Transcript HER Education Network

A Report from SABCS
Up-to-Date Review of the Treatment of
Early Breast Cancer
Maura N. Dickler, MD
Assistant Attending Physician
Breast Cancer Medicine Service
Memorial Sloan-Kettering Cancer Center
New York, NY
Up-to-Date Review of the Treatment of
Early Breast Cancer
Overview
• Chemotherapy
– Genomic profiling using the 21-Gene Recurrence Score Assay in
postmenopausal, ER+, LN+ patients
– Update of AC vs. TC
• Trastuzumab for HER2+ Early Breast Cancer: PACS04 Trial
• Endocrine Therapy: 100 month update of ATAC
• Symptom Management/Supportive Care
– Effects of endocrine therapy on bone health and arthralgias
– Prevention of AI-induced bone loss
• Bisphosphonates
• Denosumab
Chemotherapy
SABCS Abstract 10
Prognostic and Predictive Value of the
21-Gene Recurrence Score Assay in
Postmenopausal, Node-Positive (N+),
ER-Positive (ER+) Breast Cancer
SWOG 8814, TBCI 0100
K. Albain, W. Barlow, S. Shak, G. Hortobagyi, R. Livingston, I. Yeh,
P. Ravdin, C. Yoshizawa, F. Baehner, N. Davidson, G. Sledge, E. Winer,
C.
Hudis, J. Ingle, E. Perez, K. Pritchard, L. Shepherd, C. Allred,
K. Osborne, and D. Hayes for The Breast Cancer Intergroup of North America
SWOG 8814/TBCI 0100
Correlative Science Study
Rationale
• The 21-gene Recurrence Score assay (RS) is prognostic
for women with node(-), ER+ breast cancer on 5 years of
tamoxifen*
• A high RS predicts large benefit from chemotherapy in
node(-) disease, but no improvement if the RS is low**
• There are no RS data in a N+ population with a tamoxifenalone control
• SWOG 8814 is an ideal trial to explore this question
*Paik, et al. NEJM, 2004
**Paik, et al. J Clin Oncol, 2006
Albain K, et al. SABCS 2007. Abstract 10.
Phase III SWOG 8814 (TBCI 0100)
Postmenopausal, N+, ER+
RANDOMIZE
Tamoxifen x 5 yrs
(N = 361)
(N = 1477)
CAF x 6, then
tamoxifen
CAF x 6, with
concurrent tam
(N = 550)
(N = 566)
Superior Disease-Free Survival (DFS) and
Overall Survival (OS) over 10 Years
Albain K, et al. SABCS 2007. Abstract 10.
SWOG 8814/TBCI 0100
Correlative Science Study
•
Two co-primary objectives were to determine if the
RS:
─ Provides prognostic information for women with N+ disease
treated only with tamoxifen, and
─ Allows prediction of a N+ group that does not derive benefit
from chemotherapy
Albain K, et al. SABCS 2007. Abstract 10.
SWOG 8814/TBCI 0100
Correlative Science Study
Methods - I
• NCI correlative science project (#8814A-ICSC) used paraffinembedded specimens from optional central banking protocol
• Conducted RT-PCR for 16 genes + 5 reference genes by Genomic
Health, Inc; blinded to outcomes
• Calculated RS according to published criteria
• Assessed same endpoints from main trial: DFS and OS (DRFI not
available)
• Performed analysis at SWOG Statistical Center using plan finalized
before data received
Paik, et al. NEJM 2004.
Albain K, et al. SABCS 2007. Abstract 10.
SWOG 8814/TBCI 0100
Correlative Science Study
Methods - II
• Limited to tamoxifen and sequential CAF-T arms (eliminated inferior
concurrent CAFT)
• Stratified log-rank tests by nodes (1-3 vs. 4+), due to strong prognostic
effect in main trial
• Conducted Cox regression analyses on continuous RS and its
interaction with treatment
– Found violation of the proportional hazards assumption (hazard ratio not
constant over time)
– Therefore, analyses done with a split time axis: ≤ 5 and > 5 years
Albain K, et al. SABCS 2007. Abstract 10.
SWOG 8814/TBCI 0100
Correlative Science Study
Sample Size for Analysis
Patients with samples - 666
(45% of parent trial)
RT-PCR obtained - 601 (90%)
Tamoxifen alone
148
CAFT (concurrent)
234
CAF-T (sequential)
219
Final sample for primary analysis
148 + 219 = 367 (40% of parent trial)
Albain K, et al. SABCS 2007. Abstract 10.
SWOG 8814/TBCI 0100
Correlative Science Study
• Outcomes in RS subset mirror those reported in main trial: superiority of CAF-T
0.75
0.50
0.25
Stratified log-rank P-value = 0.054 at 10 years
(adjusted for nodal status)
Tamoxifen (N=148, 63 events)
CAF-T
(N=219, 74 events)
0.00
Disease-free Survival
1.00
Disease-Free Survival
0
2
4
6
Years Since Registration
8
10
Albain K, et al. SABCS 2007. Abstract 10.
SWOG 8814/TBCI 0100
Correlative Science Study
Comparative Distribution of RS
Low Risk
(RS < 18)
Int. Risk
(RS 18-30)
High Risk
(RS ≥ 31)
NSABP B14*
51%
22%
27%
NSABP B20*
54%
21%
25%
Kaiser controls*
56%
19%
25%
ECOG 2197**
49%
31%
20%
SWOG 8814***
40%
28%
32%
Study
*node(-): Paik, et al. NEJM 2004 & JCO 2006; Habel, et al. Breast Ca Res Treat 2006
**node(-) or 1-3+: Goldstein, et al. Proc ASCO 2007
***node+, postmenopausal: this analysis – no difference by age
Albain K, et al. SABCS 2007. Abstract 10.
