Transcript Tamoxifen: The Treatment of Choice for Advanced Breast Cancer?

Aromatase Inhibitors in Breast
Cancer
Development of Aromatase Inhibitors:
Activity Profiles
Toxicity
First generation
- Aminoglutethimide*
Specificity
Rash,
etc.
Potency
1
Second generation
- Fadrozole
- 4-OHA
100
Third generation
- Anastrozole
- Exemestane
- Letrozole
*No approved indication for breast cancer in the United States.
No adrenal
insufficiency,
etc.
500
to
10,000
Case #1


Clinical presentation
– 63 year-old postmenopausal woman
– 3 cm. lump detected in upper outer quadrant of
left breast
– Ipsilateral axilla clinically negative
– Remainder of physical exam normal / ECOG 0
– No significant co-morbidities
Risk factors
– HRT x 9 years
– No family history
– No prior breast abnormalities
Work Up

Lumpectomy + ALND

3.2 cm Grade 3/3 infiltrating ductal carcinoma

Resection margins clear

4/12 nodes positive

ER+, PgR–, and HER2–

CXR, bone scan, Abdominal CT negative

Laboratory profile is normal
Prognosis

32.5% probability of living @ 10 yrs
– 60% probability of cancer death
– 7.5% probability of non cancer death

Absolute benefit of chemotherapy 10%

Absolute benefit of hormonal therapy 11%

Absolute benefit of combined therapy 21%
Post-operative Management
Stop HRT
CA X 4  Paclitaxel X 4
Local Radiation Therapy
Adjuvant Endocrine Therapy
? Tamoxifen
? Aromatase Inhibitor
how long
which inhibitor
Case #2

Clinical presentation
– 75 year-old postmenopausal woman
– Mammographically-detected right-sided suspicious
calcifications
– Physical exam normal / ECOG 1

Risk factors
– Past history of postmenopausal vaginal bleeding
– Endometrial polyp with atypia
Work Up

Core biopsy reveals infiltrating lobular
carcinoma

Wire localization excision + SLND

1.2 cm grade 2/3 tumor with clear margins

0 nodes positive

ER+, PgR+, and HER2–

CXR negative

Laboratory profile negative
Prognosis

65% probability of living @ 10 yrs
– 7% probability of cancer death
– 28% probability of non cancer death

Absolute benefit of chemotherapy 1%

Absolute benefit of hormonal therapy 2%

Absolute benefit of combined therapy 3%
Post-operative Management
Local Radiation Therapy
Adjuvant Endocrine Therapy
Tamoxifen
? Aromatase Inhibitor
how long
which inhibitor
1998 Overview: Effectiveness Of Adjuvant
Therapy On Breast Cancer Mortality
Tam
Chemo
Combined
ER+
ER-
25%
0%
25%
35%
45%
--
ER+
ER-
25%
0%
10%
20%
35%
--
< 50
> 50
Risk Reduction in Early Breast Cancer
in Estrogen ReceptorPositive Patients
Mortality From Any Cause
Recurrence as First Event
100
100
79.2
80
74.9
70
75.6
60
Node -ve
64.3
58.3
50
40
44.5
30
Tamoxifen
(~5 y)
Control
78.9
Node -ve
73.3
70
Control
Node +ve
89.3
80.1
80
Tamoxifen
(~5 y)
59.7
91.8
90
% Alive
90
% Recurrence-free
Tamoxifen
(~5 y)
Control
87.4
74.2
61.4
60
Node +ve
50
50.5
40
30
Absolute Recurrence Reduction
20
Node -ve: 14.9% SD 1.4: 2P<0.00001
Node +ve: 15.2% SD 2.5: 2P<0.00001
10
0
Absolute Mortality Reduction
20
Node -ve: 5.6% SD 1.3: 2P<0.00001
Node +ve: 10.9% SD 2.5: 2P<0.00001
10
0
0
5
Years
10+
0
5
Years
Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451.
10+
Tamoxifen
(~5 y)
Control
Disease-free survival (%)
NSABP B-14 Trial: 10 Years
of Tamoxifen vs Stopping
Placebo
100
P=0.03
Tamoxifen
80
60
Patients re-randomized after 5 years of tamoxifen
40
0
1
2
3
4
Year after second randomization
Number at Risk
TAM
Stop
570
583
560
567
Fisher et al. J Natl Cancer Inst. 2001;93:684.
433
411
250
251
176
163
Rationale for Aromatase Inhibitors in
Adjuvant Therapy

