Aromatase Inhibitors in Breast Cancer

1
Aromatase Inhibitors in Breast Cancer
2
Development of Aromatase Inhibitors Activity
Profiles
Toxicity
Specificity
Potency
First generation
Rash, etc.
- Aminoglutethimide
1
Second generation
- Fadrozole - 4-OHA
100
Third generation
- Anastrozole - Exemestane - Letrozole
No adrenal insufficiency, etc.
500 to 10,000
No approved indication for breast cancer in the
United States.
3
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

4
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

5
Prognosis

• 32.5 probability of living _at_ 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

6
Post-operative Management

• Stop HRT
• CA X 4 ? Paclitaxel X 4
• Local Radiation Therapy
• Adjuvant Endocrine Therapy

? Tamoxifen ? Aromatase Inhibitor how long
which inhibitor
7
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

8
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

9
Prognosis

• 65 probability of living _at_ 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

10
Post-operative Management

• Local Radiation Therapy
• Adjuvant Endocrine Therapy

Tamoxifen ? Aromatase Inhibitor how long which
inhibitor
11
1998 Overview Effectiveness Of Adjuvant Therapy
On Breast Cancer Mortality
Tam Chemo Combined lt 50 ER 25 25 45
ER- 0 35 -- gt 50 ER 25 10 35
ER- 0 20 --
12
Risk Reduction in Early Breast Cancer in
Estrogen Receptor?Positive Patients
Mortality From Any Cause
Recurrence as First Event
100
100
91.8
Tamoxifen (5 y)
Tamoxifen (5 y)
87.4
90
90
89.3
Control
Control
78.9
79.2
80
80.1
80
74.9
Tamoxifen (5 y)
Tamoxifen (5 y)
Node -ve
73.3
Node -ve
70
70
75.6
Control
Control
64.3
74.2
61.4
60
60
59.7
Node ve
58.3
Node ve
Alive
50
50
Recurrence-free
50.5
40
40
44.5
30
30
Absolute Mortality Reduction
Absolute Recurrence Reduction
20
Node -ve 5.6 SD 1.3 2Plt0.00001 Node ve
10.9 SD 2.5 2Plt0.00001
20
Node -ve 14.9 SD 1.4 2Plt0.00001 Node ve
15.2 SD 2.5 2Plt0.00001
10
10
0
0
5
10
0
5
10
0
Years
Years
Early Breast Cancer Trialists Collaborative
Group. Lancet. 19983511451.
13
NSABP B-14 Trial 10 Years of Tamoxifen vs
Stopping
Placebo
100
P0.03
Tamoxifen
80
Disease-free survival ()
60
Patients re-randomized after 5 years of tamoxifen
40
0
1
2
3
4
Year after second randomization
Number at Risk
TAM 570 560 433 250 176 Stop 583 567 411 251 163
Fisher et al. J Natl Cancer Inst. 200193684.
14
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

15
Potential Considerations in Evaluating Aromatase
Inhibitors in the Adjuvant Setting

• Potential Risks
• Vasomotor
• Urogenital
• Bone
• Lipid
• Cognitive
• ? Other

• Potential Benefits
• Inhibit breast cancer
• Fewer endometrial cancers
• Less thromboembolism

16
Clinical Trial Strategies in Adjuvant Therapy
with Aromatase Inhibitors
TAMOXIFEN
ANASTROZOLE
ATAC
LETROZOLE
EXEMESTANE
ARNO
PLACEBO
MA-17
BIG 1-98(BIG FEMTA)

ICCG Study 96
NSABP B33
TEAM
17
ATAC Trial Design
Surgery radiotherapy chemotherapy (Patients
may start trial therapy while still receiving
radiotherapy)
18
ATAC Update SABCS 2002

• Median follow up 47 months
• Median duration of therapy 37 months
• Number of events 1373
• Patients receiving gt3 yrs of Rx 50
• Breast cancer event rate ()
• Yr. 1 A2.49 T2.30 HR1.08
• Yr. 2 A2.61 T4.28 HR0.61
• Yr. 3 A2.94 T3.72 HR0.77
• Bianco, et al. SABCS 2002,632