SWOG 8814/TBCI 0100
Correlative Science Study
Results: Prognosis
SWOG 8814/TBCI 0100
Correlative Science Study
• 21-Gene recurrence score is prognostic for DFS and OS in tamoxifen arm
Overall Survival by Risk Group
Disease-Free Survival by Risk Group
2
4
6
Years since registration
• 10-yr: Low RS = 60%, Int. RS = 49%,
High RS = 43%
0.75
1.00
8
0.25
Stratified log-rank p = 0.003 at 10 years
Low RS <18 (N=55)
Intermediate RS 18-30 (N=46)
High RS ≥31 (N=47)
0.00
Low RS <18 (N=55)
Intermediate RS 18-30 (N=46)
High RS ≥31 (N=47)
0
(tamoxifen alone)
0.50
Overall Survival
0.75
0.50
0.25
Stratified log-rank p = 0.017 at 10 years
0.00
Disease-free survival
1.00
(tamoxifen alone)
10
0
2
4
6
8
Years since registration
• 10-yr: Low RS = 77%, Int. RS = 68%,
High RS = 51%
Albain K, et al. SABCS 2007. Abstract 10.
10
SWOG 8814/TBCI 0100
Correlative Science Study
Results: Prediction
Disease-Free Survival by Treatment
0.75
0.50
Stratified log-rank p = 0.97 at 10 years
Tamoxifen (N=55, 15 events)
CAF-T
(N=91, 26 events)
0.00
• Strong benefit to CAF
if high RS
Low risk (RS < 18)
0.25
Disease-free survival
1.00
• No benefit to CAF
over time if low RS
0
2
4
6
8
10
Disease-Free Survival by Treatment
1.00
1.00
0.25
Stratified log-rank p = 0.033 at 10 years
0
2
4
6
Years since registration
8
0.75
0.50
Stratified log-rank p = 0.48 at 10 years
Tamoxifen
CAF-T
0.00
Tamoxifen (N=47, 26 events)
CAF-T
(N=71, 28 events)
Intermediate risk (RS 18-30)
0.25
0.50
0.75
High risk (RS ≥ 31)
Disease-free survival
Disease-Free Survival by Treatment
0.00
Disease-free survival
Years since registration
10
0
2
4
(N=46, 22 events)
(N=57, 20 events)
6
Years since registration
8
10
SWOG 8814/TBCI 0100
Correlative Science Study
Ten-Year DFS Point Estimates (95% CI)
Recurrence Score
Risk Category
Tamoxifen
Alone
CAF followed by
tamoxifen
Low (< 18)*
60%
(40%, 76%)
64%
(50%, 75%)
Intermediate (18-30)
49%
(32%, 63%)
63%
(48%, 74%)
High (≥ 31)
43%
(28%, 57%)
55%
(40%, 67%)
*40% event rate over 10 years and resistance to CAF
Albain K, et al. SABCS 2007. Abstract 10.
SWOG 8814/TBCI 0100
Correlative Science Study
Comparison of CAF-T to Tamoxifen Alone
DFS hazard ratios adjusted for nodal status
Overall trial
Trial Subset
Entire RS sample
Low RS
Intermediate RS
High RS
Chemotherapy benefit No chemotherapy benefit
0
.5
1
1.5
2
Hazard Ratio
Albain K, et al. SABCS 2007. Abstract 10.
SWOG 8814/TBCI 0100
Correlative Science Study
• No CAF benefit DFS either early or late in low RS, but stable impact over time if high RS
Comparison of CAF-T to Tamoxifen Alone
(DFS adjusted for nodal status)
Low RS
Intermediate RS
First 5 years
Greater than 5 years
High RS
Chemotherapy benefit No chemotherapy benefit
0
1
2
Hazard ratio
3
4
Albain K, et al. SABCS 2007. Abstract 10.
SWOG 8814/TBCI 0100
Correlative Science Study
The RS is Predictive for Overall Survival
• No benefit to CAF in low RS in first
5-years (HR 1.05) or over entire time
period (HR 1.18)
Tamoxifen
51% (35%, 65%)
CAF-T
68% (51%, 79%)
1.00
0.75
0.50
– 10-year estimates:
Stratified log-rank test p = 0.027 at 10 years
0.25
– Over entire period HR 0.56 (0.31, 1.01)
High risk (RS ≥31)
Tamoxifen (N=47, 22 deaths)
CAF-T
(N=71, 20 deaths)
0.00
– First 5-years HR 0.43 (0.21, 0.90)
Overall survival
• Strong impact of CAF in high RS:
Overall Survival by Treatment
0
2
4
6
8
Years since registration
Albain K, et al. SABCS 2007. Abstract 10.
10
SWOG 8814/TBCI 0100
Correlative Science Study
Conclusions on Primary Analysis
• The 21-gene RS is prognostic for tamoxifen-treated patients with
positive nodes
• Chemotherapy benefit is predicted when the RS is high, dominating in
the first 5-years, but carried over long-term
• A low RS may define a group of women with positive nodes who do
not appear to benefit from anthracycline-based chemotherapy
• This analysis of SWOG 8814 is just one study to evaluate the
predictive impact of RS in ER+, LN+ postmenopausal patients.
• Currently, this data should be used with caution for treatment
decisions regarding chemotherapy in LN+ patients.
Albain K, et al. SABCS 2007. Abstract 10.
SWOG 8814/TBCI 0100
Correlative Science Study
Other Perspectives
• New strategies in endocrine/biologic therapy are needed if low RS, given
event rate of 40% over 10-years
• Biology (not age) should drive treatment decisions, since for high RS
chemotherapy is beneficial regardless of age
• These data (both RS and IHC) collectively challenge chemotherapy
mandates for patients with N+, ER+ disease: not all benefit from
chemotherapy, whereas others derive greater benefit than previously
predicted
Albain K, et al. SABCS 2007. Abstract 10.