Mortality is reduced by only ~ 1/4 by
Tamoxifen

Aromatase inhibitors
– Effective after Tamoxifen
– May be superior to Tamoxifen first-line
– Well tolerated
– Low risk of endometrial carcinoma,
thromboembolic events
Potential Considerations in Evaluating
Aromatase Inhibitors in the Adjuvant Setting
Potential Risks:
Potential Benefits:
•
Vasomotor
•
Inhibit breast cancer
•
Urogenital
•
•
Bone
Fewer endometrial
cancers
•
Lipid
•
Cognitive
•
? Other
•
Less
thromboembolism
Clinical Trial Strategies in
Adjuvant Therapy with Aromatase
Inhibitors
TAMOXIFEN
ATAC
ANASTROZOLE
LETROZOLE
ARNO
EXEMESTANE
PLACEBO
MA-17
BIG 1-98
(BIG FEMTA)
ICCG Study 96
NSABP B33
TEAM
ATAC Trial Design
Postmenopausal women with invasive breast cancer

Completion of primary therapy*

Randomization 1:1:1 for 5 years



Anastrozole 1mg od
Anastrozole placebo
Anastrozole 1mg od
+
+
+
Tamoxifen placebo
Tamoxifen 20mg od
Tamoxifen 20mg od

Regular follow-up monitoring adverse events

Trial endpoints
* Surgery + radiotherapy + chemotherapy
(Patients may start trial therapy while still receiving radiotherapy)
+
ATAC Update SABCS 2002





Median follow up: 47 months
Median duration of therapy: 37 months
Number of events: 1373
Patients receiving >3 yrs of Rx: ~50%
Breast cancer event rate (%):
– Yr. 1: A=2.49 T=2.30 HR=1.08
– Yr. 2: A=2.61 T=4.28 HR=0.61
– Yr. 3: A=2.94 T=3.72 HR=0.77
Bianco, et al. SABCS 2002,#632
First Events in Overall Population
First event
Locoregional recurrence
Distant recurrence
Contralateral (invasive)
Contralateral (DCIS)
Death (non-breast cancer)
Anastrozole
n=3125 (%)
Tamoxifen
n=3116 (%)
413
(13.2)
472
(15.1)
84
(2.7)
101
(3.2)
195
(6.2)
222
(7.1)
20
(0.6)
35
(1.1)
5
(0.2)
5
(0.2)
109
(3.5)
109
(3.5)
Probability of Recurrence in
Receptor-positive Population
Proportion with recurrence (%)
20
AN vs TAM
HR
95% CI
p-value
0.78
0.65–0.93
0.007
15
Anastrozole
Tamoxifen
10
5
Absolute
Difference 2.6%
Absolute
Difference 1.8%
0
0
No. of
Pts. at risk
AN
2617
TAM
2598
6
12
18
24
30
36
42
48
54
1258
1210
602
574
Time to event (months)
2533
2516
* Censoring non-BC deaths before recurrence
2436
2386
2243
2180
Comparison of ATAC data with EBCTCG 1995
Overview1: Receptor-positive Patients >50 Years
100
Estimated % without
recurrence
4-year
recurrence-free rate:
92.2%
89.6%
90
80
70
0
0
1
Control (EBCTCG)
Tamoxifen (EBCTCG)
2
3
4
Anastrozole (ATAC)
Tamoxifen (ATAC)
5+
years
1Lancet
1998;
351: 1451–1467
Time to Recurrence by Subgroups
Receptor status
+ve
–ve
Nodal status
0
1–3
4+
Previous chemo
no
yes
0.30
0.40
0.60
In favour of Anastrozole
0.80
1.00
1.25 1.50
2.00
In favour of Tamoxifen
Hazard ratio (AN/TAM)
ATAC Trial:Adverse Events
In favor of
anastrozole
Hot flushes
In favor of
tamoxifen
-5.4%
6.6%
Weight gain*
-1.8%
2.1%
Fractures
0.8%
Vag. bleeding
Vag. discharge
Endo ca
MSK disorders
Fractures of hip,
spine, wrist
-3.6%
-8.6%
-0.4%
-1.1%
ICVA
VTE
-1.4%
-0.7%
DVT
-10
-5
0
5
10
Difference between anastrozole and tamoxifen AEs (%)
*Proportion with 10% gain in body weight from baseline to year 2.
Baum et al. San Antonio Breast Cancer Symposium. 2001.
ATAC Trial: Bone Mineral Density
A (80)
T(87)
Comb.(82) Cont.(39)
% change @ 1 yr
LS Spine
-2.59
1.01
0.21
-.36
Femur
-1.68
0.48
0.78
-.13
Lipid Effects of Aromatase Inhibitors

Anastrazole (n=1,021)
LDL

Letrozole (n=20)
TC, LDL,
HDL

Exemestane (n=76)
TG
TC, HDL,TC/HDL ratio unchanged
Summary of
ASCO Panel Consensus





Results of ATAC are preliminary
5 years of Tamoxifen remains standard
There is no reported survival advantage with
anastrozole
All 3 AI’s are generally comparable in MBC, the
only data in adjuvant setting is with Arimidex
Use Arimidex if Tamoxifen contraindicated,
have already received Tamoxifen (?raloxifene)
or significant side effects with Tamoxifen
Case #3

