Clinical Updates
Hormonally Sensitive, Early-Stage Breast Cancer
Hormonally Sensitive Early-Stage Breast Cancer
Current Considerations and New Directions
Terry Mamounas, MD, MPH
Professor of Surgery
Northeastern Ohio Universities College of Medicine
Medical Director
Aultman Cancer Center
Canton, OH
Breast Cancer Mortality in US and UK
WHO Mortality and UN Population Estimates
Factors Associated with Reduction
In Breast Cancer Mortality
Early Detection
Mammography
LR Therapy
Surgery
XRT
Treatment of
Advanced Disease
Hormonal Therapy,
Chemotherapy,
Trastuzumab
Adjuvant Systemic
Therapy
Hormonal Therapy
and Chemotherapy
Overview Analysis:
Benefit from Tamoxifen
2005 Overview Analysis
Current Considerations and New
Directions with Endocrine Therapy
• Recurrence patterns of ER-positive BC
• Optimal tamoxifen duration
• Aromatase Inhibitors
– Overview of efficacy data
– Remaining questions
• Combinations of AIs with other promising agents:
– EGFR Inhibitors
– mTOR Inhibitors
– Bisphosphonates
Long-Term Risk of Breast Cancer
Recurrence Remains High in ER+ Patients
0.3
Recurrence hazard rate
ER+ (n=2,257)
ER– (n=1,305)
0.2
0.1
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Years
• A substantial proportion of breast cancer recurrences occur >5 years postsurgery
• The annual risk of late recurrence is higher in ER+ tumors
Saphner et al. J Clin Oncol. 1996;14:2738.
More Than Half of Breast Cancer Recurrences
and Deaths Occur Post-Tamoxifen
Recurrences
15%
100
17%
9%
100
85.2
55%
62.7
54.9
40
Tamoxifen
Control
% of patients
68%
73.7
20
91.4
80
68.2
60
18%
80.9
76.1
80
% of patients
Breast Cancer Deaths
87.8
73.0
73%
73.2
64%
60
64.0
40
Tamoxifen
Control
20
0
0
0
5
10
Years
15
0
5
10
15
Years
Adapted with permission.
Early Breast Cancer Trialists’ Collaborative Group Meeting, 2000.
NSABP B-14
Tamoxifen Duration
Disease-Free Survival
Node-Negative ER-Positive
100
Randomization
Registration
80
Placebo
X 5 yrs
TAM
X 5 yrs
Placebo
X 5 yrs
TAM
X 5 yrs
TAM
X 5 yrs
60
TRT
PLAC
TAM
40
0
1
2
N
569
583
Events
106
137
3
4
5
p=0.03
6
7
Years
Fisher et al: JNCI, 2001
Adjuvant Tamoxifen
Postmenopausal
women with
invasive tumors
Preliminary Data
RANDOMIZE
Longer Against Shorter (ATLAS)
Tamoxifen 20 mg PO qd × 5 years
Tamoxifen 20 mg PO qd × 10 years
N = 11,500
Woman
Years
Number of
Recurrences
Annual Rate of
Recurrence
Years 5 - 9
42,000
1353
3%
Years 10 - 14
8000
211
3%
Recurrence
3.4% × 5-yr tamoxifen
Annual Event Rate
2.9% × 10-yr tamoxifen
Breast Cancer Mortality Annual
Event Rate
1.5% × 5-yr tamoxifen
1.4% × 10-yr tamoxifen
Rate Ratio 0.866
SE (0.048)
Rate Ratio 0.895
SE (0.070)
Peto R, et al. 30th Annual San Antonio Breast Cancer Symposium. December 13-16, 2007; San Antonio, TX. Abstract 48.
ATLAS Preliminary Results
• Partial data suggest
– About 12% risk reduction in breast cancer recurrence years
5 - 9 from diagnosis with continued tamoxifen
• Limitations
– Incomplete biomarker testing
– 59% confirmed ER(+)
– Adherence ~ 80%
– Incomplete toxicity profile
Peto R, et al. 30th Annual San Antonio Breast Cancer Symposium.
December 13-16, 2007; San Antonio, TX. Abstract 48.