SABCS Abstract 12
Extended Follow-up and Analysis by Age of
the US Oncology Adjuvant Trial 9735:
Docetaxel/Cyclophosphamide is Associated
with an Overall Survival Benefit Compared to
Doxorubicin/Cyclophosphamide and is Welltolerated in Women 65 or Older
Jones SE, Holmes FA, O’Shaughnessy JA, Blum JL,
Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL,
Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA,
Mennel RG, Boehm KA, Meyer WG, Asmar L, Muss HB, Savin MA
AC vs. TC Adjuvant Trial
Trial Design
R
A
N
D
O
MI
Z
E
Doxorubicin
60 mg/m2 IV Day 1
Cyclophosphamide
600 mg/m2 IV Day 1
Every 21 days X 4 Cycles
Docetaxel
75 mg/m2 IV Day 1
Cyclophosphamide
600 mg/m2 IV Day 1
Every 21 days X 4 Cycles
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
Objectives of this Analysis
• Primary Objective:
– To compare disease-free survival (DFS) and overall survival
(OS) of AC vs. TC in early operable breast cancer at a median
followup of 7-years
• Secondary Objectives:
– To determine outcome by age and treatment regimen
– To assess the impact of HER2 status on DFS (limited sample)
– To determine toxicity profiles by age and treatment regimen
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
Inclusion Criteria
• Patients with Stage I, II, or operable Stage III invasive
breast cancer
• Complete surgical excision of the primary tumor
• Age >18 years
• Adequate renal function
• Adequate hematologic function
• Adequate hepatic function
• Karnofsky PS >80%
• Signed informed consent
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
Demographics by Treatment and Age
<65 Years
TC
AC
Number of pts
428 Pts
428 Pts
≥65 Years
TC
AC
78 Pts
82 Pts
ER+
PR+
298 (70%) 275 (64%)
268 (63%) 258 (60%)
52 (67%)
47 (60%)
58 (71%)
49 (60%)
Nodes
0
1 to 3
4+
212 (50%) 217 (51%)
174 (41%) 174 (41%)
42 (10%)
37 (9%)
28 (36%)
35 (45%)
15 (19%)
31 (38%)
38 (46%)
13 (16%)
Median Age (yrs)
Range
50
49
69
68
(27 - 64)
(27 - 64)
(65 - 77)
(65 - 77)
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
DFS by Treatment
1.00
0.95
0.90
TC
0.85
81%
0.80
P = 0.033
HR = .74
0.75
AC
Proportion DFS
75%
0.70
0.65
0.60
0
At Risk TC 506
AC 510
12
24
36
48
60
72
84
96
434
412
425
401
420
396
418
392
Months
495
498
473
477
454
442
442
422
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
DFS by Treatment and Age Group
1.0
0.9
<65TC
<65 AC
0.8
65+ TC
0.7
0.6
Proportion DFS
65+ AC
0.5
0.4
0
12
24
36
48
60
72
84
96
Months
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
Assessment of HER2 Status by FISH* for 170 Patients
TC
AC
Total
# of Patients
83
87
170
Negative
55
69
124 (73%)
Positive
28
18
46 (27%)
*FISH+ = Gene copy ratio of 2.0 or greater
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
DFS for HER2 Positive Status
1.0
0.9
0.8
0.7
0.6
TC
0.5
0.4
AC
HR = .73
Proportion DFS
0.3
0.2
0.1
0.0
0
At Risk TC 28
AC 18
12
24
36
48
60
72
84
96
17
8
16
8
16
8
16
8
Months
27
17
21
14
20
10
17
9
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
DFS for HER2 Negative Status
1.0
0.9
TC
0.8
0.7
AC
0.6
0.5
HR = .56
0.4
Proportion DFS
0.3
0.2
0.1
0.0
0
At Risk TC 55
AC 68
12
24
36
48
60
72
84
96
42
44
41
40
40
38
Months
53
61
49
51
45
47
42
45
42
44
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
DFS Hazard Ratios (CI) for Key Subgroups
Overall HR for DFS = 0.74
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
Overall Survival by Treatment
1.00
0.95
TC
0.90
87%
0.85
AC
P = 0.032
HR = .69
0.80
82%
0.75
Proportion Surviving
0.70
0.65
0.60
0
At Risk TC 506
AC 510
12
24
36
48
60
72
461
448
454
432
84
96
Months
502
504
495
493
481
476
466
459
449
429
448
427
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
Overall Survival by Treatment and Age Group
1.0
<65TC
0.9
<65AC
0.8
65+TC
Insert graphics
here
0.7
65+AC
0.6
Proportion Surviving
0.5
0.4
0
12
24
36
48
60
72
84
96
Months
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
Grade 3/4 Hematologic Toxicity by Treatment & Age (%)
≥65 Years
TC
AC
<65 Years
TC
AC
Adverse Event
Anemia
Neutropenia
Thrombocytopenia
Febrile Neutropenia
428 Pts 428 Pts
<1
1
60
54
<1
1
4
2
78 Pts
<1
52
0
82 Pts
5
59
<1
8
4
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
Grade 3/4 Nonhematologic Toxicity by Treatment & Age (%)
<65 Years
TC
AC
Adverse Event
Asthenia
Edema
Fever
Infection
Myalgia
Arthralgia
Stomatitis
Diarrhea
Nausea
Vomiting
Phlebitis
428 Pts
3
1
4
7
2
1
1
2
2
1
<1
428 Pts
4
<1
3
10
1
1
2
1
7
6
<1
≥65 Years
TC
AC
78 Pts
6
0
6
6
0
<1
0
5
3
0
<1
82 Pts
9
<1
4
2
<1
<1
<1
1
5
0
0
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
Long-term Fatal Toxicities
• 3 additional long-term fatal toxicities all on the AC arm
– CHF (45 yrs - AC)
– Myelodysplastic syndrome (63 yrs - AC)
– Myelofibrosis (66 yrs - AC)
Jones SE, et al. SABCS 2007. Abstract 12.
AC vs. TC Adjuvant Trial
Conclusions
• At 7 Years, 4 cycles of TC compared to AC was
associated with:
– Superior DFS (P = 0.033)
– Superior Overall Survival (P = 0.032)
– Efficacy in HER2+ as well as HER2- disease (limited sample)
• TC was effective in older as well as younger patients
• Numerically, slightly more febrile neutropenia with TC
but more anemia with AC in older patients
• Less long-term toxicities (cardiac and bone marrow)
with TC
Jones SE, et al. SABCS 2007. Abstract 12.
