Download NSABP B-20 - Society of Surgical Oncology

From Radical Mastectomy to Targeted
Molecular Therapy: The NSABP
Breast Clinical Trials
Thomas B. Julian, MD, FACS
Professor of Surgery - Drexel University College of Medicine
Senior Surgical Director-Medical Affairs - NSABP
Director-Breast Surgical Oncology - WPAHS
Pittsburgh, PA
We’ve come a long way William
WILLIAM HALSTED - 1895
“ There is a definite, more or less uninterrupted, or quite
uninterrupted connection between the original focus and the
outlying deposits of cancer…the centrifugal spread annexing
by continuity a very large area in some cases. Thus the liver
may be involved by way of the deep fascia, the linea alba
and the round ligament, the brain by the lymphatics
accompanying the middle meningeal artery... ”
WILLIAM HALSTED - 1895
“ Although it undoubtedly occurs, I am not sure
that I have observed from breast cancer,
metastasis which seemed definitely or have been
conveyed by way of the blood vessels... ”
Halstead Mastectomy
Effect of Primary Tumor Removal on the Growth
Kinetics of Metastases
• 1956 B. Fisher: 24 hours following
removal of a primary tumor, there is an
increase in the labeling index of the
metastases which persists for a variable
period of time (e.g. five to seven days)
and results in a decrease in tumor
doubling time with a measurable
increase in tumor size.
Clinical Trial Requirements
• Translation of biological concepts in to
clinical trials
• Patient selection
• Randomization
• Treatment
• Analysis
1958
1957
NIH
sponsored a
program
called the
NSABP
1st patient
826 patients
23 researchers
1958-61
NSABP B-01
NSABP B-02
NSABP B-03
NSABP B-04: LOCO-REGIONAL
Operable Breast Cancer
Clinic. Negative Node
Radical
Mast.
Total
Mast.
Total Mast.
+
XRT
Opened : July 1971
Closed : September 1974
Clinic. Positive Node
Radical
Mast.
Total Mast.
+
XRT
NSABP B-04: LOCO-REGIONAL
RFS (25 yrs) RFS (25 years)
Negative Node Positive Node
P = .46
P = .40
Radical mastectomy
53%
36%
Total mastectomy + XRT
52%
33%
Total mastectomy
50%
--
* 31% of patients died without
breast cancer recurrence
Fisher, B. et al., NEJM 2002;347(8):567-575.
B-04 SURVIVAL
100
Node-Negative Pts. P= 0.68
Radical M. vs
Total M. + XRT P= 0.38
Total M.
P= 0.72
80
60
40
Node-Positive Pts.
Radical M. vs
Total M. + XRT P= 0.49
20
0
0
5
10 Years 15
20
25
TWO DIVERGENT HYPOTHESES
OF TUMOR BIOLOGY
HALSTEDIAN
ALTERNATIVE
Operable breast cancer is Operable breast cancer is
a locoregional disease.
a systemic disease.
The extent and nuances of Variations in locoregional
operation are the
therapy
dominant factors
are unlikely to substantially
influencing patient
affect survival
outcome
Fisher, 1979
NSABP B-06: LOCO-REGIONAL
Clinical Tumor Size  4.0 cm
Stratification
 Clinical Nodal Status
 Clinical Tumor Size
Total
Mastectomy
+ Ax. Diss.
Lumpectomy
+ Ax. Diss.
Lumpectomy
+ Ax. Diss.
+ XRT
All patients with histologically positive axillary nodes receive
L-PAM + 5 FU
Total mastectomy performed in event of ipsilateral breast
tumor recurrence
NSABP B-06: LOCO-REGIONAL
% DFS
Disease-free Survival
120
100
80
60
40
20
0
No of Events
TM
SM
SM+XRT
0
2
4
6
589
634
628
8
Years
330
379
342
10
P = 0.46
P = 0.25
12
14
20
NSASBP B-06: LOCO-REGIONAL
No of Deaths
20
14
Years
P = 0.25
P = 0.62
12
10
314
366
355
8
589
634
628
6
4
TM
SM
SM+XRT
2
120
100
80
60
40
20
0
0
% Surviving
Survival
EVOLUTION
OF SYSTEMIC APPROACHES
Treatment
of metastatic
disease
Treatment
of occult
disease after
surgery
(adjuvant)
1960-69
1970-79
Questions?
