Transcript Dia 1

Aromatase Inhibitors (AI) for
Premenopausal Women
(early stage breast cancer)??
Monique Bos
RdGG, Delft
June 29 2005
29 juni2005, mb
“AI” Pre-men
Endocrine therapy for breast cancer
1896
1950
1970
1980
1985
1995
2004
Ovariectomy
High estrogens
Tamoxifen and other SERMs
Non selective AI
Magesterol acetate (Megace®)
Selective AI, 3rd generation
Fulverstant (Faslodex®)
•only effective if Er+ and/or Pr+
•metastatic breast cancer
•adjuvant therapy
•pre- en postmenopausal women
•side effects
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“AI” Premen
DFS Premenopausal women
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“AI” Pr-men
DFS Pre-menopausal women
Age < 35 yr
Age > 35 yr
Er+
Aebi, Lancet 2000
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“AI” Premen
Activity 3rd generation AI
cyt.450
Estrogen
Testosteron
cyt.450
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Type I: steroidal AIs
irreversible
Examestane.
Type II: nonsteroidal AIs
reversible
Anastrozole,
Letrozole.
“AI” premen
aromatase “”?
cholesterol
pregnenolon
Adrenal
cortex
progesteron
17 αOH-progesteron

aldosteron
cortisol
90% ovaries
Premenopause
10%
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androgen

estrogen
muscle
liver
adrenal
fat
breast(tumor)
“AI” Premen
Specific aromatase inhibitors
cholesterol
adrenals
17
αOH-progesteron
androstedion

Oestron
E1
testosteron
anastrozole

letrozole
examestane
Oestradiol
E2
fat
muscle
Liver
breast tissue
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dihydrotestosteron
ovaries
“AI” Premen
In premenopausal women
90% estrogens produced in ovaries
Ovarian aromatase not (incompletely)
inhibited by current AI
•Direct toxicity
•“hairy woman syndrome”
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“AI” Premen
Chances on
menopause
after chemotherapy
DeVita, 7th edition
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“AI” premen
Disease-Free Survival in CAF Patients
Probability
1.0
0.8
Amenorrhea
0.6
0.4
No amenorrhea
0.2
0.0
0
1
2
3
4
5
6
7
8
9
Disease-Free Survival (Years)
Nancy Davidson, San Antonio Breast Cancer Conference, December 2001
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10
“AI” premen
Beneficial effect
OFS in
Er+ breast cancer
DFS
ER+
CMF = Zoladex®
ZEBRA trial,
n= 1640,
Stage 2
CMF
CMF vs Zoladex®
Adjuvant
m fu 7.3 yr
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Kaufmann, 2003
DFS
ERZoladex®
“AI” premen
“Vietnamese trial”
n= 709, adjuvant
Oophorectomy + tamoxifen vs observation
ER+ , 288 pts
Ooph.+Tam
observation
Love, 2002
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“AI” Premen
Optimizing AI in premenopausal women
Ovarian function suppression
1) Surgical ophoorectomy: hospitalisation/anasthesia
irreversible & absolute
cost-effective
2) Radiation: cost-effective
outpatient clinic
inconsistent 13% menstruating
35% failure
slow decline estradiol levels
long term side effects
3) LH-RH analogs: decline estrogen levels <2-3 weeks
reversible
expensive
monthly sc
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“AI” premen
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Optimizing aromatase inhibitors
in premenopausal women
“AI” premen
Effect of aromatase inhibitors on estrogens in
postmenopausal women
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Geisler, 2002
“AI”Pr-men
chemical ovarian function suppression!