HER2+ Early Breast Cancer
SABCS Abstract 72
Trastuzumab Following Adjuvant
Chemotherapy in Node-Positive,
HER2-Positive Breast Cancer Patients
4-Year Follow-Up Results of the PACS-04 Trial
M Spielmann, H Roché, JP Machiels, T Delozier, H Bourgeois,
D Serin, G Romieu, JL Canon, A Monnier, G Piot,
M Maerevoet, H Orfeuvre, JM Extra, AC Hardy, AL Martin,
A Kramar, and J Genève
PACS-04: Background
Results of Adjuvant Trastuzumab Trials
Nr. of patients
Median follow-up
 risk of relapse
3,387
1-yr
46 %
3,401
2-yrs
36 %
NSABP B-31
3,351
2-yrs
52 %
NCCTG 9891 (3,4)
3,968
4-yrs
52 %
BCIRG 006 (5)
3,222
3-yrs
39 %
231
3-yrs
58 %
Study
HERA
(1,2)
FinHer (6)
(1)
(2)
(3)
Piccart et al, N Engl J Med, 2005;353:1659-72
Smith et al, Lancet, 2007;369:29-36
Romond et al, N Engl J Med, 2005;353:1673-84
(4)
(5)
(6)
Perez et al, ASCO, 2007: abstr # 512
Slamon et al, SABCS, 2006: abstr # 1
Joensuu et al, N Engl J Med, 2006;354:809-20
PACS-04: Aim of the Study
• The PACS-04 trial evaluated the efficacy of a
one-year trastuzumab therapy following adjuvant
chemotherapy in HER2-overexpressing, nodepositive breast cancer patients
Spielmann M, et al. SABCS 2007. Abstract 72.
PACS-04: Treatment Protocol
Stratified on:
 Center
 N (<4 vs.  4)
S
U
R
G
E
R
Y
Trastuzumab (T)
6 FEC100 q3w
R1
RT*
2nd randomization
performed as soon as
HER2 expression
determined
6 ED75 q3w
HT
Trastuzumab
started after
chemotherapy and RT
R2
RT*
Loading dose 8 mg/kg
Maintenance 6 mg/kg q3w
for 1 year = 18 injections
HT
Observation
* RT was delivered within 4 weeks after the last chemotherapy cycle
Spielmann M, et al. SABCS 2007. Abstract 72.
PACS-04: Major Inclusion Criteria
First Randomization
• Histologically proven unilateral breast cancer with
complete resection (T1-T2-T3)
• Axillary node-positive
• M0 (bone scan, liver ultrasonography, chest X-ray)
• Age > 18 years and  65 years
• Left ventricular ejection fraction (LVEF)  50% as
measured by MUGA scan or echocardiography
Spielmann M, et al. SABCS 2007. Abstract 72.
PACS-04: Second Randomization
• Performed as soon as results of HER2 assessment
available
• HER2-positive status defined by following:
– HER2 3+ (IHC) i.e. > 10% stained cells
– HER2 2+ and FISH positive (cut-off: 2.2 copies)
• HER2 status reviewed by central reference centers
• The median time between R1 and R2 was 2.6 months
Spielmann M, et al. SABCS 2007. Abstract 72.
PACS-04: Statistics
Second Randomization
• Primary endpoint = 3-year DFS
• Hypothesis: Trastuzumab decreases by 33% the risk of
relapse
• Based on an expected 3-year DFS of 70% for the
observation arm
–  = 5% and 1 -  = 80%
– Number of events required = 118
– Number of patients required = 540
• Intent-to-treat analysis
• Overall number of patients required at R1 = 3,000
Spielmann M, et al. SABCS 2007. Abstract 72.
PACS-04: Study Flow Chart
• Between February 2001 and August 2004, 3,010 patients from 82 French
and Belgian institutions were randomized
R1 = 3,010
Reasons
R2 = 528
Obs. = 268
T = 260
N = 26
Refusal
17
Cardiac toxicity under CT
5
Progression
2
Second cancer
1
Other reason
1
Not treated with T
Treated = 234
Spielmann M, et al. SABCS 2007. Abstract 72.
PACS-04: Exposition to Trastuzumab
176 (75%)
180
Reason for discontinuation
160
N
1 to 5
6 to 10
11 to 15
16 to 18
140
Cardiac events
15
17
9
1
120
Progression
2
4
4
0
100
18%
80
60
40
19 (8%)
23 (10%)
16 (7%)
20
0
1 to 5
6 to 10
11 to 15
16 to 18
Number of injections
Spielmann M, et al. SABCS 2007. Abstract 72.
PACS-04: Cardiac Safety
Obs.
T
Number of patients
268
260
T discontinued due to cardiac events*, all grade
NA
42
Cardiac death
0
0
CHF
1
4
LVEF < 45% without symptoms
6
11
* Stopping rules of trastuzumab in case of cardiac toxicity were as follows:
• LVEF <45% or [45%-50%] + relative decrease  15%
• LVEF [50%-55%] or [45%-50%] + relative decrease < 15% → cardiologist decision
Spielmann M, et al. SABCS 2007. Abstract 72.
PACS-04: Efficacy Results
Median follow-up from the initiation of adjuvant
chemotherapy = 48 months
PACS-04: Disease-Free Survival (ITT)
Kaplan-Meier
survival
estimates
Kaplan-Meier
curves, and
log-rank
test stratified on N
1.00
80.9%
0.75
77.9%
72.7 %
73.2%
HR=0.86: 95%CI [0.61-1.22]
0.50
HR = 0.86; 95%CI [0.61-1.22]
P = 0.41
0.25
Observation
0.00
0
12
24
Trastuzumab
36
p=0.41
48
60
93
78
21
10
Months
Number at risk
Observation 268
Trastuzumab 260
250
251
225
221
168
149
Spielmann M, et al. SABCS 2007. Abstract 72.
PACS-04: Hazard Rates of First Event
Exploratory Analysis
Smoothed hazard estimates
.012
HR = 0.57
95%CI (0.30-1.09)
Hazard rate
.01
HR = 1.04
.008
.006
.004
.002
HR=0.57: 95%CI [0.30-1.09]
0
6
12
No interaction between time
and treatment efficacy (P = 0.22)
18
24
Months
HR=1.04
30
36
42
48
Observation
Trastuzumab
Spielmann M, et al. SABCS 2007. Abstract 72.