Adjuvant Tamoxifen To Offer More
Postmenopausal
women with
invasive tumors
who received
≥ 2 years of
tamoxifen
N = 6934
RANDOMIZE
(aTTom)
Discontinue Tamoxifen 20 mg PO qd
Tamoxifen 20 mg PO qd
× 5 additional years
Median Follow-up 4.2 Years of 15-Year Analysis
Preliminary Data
N = 6952
Discontinued
Tamoxifen
Continued
Tamoxifen
Relative Risk
P Value
Disease Recurrence
447
445
0.95
NS
Gray R, et al. J Clin Oncol. 2008;26(15S): Abstract 513.
Primary Endpoint:
Disease Recurrence
40
No.
Patients
% Recurred
35
No.
Obs.
Events
Exp.
Continue
3468
437
447-9
Stop
3484
456
445-1
35%
34%
30
25
20
RR = 0.95
(0.83 - 1.09; P = NS)
15
10
continue
stop
5
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Years From Randomization
At risk:
continue
3468
3152
2831
2320
1803
1303
916
629
422
254
139
54
8
stop
3484
3160
2829
2308
1786
1284
916
635
412
250
122
49
11
Gray R, et al. J Clin Oncol. 2008;26(15S): Abstract 513.
Preliminary aTTom Results
• Limitations
– Confirmed ER(+) = 40%
– Various durations of tamoxifen use
– Adherence ~ 80%
– Incomplete toxicity profile
• Statistically, only 68% of the true effect of 10-year
tamoxifen will be observed
Gray R, et al. J Clin Oncol. 2008;26(15S): Abstract 513.
Adjuvant Aromatase Inhibitors
Replacing 5 Years of Tamoxifen as the Gold Standard
Three Strategies
AIs as
Initial Therapy
AIs After
2-3 Yrs of TAM
TAM X 5 Yrs
TAM X 5 Yrs
AIs After
5 Years of TAM
AI X 5 Yrs
TAM X 5 Yrs
AI X 5 Yrs
TAM X 2-3
AI X 2-3
PLAC X 5 Yrs
Relative Reductions in DFS Event in
8 Reported AI Adjuvant Trials
70
60
Anastrozole
Letrozole
Exemestane
ITA
52 m
Percent
58%
50
40
IES
55 m
30
20
10
ATAC
68 m
BIG
26 m
ABCSG/
ARNO
28 m
MA.17
30 m
40%
42%
ABCSG-6
60 m
36%
B-33
30 m
32%
24%
19%
13%
0
Up-Front
Howell A, et al: SABCS 2004
Thurlimann et al. N Engl J Med 2005.
After 2-3 yrs of TAM
Coombs et al. ASCO 2006
Boccardo et al. ASCO 2005
Jakesz et al. Lancet 2005.
After 5 yrs of TAM
Goss et al. JNCI 2005
Jakesz et al. ASCO 2005
Mamounas et al. SABCS 2006
Reductions in Contralateral BC
in 7 Reported AI Adjuvant Trials
70
Anastrozole
Letrozole
Exemestane
75%
Percent
60
50
40
ATAC BIG 1-98
68 m
26 m
42%
30
B-33
30 m
42%
(ns)
ITA
36 m
IES
37 m
50%
(ns)
50%
MA.17
30 m
ABCSG/
ARNO
28 m
46%
25%
20
10
0
Up-front
Howell et al. SABCS 2004.
Thurlimann et al. ASCO 2005.
After 2-3 y of TAM
Boccardo et al. JCO 2004
Coombs et al. SABCS. 2004.
After 5 y of TAM
Jakesz et al. SABCS 2004.
Goss et al. JNCI 2005.
Mamounas et al. SABCS 2006
Aromatase Inhibitors
Remaining Questions
•
Are there significant differences in efficacy and toxicity
between different AIs?
•
What is the proper time to initiate AIs?
•
What is the optimal duration of AIs?
•
What is the role of AIs in premenopausal women who
undergo ovarian function suppression?