Effect Goserelin (Zoladex®) on estradiol levels
Start anastrozole (Arimidex®)
Oestradiol (pg/ml)
300
250
200
150
(n=7)
100
Postmenopausal
threshold
50
0
0
1
2
3
4
5
6
7
8
12 16 20
Time (weeks)
1
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2
3
4
‘Zoladex’ 3.6mg depot
5
6
“AI” Premen
In Er+, Premenopausal pts:
1.Better prognosis when OFS
2.Preferable by LH-RH
3.Sufficient decline of estrogens
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“AI” Premen
Interpretations to the clinic:
1.Postmenopausal M1 studies
2.Postmenopausal adjuvant studies
3.Premenopausal M1 studies
4.“Expert Opinion”
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“AI” clinical data
Phase 3 data metastatic breast cancer
postmenopausal women
pts
in favor
of AI
Second line, after Tamoxifen
Letrozole vs magesterol
Anastrozole vs megesterol
Examestane vs megesterol
602
764
769
TTP
Survival
Survival
First line
Anastrozole vs tamoxifen (353+668)
Letrozole vs tamoxifen
Examestane vs tamoxifen
1021
907
382
TTP, CB
TTP, CB, OR
RR, TTP
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JANICKE,2004
“AI” in breast ca
Phase 3 data metastatic breast cancer
postmenopausal women
First line
Anastrozole vs tamoxifen (353+668)
Letrozole vs tamoxifen
pts
1021
907
Letrozole
Tam
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Tam
JANICKE,2004
in favor of AI
TTP, CB
TTP, CB, OR
Anastrozole
“AI” in breast ca
early stage breast cancer trials
postmenopausal women
Vanaf 1995
duration
pts
1) Italian
Tamoxifen +/- Aminoglutetamide 5 jaar
380
2) MA-17
3) ATAC
4) TEAM
5) BIG 1-98
6) ICCG 96
7) ARNO
8) Z(O)-FAST
Tamoxifen  Letrozole
Tamoxifen vs Anastrozole
Tamoxifen vs/  Examestane
Tamoxifen vs Letrozole
Tamoxifen  Examestane
Tamoxifen  Anastrozole
Letrozole +/- Zoledronaat
5200
9000
1000
8000
5000
3100
1500
total
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8 jaar
5 jaar
5 jaar
5 jaar
5 jaar
5 jaar
5 jaar
>28000
“AI” premen
ATAC
Recurrence and ER/PR status
Patient group
HR+
ER+PgR+
ER+PgR-
Hazard ratio
0.79
0.84
0.43
Patients (%)
25
20
Tamoxifen
ER+/PgR-
15
10
Anastrozole
5
0
0
1
2
3
4
Follow-up time (years)
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5
6
“AI” premen
Postmenopausal adjuvant studies
IMPACT:
Neo-adjuvant Anastrozole, Tamoxifen of combinatie
12 w, n = 330
Response in Her-2 pos.
patients per arm
70
60
58%
50
40
31
30
22%
20
10
0
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A
T
C
7/12
2/9
4/13
Smiths & Dowsett
Totaal 39/330
“AI” premen
Postmenopausal adjuvant studies
IMPACT: rationale results
“Cross talk different receptor signaling”
proliferation
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“AI” premen
Premenopausal M1 studies
Study design
respons
T
OR 75%
BJC, ’04
(n=16)
Gos. + Tamoxifen
 pod
Gos. + anastrozole
TTP
>17
mnd
Carlson,
BCRT, ’04
(n=18, so far)
Fase 2, 2e lijn
Gosereline +
Anastrozole
OR 28%
SD 44%
TTP
10 mnd
MillaSantos
BCRT, ’02
(n=119)
Gosereline +
Tamoxifen (58)
Anastrozole (61)
OR= 53%
OR= 80%
Med.S
13.3
18.9
Forward
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“AI” premen
oestradiol (pmol/L)
Estrogen levels in Gosereline and Anastrozole
250
p<0.0001
200
beyond
menopause
150
100
p<0.0001
50
0
Baseline
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Forward, BJC, 2004
Zoladex +
tamoxifen
Zoladex +
Arimidex
“AI” premen
Postmenopausal adjuvant studies
Tamoxifen
Side effects
Hot flushes
CVA
Thrombosis
Endometrial cancer
Vag. bleeding
Vag. discharge
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Aromatase inhibitors
Fractures
bone pain
joint pain
osteoporosis
muscle ache
“AI” premen
Postmenopausal adjuvant studies
Side effects
“often” = 1-10%:
Weight gain
Edema
Malaise
Headache/dizziness
Hair loss
Dig.tract symptoms
Rash
Fatigue
Increased appetite
Loss of appetite
Hypercholestermia
“only for 5 years!!”
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“AI” premen
Side effects
QOL among younger women with breast cancer
N.E.Avis, May, 2005
P3322-3329
Conclusion
“younger breast cancer survivors are at
risk for impaired QOL”
Related to menopausal symptoms,
problems with sexual functioning and
body image”
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“AI” Pre-men
Translation to the clinic:
1. Preclinical data
2. Postmenopausal adjuvant studies
3. Premenopausal M1 studies
4. “Expert Opinion”
St Gallen Jan.2005
SABCC Dec.2004
ASCO May 2005
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ABCSG12
not much!!!