•
•
•
•
•
•
Mono or polychemotherapy?
Targeting estrogen receptors?
Role of anthracyclines?
Duration of chemotherapy?
Intensity of chemotherapy?
Chemotherapy: Before or after surgery?
NSABP B-05
L-PAM as adjuvant systemic therapy for breast cancer
NSABP PROTOCOLS:
NODE POSITIVE PATIENTS
B-05
LPAM vs Placebo x 2 years
B-07
LPAM + 5 Fu vs LPAM x 2 years
B-08
LPAM + 5 Fu + MTX vs LPAM + 5 Fu
 15 yr DFS: 24% PMF vs 32% PF (p = 0.05)
NSABP PROTOCOLS:
NODE POSITIVE PATIENTS
B-11 LPAM + 5 Fu vs LPAM + 5 Fu+ Adriamycin
(ER-)

Differences in DFS (p = 0.02) and survival (p = 0.07) favoured PAF
(results as of 31 December, 1994)
B-12 LPAM + 5 Fu + Adriamycin vs LPAM
+ 5 Fu + Adriamycin + Tamoxifen (ER+)
NSABP PROTOCOLS:
NODE POSITIVE PATIENTS
B-15 AC x 4 vs CMF x 6 vs AC x 4 followed by
CMF x 3 (ER-)
B-16 AC x 4 + Tamoxifen vs LPAM + 5 Fu +
Adriamycin x 2 years vs Tamoxifen (ER+)
 DFS was significantly higher in patients receiving ACT (35%) vs
Tamoxifen alone (31%, p = 0.03) 15 years after randomization
NSABP B-22 and B-25:
NODE POSITIVE PATIENTS
Role of chemotherapy dose
intensification
(dose intense)
NODE POSITIVE PATIENTS:
NSABP B-28 and B-30
B-28 Role of taxol
• AC x 4 + Tam x 5yrs vs AC x 4 + Tam x 5yrs + Taxol x 4
B-30 Optimal method of taxotere administration
• AC x 4 + Tam x 5yrs vs AT x 4 + Tam x 5yrs vs ATC x 4
+ Tam x 5 yrs
% Disease-Free
20
40
60
80
100
NSABP B-30
Disease-Free Survival (Intention-To-Treat)
0
N
0
# Events
HR
ACT
1,753
388
AT
1,753
468
TAC
1,758
457
2
4
p-value
0.83 vs.TAC
0.80 vs. AT
0.006
0.001
0.96 vs. AT
0.58
6
Years After Randomization
8
10
NSABP B-30
% Disease-Free
20
40
60
80
100
Disease-Free Survival (Combined)
0
Status
N Events
Amenorrhea
1868 424
RR*=0.70
No Amenorrhea 475 173
p*=0.00041
0
2
4
6
Years After Randomization
*Hazard ratio and p-value were adjusted by trt, ER, age, LN,
tumor size, hormonal therapy
8
NSABP B-30
% Surviving
40
60
80
100
Overall Survival (Combined)
0
20
Status
N Events
Amenorrhea
1868 247
RR*=0.76
p*=0.038
No Amenorrhea 475 103
0
2
4
6
Years After Randomization
*Hazard ratio and p-value were adjusted by trt, ER, age, LN,
tumor size, hormonal therapy
8
HER-2/NEU
GENE DETECTION USING FISH
HER-2 gene
Normal
ratio = 1.0
CEP17 : control for
chromosome 17
Amplified
ratio = 2.2-14.0
NODE POSITIVE PATIENTS:
NSABP B-31
Control: ACT
Experimental arm: ACTH
= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4
= paclitaxel (T) 175 mg/m2 q 3 wk x 4
= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51
100
Survival
94%
90
Disease-Free Survival
90
100
NSABP B-31/ INTERGROUP N9831