70 years old with performance status 0

Presents with 7 cm mass in right breast that
has been present for > one year

Biopsy reveals ER+, PgR+, HER2– breast
cancer

CT reveals a single liver metastasis

Bone scan + with several areas of uptake
Treatment Options

Tamoxifen

Anastrozole

Letrozole

Exemestane

Chemotherapy
Third-Generation AIs in
First-Line Studies
R
A
N
D
O
M
I
Z
E
Tamoxifen 20 mg
Third-generation AIs
 Anastrozole 1 mg
or
 Letrozole 2.5 mg
or
 Exemestane 25 mg
Indirect Comparison of AI’s and Tamoxifen
Phase III First-Line Data
Letr. Tam. Anast. Tam.
Exem.
Tam
Patients(n)
294
305
305
306
31
32
TTP(mo)
9.7
6.0
10.7
6.4
8.9
5.2
Survival(mo) 34
30
NR
NR
NR
NR
Letrozole vs Tamoxifen
Overall Survival
1-yr. survival
rate
Kaplan-Meier Estimate (%)
100
90
0.8
2 yr. survival
rate
Overall
Survival
Letrozole
83%
64%
35 mo
Tamoxifen
75%
58%
32 mo
0.004
0.02
0.514
P (log-rank test)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
4
3
5
Years
99% of patients crossed over by 36 months
Initial therapy:
Letrozole
Mouridsen et al. J Clin Oncol. 21:2101-2109, 2003.
Tamoxifen
Kaplan-Meier estimate
Letrozole vs Tamoxifen: Time to
Chemotherapy
1.0
0.9
Median time to chemotherapy
Letrozole 16 mo
Tamoxifen 9 mo
P=0.005 (log-rank test)
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
Months
Initial therapy:
Letrozole (n=453)
Mouridsen et al. J Clin Oncol. 21:2101-2109, 2003.
Tamoxifen (n=454)
60
Anastrazole v Tamoxifen as First Line Therapy in MBC.
(#255 SABCS 2002. Thuerlimann et al, Switzerland)

Swiss patients enrolled in protocol 027

60 pts: ER/Pr +: 56, 4 unknown
A (31)
T (29)
TTP 1st line
11.3 mo
8.3 mo
TTP 2nd line
6mo
Total TTP28.2mo
(18)
(19)
6mo
19.5 mo*
*p=.36
Exemestane After Failure of
Nonsteroidal AI’s

Phase II trial

N= 241

Prior therapies
– aminoglutethimide, letrozole, anastrazole,
vorozole

Rx: Exemestane 25 mg daily
Lonning et al. JCO.11:2234, 2000
Exemestane After Failure of
Nonsteroidal AI’s

OR n (%)
16 (6.6)

CR n (%)
3 (1.2)

PR n (%)
13 (5.4)

SD (>6mo) (%)
42 (17.4)

Clinical benefit
74 (24.3)
Lonning et al. JCO.11:2234, 2000
GONO-MIG 8: Sequential Use of AI’s
in Metastatice Breast Cancer
A
No Prior AI
Exemestane
B
Prior Exemestane
Letrozole or
anastrazole
C
Prior letrozole or
anastrazole
Exemestane
Bertelli, ASCO 2002.238
Letrozole or
anastrazole
GONO-MIG 8: Sequential Use of AI’s
in Metastatice Breast Cancer
EL/A
L/AE
A (32)
B(10)
C(24)
PR n (%)
6 (18.4)
1(10)
1(4.2)
SD>6mo
9 (28.1)
3(30)
5(20.8)
Clin. Benefit
15(46.9)
4(40)
6(25)
Bertelli, ASCO 2002.238
Randomized Trials of AIs in First Line
Setting : Conclusions

The aromatase inhibitors (anastrazole,
letrozole, exemestane) are at least as
effective as tamoxifen

TTP favors AI in all trials

Survival data reported only for letrozole

No direct comparisons available

Optimal sequence not clear
Neoadjuvant Femara vs. Tamoxifen: Response
by ErbB1+ and ErbB2+ Category
Analysis on ER positive and/or PgR positive cancers only
Category
Letrozole Tamoxifen Odds Ratio P Value
Let vs Tam
ErbB1/2+
ER+
15/17
(88%)
4/19
(21%)
28
(4.5-177)
0.0004
ErbB1/2–
ER+
55/101
(54%)
42/100
(42%)
1.7
(0.9-2.9)
0.078
Ellis MJ et al. J Clin Oncol. 19:3808-3816, 2001.
Breast Cancer-2003
Sequential Use of Hormones
P
R
E
V
E
N
T
I
O
N
Tamoxifen
Adjuvant
First line
Tamoxifen
Nonsteroidal
SERD
Steroidal AI
Or
AI or
Or
Or
Anastrazole
Second line Third line
SERD or Tam Steroidal AI
MA
R
E
S
I
S
T
A
N
C
E