PACS-04: Overall Survival (ITT)
Kaplan-Meier survival estimates
96.5%
93.0%
95.7%
91.5%
1.00
0.75
HR=1.27:
[0.68-2.38]
HR = 1.27;
95%CI95%CI
[0.68-2.38]
0.50
0.25
Observation
0.00
0
12
24
Trastuzumab
36
48
60
115
96
26
11
Months
Number at risk
Observation 268
Trastuzumab 260
264
256
255
244
203
177
Spielmann M, et al. SABCS 2007. Abstract 72.
PACS-04: Conclusions
• After 4-years of follow-up and the occurrence of the
required number of events, the present study did
not detect any significant difference between T and
non-T arms
• Trend to have a better efficacy of trastuzumab
during the first 18 months of follow-up
• The risk of cardiac toxicity remains low
Spielmann M, et al. SABCS 2007. Abstract 72.
Summary of Trastuzumab Adjuvant Trials
Study
FU, yrs
N
HR
1
3,387
0.54
2
3,401
0.64
NSABP B-31/
2
3,351
0.48
NCCTG 9891
4
3,968
0.48
BCIRG 006
3
3,222
0.61
FinHer
3
231
0.42
PACS 04
4
528
0.86
HERA
0
In favor of T
1
In favor of Obs.
2
Endocrine Therapy
SABCS Abstract 41
ATAC: 100 Month Median Follow-Up (FU)
Shows Continued Superior Efficacy and No
Excess Fracture Risk for Anastrozole (A)
Compared With Tamoxifen (T) After Treatment
Completion
Forbes JF, Cuzick J, Buzdar A, Howell A, Baum M,
on behalf of the ATAC Trialists' Group
ATAC: Trial Design
Anastrozole 5Y
(N = 3125)
Postmenopausal
women with invasive
breast cancer
(N = 6241)
Commenced July 1996
21 Countries (USA 24%)
ITT population
N = 3125
Safety population
N = 3092
HR+ subpopulation
N = 2618
Randomised
Double blind
Tamoxifen 5Y
(N = 3116)
ITT population
N = 3116
Safety population
N = 3094
HR+ subpopulation
N = 2598
ITT: intent-to-treat; HR+: hormone receptor-positive
Forbes JF, et al. SABCS 2007. Abstract 41.
ATAC: Background
• Previous reports1 at a median FU of 33 and 68 months
showed that anastrozole is more effective, has fewer
serious side effects and is better tolerated than
tamoxifen during the active treatment period
• It is not known whether efficacy benefits or side effects
persist long term after treatment completion
1ATAC
Trialists’ Group: Lancet 2002; 359: 1832-33; Lancet 2005; 365: 60-62.
Forbes JF, et al. SABCS 2007. Abstract 41.
ATAC: Update
Median follow-up 100 months
• All treatments completed prior to this analysis
• Total follow-up: 46,292 women years (increment 38%)
• Total events: 1704 (increment 39%)
• Compliance on treatment: A 88%, T 87%
• Blinding maintained post treatment
• Mean age at this analysis: 72 years
Forbes JF, et al. SABCS 2007. Abstract 41.
ATAC: Time to Recurrence
HR+ Patients
HR
30
95% CI
P-value
30
HR+ 0.76 (0.67, 0.87) 0.0001
Patients (%)
25
Tamoxifen (T)
Anastrozole (A)
20
25
21.8%
20
15
12.5%
15
17.0%
10
10
9.7%
5
Absolute
Difference 2.8%
0
0
At risk:
A
T
1
2
3
4
5
5
Absolute
Difference 4.8%
6
7
8
9
1801
1711
1492
1396
608
547
Follow-up time (years)
2618
2598
2541
2516
2453
2400
2361
2306
2278
2196
2159
2075
1995
1896
Forbes JF, et al. SABCS 2007. Abstract 41.
ATAC: Time to Recurrence
Smoothed Hazard Estimates for HR+ Patients
Annual hazard rates (%)
4.0
4.0
HR = 0.75
HR = 0.77
3.0
3.0
2.0
2.0
Tamoxifen (T)
Anastrozole (A)
1.0
1.0
0.0
0.0
0
1
2
3
4
5
6
7
8
9
Follow-up time (years)
Forbes JF, et al. SABCS 2007. Abstract 41.
ATAC: Time to Recurrence
Carryover Effect, Post-treatment Period, HR+ Patients
• Recurrence rates continue to be lower with anastrozole
after treatment completion
• The absolute difference in recurrence increased
from 2.8% after 5-years to 4.8% after 9-years
• Statistically significant larger carryover effect for anastrozole vs.
tamoxifen years 5-9: HR = 0.75 (95% CI 0.61-0.94), P = 0.01
• Carryover effect (risk reduction) in years 5-9:
─ Tamoxifen:
33%, (EBCTCG overview1)
─ Anastrozole (est): 50%
1Early
Breast Cancer Trialists’ Collaborative Group. Lancet 2005; 365: 1687-1717
Forbes JF, et al. SABCS 2007. Abstract 41.
ATAC: Time to Distant Recurrence
HR+ Patients
30
30
HR
Patients (%)
25
HR+ 0.84 (0.72, 0.97)
P-value
25
0.022
20
20
Tamoxifen (T)
Anastrozole (A)
15
15.6%
9.1%
10
13.2%
1.3%
0
0
1
2
3
4
5
15
10
5
7.8%
5
2.4%
6
7
8
9
1854
1809
1536
1484
636
591
0
Follow-up time (years)
At risk:
A
T
95% CI
2618
2598
2551
2533
2470
2440
2393
2363
2320
2263
2201
2151
2042
1982
Forbes JF, et al. SABCS 2007. Abstract 41.