“AI” Pre-men
St Gallen 2005
Primary Therapy of Early Breast Cancer
Concensus Statement
1) Moving away from only pure “level 1” evidence
2) Pivotal role for endocrine responsiveness”
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“AI” Pre-men
“Concensus Panel” 2005
Premenopausal women
Er+
and/or
Pr+
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Intermediate risk
High risk
(<35jr, BR>2, T2, N0-3,
Her2-, no vasc invasion)
(N4+, N+vasc invasion,
N+ her2+)
Chemotherapy
CAF, AC, FEC
Chemotherapy
CAF, AC, FEC
(Taxanes)
Endocrine therapy
Tamoxifen
(OFS)
Endocrine therapy
Tamoxifen
(OFS)
Aromatase inhibitor
+ OFS
Aromatase inhibitor
+ OFS
“AI” Pre-men
“Concensus Panel” 2005
Premenopausal women
Er+
and/or
Pr+
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Intermediate risk
High risk
(<35jr, BR>2, T2, N0-3,
Her2-, no vasc invasion)
(N4+, N+vasc invasion,
N+ her2+)
Chemotherapy
CAF, AC, FEC
Chemotherapy
CAF, AC, FEC
(Taxanes)
Endocrine therapy
Tamoxifen
(OFS)
Endocrine therapy
Tamoxifen
(OFS)
Aromatase inhibitor
+ OFS
Aromatase inhibitorr
+ OFS
“AI” Pre-men
“Concensus Panel” 2005
Premenopausal women
Er+
and/or
Pr+
29juni2005, mb
Intermediate risk
High risk
(<35jr, BR>2, T2, N0-3,
Her2-, no vasc invasion)
(N4+, N+vasc invasion,
N+ her2+)
Chemotherapy
CAF, AC, FEC
Chemotherapy
CAF, AC, FEC
(Taxanes)
Endocrine therapy
Tamoxifen
(OFS)
Endocrine therapy
Tamoxifen
(OFS)
Aromatase inhibitor
+ OFS
Aromatase inhibitor
+ OFS
“AI” Pre-men
“Concensus Panel” 2005
Premenopausal women
Er+
and/or
Pr+
29juni2005, mb
Intermediate risk
High risk
(<35jr, BR>2, T2, N0-3,
Her2-, no vasc invasion)
(N4+, N+vasc invasion,
N+ her2+)
Chemotherapy
CAF, AC, FEC
Chemotherapy
CAF, AC, FEC
(Taxanes)
Endocrine therapy
Tamoxifen
(OFS)
Endocrine therapy
Tamoxifen
(OFS)
Aromatase inhibitor
+ OFS
Aromatase inhibitorr
+ OFS
“AI” Pre-men
“Concensus Panel” 2005
Premenopausal women
Er+
and/or
Pr+
Intermediate risk
High risk
(<35jr, BR>2, T2, N0-3,
Her2-, no vasc invasion)
(N4+, N+vasc invasion,
N+ her2+)
Chemotherapy
CAF, AC, FEC
Chemotherapy
CAF, AC, FEC
(Taxanes)
Endocrine therapy
Tamoxifen
(OFS)
Endocrine therapy
Tamoxifen
(OFS)
?
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“AI” premen
Conclusion 1:
“Preclinical data, postmenopausal data and
M1 premenopausal data
are likely to reflect beneficial effects of aromatase
inhibitors in early stage breast cancer for
premenopausal women.”
Studies are ongoing
Are we waiting ?
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“AI” premen.
Adjuvant studies, LH-RH + AI pre-men.women
design
No pts
duration
comment
Tam vs Ana.
+/zoledronaat
2000
1:1:1:1
3 jr
>1999
Bonedensity
data SABCC ‘04
SOFT
CT 
Tam vs
Tam + OFS vs
Exa + OFS
3000
1:1:1
5 jr
LH-RH q 28 d or
Laparoscopy or
Radiation
TEXT
+/- CT
OFS + Tam vs
OFS + Exa.
1845
5 jr
+/- CT in low risk
pts
PERCHE
+/- CT
OFS + Tam vs
OFS + Exa
1750
5 jr
+/- CT in low risk
pts
Promise
OFS + Ana
+/- FE90C
2300
1:1
5 jr
Zoladex q 4 12 w
“high risk” = TAC
No Tamoxifen
ABCSG12
“young ATAC”
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“AI” premen
“PROMISE is”
Promising?
Progressive?