•
What is the role of AIs in patients with DCIS
NCIC MA.27 Trial:
Anastrozole vs. Exemestane
Placebo
 3 years
Anastrozole
 5 years
Postmenopausal
ER+ and/or PgR+
Chemo or not
Exemestane
 5 years
Celecoxib
 3 years
Placebo
 3 years
Celecoxib
 3 years
Activated: 6/03
Accrual: 6,830
NCIC MA.27 Trial:
Anastrozole vs. Exemestane
Placebo
 3 years
Anastrozole
 5 years
Postmenopausal
ER+ and/or PgR+
Chemo or not
Exemestane
 5 years
Activated: 6/03
Accrual: 6,830
Celecoxib
 3 years
Placebo
 3 years
Celecoxib
 3 years
Head-to-Head Adjuvant Phase IIIb Trial:
Femara® vs Anastrozole Clinical Evaluation (FACE)
Early Breast Cancer
• Postmenopausal
• ER+ and/or PgR+
• Node-positive
• Primary end point:
R
A
N
D
O
M
I
Z
E
Letrozole 2.5 mg/d
N=4,000
Anastrozole 1 mg/d
Disease-free survival
• Secondary end points: Safety, overall survival, time to distant
mets, time to CBC, BC-specific survival
De Boer et al. J Clin Oncol. 2006;24(18S):582s.
BIG 1-98
Trial Design
Tamoxifen 20 mg
n=2,446
Letrozole 2.5 mg
n=2,446
RANDOMIZATION
(Following complete
tumor resection)
0
Tamoxifen 20 mg
Letrozole n=1,530
Letrozole 2.5 mg
Tamoxifen n=1,530
2
5 years
Sequential Treatment Comparisons
Median Follow-up 71 months
Tam→Let vs. Let
Let→Tam vs. Let
Mouridsen HT, et al: SABCS 2008, Abstr. 13
Breast Cancer Events
TamLet vs. Let
Overall
By Nodal Status*
*42% of the population is node positive; 58% node negative
Mouridsen HT, et al: SABCS 2008, Abstr. 13
Breast Cancer Events
LetTam vs. Let
Overall
By Nodal Status*
*42% of the population is node positive; 58% node negative
Mouridsen HT, et al: SABCS 2008, Abstr. 13
TEAM
Exemestane vs. Tamoxifen
Tamoxifen  5 y
TEAM
Exemestane  5 y
Completed accrual: 5,700 pts (1,600 pts from US)
TEAM Trial Amendment:
TAM  2-3 y
EXE  2-3 y
TEAM
EXE  5 y
MA.17: Disease-Free Survival
Hazard Ratios of Letrozole to Placebo
0.8
Upper 95% CL
Hazard ratio
0.6
Ratio
estimate
0.4
Lower 95% CL
0.2
P<0.0001 for hazard ratio trends based
on time dependent Cox model
0.0
0
6
12
18
24
30
36
42
48
Months after randomization
Ingle JN, et al: San Antonio, 2005 # 17
Duration of AIs
MA.17 Extended Adjuvant: 5 vs. 10 Yrs
Tamoxifen
Letrozole
Placebo
(n=900)
(n=900)
MA.17
0y
5y
MA.17
Extension
10 y
15 y
Status of Trial
949 patients enrolled as of August 26, 2008
Adapted from Goss. ASCO, 2004.
NSABP B-42
Trial Evaluating Adjuvant AI Duration
Postmenopausal, Disease-free, Stage I, II, or III invasive BC
at diagnosis ER-positive and/or PgR-positive
AI X 5 yrs
TAM X 2-3 yrs
AI X 3-2 yrs
• Primary Endpoint
Disease-free survival
• Secondary Endpoints
Overall survival
Time to treatment failure
Osteoporosis-related fractures
Letrozole X 5 yrs
Placebo X 5 yrs
Current Accrual:
1,882 / 3,840
SOFT (IBCSG 24-02, BIG 2-02)
Patients who remain premenopausal within 6 months after CT
or receive tamoxifen alone as adequate treatment
Premenopausal
ER+ 10% and/or
PgR+ 10%
Patients with estradiol
(E2) in the
premenopausal range
either after CT or
without CT
*
Strata
Any CT
No CT
R
A
N
D
O
M
I
Z
E
TAM  5 y
OFS + TAM  5 y
OFS + EXE  5 y
Target sample size: 3,000 patients
*Randomization within a 6-month evaluation period after end of CT, or within 12 weeks after
definitive surgery for patients with no CT.