ATAC: Contralateral Breast Cancer
HR+ Patients
5
5
HR
HR+ 0.60 (0.42, 0.85)
Patients (%)
4
P-value
4.2%
0.004
4
3
3
Tamoxifen (T)
Anastrozole (A)
2
2.5%
1
1.8%
2
1.0%
1
0.8%
0
0
1
2
3
4
1.7%
5
6
0
7
8
9
1801
1711
1493
1396
608
547
Follow-up time (years)
At risk:
A
T
95% CI
2618
2598
2541
2516
AD, absolute difference
2453
2400
2361
2306
2278
2196
2159
2075
1995
1896
Forbes JF, et al. SABCS 2007. Abstract 41.
ATAC: Endpoints
HR+ Patients
Favours
anastrozole (A)
Hazard ratio
(95% CI)
P-value
Disease-free survival
0.85 (0.76-0.94)
0.003
Time to recurrence
0.76 (0.67-0.87)
0.0001
Contralateral breast cancer
0.60 (0.42-0.85)
0.004
Time to distant recurrence
0.84 (0.72-0.97)
0.022
Death after recurrence
0.90 (0.75-1.07)
0.2
Death: all causes
0.97 (0.86-1.11)
0.7
0.2
0.4
0.6
Favours
tamoxifen (T)
0.8 1.0 1.2 1.5
2.0
Hazard ratio (A / T) and 95% CI
Forbes JF, et al. SABCS 2007. Abstract 41.
ATAC: Serious Adverse Events (SAEs)
On- and Off-Treatment (safety population)
On-treatment
SAE
Off-treatment
Anastrozole
Tamoxifen
Anastrozole
Tamoxifen
153
284
49
57
Endometrial cancer
4
12
1
12
Myocardial infarction
34
33
26
28
Cerebrovascular accident
20
34
22
20
Fracture episodes*
375
234
146
143
Treatment-related
*A fracture episode comprised one or more fractures on the same day based on adverse events and
serious adverse event report. A patient may have had more than one episode.
Forbes JF, et al. SABCS 2007. Abstract 41.
Annual fracture episode rates (%)
ATAC: Fracture Episode Rates Throughout Study
4
Anastrozole (A)
Tamoxifen (T)
3
2
1
RR = 1.55
P < 0.0001
RR = 1.03
P = 0.79
0
0
1
2
4
5
6
7
8
9
1713
1645
702
659
Time since randomization (years)
At risk:
A
T
3
2984
2976
2859
2824
2745
2699
2640
2572
2496
2419
2306
2208
2077
2000
Forbes JF, et al. SABCS 2007. Abstract 41.
ATAC: Conclusions
Efficacy
• At 100-month median follow-up, anastrozole is
significantly superior to tamoxifen in preventing breast
cancer recurrence
• The absolute difference in recurrence rates continues
to increase after treatment completion
• First demonstration of significant long-term carryover
effect for an AI:
− HR+ population: 2.8% at 5-years to 4.8% at 9-years
− HR = 0.75 for A vs. T (years 5-9) (P = 0.01)
Forbes JF, et al. SABCS 2007. Abstract 41.
ATAC: Conclusions
Safety
• After completion of 5-years treatment with anastrozole:
− No excess fracture rate
− No new morbidity or mortality concerns
Forbes JF, et al. SABCS 2007. Abstract 41.
SABCS Abstract 2071
Risk Factors for Joint Symptoms
in the ATAC Trial
Sestak I, on Behalf of the ATAC Trialists' Group
Risk Factors for Joint Symptoms: ATAC Trial
Trial Design
• Current study examined risk factors for joint symptoms
among women randomized in ATAC trial
– No joint symptoms at baseline
• Joint symptoms occurring during treatment or within
14-days of stopping therapy
–
–
–
–
Arthralgia
Arthritis
Arthrosis
Joint disorder
• 2,095 joint symptoms were reported at 5-years
– 1,128 (36.5%) anastrozole vs. 957 (30.9%) tamoxifen
Sestak I, et al. SABCS 2007. Abstract 2071.
Risk Factors for Joint Symptoms: ATAC Trial
Results
• Joint symptoms were more frequent with anastrozole
vs. tamoxifen
– 36.5% vs. 30.9% (OR: 1.28, P < 0.001)
• Most joint symptoms were mild to moderate and
decreased with increased time on treatment
• Major risk factors for developing joint symptoms were:
–
–
–
–
Prior HRT (OR: 1.52, P < 0.001)
Anastrozole treatment (OR: 1.31, P < 0.001)
Prior chemotherapy (OR: 1.20, P = 0.01)
Obesity (BMI ≥ 30 (OR: 1.36, P < 0.001)
• There was no clear indication of any interaction between
factors
Sestak I, et al. SABCS 2007. Abstract 2071.
Supportive Care
SABCS Abstract 27
The Effect of Zoledronic Acid on Aromatase
Inhibitor-Associated Bone Loss in
Postmenopausal Women With Early Breast
Cancer Receiving Adjuvant Letrozole:
The Z-FAST Study 36-Month Follow-up
Brufsky A, Bosserman L, Caradonna R, Haley B, Jones M, Moore H,
Dong M, Warsi G, Lacerna L, Perez E. Z-FAST Study Group
Aromatase Inhibitor-Associated Bone Loss
• Aromatase inhibitors (AIs) rapidly and profoundly
suppress estrogen production,1,2 resulting in
– Increased rate of bone turnover2-6
– Accelerated bone loss2-4,6-8
• Bone loss is more rapid than in postmenopausal women
• Fracture rate increases with AI use
1. Lǿnning P, et al. Semin Oncol. 2003;30:23-32; 2. Coleman RE, et al. Lancet Oncol. 2007;8:119-127; 3. Eastell R, et al. J
Bone Miner Res. 2006;21:1215-1223; 4. Geisler J, et al. Eur J Cancer. 2006;42:2968-2975; 5. Gonnelli S, et al. Bone.
2007;40:205-210; 6. Perez EA, et al. J Clin Oncol. 2006;24:3629-3635; 7. Coleman RE, et al. J Clin Oncol. 2006;24:5s.
Abstract 511; 8. Asmar L, et al. Breast Cancer Res Treat; 2006;100:S115. Abstract 2102.
