANK YOU

48. EVOLVING ROLE OF RADIATION IN
BREAST CANCER MANAGEMENT
 After breast conserving surgery
 Whole breast radiation
 Accelerated partial breast radiation
 After mastectomy
 Positive margin
 >3 positive nodes
 Tumor > 5 cm with positive nodes
 Stage III
 Controversial: 1-3+ nodes

49. Value of Local Control for Survival
Lancet 366:2087, 2005
 Oxford overview 2005
 Node positive breast cancer
treated with mastectomy,
radiation reduced local recurrence
from 29% to 8% at 15 years
 5% increase in overall survival for
node positive with radiation

50. OVERCOMING RADIATION
CONCERNS: ACCELERATED
PARTIAL BREAST RADIATION
Vicini, J Clin Oncol 2001;19:1993-2001,
Brachytherapy 1 (2002) 184–190
 Administer radiation to lumpectomy site ONLY
instead of whole breast
 Treatment complete in 4-5 days instead of 5-7
weeks
 Alternative methods of local radiation:
 Internal devices
 External beam
 Limited to specific circumstances
 Clinical trial at UT Southwestern for Cyberknife
application of PBI

51. INITIAL CRITERIA FOR SELECTING
PATIENTS FOR PARTIAL BREAST
RADIATION (PBI)
ABS ASBS
AGE >45 >50
HISTOLOGY Solitary tumor, Invasive or
Node negative invasive ductal in situ ductal
Tumor size < 3 cm < 2 cm
Margins Negative > 2 mm

52. ACCELERATED PARTIAL BREAST IRRADIATION
CONSENSUS STATEMENT FROM
THE AMERICAN SOCIETY FOR RADIATION
ONCOLOGY (ASTRO) 2009
- Defined
Suitable candidates – age > 60
At variance with prior guidelines
Cautionary – age 50-59yrs
Unsuitable - < 50 yrs

53. COMPARATIVE CRITERIA FOR
SELECTING PATIENTS FOR PARTIAL
BREAST RADIATION (PBI)
ABS ASBS ASTRO
AGE >45 >50 > 60
HISTOLOGY Solitary tumor, Invasive ductal Invasive ductal
Node negative invasive ductal DCIS no DCIS
Tumor size < 3 cm < 2 cm < 2cm
Margins Negative > 2 mm > 2 mm

56. Breast Cancer Statistics, 2011 : Trends in Female Breast
Cancer Death Rates by Race and Ethnicity, 1975 to 2007
CA: A Cancer Journal for Clinicians
pages n/a-n/a, 3 OCT 2011 DOI: 10.3322/caac.20134
http://onlinelibrary.wiley.com/doi/10.3322/caac.20134/full#fig3

57. Overall Survival by Bone Marrow IHC
100
90
80
70
60
% Alive
50
40
30 P-value = 0.01
20 Negative
10 Positive
0
0 1 2 3 4 5 6 7 8 9 10
Time in Years

58. Associations of Prognostic Variables
with Overall Survival
Univariable Analysis Multivariable Analysis
P value P value
Treatment Arm NS NS
Age (< 50, > 50) 0.002 0.006
ER status 0.012 0.013
PR status NS NS
# Positive Total LN 0.044 NS
LVI present vs. absent NS NS
Histologic Type NS NS
SN Metastasis Size NS NS
Tumor Size 0.042 NS
Adjuvant Systemic Therapy 0.020 0.025
Grade NS NS
58