JOINT ANALYSIS
87%
91%
92%
85%
70
75%
70
67%
0
1
2
3
Years
4
60
N Events
AC->T
1679 261
AC->TH 1672 134
HR=0.48, 2P=3x10-12
50
60
50
80
80
87%
5
0
N Deaths
AC->T
1679 92
AC->TH 1672 62
HR=0.67, 2P=0.015
1
2
3
Years
4
5
NSABP B-04 AND B-06 OUTCOMES:
NODE NEGATIVE PATIENTS
5 years
10 years
RECURRENCE
25%
43%
SURVIVAL
85%
66%
NSABP B-14
• Tumors With ER  10 fmol/mg
• Histologically Neg. Axillary Nodes
• TM or Lump. + Ax. Diss. +XRT
Stratification
• Age
• Clinical Tumor
Size
• Quantitative ER
• Type of Operation
Placebo
TAM
NSABP B-14:
NODE NEGATIVE PATIENTS
Tamoxifen
Placebo
p Value
DFS
56%
46%
< 0.0001
S
71%
65%
= 0.0015
*Through 15 years in 2871 patients
NSABP B-14 EXTENDED THERAPY:
PLACEBO vs TAMOXIFEN
5 years
More than
5 years
p Value
DFS
66%
63%
0.133
S
81%
79%
0.331
*Through 12 years in 1152 patients rerandomized
NSABP PROTOCOLS:
NODE NEGATIVE PATIENTS
B-13
Methotrexate followed by 5 Fu
+ Leucovorin vs No chemo (ER-)
 13 yr DFS: 65% treatment group vs 51% surgery-only
patients (p = 0.00001)
 12 yr syrvival: 77% treatment group vs 70% surgeryonly patients (p = 0.014)
B-19
Methotrexate followed by 5 Fu +
Leucovorin vs CMF (ER-)
B-23
CMF x 6 + Tam vs CMF x 6 +
placebo vs AC x 4 + Tam vs AC
x 4 + Placebo (ER-)
NSABP B-20: NODE NEGATIVE
NSABP Protocol B-20 (Age < 50)
Figure 1. Disease-Free Survival
% Disease-free
20
40
60
80
100
NSABP B-20: NODE NEGATIVE
0
Trt
Tamoxifen
M->F+T
CMF+T
0
2
4
N
345
342
354
Events
102
66
RR=0.62
67
RR=0.60
6
8
Years After Surgery
p=0.0019
p=0.0010
10
12
NSABP B-20 : OUTCOMES
 Data after 12 years indicate that the addition
of classical CMF or of M-F to Tamoxifen
benefitted the patients under 50 y.o.a. as
compared with Tamoxifen alone
 This benefit was not observed in patients over
50 y.o.a.
THREE BREAST CANCER STUDIES
USED TO SELECT 21 GENE PANEL
16 Cancer and 5
Reference Genes
• Best RT-PCR
performance and
most robust
predictions
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
GSTM1
CD68
HER2
GRB7
HER2
BAG1
ESTROGEN
ER
PR
Bcl2
SCUBE2
INVASION
Stromolysin 3
Cathepsin L2
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
THREE BREAST CANCER STUDIES USED TO DEVELOP
RECURRENCE SCORE (RS) ALGORITHIM
RS = + 0.47 x HER2 Group Score
- 0.34 x ER Group Score
+ 1.04 x Proliferation Group Score
Scale: 0 to 100
+ 0.10 x Invasion Group Score
+ 0.05 x CD68
- 0.08 x GSTM1
- 0.07 x BAG1
Category
Recurrence Score (RS)
Low risk
Less than 18
Intermediate risk
Greater than or equal to 18, less than 31
High risk
Greater than or equal to 31
NSABP B-20/Genomic Health:
Ten Year DRFS Results
Tam vs Tam + Chemo – Low Risk (RS < 18)