Adjuvant AI Breast Cancer Studies
Median
follow-up
AI
Tamoxifen
Study
N
(mos)
% Fx
% Fx
P-value
ATAC1
6,186
68
11.0
7.7
< .0001
BIG 1-982
8,028
51
8.6
5.8
< .001
IES3
4,724
56
7.0
4.9
.003
ARNO4
3,224
28
2.0
1.0
.015
Placebo
% Fx
MA.175
5,187
30
5.3
4.6
.25
ATAC, Arimidex, Tamoxifen, Alone or in Combination; BIG 1-98, Breast International Group 1-98 Collaborative Group;
IES, Intergroup Exemestane Study; ARNO, Arimidex, Nolvadex 95 Study; Fx, fracture; MA.17, National Cancer Institute of
Canada Clinical Trials Group.
1. Howell A, et al. Lancet. 2005;365:60-62; 2. Coates AS, et al. J Clin Oncol. 2007;25:486-492; 3. Coombes RC, et al.
Lancet. 2007;369:559-570; 4. Jakesz R, et al. Lancet. 2005;366:455-462; 5. Goss PE, et al. J Natl Cancer Inst.
2005;97:1262-1271.
Z-FAST Study Design
R
A
N
D
O
M
I
Z
E
D
Eligibility
•
BCa
• PMW with
T score ≥ -2
ER+/PgR+
Stratification
• Adjuvant Chemo
(yes or no)
• T score (> -1 or
between -1 and -2 )
Zoledronic acid 4 mg IV q 6 mo UPFRONT
+ Letrozole (2.5 mg/d)a
Zoledronic acid 4 mg IV q 6 mo DELAYEDb
+ Letrozole (2.5 mg/d)a
0
1-year
3-years
5-years
Final analysis
ER, estrogen receptor; PgR, progesterone receptor, IV, intravenously; PMW, postmenopausal women.
aPlus daily calcium (1,000–1,200 mg) and vitamin D (400–800 IU)
bInitiation of zoledronic acid determined by postbaseline T score < -2.0, any clinical fracture, or any asymptomatic
fracture at 36 mo.
Brufsky A, et al. SABCS 2007. Abstract 27.
Zoledronic Acid Initiation in Delayed Group
Delayed Group Patients Who Initiated Zoledronic Acid
12-mo visit
All patients
Per protocola
24-mo visit
All patients
Per protocola
36-mo visit
All patients
Per protocola
First Zoledronic Acid Infusion in Delayed Group
Mean (SD)
Median
Range
No. of Patients (%)
44 (14.7)
28 (9.3)
54 (18.0)
37 (12.3)
62 (20.7)
45 (15.0)
Time to Initiation, mo
13.5 (10.2)
11.5
0.03–37.1
aInitiation
of zoledronic acid determined by postbaseline T score < -2.0, any clinical fracture, or any asymptomatic fracture
at 36 mo.
Brufsky A, et al. SABCS 2007. Abstract 27.
Mean (SEM) Percentage Change
in Bone Mineral Density
Percentage Change in Bone Mineral
Density
5
N = 189
N = 204
4
3
N = 251
N = 189
N = 251
2
Upfront
group
Delayed
group
N = 206
1
0
-1
-2
-3
N = 256
N = 256
-4
N = 199
N = 188
N = 197
-5
P < .0001
Month 12
N = 187
P < .0001
Month 24
Month 36
Lumbar Spine
SEM, standard error of the mean.
Month 12
Month 24
Month 36
Total Hip
Brufsky A, et al. SABCS 2007. Abstract 27.
Shift in LS T Score in Patients with Normal
Baseline T Score (T Score > -1)
T Score > - 1
T Score between - 1 and - 2
100
Patients (%)
P = .0024a
80
60
40
20
0
Upfront Group
(N = 140)
Delayed Group
(N = 133)
aP
value corresponds to INTERGROUP comparison at 36 mo.
LS, lumbar spine.
Brufsky A, et al. SABCS 2007. Abstract 27.
Shift in LS T Score in Patients With Low Baseline
T Score (T Score Between -1 to -2)
T Score > - 1
T Score between -1 and -2
T Score < - 2
100
Patients (%)
80
P = .0011a
60
40
20
0
Upfront
Group (N=47)
Delayed
Group (N=52)
aP
value corresponds to INTERGROUP comparisons at 36 mo.
LS, lumbar spine.
Brufsky A, et al. SABCS 2007. Abstract 27.
Fracture Rates
No. of Patients (%)
Type of Fracture
Upfront Group
Delayed Group
(N = 300)
(N = 300)
11 (3.7)
12 (4.0)
2 (0.7)
3 (1.0)
Asymptomatic
2 (0.7)
1 (0.3)
Other
1 (0.3)
2 (0.7)
Radiological spine
1 (0.3)
1 (0.3)
17 (5.7)
19 (6.3)
Clinical
Significant trauma
Minimal or no trauma
Total
Brufsky A, et al. SABCS 2007. Abstract 27.
Disease Recurrence
No. of Patients (%)
Kaplan-Meier percent (95% CI)
Upfront Group
Delayed Group
(N=300)
(N=300)
3.5 (1.2, 5.7)
6.9 (3.5, 10.2)
Bone
2 (0.7)
4 (1.3)
Breast
2 (0.7)
2 (0.7)
CNS
0 (0.0)
2 (0.7)
Liver
1 (0.3)
2 (0.7)
Lung
3 (1.0)
2 (0.7)
Other
1 (0.3)
7 (2.3)
Number of patients
9 (3.0)
16 (5.3)
P-value
0.1266
Site of recurrence
CI, confidence interval; CNS, central nervous system.
Brufsky A, et al. SABCS 2007. Abstract 27.
