prof. giuseppe naso oncologia medica policlinico umberto i
DESCRIPTION
FULVESTRANT. prof. Giuseppe Naso ONCOLOGIA MEDICA POLICLINICO UMBERTO I. ER – a ER - b. ER +. Androstenedione Testosterone Estrone Estradiolo. Aromatase inhibitors. Aromatase (Ovary, Fat, Liver, Breast). Tamoxifen. - PowerPoint PPT PresentationTRANSCRIPT
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prof. Giuseppe Naso
ONCOLOGIA MEDICA
POLICLINICO UMBERTO I
prof. Giuseppe Naso
ONCOLOGIA MEDICA
POLICLINICO UMBERTO I
FULVESTRANT
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ER +
ER – ER -
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Androstenedione Testosterone
Estrone Estradiolo
ER +cells
ER-cells
Aromatase inhibitorsAromatase(Ovary, Fat,Liver, Breast)
Tamoxifen
Er-Er-
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ER- HER-2
PI3K RAS
AKT (PKB)
MAP ER PHOSPHORYLATION (SERINE 167-activation and ER indipendent pathway)
Cellular proliferation Anti-apoptotic response
PTEN
APOPTOSYS
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Androstenedione Testosterone
Estrone Estradiolo
ER +cells
Aromatase inhibitorsAromatase(Ovary, Fat,Liver, Breast)
Tamoxifen
Er-Er- ?
Tumor cell
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ERAF1
AF2
ESTRADIOLO
ERE
ERE
ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE
AF1
Meccanismo d’azione di Estradiolo e Tam a confronto
Nella mammella 98% attività trascrizionale
nella mammella2% attività trascrizionale
Pstimola la trascrizione di PgR
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AF-1 (in assenza di HER-2)
Pgr
Trascrizione
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ERAF1
AF2
ESTRADIOLO
ERE
ERE
ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE
ERTAMOXIFENAF1
AF2
ERE ATTIVAZIONE PARZIALEDELLA TRASCRIZIONE
(solo AF1)
Meccanismo d’azione di Estradiolo e Tam a confronto
Agonista
Antagonista
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EGFTGF
Amphiregulin-cellulinHB-EGF
Epiregulin Heregulins
NRG2NRG3
Heregulins-cellulin
Cysteine-richdomains
Tyrosine kinasedomain
ErbB-1Her1
EGFR
ErbB-2Her2neu
ErbB-3Her3
ErbB-4Her4
C-terminus
100
100
100
44
82
33
36
59
24
48
79
28
The EGFR (ErbB) family and ligands
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Expression of growth factor receptors in breast cancer
% expression Receptor in breast cancer
KIT 80%
PDGFR 50%-90%
EGFR 14%-91%
EGFR vIII 20%-78%
HER2 20%-25%
HER3 20%-70%
HER4 7%-18%
IGF-IR Induced by estrogen
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HER hierarchy
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Bivalence of EGF-like ligands
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Relative potency of HER dimers
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TyrosineKinase
GRB2
SOSras-GDP ras-GTP
raf
MEK
MAPK
ATP
ATP
ATP
forma inattiva Forma attivata
fosmycjun
MAP
La cascata delle chinasi della via rasLa cascata delle chinasi della via ras
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TyrosineKinase
GRB2
SOSras-GDP ras-GTP
raf
MEK
MAPK
ATP
ATP
ATP
forma inattiva Forma attivata
fosmycjun
MAP
La cascata delle chinasi della via rasLa cascata delle chinasi della via ras
AKT
AF
1
COREPRESSORE
COATTIVATORE MAPATP
Hormone-dependent growth
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AF-1 (in assenza di HER-2)
Pgr
Trascrizione
AF-1 (in prezsenza di HER-2)
Pgr
Trascrizione
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ERAF1
AF2
ESTRADIOLO
ERE
ERE
ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE
ERAF1
AF2
BLOCCO COMPLETODELLA TRASCRIZIONEEs
A.I.FASLODEX
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Chemical StructuresChemical Structures
RaloxifeneRaloxifene
HOHOSS
OHOH
OO OO
NN
OHOH
EstradiolEstradiol
HOHO
TamoxifenTamoxifenOO
NMeNMe22
OHOH
(CH(CH22))99SO(CHSO(CH22))33CFCF22CFCF33
‘‘Faslodex’ Faslodex’ (fulvestrant)(fulvestrant)
HOHO77
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ONCOER: Interazione con Fulvestrant
La struttura di Fulvestrant è molto simile a quella dell’estradiolo ma con una catena laterale. Questa struttura è responsabile:•dell’innovativo meccanismo d’azione • di una più elevata affinità per il recettore rispetto al TAM.Quando Fulvestrant si lega al recettore questo cambia
leggermente la sua conformazione, ma entrambi AF1 e AF2 rimangono inattivi
ANTIESTROGENO SENZA ALCUN EFFETTO
AGONISTA
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ONCOER: Interazione con Fulvestrant
Dei pochi dimeri che si formano alcuni riescono a
passare nel nucleo e a legarsi al DNA, ma non
essendoci il reclutamento dei coattivatori, l’attività dell’RNA polimearsi 2 è
completamente bloccata e di conseguenza nessun gene verrà trascritto.