1.0
96%
95%
0.9
0.8
DRFS
0.7
0.6
0.5
0.4
0.3
Low Risk Patients (RS < 18)
Tam + Chemo
Tam
0.2
0.1
0.0
0
2
4
6
8
Years
N
218
135
10
Events
11
5
12
p = 0.76
NSABP B-20/Genomic Health:
Ten Year DRFS Results
Tam vs Tam + Chemo – Int Risk (RS 18–30)
1.0
89%
90%
0.9
0.8
DRFS
0.7
0.6
0.5
0.4
Int Risk Patients (RS 18 - 30) N
Tam + Chemo
89
45
Tam
0.3
0.2
0.1
Events
9
8
0.0
0
2
4
6
8
Years
10
12
p = 0.71
NSABP B-20 / GENOMIC HEALTH:
Ten Year DRFS Results
Tam vs Tam + Chemo – High Risk (RS ≥ 31)
1.0
0.9
88%
0.8
DRFS
0.7
0.6
60%
0.5
HR = 0.26 (95% CI 0.13 - 0.53)
0.4
0.3
High Risk Patients (RS ≥ 31)
0.2
Tam + Chemo
Tam
0.1
N
117
47
Events
13 p = 0.001
18
0.0
0
2
4
6
Years
8
10
12
NSABP B-21: OUTCOMES
PATIENTS
(n)
TREATMENT
% IBTR
F/u
% RISK
(years)
REDUCTION
334
TAM
7
16.5
--
332
RT + Placebo
--
9.3
49
334
TAM + RT
--
2.8
81/63
Fisher, B. et al., J Clin Onco 20: 4141-4149, 2002
THE YEARS 1980-90
 Introduction of breast cancer screening
programs
 Increase in incidence of DCIS and LCIS
 Little information on disease evolution and
optimal treatment
NSABP DCIS TRIALS:
B-17 and B-24
Ipsilateral Breast
Tumor Recurrence
NSABP B-17
818 Patients
Median F/u : 192 m
%
NSABP B-24
1799 Patients
Median F/u : 146 m
%
S
S + RT
All
34.1
17.5
14.9
11.7
Invasive
19.1
9.0
7.7
5.6
15
8.5
7.0
5.9
Non invasive
(p.0001)
S + RT S + RT + TAM
(p.008)
NSABP B-35: DCIS
 Postmenopausal women
 DCIS treated by lumpectomy
 ER-positive or PgR-positive by
immunohistochemistry (IHC)
GROUP 1
Tamoxifen 20 mg/day
and placebo
(Anastrozole look-alike)
for 5 years
+
Breast radiation therapy
GROUP 2
Anastrozole 1 mg/day
and placebo
(Tamoxifen look-alike)
for 5 years
+
Breast radiation therapy
ADJUVANT TREATMENT
 Results moderately favorable (treatment
more effective on smaller foci)
 No information on effectiveness for
individual patients (blind treatment)
EVOLUTION
OF SYSTEMIC APPROACHES
Treatment
of metastatic
disease
Treatment
of occult
disease after
surgery
(adjuvant)
1960-69
1970-79
Treatment
before
surgery
(neoadjuvant)
1980-89
NSABP B-18:
NEOADJUVANT VS ADJUVANT AC
Operable Breast Cancer
Stratification
• Age
• Clinical Tumor Size
• Clinical Nodal Status
Surgery
AC x 4
AC x 4
Surgery
 Clinical Response : 79%
 pCR : 13%
 16% increase in lumpectomy
rate
 31% downstaging of (+)
axillary nodes
 No difference in DFS or OS
 Significant correlation
between pCR and outcome
Tamoxifen x 5 years for patients
> 50 after completion of chemo
Fisher, B. et al., JCO 1997, JCO 1998; Wolmark, N. et al., JNCI 2001
JCO 2008;26(5):778-785.
Adapted from JCO 2008;26(5):778-785.
