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Aromatase inhibitors in the era ofAromatase inhibitors in the era ofEvidence Based MedicineEvidence Based Medicine
dr. Vivianne Tjan-Heijnen dr. Vivianne Tjan-Heijnen UMC St RadboudUMC St RadboudNKI symposium NKI symposium
29 juni 200529 juni 2005
Aromatase inhibitors in the era ofAromatase inhibitors in the era ofEvidence Based MedicineEvidence Based Medicine
Evidence or believe
That is the question
What does a patient expect when What does a patient expect when receiving a treatment?receiving a treatment?
That the treatment
is proven to be effective
has no unnecessary side-effects
has no unpleasant surprises
The patient wants some certainty
Letrozole
Non-steroidal(Type II)
Steroidal(Type I)
Anastrozole
NC CN
NN
N
ExemestaneO
CH2
OCH3
CH3
CH3 H3C
NC CN
NN
N
H3C CH3
All aromatase inhibitors are equal,All aromatase inhibitors are equal,but some are more equal than othersbut some are more equal than others
Clinical pharmacology of Clinical pharmacology of newer-generation AIsnewer-generation AIs
Anastrozole Letrozole Exemestane
Daily clinical dose 1mg 2.5mg 25mg
Effects on corticosteroids No Yes No
Half-life 41 hours 2–4 days 27 hours
Time to steady stateplasmalevels 7 days 60 days 7 days**
Androgenic metabolites No No Yes
Class of AI Type II Type II Type I
% of E2 suppression 84-85 88 62-65
Adapted from: Buzdar A et al. Cancer 2002; 95: 2006–16
Anastrozole versus Exemestane Anastrozole versus Exemestane in patients with visceral metastasesin patients with visceral metastases
Cameron et al. Proc ASCO 2004; abs 628
0
1
2
3
4
5
ve
rsc
hil
in T
TP
(m
aa
nd
en
)
Anastrozole versus Letrozole 2Anastrozole versus Letrozole 2ndnd line lineTime to progressionTime to progression
0
1
2
3
4
5
6
7
maa
nd
en
overall HR+
Arimidex
letrozol
Rose et al. EJC 2003
%RFS
100
80
0 1 2 3 4 5
years
90
70
100
3215 40033116 4007
2362 208 2372 218
2575 3872582 469
% node +ve39 49Age64
50% ER/PR+ve82
62
9884
64
6 7 7.5
2663
100
IESIES
1606
42100
61
HR RFS0.83* 0.79 0.68 0.59 0.57
ATACATAC BIG 1-98BIG 1-98
1618
ITAITA ARNO/ABCSGARNO/ABCSG
MA17MA17
Anastrozole
Letrozole
Exemestane
63100
100
0.43
ABCSGABCSG
6231
97
0.64Follow up29 6037 52 282668
*ER+ population
Aromatase inhibitors in early breast cancerAromatase inhibitors in early breast cancer
Anastrozole1 Letrozole2 Exemestane3
Initial adjuvant therapy
Efficacy vs tamoxifen
Tolerability
Switching from tamoxifen
Efficacy vs tamoxifen
Tolerability
Extended adjuvant setting
Efficacy vs placebo
Tolerability
Full risk:benefit profile
?
1) ATAC trialists’ Lancet 2005; Boccardo et al. ASCO 2005; Jakesz et al. SABCS 2004; Jakesz et al. ASCO 2005
2) Thurlimann St. Gallen 2005; Goss et al. NEJM 2003
3) Coombes et al. NEJM 2004
Neoadjuvant Anastrozole (OR%)Neoadjuvant Anastrozole (OR%)Mastectomy / inoperable at baseline (n=344)Mastectomy / inoperable at baseline (n=344)
47%
35%
0
10
20
30
40
50
A T
OR
R (
%)
36%
26%
0
10
20
30
40
50
A T
OR
R (
%)
Calliper Ultrasound
A vs T: OR 1.65 (CI 1.06, 2.56) p=0.026 A vs T: OR 1.60 (CI 1.00, 2.55) p=0.048
68/18888/188 55/156 41/156
Statistically significant difference in favour of anastrozole
Indirect comparison with letrozole trialIndirect comparison with letrozole trialObjective response rate (%)Objective response rate (%)
OR (%) L T L vs T A T A vs T
Ultrasound 35 25 p=0.042 36 26 p=0.048
Eiermann et al. Ann Oncol 2001; 12: 1527–1532.
EfficacyEfficacyConclusionsConclusions
Head to head studies in advanced breast cancer demonstrate similar efficacy of aromatase inhibitors
There are no direct comparisons of aromatase inhibitors in early breast cancer Indirect comparisons in primary endpoints
show similar efficacy
Differences in pharmacology do not seem to translate into differences in clinical efficacy
ASCO technology assessment 2004ASCO technology assessment 2004
In breast cancer therapy, ASCO currently
recommends the use of the AI ‘that has been
studied in the setting most closely
approximating any individual patient’s clinical
circumstance’
Winer et al. JCO 2005
Anno 2005:
Evidence is what matters
SafetySafety
Differences in pharmacology do not seem to translate into differences in clinical efficacy
Do these differences translate into different side effect profiles ?