Viene accelerata la degradazione e quindi la perdita
della maggior parte dei recettori.
EFFETTO DOWN REGULATOR
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ONCOSELETTIVITÀ LEGAME 3H-ESTRADIOLO/RE
ESTRADIOLO VS FULVESTRANT VS TAM
0
10
20
30
40
50
60
70
80
90
100
1 5 10 50 100 300 1000 3000 10000
Concentrazione (nM)
Perc
en
tuale
di in
ibiz
ion
e
E2
Fulvestrant
Tam
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Adapted from: Osborne CK et al. J Natl Cancer Inst 1995; 87: 746–750.Adapted from: Osborne CK et al. J Natl Cancer Inst 1995; 87: 746–750.
0
200
400
600
Mea
n t
um
ou
r vo
lum
e (m
m3 )
0 100 200 300 400
–Estradiol
Tamoxifen
Fulvestrant800
1000
1200
Days
EstrogenEstrogenwithdrawalwithdrawal
Effects of Estrogen Withdrawal, Tamoxifen andEffects of Estrogen Withdrawal, Tamoxifen and ‘Faslodex’ (fulvestrant) on MCF-7 Tumour Growth ‘Faslodex’ (fulvestrant) on MCF-7 Tumour Growth
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Adapted from: Osborne CK et al. Cancer Chemother Pharmacol 1994; 34: 89–95.Adapted from: Osborne CK et al. Cancer Chemother Pharmacol 1994; 34: 89–95.
Effect of ‘Faslodex’ (fulvestrant) on Effect of ‘Faslodex’ (fulvestrant) on Tamoxifen-stimulated Tumour GrowthTamoxifen-stimulated Tumour Growth
0
200
400
0 20 40 60 80 100 120
Tamoxifen
Tamoxifen + fulvestrant
FulvestrantFulvestrant
100
300
500
Days
Mea
n t
um
ou
r vo
lum
e (m
m3 )
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Summary of Preclinical Data for ‘Faslodex’ Summary of Preclinical Data for ‘Faslodex’ (fulvestrant): The First of a New Type of (fulvestrant): The First of a New Type of
Antitumour AgentAntitumour Agent
Downregulates estrogen receptors in breast cancer cells
No estrogenic activity
Completely blocks estrogen action
Greater efficacy than tamoxifen in breast cancer models
Effective in tamoxifen-resistant breast cancer models
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Robertson JFR et al. Cancer Res 2001; 61: 6739–6746.Robertson JFR et al. Cancer Res 2001; 61: 6739–6746.
Post-treatment Mean ER H-scoresPost-treatment Mean ER H-scores
NS = not significantNS = not significant
p=0.0001
0
20
40
60
80
100
120
Mea
n ±
1S
EM
p=0.0006
NSNS
p=0.024
p=0.026
Overall treatment effect p=0.0003
Placebo(n=29)
50mgFulvestrant
(n=31)
125mgFulvestrant
(n=32)
250mgFulvestrant
(n=32)
Tamoxifen(n=25)
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Robertson JFR et al. Cancer Res 2001; 61: 6739–6746.Robertson JFR et al. Cancer Res 2001; 61: 6739–6746.
Post-treatment Mean PgR H-scoresPost-treatment Mean PgR H-scores
NS = not significantNS = not significant
0
20
40
60
80
100
NS
p=0.003
p=0.0002
p=0.0001p=0.0001
p=0.0001
Placebo(n=28)
50mgFulvestrant
(n=29)
125mgFulvestrant
(n=29)
250mgFulvestrant
(n=29)
Tamoxifen(n=21)
Mea
n ±
1S
EM
Overall treatment effect p=0.0001
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Antitumour Effects of Single Doses of Antitumour Effects of Single Doses of ‘Faslodex’ (fulvestrant) in Postmenopausal ‘Faslodex’ (fulvestrant) in Postmenopausal
Patients with Primary Breast CancerPatients with Primary Breast Cancer
Post-treatment meanER H-scores p=0.0001 p=0.024
Post-treatment meanPgR H-scores p=0.0002 p=0.0001
Post-treatment meanKi67 values p=0.0002 NS
Post-treatment meanapoptotic index values NS NS
Fulvestrant 250mgFulvestrant 250mgvs placebovs placebo
Fulvestrant 250mgFulvestrant 250mgvs tamoxifenvs tamoxifen
Robertson JFR et al. Cancer Res 2001; 61: 6739–6746.Robertson JFR et al. Cancer Res 2001; 61: 6739–6746.