19
First Events in Overall Population
Tamoxifenn3116 ()
Anastrozolen3125 ()
First event 413 (13.2) 472
(15.1) Locoregional recurrence 84
(2.7) 101 (3.2) Distant recurrence 195
(6.2) 222 (7.1) Contralateral (invasive) 20
(0.6) 35 (1.1) Contralateral (DCIS) 5
(0.2) 5 (0.2) Death (non-breast cancer) 109
(3.5) 109 (3.5)
20
Probability of Recurrence inReceptor-positive
Population
HR 95 CI p-value
AN vs TAM 0.78 0.650.93 0.007
Proportion with recurrence ()
0
0
6
12
18
24
30
36
42
48
54
No. of Pts. at risk
Time to event (months)
AN TAM
2617 2598
2533 2516
2436 2386
2243 2180
1258 1210
602 574
Censoring non-BC deaths before recurrence
21
Comparison of ATAC data with EBCTCG 1995
Overview1 Receptor-positive Patients gt50 Years
100
90
Estimated without recurrence
80
70
0
years
0
1
2
3
4
5
1Lancet 1998351 14511467
Control (EBCTCG) Tamoxifen (EBCTCG)
Anastrozole (ATAC)
Tamoxifen (ATAC)
22
Time to Recurrence by Subgroups
0.30
0.40
0.60
0.80
1.00
1.25
1.50
2.00
In favour of Anastrozole
In favour of Tamoxifen
Hazard ratio (AN/TAM)
23
ATAC TrialAdverse Events
In favor of anastrozole
In favor of tamoxifen
-5.4
Hot flushes
MSK disorders
6.6
-1.8
Weight gain
Fractures
2.1
Fractures of hip,spine, wrist
0.8
-3.6
Vag. bleeding
-8.6
Vag. discharge
Endo ca
-0.4
-1.1
ICVA
VTE
-1.4
-0.7
DVT
-10
-5
0
5
10
Difference between anastrozole and tamoxifen AEs
()
Proportion with ³10 gain in body weight from
baseline to year 2. Baum et al. San Antonio
Breast Cancer Symposium. 2001.
24
ATAC Trial Bone Mineral Density

• A (80) T(87) Comb.(82)
  Cont.(39)
• change _at_ 1 yr
• LS Spine -2.59 1.01 0.21 -.36
• Femur -1.68 0.48 0.78 -.13

Eastell R. ESMO. 2002
25
Lipid Effects of Aromatase Inhibitors

• Anastrazole (n1,021)
• LDL
• Letrozole (n20)
• TC, LDL,
• HDL
• Exemestane (n76)
• TG
• TC, HDL,TC/HDL ratio unchanged

26
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 AIs 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

27
Case 3

• 70 years old with performance status 0
• Presents with 7 cm mass in right breast that has
  been present for gt one year
• Biopsy reveals ER, PgR, HER2 breast cancer
• CT reveals a single liver metastasis
• Bone scan with several areas of uptake

28
Treatment Options

• Tamoxifen
• Anastrozole
• Letrozole
• Exemestane
• Chemotherapy

29
Third-Generation AIs in First-Line Studies
Tamoxifen 20 mg
RANDOMIZE

• Third-generation AIs
• Anastrozole 1 mg
• or
• Letrozole 2.5 mg
• or
• Exemestane 25 mg

30
Indirect Comparison of AIs 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

31
Letrozole vs Tamoxifen Overall Survival

1-yr. survival rate
2 yr. survival rate
Overall Survival
100

Letrozole
83
64
35 mo
90
Tamoxifen
75
58
32 mo
0.8
P
0.004
0.02
(log-rank test)
0.514

0.7
0.6
0.5

Kaplan-Meier Estimate ()
0.4
0.3
0.2
0.1
0.0
0
1
2
4
5
3
Years
Mouridsen et al. J Clin Oncol. 212101-2109, 2003.
32
Letrozole vs Tamoxifen Time to Chemotherapy
1.0
Median time to chemotherapy Letrozole 16
moTamoxifen 9 mo P0.005 (log-rank test)
0.9
0.8
0.7
0.6
0.5
Kaplan-Meier estimate
0.4
0.3
0.2
0.1
0.0
0
12
18
24
30
36
42
48
54
60
6
Months
Letrozole (n453)
Tamoxifen (n454)
Initial therapy
Mouridsen et al. J Clin Oncol. 212101-2109, 2003.
33
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 6mo
• Total TTP 28.2mo 19.5 mo
• 
  p.36

(18)
(19)
34
Exemestane After Failure of Nonsteroidal AIs

• Phase II trial
• N 241
• Prior therapies
• aminoglutethimide, letrozole, anastrazole,
  vorozole
• Rx Exemestane 25 mg daily

Lonning et al. JCO.112234, 2000
35
Exemestane After Failure of Nonsteroidal AIs

• OR n () 16 (6.6)
• CR n () 3 (1.2)
• PR n () 13 (5.4)
• SD (gt6mo) () 42 (17.4)
• Clinical benefit 74 (24.3)

Lonning et al. JCO.112234, 2000
36
GONO-MIG 8 Sequential Use of AIs in
Metastatice Breast Cancer
A
Letrozole or anastrazole
No Prior AI
Exemestane
B
Letrozole or anastrazole
Prior Exemestane
C
Prior letrozole or anastrazole
Exemestane
Bertelli, ASCO 2002.238
37
GONO-MIG 8 Sequential Use of AIs 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)
• SDgt6mo 9 (28.1) 3(30) 5(20.8)
• Clin. Benefit 15(46.9) 4(40) 6(25)

Bertelli, ASCO 2002.238
38
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

39
Neoadjuvant Femara vs. Tamoxifen Response by
ErbB1 and ErbB2 Category
Analysis on ER positive and/or PgR positive
cancers only
0.078
1.7 (0.9-2.9)
42/100 (42)
55/101 (54)
ErbB1/2 ER
Ellis MJ et al. J Clin Oncol. 193808-3816, 2001.
40
Breast Cancer-2003Sequential Use of Hormones
R E S I S T A N C E