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Implications of NSABP B-32
and Loco-Regional Therapy
Considerations After
Neoadjuvant Chemotherapy
Terry Mamounas, M.D., M.P.H, F.A.C.S.
Professor of Surgery
Northeastern Ohio Medical University
Medical Director
Aultman Cancer Center
NSABP B-04
Operable
Breast Cancer
N=1079
80
Clinically
Node-Negative
Radical
Mast.
Total
Mast.
HR: 1.03
(95% CI 0.87-1.23; P=0.72)
Overall Survival
100
Global p=0.68
60
Total
Mast.
+
XRT
40
20
0
Patients
RM
362
TMR
352
TM
365
0
5
10
• 40% of pts in the RM group had + nodes
• Thus, only about 290 pts contribute to the
comparison of RM with TM (about 145/group)
Deaths
259
274
259
15
20
25
Years
Fisher B: NEJM, 2002
NSABP B-32 Schema
Clinically Negative Axillary Nodes
N=5611
Stratification
• Age
• Clinical Tumor Size
• Type of Surgery
Randomization
GROUP 1
Sentinel Node
Biopsy
Axillary
Dissection
GROUP 2
Sentinel Node
Biopsy*
*Axillary node dissection
only if the SN is positive
NSABP B-32
Technical Results
• Identification Rate:
97%
• False Negative Rate:
9.7%
• Average number of SNs:
2.9
• Factors significantly affecting ID rate:
–Age, Tumor Size and Tumor Location
• Factors significantly affecting FN rate:
–Type of Biopsy and Number of Removed SNs
Krag D, et al: Lancet Oncol 2007
4
Clinically Negative Axillary Nodes
B-32
Randomization
GROUP 1
GROUP 2
SN +AD
SN
Stratification
• Age
• Clinical Tumor Size
• Type of Surgery
Intraop cytology &
postop HE
SN Pos
829 pts
SN Neg
(SN+AD)
SN pos
+ AD
SN Neg
(SN only)
FU
793 pts
FU
1,975 pts
2,011 pts
Krag D et al: ASCO 2010 Abstr. LBA 505
NSABP Protocol B-32
% Surviving
20 40 60 80
100
Overall Survival for SN Negative Patients
N
Deaths
1975 140
2011 169 HR=1.20 p=0.117
0
Trt
SNR+AD
SNR
Data as of December 31, 2009
0
2
4
6
8
Years After Entry
* 300 deaths triggered the definitive analysis
* 309 reported as of 12/31/2009
Krag D et al: Lancet Oncol 2010
NSABP Protocol B-32
% Disease-Free
20 40 60 80
100
Disease-Free Survival for SN Negative Pts
N
Events
1975 315
2011 336 HR=1.05 p=0.542
0
Trt
SNR+AD
SNR
0
Data as of December 31, 2009
2
4
Years After Entry
6
8
Krag D et al: Lancet Oncol 2010
B-32 Hazard Ratios Between Groups
According to Site of Treatment Failure
Dead, NED
2nd cancers
Opposite Breast Cancers
Distant Recurrences
Local Regional Recurrences
All events
SNR better
HR= 1.05
SNR+AD better
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Hazard Ratio
Krag D et al: Lancet Oncol 2010
9
NSABP B-32: Local and Regional
Recurrences as First Events
3.0
2.7
2.4
Patients (%)
2.5
SNR + ALND (n = 1975)
SNR (n = 2011)
2.0
1.5
1.0
0.5
0.3
0.1
0.25 0.3
0
Local
Axillary
Extra-axillary
Recurrence Type
Krag D et al: Lancet Oncol 2010
10
NSABP B-32: Significantly Lower
Morbidity Without vs. With ALND
P < .001
35
P < .001
Patients (%)
28
25
P < .001
20
19
15
SNR + ALND (n = 1975)
SNR (n = 2011)
31
30
P < .001
17
13
13
10
8
7
5
0
Shoulder
Abduction
Deficit
Arm Volume
Difference
> 5%
Arm
Numbness
Arm
Tingling
Ashikaga T: J Surg Oncol 2010
B-32: Conclusion
• No significant differences were observed
OS, DFS, or Regional Control
• Morbidity decreased
When the SN is negative, SN surgery alone
with no further AD is appropriate, safe, and
effective therapy for breast cancer patients
with clinically negative lymph nodes.
Krag D et al: Lancet Oncol 2010
B-32 In Perspective
• Could the B-32 trial ever show more than
2% difference in overall survival?