NS = not significantNS = not significant
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‘‘Faslodex’ (fulvestrant): Faslodex’ (fulvestrant): Phase I Clinical SummaryPhase I Clinical Summary
Phase I: Dose-dependent reduction in ER and PgR, greater than tamoxifen and reduction in Ki67 index
Antiestrogenic and therapeutic effects demonstrated in breast cancer
ER downregulation demonstrated in clinical tumour samples
Robertson JFR et al. Breast 1997; 6; 186–189.Robertson JFR et al. Breast 1997; 6; 186–189. Robertson JFR et al. Breast Cancer Res Treat 2001; 69: 289, Abstr 451.Robertson JFR et al. Breast Cancer Res Treat 2001; 69: 289, Abstr 451.
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Potential Clinical Advantages of ‘Faslodex’ Potential Clinical Advantages of ‘Faslodex’ (fulvestrant) — Under Investigation in (fulvestrant) — Under Investigation in
Ongoing Clinical Trial ProgrammeOngoing Clinical Trial Programme
Higher tumour response rate and/or longer durationof response
Lack of cross-resistance with tamoxifen
Lack of tumour flare
No agonist activity on endometrium
Lack of CNS effects related to estradiol antagonism
Reduced risk of thromboembolic disease
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‘‘Faslodex’ (fulvestrant):Faslodex’ (fulvestrant):Clinical Development Clinical Development Programme: Phase IIProgramme: Phase II
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Howell A et al. Lancet 1995; 345: 29–30.Howell A et al. Lancet 1995; 345: 29–30.
‘‘Faslodex’ (fulvestrant): Phase II StudyFaslodex’ (fulvestrant): Phase II Studyin Advanced Breast Cancerin Advanced Breast Cancer
Monthly injection (250mg i.m.)
Nineteen postmenopausal women
Relapsed following previous response to tamoxifen for advanced breast cancer or >2 years’ adjuvant therapy
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‘‘Faslodex’ (fulvestrant): Phase II ResultsFaslodex’ (fulvestrant): Phase II ResultsClinical Efficacy — Response RateClinical Efficacy — Response Rate
nn %%
Complete response (CR) 0 0
Partial response (PR) 7 37
Stable disease (SD) 6 32
Progression 6 31
Total 19 100
Howell A et al. Lancet 1995; 345: 29–30.Howell A et al. Lancet 1995; 345: 29–30.
} 69
69% of patients achieved OR (= CR+PR) or SD 24 weeks
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Howell A et al. Lancet 1995; 345: 29–30.Howell A et al. Lancet 1995; 345: 29–30.Howell A et al. Br J Cancer 1996; 74: 300–308.Howell A et al. Br J Cancer 1996; 74: 300–308.
‘‘Faslodex’ (fulvestrant):Faslodex’ (fulvestrant):Summary of Tolerability from the Phase II Study Summary of Tolerability from the Phase II Study
No reports of hot flushes or vaginal dryness (n=19)
No change in endometrial thickness in five patients assessed
No apparent effect on prolactin, SHBG, cholesterol (HDL, LDL) or triglycerides
Initial rise in LH/FSH — due to tamoxifen withdrawal?
No deaths, withdrawals or drug-related serious AEs
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‘‘Faslodex’ (fulvestrant):Faslodex’ (fulvestrant):Phase II Clinical SummaryPhase II Clinical Summary
Antiestrogenic effects demonstrated in breast cancer Therapeutic effects demonstrated in advanced
breast cancer Lack of cross-resistance with tamoxifen confirmed High response rates and long DoRs in tamoxifen
failures (n=19) No major local or systemic safety issues in patients ER downregulation demonstrated in clinical breast
tumour samples Median survival for fulvestrant-treated patients in
second-line advanced breast cancer = 54 months1
1. Robertson JFR et al. Breast Cancer Res Treat 2001; 69: 289, Abstr 451.1. Robertson JFR et al. Breast Cancer Res Treat 2001; 69: 289, Abstr 451.