NSABP B-27 : IMPACT OF TAXOTERE
Operable Breast Cancer
Randomization
AC x 4
Tam x 5 yrs
AC x 4
Tam x 5 yrs
AC x 4
Tam x 5 yrs
Surgery
Taxotere x 4
Surgery
Surgery
Taxotere x 4
II
III
I
NSABP B-27 : IMPACT OF TAXOTERE
ON PATHOLOGICAL RESPONSE RATE (pCR)
IN THE BREAST
No Tumor
30%
Non-Invasive
P < 0.001
20%
18.7%
9.8%
10%
13.7%
0
25.6%
3.9%
6.9%
AC
(1492 pts)
AC Taxotere
(718 pts)
NSABP B-27: SURVIVAL
Overall Survival
100
-A-
90
80
%
70
Group
I
II
III
60
50
Disease-Free Survival
100
-B-
90
80
70
70
Group
I
II
III
50
N Events
802 276
803 260 HR=0.90 p=0.22
799 254 HR=0.90 p=0.24
40
40
0
1
2
3
4
5
6
7
-C-
90
80
60
N Deaths
802 157
803 156 HR=0.97 p=0.82
799 171 HR=1.08 p=0.51
Relapse-Free Survival
100
Group
I
II
p=0.08
III
p=0.30
60
50
40
0
1
2
3
4
5
Years after Surgery
6
7
0
1
2
N Events
802 258
803 231 HR=0.85
799
3
239
4
HR=0.91
5
6
7
Survival By Pathologic
Complete Response in
Patients Who Receive
Pre-op AC in NSABP
Protocole B-18 and B-27:
All Patients
Rastogi et al, JCO 2008
EVOLUTION
OF SYSTEMIC APPROACHES
Treatment
of metastatic
disease
Treatment
of occult
disease after
surgery
(adjuvant)
1960-69
1970-79
Treatment
before
surgery
Treatment
of occult
carcinoma
before it
appears
(neoadjuvant)
(chemoprevention
therapy)
1980-89
1990-99
NSABP B-14:
PRELUDE TO PREVENTION
Second cancer in the controlateral breast
8
6
Placebo 1424 pts
Tamoxifen 1419 pts
p = 0.001
%
4
2
0
55
28
Number of cancers
NSABP P-1: TIME TO INVASIVE
BREAST CANCER
Cumulative Rate/1000
Invasive Cancer
50
# Events
Placebo
250
Tamoxifen 145
40
30 P < 0.0001
20
10
0
1
2
3
4
5
6
7
Time to Breast Cancer
Fisher, B., et al., J Natl Cancer Inst 2005
NSABP P-2: STAR Trial
Risk-Eligible
Postmenopausal Women
Tamoxifen
+
Placebo
(Raloxifene look-alike)
Raloxifene
+
Placebo
(Tamoxifen look-alike)
20 mg/day x 5 years
60 mg/day x 5 years
P-2 STAR
Cumulative Incidence (per 1000)
Cumulative Incidence of
Invasive Breast Cancer
40
35
Treatment
Tamoxifen
Raloxifene
30
At Risk by Year
0
3
6
9726 6653 809
9745 6703 833
# of
Events
163
168
Rate/1000
at 6 yrs. P-value
25.1
0.83
24.8
25
20
15
10
5
0
0
6
12
18 24 30 36 42 48
Time Since Randomization
(months)
54
60
66
72
P-2 STAR
Cumulative Incidence (per 1000)
Cumulative Incidence of
Invasive Breast Cancer
45
40
Treatment
Tamoxifen
Raloxifene
35
30
At Risk by Year
0
6
8
9736 5833 2621
9754 5999 2650
# of
Events
247
310
Rate/1000
at 8 yrs. P-value 0.01
29.9
39.9
25
20
15
10
5
Median follow-up 81 mo.
0
0
NSABP
AACR 4-10
6
12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Time Since Randomization (months)
Clinically Negative Axillary Nodes
NSABP B-32
Stratification
• Age
• Clinical Tumor Size
• Type of Surgery
Randomization
GROUP 1
Sentinel Node Resection*
Followed By
Axillary Dissection
GROUP 2
Sentinel
Node
Resection *
Path. Pos.
Sentinel Node
Axillary Dissection
Path. Neg.