“the short cut”
Side studies:
 Micro array analysis for prognostic factors
 2 different bifosfonates
 Gosereline q 4w vs q 12w estrogen/FSH levels
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“AI” premen
Intensive follow up estradiol/FSH/LH
“Highly variable effects on E2 levels
by AI in premenopausal women”
Dowsett, J.Ster.Bioch&Mol.Biol., 2003
29juni2005, mb
“AI” premen
Intensive follow up estradiol/FSH/LH
“Highly variable effects on E2 levels
by AI in premenopausal women”
Dowsett, J.Ster.Bioch&Mol.Biol., 2003
29juni2005, mb
“AI” premen
Intensive follow up estradiol/FSH/LH
“Highly variable effects on E2 levels
by AI in premenopausal women”
No effect on proliferation in the breast tumors
Dowsett, J.Ster.Bioch&Mol.Biol., 2003
29juni2005, mb
“AI” premen
Intensive follow up estradiol/FSH/LH
“Variable FSH levels by AI in premenopausal women”
Estradiol
Forward, Br.J.Cancer, 2004
N=16
FSH
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Anastrozole
“AI” Pre-men
Possible adverse effect LH-RH + AI
1) LH-RH  FSH 
androgens
2) AI  estradiol   FSH  aromatase 
estradiol
+
FSH
&
estradiol
Check estradiol levels!!
29juni2005, mb
“AI” premen
Conclusion 2
1. If not in protocol:
AI in premenopausal women when
ER+/PRHer-2/neu 3+/FISH+
2. Intensive follow up estradiol and FSH levels (while on
LH-RH)
3. Care for the whole patient (not muscle-skeletal only)
4. Preferable by medical oncologists
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“AI” premen
29juni2005, mb
“AI” premen
Wat zou je doen….?
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Enkele patiënten
♀ 40jr, Ø3.5cm, Nscln+, M”0”, Er+, Pr-, Her2pos
♀ 43jr, Ø 2cm, N3+ Er+Pr+, Her2pos
♀ 27jr, Ø 5cm, N0, Er+Pr-, Her2 pos
♀ 45jr, Ø1.5cm, N11+, Er+Pr+,Her2 pos, HERA trial
♀ 32jr
li:Ø1.8cm, N0, Er-Pr+, Her2 pos
re: Ø 3 cm, N4+, Er+Pr-, Her2 neg
♀40jr, actieve RA, Ø2.5, N2+, Er+Pr-, Her2pos
♀44jr , 2000:Ø4cm, N1+, Er+Pr+, Her2pos, Tam tot 9/2005
♀38jr, Ø3.8cm, N8+, Er+Pr-, Her2neg
29juni2005, mb
casus
(na antracyclines)
♀ 40jr,
Ø3.5cm, Nscln+,M”0”
Er+, Pr-, Her2pos
♀ 43jr,
Ø 2cm, N3+
Er+Pr+, Her2pos
♀ 27jr
Ø 5cm, N0
Er+Pr-, Her2 pos
♀ 45jr,
Ø1.5cm, N11+
Er+Pr+,Her2 pos
HERA trial
♀ 32jr
li:Ø1.8cm, N0
Er-Pr+, Her2 pos
re: Ø 3 cm, N4+
Er+Pr-,Her2 neg
♀40jr,
actieve RA
Ø2.5, N2+,Her2pos
♀44jr
2000:Ø4cm, N1+,
Er+Pr+, Her2pos
Tam tot 9/2005
♀38jr,
Ø3.8cm, N8+,
Er+Pr-, Her2neg
29juni2005, mb
advies
tav hormonale
therapie
preventieve maatregelen/
adviezen
kort commentaar (optioneel)
“AI” Pre-men
Specific aromatase inhibitors
1egen.:
Aminoglutetamide (Orimeten®)
fatigue, nausea, rash
Rx/Corticosteroids
2egen.:
Formestane
3egen.:
Vorozole
withdrawn
Fadrozole
Japan
Anastrozole (Arimdex®)
Letrozole (Femara®)
“Patient
Examestane (Aromasin®) Compliance”
26jui2005, mb
2 monthly im
“AI” Pre-men
Ovarian aromatase not
(incompletely) inhibited
LH-RH agonists Gosereline (Zoladex®)
Leuproide ( Lucrin®)
90% ovaries
29juni2005, mb
10%
adrenals
fat
muscle
liver
(breast – tumor)
“AI” pre-men
Effect of aromatase inhibitors on estrogens in
premenopausal women
29juni2005, mb
“AI” pre-men
Translation to the clinic
Postmenopausal adjuvant studies
Tamoxifen #
Anastrozol #
#
ATAC
29juni2005, mb
#
“AI” premen
Embryonal cryopreservation
in young breast cancer patients
with letrozole
Protocol:
Letrozol
CT
FSH
Menstruation
HCG
Oktay 2003
har
ves
ting
“AI” premen
Breast cancer recurrence in patients
after cryopreservation protocol
6-57 months follow-up, n= 61
• 3/20 Tamoxifen patients
• 0/11 Letrozole patients
• 3/30 control patients
Oktay ASRM 2004
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