Focus on bone and cardio vascular effects
Interactions with the Interactions with the cytochrome P450 systemcytochrome P450 system
Anastrozole Letrozole Exemestane
Inhibits CYP1A2,CYP2C9 at relatively highconcentration
No activity onCYP2A6 orCYP2D6
Metabolised byN-dealkylation,hydroxylation andglucuronidisation
Strongly inhibitsCYP2A6
Moderatelyinhibits CYP2C19
Metabolised byCYP3A4 andCYP2A6
No inhibition ofCYP1A2, CYP2C9,CYP2D6, CYP2E1 orCYP3A4
Metabolised by CYP3A4and aldoketoreductase
Adapted from: Buzdar A et al. Cancer 2002; 95: 2006–16
Anastrozole 10mg: ACTH stimulation Anastrozole 10mg: ACTH stimulation cortisol cortisol and aldosteroneand aldosterone
Adapted from: Plourde et al. J Ster Biochem Mol Biol 1995; 53: 175–9; Esparza-Guerra, Buzdar. Proc ASCO 2001; 20 (Pt 2): 52b, Abstr 1954
Baseline 30min 60min
nm
ol/
Ln
mo
l/L
AldosteroneAldosterone
Time after ACTH stimulation
0
200
400
600
800
1000
1200
Baseline 30min 60min
nm
ol/
Ln
mo
l/L
CortisolCortisol
Time after ACTH stimulation
0
200
400
600
800
1000
1200
Screening
Day 28
Day 115
Adapted from: Bajetta E et al. Eur J Cancer 1999; 35: 208–13
Letrozole: ACTH stimulation Letrozole: ACTH stimulation cortisol and aldosteronecortisol and aldosterone
LET = letrozole
800
600
400
200
0
1000
p=0.04
p=0.015
Baseline 30min 60min
Time after ACTH stimulation
nm
ol/
Ln
mo
l/L
nm
ol/
Ln
mo
l/L
800
600
400
200
0
1000
Baseline 30min 60min
Time after ACTH stimulation
Baseline
1 month (2.5mg LET)
3 months (2.5mg LET)
AldosteroneAldosteroneCortisolCortisol
SafetySafety ATAC vs. BIG 1-98 vs. IES ATAC vs. BIG 1-98 vs. IES
Upfront Anastrozole in favour of tamoxifen (ATAC):
hot flashes, vaginal bleeding, vaginal discharge, endometrial cancer, ischemic cerebrovascular events and venous thromboembolic events.
Letrozole in favour of tamoxifen (BIG 1-98): hot flashes, vaginal bleeding and thromboembolic events.
Switch Exemestane in favour of tamoxifen (IES):
vaginal bleeding, cramps and venous thromboembolic events.
1) ATAC trialists’ Lancet 2002,2005;
2) Thurlimann St. Gallen 2005;
3) Coombes et al. NEJM 2004
SafetySafety ATAC vs. BIG 1-98 vs. IES ATAC vs. BIG 1-98 vs. IES
BIG 1-98 ATAC (1st analysis)
ATAC(2nd analysis)
Cardiac death 26 L, 13 T 19 A, 20 T 49 A, 46 T
Cerebrovascular death 7 L, 1 T 3 A, 13 T 14 A, 21 T
IES
Myocardial infarct: 20 exemestane; 8 tamoxifen
Cardiac death / cerebrovascular death: to be reported
1) ATAC trialists’ Lancet 2002, 2005;
2) Thurlimann St. Gallen 2005;
3) Coombes et al. SABCS 2004
SafetySafetyBoneBone
In all adjuvant trials aromatase inhibitors lead to more fractures than tamoxifen both in upfront and switching trials1-3
Effects on bone do not seem to increase over time1
1) ATAC trialists’ Lancet 2005;
2) Thurlimann St. Gallen 2005;
3) Coombes et al. SABCS 2004
Estimated change (95% CI) in lumbar Estimated change (95% CI) in lumbar spine BMD over timespine BMD over time
Estimated % changes from baseline lumbar spine BMD
4
Anastrozole
71 58
Tamoxifen
69 64
1 year2 year3
2
1
0
-1
-2
-3
-4
-5
-6
101 105
Exe Tam
122 104
Let Plac
Coleman EBCC 2004 abs 289, Coleman SA 2004 Abs 401 , Perez Abs 404
FracturenFracturen
UPFRONT SEQUENTIEEL
ATAC
anastrozol vs tam
BIG 1-98
letrozol vs tam
IES-031
exemestanevs tam
ABCSG8/ARNO95
anastrozol vs tam
FU: 36 mnd
5.9% vs 3.7%
(p< 0.0001)
FU: 26 mnd
5.8% vs 4.1% (P=0.0006)
FU: 37,4 mnd
3.9% vs 2.9% (p=0.06)
FU: 28.0 mnd
2.4% vs 1.2% (significant)
SafetySafetyConclusionsConclusions
Differences in potency and pharmacology do seem to translate into differences in side effect profiles
Longer follow up is needed to confirm this
With 68 months of follow up in ATAC anastrozole has the most robuust safety data
Evidence or believeIt is not a question !
My patients with breast cancer expect My patients with breast cancer expect me to be sure of what I am doingme to be sure of what I am doing
VOOR DE DISCUSSIE
Hortobagyi ASCO 2005
Conclusions about AIsConclusions about AIs
Upfront AI is clearly more effective/better tolerated than upfront
TAM. AIs reduce events from the beginning. This is a fact.
Crossover from TAM to an AI after 2-5 years of TAM is clearly
effective. However, 1.5-3.8%/year of TAM-treated pts develop
treatment failure before crossover. The superiority of crossover
regimens over AI upfront is a hypothesis only.
Until proven otherwise an AI upfront should be the preferred
strategy.