OFS = ovarian function suppression.
NSABP B-35
Postmenopausal women
ER- or PgR-positive DCIS
Lumpectomy with free margins
Randomization
1/03-6/06
Accrual: 3,104
XRT
Tamoxifen
Anastrozole
Recent data with AIs
in combination
with other agents:
EGFR Inhibitors
mTOR Inhibitors
Bisphosphonates
EGFR Interaction with the ER
E2
H
B
E
R
H
B
MMPs
MAPK
c-Src
E2
P CoA
ER
ER
AF1
P
E2
EREs
nucleus
E2
Growth and
survival
Gefitinib in Breast Cancer
 Previous clinical trials in breast cancer studies showed
mainly negative results1-3
 Osborne et al 4 recently reported the first randomized,
placebo controlled phase II study of tamoxifen and
gefitinib:
 A modest improved PFS in patients with hormonal-naïve disease
or who had completed adjuvant tamoxifen >1 year (10.9 vs. 8.8
months, P=0.31)
1Albain
KS, et al SABC 2002
2Dennison SK, et al Breast Cancer Res Treat 2007
3Smith IE, et al J Clin Oncol ,2007
4Osborne CK, SABC 2007
Anastrozole +/- Gefitinib
Randomized Phase II Trial
Patients
• Postmenopausal
women
• Age
≥ 18 years
• Newly
diagnosed ER
and / or PgR positive
metastatic breast
cancer
Gefitinib 250 mg / day
+
Anastrozole 1 mg / day
Primary
• Progression-free survival
1:1 randomization
• No
prior hormonal
therapy, or
development of
metastatic disease
during / after adjuvant
tamoxifen
Response variables
Placebo
+
Anastrozole 1 mg / day
Secondary
• Objective response rate
• Clinical benefit rate
• Overall survival
• Safety and tolerability
• Measurable
or nonmeasurable disease
(via RECIST)
• Trial closed early due to poor accrual
• 94 patients randomized
Cristofanilli et al, ASCO 2008,
Abstract 1012
Progression-Free Survival
Gefitinib + Placebo +
anastrozole anastrozole
(n = 43)
(n = 50)
Probability 1.0
of PFS
Events
22
Median PFS (months)14.5
0.8
32
8.2
0.6
0.4
0.2
HR (95% CI) = 0.55 (0.32, 0.94)
0.0
0
3
6
9
12
15
18
21
24
27
50
43
35
40
23
28
13
22
9
13
6
10
5
6
3
3
1
2
1
30
Months
At risk:
Placebo
Gefitinib
Cristofanilli et al, ASCO 2008, Abstract 1012
Objective Response and Clinical Benefit Rate
(RECIST)
Gefitinib + anastrozole (n = 43)
Placebo + anastrozole (n = 50)
60
Response
rate (%)
48.8%
50
40
34%
30
20
12%
10
0
2.3%
Objective response rate
(CR+PR)
Clinical benefit rate (CBR)
(CR+PR+SD > 24 weeks)
ORR, objective response rate; CBR, clinical benefit rate;
CR, complete response; PR, partial response; SD, stable disease
Cristofanilli et al, ASCO 2008, Abstract 1012
Neoadjuvant Letrozole
+/- RAD001 (Everolimus)
• Study design
– Phase II, randomized double-blind placebo-controlled trial
– Postmenopausal women with >T2 tumors
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
Tumor biopsies
(pretreatment)
n = 138
Letrozole 2.5 mg/d
Everolimus 10 mg/d
Surgery
Letrozole 2.5 mg/d
Placebo
n = 132
16 weeks
Tumor biopsies
(day 15)
Tumor samples
(surgery)
Baselga et al, ASCO 2008, Abstract 530
Neoadjuvant Letrozole
+/- RAD001 (Everolimus)
• Higher response with combination
– PE: 68.1% vs. 59.1%, P = 0.062
– US: 58% vs 47%, P = 0.035
• Greater decrease in Ki67