ID Rate 97%
SNB + AND
2807 pts
157 pts had no SNB
829 pts
1,975 pts*
Neg SN
75 Pts
Had Negative SN and
Positive NSNs on AND
*3 pts had no F/U
SNB Alone
2804 pts
793 pts
Node-Positive
SND + AND
2.6%
Reg. Nodal
Recurrence
8 vs. 14
2,011 pts
Neg SN
About 75 Pts
Positive NSNs
and did not have AND
B-32 In Perspective
• Could the B-32 trial ever show more than
2% difference in overall survival?
ID Rate 97%
SNB + AND
2807 pts
157 pts had no SNB
SNB Alone
2804 pts
1:40 Dilution
ofptsAny Real
829 pts 793
2,011 pts
Node-Positive
1,975 pts*
Benefit
from
ALND!
SND + AND
Neg SN
Neg SN
75 Pts
Had Negative SN and
Positive NSNs on AND
*3 pts had no F/U
2.6%
Reg. Nodal
Recurrence
8 vs. 14
About 75 Pts
Positive NSNs
and did not have AND
NSABP B-32: Occult Metastases
14
Clinically Negative Axillary Nodes
Randomization
GROUP 1
Sentinel Node
Biopsy
Axillary
Dissection
GROUP 2
Sentinel Node
Biopsy*
*Axillary node dissection
only if the SN is positive
IHC and detailed pathologic examination of the SNs
performed centrally and results were not disclosed
Weaver D et al: N Engl J Med 2011
NSABP B-32: Effect of Occult Metastases on
Survival in Node-Negative Breast Cancer
15.9%
Weaver D et al: N Engl J Med 2011
NSABP B-32: Effect of Occult Metastases on
Survival in Node-Negative Breast Cancer
Weaver D et al: N Engl J Med 2011
Loco-Regional Therapy
Considerations
After Neoadjuvant
Chemotherapy
Individualizing Loco-Regional Therapy with
Neoadjuvant Chemotherapy
Achievements
• Conversion of patients with inoperable tumors
to operable candidates
• Conversion of mastectomy candidates to
candidates for BCS
• Improvement in cosmesis by reducing the size
of lumpectomy in BCS candidates with large
tumors
Individualizing Loco-Regional Therapy with
Neoadjuvant Chemotherapy
Promises
• Reduction in the extent of axillary surgery by
down-staging involved axillary nodes (SNB)
• Reduction in the extent of L-R XRT by downstaging primary tumors and axillary nodes
• Potential for eliminating some loco-regional
therapy altogether (surgery or XRT) with the use
of more active regimens and/or with appropriate
patient selection with biomarkers
Surgical Management of Axillary Nodes
After NC
• NC down-stages axillary
nodes in 20-40% of the
patients
• Potential for decreasing
the extent of axillary
surgery with SNB
% Conversion
From Node (+)
To Node (-)
40
30
20
37
30
10
43
19
0
AC
FEC
NSABP B-18 EORTC
ATCMF ACTXT
ECTO NSABP B-27*
*Assuming 30% nodal downstaging
with neoadjuvant AC
SNB After NC
Multi-Center Studies: NSABP B-27
(n=428)
• Identification Rate: 85%
• With blue dye: 78%
• With isotope + blue dye: 88-89%
• False Negative Rate: 11%
• With blue dye: 14%
• With isotope + blue dye: 8.4%
Clinically Node (-): 12.4%
Clinically Node (+): 7.0%
P=0.51
Mamounas EP: J Clin Oncol, 2005
SNB After NC
Meta-Analysis of Single-Institution
and Multi-Center Studies
• 24 studies
• 1779 patients
Conclusion:
• Identification
Rates: 63-100%
SNB isestimate:
a reliable
tool for
–Pooled
89.6%
planning
treatment
after NC
• False
Negative
Rates: 0-33%
–Pooled estimate: 8.4%
Kelly A et al: Acad Radiol 2009
SNB After NC: Single Institution Series
Positive Axillary Nodes Before NC
Author
Stage
Shen, 2006
T1-T4, N1-N3
Lee, 2006
T1-T4, N1
(Palpable and FNA (+)
or > 1cm thick with
loss of fat hilum on
US and SUV > 2.5
Newman,
2007
Resectable
T1-3, N1
(FNA (+) under US)
All
# Pts
(Node +)
Success
Rate ( %)
FN Rate
(%)
Accurate
69(40)
93
25
No
219 (124)
78
6
Yes
40 (28)
98
11
Yes
328 (172)
84
11.6
Z1071: SLNB + AND After NC
T1-4 N1-2 invasive breast cancer
(pretreatment axillary ultrasound with FNA or core biopsy
documenting axillary metastases)
↓
REGISTER*
↓
Patients receive neoadjuvant chemotherapy
(stratify patients by age, stage and
number of cycles and type of chemotherapy)
↓
Target
Accrual:
550 pts
REGISTER*
↓
SLN and ALND
SNB Before NC: Pros and Cons
• Helpful if the SN is negative
• Patients with large operable breast
cancer have high likelihood of positive
nodes (50-70%)
• Does not take advantage of the
downstaging effects of NC on nodes:
30-40% conversion from (+) to (-)
• Requires two surgical procedures
SNB Before NC:
Selection of Loco-Regional XRT?