Sentinel Node
No Axillary
Dissection
NSABP Protocol B-32
% Surviving
40
60
80
100
Overall Survival for Sentinel Node Negative Patients
N
Deaths
1975 140
2011 169 HR=1.20 p=0.117
0
20
Trt
SNR+AD
SNR
Data as of December 31, 2009
0
2
4
Years After Entry
* 300 deaths triggered the definitive analysis
* 309 reported as of 12/31/2009
6
8
NSABP Protocol B-32
% Disease-Free
20
40
60
80
100
Disease-Free Survival for Sentinel Node Negative Patients
N
Deaths
1975 315
2011 336 HR=1.05 p=0.542
0
Trt
SNR+AD
SNR
Data as of December 31, 2009
0
2
4
Years After Entry
6
8
Local and Regional Recurrences
as First Events
Group 1
Group 2
54 (2.7%)
49 (2.4%)
Axillary
2 (0.1%)
8 (0.3%)
Extraaxillary
5 (0.25%
6 (0.3%)
Local
NSABP B-40
Tissue for
Biomarkers
Tissue for
Biomarkers
T
A A A A
C C C C
T T T T
X X X X
A A A A
C C C C
T T T T
G G G G
A A A A
C C C C
B B B
B B
T
Operabl
e
Breast
Cancer
R
+/-
T
T
B
S
U
R
G
E
R
Y
Accrual Completed: 1205
+/B
X 10
NSABP B-40
Pathologic Complete Responses (Breast)
for HR+ and TN Breast Cancer
% pCR (Breast)
N=243
N=349
N=236
N=352
OR = 1.70
p=0.008
OR = 1.17
p=0.44
Interaction p value = 0.166
TCH Regimen
CIRG/NSABP/Independent
HER2+
TCH
6 x Docetaxel and Carboplatin
RT
(Central Testing)
N+ or high
risk N-
1 Year Trastuzumab
6 x Docetaxel and Carboplatin
TCHB
RT
1 Year Trastuzumab
Completed Accrual: 3500
1 Year Bevacizumab
NSABP B-39/RTOG 0413
Eligible Patients with Lumpectomy
RANDOMIZED
Whole Breast Irradiation after
Adjuvant Chemotherapy
Partial Breast Irradiation prior
to Adjuvant Chemotherapy
50 Gy (2.0 Gy/fraction) or
50.4 Gy (1.8 Gy/fraction) to whole
breast, followed by optional boost to
> 60 Gy
For a total of 10 treatments given
on 5 days over 5 to 10 days:
34 Gy in 3.4 Gy fractions
Interstitial Brachytherapy or
Mammosite Balloon Catheter
or
38.5 Gy in 3.85 Gy fractions
3D Conformal External Beam
Endpoints: 10 IBTR
20 DFS/OS
77
NSABP B-43:
Trastuzumab + XRT for HER-2 + DCIS
Radiation
Therapy
Hormonal
Rx PRN
HER2+
DCIS
Lx
Radiation Therapy + Trastuzumab
q3-week Trastuzumab cycles x 2
Trastuzumab 8 mg/kg loading dose
Trastuzumab 6 mg/kg final dose
B-46/USO 06-090R
Node-Positive and High Risk Node Negative,
HER2 Negative Breast Cancer
STRATIFICATION
– Number of positive Nodes (1-3, 4-9, 10+)
– Hormone Receptor Status (+/-)
TC x 6
TAC x 6
TC x 6 + BEV
B-47 Adjuvant Trastuzumab in Patients with
Normal HER2 Expression (FISH Negative,
IHC 1+, 2+) Breast Cancer
High Risk Primary Breast Cancer
IHC 1+ or 2+ for HER2
FISH Negative,
Randomization
Docetaxel 75mg/m2 +
CTX 600mg/m2 Q3wk x 6
Or (MD Choice)
ACx4, + Paclitaxel Qwk x 12
Std or DD AC
Docetaxel 75mg/m2 +
CTX 600mg/m2 Q3wk x 6
Or (MD Choice)
ACx4, Paclitaxel Qwk x 12
Std or DD AC
+Trastuzumab x 1 yr
beginning with TC or WP
Summary/Conclusions
• Several of the pivotal NSABP breast
cancer clinical trials have been
instrumental in establishing/changing the
standard of care for patients with early
stage breast cancer:
– Loco-regional management
– Adjuvant hormonal therapy
– Adjuvant chemotherapy
– Adjuvant targeted therapy with biologics
– Neoadjuvant chemotherapy
CHANGE IN LOCAL AND REGIONAL
TREATMENT PHILOSOPHY
1970
from
maximum
tolerable
treatment
2000
to
minimum
personalized
treatment