• Increased toxicity
– Hyperglycemia, stomatitis, infections, interstitial lung disease
ABCSG-12 Trial Design
•
•
•
•
•
•
•
Accrual 1999-2006
1,803 premenopausal breast cancer patients
Endocrine-responsive (ER and/or PR positive)
Stage I & II, <10 positive nodes
No chemotherapy except neoadjuvant
Treatment duration: 3 years
Primary endpoint: DFS
Surgery
(+RT)
Goserelin
3.6 mg q28d
Randomize
1:1 : 1:1
Tamoxifen 20 mg/d
Tamoxifen 20 mg/d
+ Zoledronic acid 4 mg q6m
Anastrozole 1 mg/d
Median follow-up: 60 months
Anastrozole 1 mg/d
+ Zoledronic acid 4 mg q6m
Gnant et al, ASCO 2008, LBA 4
ABCSG-12:
Patient Characteristics
Tamoxifen
n = 452
Tamoxifen + ZA
n = 449
Anastrozole
n = 450
Anastrozole + ZA
n = 449
Median Age
(years)
45.5
45.3
45.8
44.5
T1
75%
75%
77%
76%
≥ T2
22%
22%
21%
22%
Node Negative
67%
66%
67%
67%
Grade 3
Disease
21%
20%
22%
22%
Neoadjuvant
Chemotherapy
5%
5%
5%
6%
Breast
Conservation
80%
80%
80%
80%
Gnant MF, et al. J Clin Oncol. 2008;26(18S):LBA4.
First Efficacy Results
Median Follow-up 60 Months
N = 1801
Hazard Ratio
P Value
Primary Endpoint: Disease-free Survival
Tamoxifen vs Anastrozole
1.01 (0.79 - 1.54)
.59
Endocrine Therapy + ZA vs Endocrine
Therapy Alone
0.64 (0.46 - 0.91)
.01
Secondary Endpoints
Relapse-free Survival
Endocrine Therapy + ZA vs Endocrine
Therapy Alone
0.65 (0.46 - 0.92)
.015
0.60 (0.32 - 1.11)
.10
Overall Survival
Endocrine Therapy + ZA vs Endocrine
Therapy Alone
Gnant MF, et al. J Clin Oncol. 2008;26(18S):LBA4.
ABCSG-12: Primary Endpoint: DFS
Anastrozole vs. Tamoxifen
100
90
Disease-free Survival
80
70
60
50
40
30
20
10
0
ANA
TAM
0
No. of
events
Hazard ratio (95% CI)
vs TAM
72/903
65/900
1.008 (0.79 - 1.54)
P Value
.593
12
24
36
48
Time Since Randomization (months)
60
72
84
Number at risk
TAM
944
849
736
589
439
264
141
60
ANA
963
849
743
558
436
271
151
59
Gnant MF, et al. J Clin Oncol. 2008;26(18S):LBA4.
ABCSG-12: Primary Endpoint: DFS
+/- Zoledronic Acid
100
Disease-free Survival
90
80
70
60
50
40
30
Hazard ratio (95% CI)
P Value
vs No ZA
.011
0.64 (0.46 - 0.91)
54/904
83/899
No. of
events
20
ZA
No ZA
10
0
0
12
24
36
48
60
72
84
838
735
565
441
265
161
60
851
744
573
434
270
131
59
Number at risk
No ZA
ZA
904
899
Gnant MF, et al. J Clin Oncol. 2008;26(18S):LBA4.
ABCSG-12
ITT Population First Events
45
40
Number First Event
35
Locoregional recurrence
41
30
Distant recurrence
25
29
Contralateral BCA
20
15
Seconary malignancy
20
10
5
Death without recurrence
10 10
2
10
6 9
0
0
No ZA
ZA
Gnant MF, et al. J Clin Oncol. 2008;26(18S):LBA4.
ABCSG-12
Clinical Impact
• Select, premenopausal patient population
– Unknown if results can be extrapolated to postmenopausal women
or more advanced disease
• Await data from ongoing clinical trials to confirm and
expand findings
– AZURE, NSABP B-34, Z-FAST/ZO-FAST, SWOG 0307
– SOFT and TEXT
• Not yet practice changing
Clinical Updates
Hormonally Sensitive, Early-Stage Breast Cancer
Hormonally Sensitive Early-Stage Breast Cancer
Current Considerations and New Directions
Concluding Remarks