• Breast XRT: Should be always given after
lumpectomy
• Chest
Regional
XRT:
Consider
CanWall
Weand
Use
Tumor
and
Nodal
factors predicting local-regional failure after
Response
to
NC
in
Order
to
NC
Individualize the Use of L-R XRT?
• These factors may predict LR failure more
accurately than the original pathologic nodal
status before NC
Combined Analysis of B-18/B-27
Independent Predictors of LRF
Lumpectomy + XRT
Mastectomy
(1890 Pts, 190 Events)
(1070 Pts, 128 Events)
Age
Clinical Tumor Size
(>50 years vs. <50 years)
(>5 cm vs. <5 cm)
Clinical Nodal Status
Clinical Nodal Status
(+) vs. (-)
(+) vs. (-)
Breast/Nodal Path Status
Breast/Nodal Path Status
Node(-)/No pCR vs. Node(-)/pCR
Node(+) vs. Node(-) /pCR
Node(-)/No pCR vs. Node(-)/pCR
Node(+) vs. Node(-) /pCR
Mamounas et al: ASCO Breast 2010, Abstr. 90
10-Year Cum. Incidence of LRF
Lumpectomy Patients, >50 years
20
I B TR
R e gi ona l
n=122
15
Clin. Node (-)
10
n=348
n=90
Clin. Node (+)
n=58
n=212
n=31
5
0
Mamounas et al: ASCO Breast 2010, Abstr. 90
10-Year Cum. Incidence of LRF
Lumpectomy Patients, <50 years
25
I B TR
20
Clin. Node (-)
R e gi ona l
Clin. Node (+)
n=84
15
10
n=154
n=223
n=376
n=135
n=57
5
0
Mamounas et al: ASCO Breast 2010, Abstr. 90
10-Year Cum. Incidence of LRF
Mastectomy Patients, < 5 cm
20
C h e st Wa l l
15
R e gi ona l
n=143
Clin. Node (+)
Clin. Node (-)
n=37
n=183
10
n=46
n=178
5
n=21
0
Mamounas et al: ASCO Breast 2010, Abstr. 90
10-Year Cum. Incidence of LRF
Mastectomy Patients, > 5 cm
25
C h e st Wa l l
R e gi ona l
n=128
20
Clin. Node (+)
Clin. Node (-)
n=179
15
n=95
n=33
10
n=16
5
n=11
0
Mamounas et al: ASCO Breast 2010, Abstr. 90
Nomogram for Prediction of
10-Year Rate of LRF After NC
30
pos,
pos,
pos,
neg,
neg,
neg,
Node
Node
Node
Node
Node
Node
(+)
(-),
(-),
(+)
(-),
(-),
No pCR
pCR
No pCR
pCR
5
10
15
20
25
CNS
CNS
CNS
CNS
CNS
CNS
0
10-Year Probability of LRF
10-year probability (%) of being Local Failure Free
Lumpectomy + XRT
40
45
50
55
60
AgeAge
at Entry
at Entry(Years)
(Years)
65
70
Nomogram for Prediction of
10-Year Rate of LRF After NC
30
pos,
pos,
pos,
neg,
neg,
neg,
Node
Node
Node
Node
Node
Node
(+)
(-),
(-),
(+)
(-),
(-),
No pCR
pCR
No pCR
pCR
5
10
15
20
25
CNS
CNS
CNS
CNS
CNS
CNS
0
10-year probability
(%) of being Local Failure
Free
of LRF
Probability
10-Year
Mastectomy
0
1
2
3
Clinical Tumor
atSize
Entry
(cm)
Clinical Size
Tumor
(cm)
4
5
Summary/Conclusions
• SNB alone is the standard of care for staging the axilla in
patients with negative SNB
• SNB alone appears reasonable for patients with occult
mets, micromets or macromets (not identified
intraoperatively or by routine H & E assessment)
• Following neoadjuvant chemotherapy loco-regional
therapy can be tailored based on clinico-pathologic tumor
response in the breast and axillary nodes
• This approach holds great promise as NC regimens (+
targeted biologics) become considerably more effective
and as genomic and imaging technology allows for more
accurate prediction and identification of pathologic
complete responders
34