Adverse Events Occurring in > 10% of Patients
No. of Patients (%)
Adverse Event
Upfront Group
(N = 300)
Delayed Group
(N = 300)
109 (36.3)
111 (37.0)
Hot flashes
92 (30.7)
99 (33.0)
Fatigue
78 (26.0)
67 (22.3)
Myalgia
49 (16.3)
36 (12.0)
Bone pain
39 (13.0)
20 (6.7)
Nausea
33 (11.0)
27 (9.0)
Extremity pain
32 (10.7)
23 (7.7)
Headache
30 (10.0)
32 (10.7)
Back pain
28 (9.3)
32 (10.7)
Depression
26 (8.7)
35 (11.7)
Arthralgia
Brufsky A, et al. SABCS 2007. Abstract 27.
Additional Adverse Events
• Renal disorders
– Grade 1-2 renal failure
• Upfront group, 2 patients
• Delayed group, 0 patients
– Both suspected to be related to zoledronic acid
• Atrial fibrillation
– Grade 1-2
• Upfront group: 3 patients
• Delayed group: 0 patients
– Grade 3-4
• Upfront group: 4 patients
• Delayed group: 4 patients
– None suspected to be related to study drugs
• Osteonecrosis of the jaw
− No confirmed cases
Brufsky A, et al. SABCS 2007. Abstract 27.
Conclusions
• Upfront administration of zoledronic acid (4 mg IV
every 6 months) is effective in preventing bone loss
in postmenopausal women on AI therapy
– Increased lumbar spine and total hip bone mineral density
– Trend towards lower fracture rate
– Bone-specific alkaline phosphatase effectively suppressed
• Trend towards lower disease recurrence with upfront
therapy
• Zoledronic acid was safe and well tolerated
Brufsky A, et al. SABCS 2007. Abstract 27.
SABCS Abstract 47
A Phase 3 Study of the Effect of Denosumab
Therapy on Bone Mineral Density in Women
Receiving Aromatase Inhibitors for
Non-Metastatic Breast Cancer
Ellis G, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J,
Fan M, Jun S
Effect of Denosumab Therapy on BMD in Women
Receiving AI for Non-Metastatic Breast Cancer
Study Design
Women with HR+ non-metastatic
breast cancer receiving adjuvant
AI therapy
• Evidence of bone loss
• No osteoporosis (T score < -2.5)
(N = 252)
Denosumab*
60 mg SC every 6 mos. x 4
(N = 127)
Placebo*
60 mg SC every 6 mos. x 4
(N = 125)
• Primary endpoint: percent change in lumbar BMD at 12-months
• Stratify: duration of AI therapy (≤ 6 vs. > 6 mos.)
*All patients were instructed to take calcium and vitamin D daily.
Ellis G, et al. SABCS 2007. Abstract 47.
Effect of Denosumab Therapy on BMD in Women
Receiving AI for Non-Metastatic Breast Cancer
Baseline Characteristics
Denosumab
Placebo
(N = 127)
(N = 125)
59.2%
59.7%
% white
91%
95%
≥ 10 yrs since last menstrual period
50%
50%
Anastrozole
56%
54%
Letrozole
33%
31%
Exemestane
11%
14%
Previous AI > 6 mos.
63%
63%
Previous chemotherapy
65%
62%
Previous tamoxifen
46%
42%
Mean age, yrs
AI therapy at randomization
Ellis G, et al. SABCS 2007. Abstract 47.
Effect of Denosumab Therapy on BMD in Women
Receiving AI for Non-Metastatic Breast Cancer
Results
• There was greater preservation (> 0% change from baseline) of lumbar
spine BMD with denosumab vs. placebo
–
97% vs. 36% (P < 0.0001) at 12 months
–
95% vs. 34% (P < 0.0001) at 24 months
• Lumbar spine BMD increased with denosumab vs. placebo
–
5.5% (P < 0.0001) at 12 months
–
7.6% (P < 0.0001) at 24 months
• Hip BMD increased with denosumab vs. placebo
–
3.7% (P < 0.0001) at 12 months
–
4.7% (P < 0.0001) at 24 months
• Distal 1/3 radius increased with denosumab vs. placebo
–
3.8% (P < 0.0001) at 12 months
–
6.1% (P < 0.0001) at 24 months
Ellis G, et al. SABCS 2007. Abstract 47.
Effect of Denosumab Therapy on BMD in Women
Receiving AI for Non-Metastatic Breast Cancer
Toxicities
•
•
•
Treatment-related AEs were similar between denosumab and placebo
–
Any AEs: 91% vs. 90%
–
AEs (grade 3,4,5): 23% vs. 23%
SAEs occurred in 15% of denosumab treated patients vs. 9% of placebo patients
–
None of the SAEs were considered treatment-related
–
No specific type of AE accounted for the slight imbalance
–
One death in each arm due to metastatic disease
Most frequent AEs:
–
Arthralgia: 24% vs. 25%
–
Extremity pain: 15% vs. 12%
–
Back pain: 14% vs. 13%
–
Fatigue: 13% vs. 14%
–
Constipation: 12% vs. 9%
–
Cough: 10% vs. 4%
–
Insomnia: 9% vs. 12%
Ellis G, et al. SABCS 2007. Abstract 47.
Effect of Denosumab Therapy on BMD in Women
Receiving AI for Non-Metastatic Breast Cancer
Conclusions
• In women with non-metastatic breast cancer who had
low bone mass and were receiving adjuvant AI therapy,
twice yearly administration of denosumab consistently
increased BMD over 24-months at trabecular and
cortical bone sites
• Overall AE rates were similar to placebo
Ellis G, et al. SABCS 2007. Abstract 47.
Oral Chemotherapy for Early Disease
Neoadjuvant Trials – Capecitabine
• Three ongoing trials evaluating the potential benefit of
adding capecitabine into neoadjuvant therapy
–
Abstract 79, von Minckwitz: EC→T vs. EC→TX vs. EC→T→X
• More non-hematologic toxicity in capecitabine arms
• Final results pending
– Abstract 5057, Roché: CEX vs. FEC (oral vs. IV 5-FU)
• Improved pCR with CEX without compromising toxicity
• Final results pending
– Abstract 5059, Tripathy: XT ± H with p53 mutation analysis
• Active and well tolerated non-anthracycline option
• Final results pending
Treatment of Early Breast Cancer
Closing Comments
Maura N. Dickler, MD