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Fulvestrant inpostmenopausal women with
tamoxifen-resistantadvanced breast cancer
Phase III Trials 0020 and 0021: prospective combined analysis
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ONCOFulvestrant: disegni dello studio
Donne in postmenopausa con carcinoma mammario avanzato precedentemente trattate con
endocrinoterapia per carcinoma mammario precoce o avanzato
Studio 0020: internazionale, randomizzato 1:1, aperto, a gruppi paralleli
Studio 0021: nordamericano, randomizzato 1:1, in doppio cieco,, a gruppi paralleli
Anastrozolo 1 mg in monosomministrazione
orale giornalieraStudio 0020: (n=229)Studio 0021: (n=194)
Fulvestrant 250 mg i.m. depot mensileStudio 0020: 1 x 5 ml (n=222)
Studio 0021: 2 x 2,5 ml (n=206)
Analisi combinata
Studi 0020 e 0021: reclutamento tra maggio 1997 e agosto 1999
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ONCO
Time to progression (months)
Pro
port
ion
not
pro
gre
ssed
Fulvestrant 250 mgFulvestrant 250 mg
Anastrozolo 1 mgAnastrozolo 1 mg
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
0 6 12 18 24 30 36
Median TTP:Fulvestrant 5,5 monthsAnastrozolo 4,1 months
Hazard Ratio (95%CI): 0.95 (0.82–1.10); p=0.48
Robertson ,Cancer, 2003
Tempo alla progressione: Studi EU – USAANALISI COMBINATA
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ONCOFulvestrant vs Anastrozole durata della risposta (analisi
combinata)
Duration of Response (months)
Durata Mediana:Fulvestrant 16,7 monthsAnastrozole 13,7 months
Ris
po
sta
Ris
po
sta
Fulvestrant 250 mgFulvestrant 250 mg
Anastrozole 1 mgAnastrozole 1 mg
0,00,0
0,10,1
0,20,2
0,30,3
0,40,4
0,50,5
0,60,6
0,70,7
0,80,8
0,90,9
1,01,0
0 6 12 18 24 30 36
Robertson JFR et al. Cancer 2003; 98: 229-238
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ONCOFulvestrant: analisi prospettica combinata. Miglior risposta
obiettiva
Risposta completa Risposta completa (CR)(CR)
Risposta parziale Risposta parziale (PR)(PR)
Risposta obiettiva Risposta obiettiva (CR+PR)(CR+PR)
2020 (4,7)(4,7) 1111 (2,6)(2,6)
6262 (14,5)(14,5) 5959 (13,9) (13,9)
8282 (19,2)(19,2) 7070 (16,5)*(16,5)*
Malattia stabile Malattia stabile 24 settimane24 settimane
Beneficio clinico Beneficio clinico (CR+PR+SD (CR+PR+SD 24 settimane)24 settimane)
104104 (24,3) (24,3) 103103 (24,3) (24,3)
186186 (43,5) (43,5) 173173 (40,9)(40,9)
Numero di pazienti (%)Numero di pazienti (%)
AnastrozoleAnastrozole((nn=423)=423)
FulvestrantFulvestrant((nn=428)=428)
*Odds ratio (95,14% CI):1,21 (0,84–1,74); p=0,31 Robertson JFR et al. Cancer 2003; 98: 229–238.Robertson JFR et al. Cancer 2003; 98: 229–238.
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ONCODURATA RISPOSTA OBIETTIVA IN BASE ALLA PRESENZA/ASSENZA DI METASTASI VISCERALI: STUDI EU -
USA
Mauriac, Eur J Cancer, 2003
(a) senza metastasi viscerali, (b) con metastasi viscerali (c) con metastasi solo viscerali
(a) without visceral metastases
(a) without visceral metastases (a) without visceral metastases
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ONCO
Vampate di calore 89 (21,0) 87 (20,6) 0,91
Disturbi gastrointestinali 196 (46,3) 185 (43,7) 0,53
Aumento di peso 4 (0,9) 7 (1,7) 0,35
Vaginiti 11 (2,6) 8 (1,9) 0,51
Eventi tromboembolici 15 (3,5) 17 (4,0) 0,68
Dolori articolari 23 (5,4) 45 (10,6) 0,0036
Infezioni tratto urinario 31 (7,3) 18 (4,3) 0,062
Numero di eventi avversi (%)
Anastrozolo(n=423)
Fulvestrant(n=423)
pp value value
TOLLERABILITÀ STUDI EU - USA
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ONCO
SECONDA LINEA DI TRATTAMENTO:OPPORTUNITA’ TERAPEUTICHE
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ONCO
CB 20%1
CB 43%2CB 43%2
EFFICACIA DELLA TERAPIA ENDOCRINA DOPO PROGRESSIONE DA AI NON
STEROIDEI
AI nsAI ns
ExemestaneExemestane(n=105)(n=105)
ExemestaneExemestane(n=30)(n=30)
CB = clinical benefit
1 Lønning PE et al. J Clin Oncol 2000; 18: 2234–22442 Carlini et al. Ann Oncol 2002; 13 (Suppl 5): 48, Abstr 171P
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ONCO
Ingle JN et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S38, abs 409
STUDIO DI FASE II DEL NORTHCENTRAL CANCER TREATMENT
GROUP
• Donne con ca mammario in post menopausa con ER e/o PgR +
• Progressione da AI
Criteri di eligibilitàCriteri di eligibilità
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ONCOCARATTERISTICHE DELLE PAZIENTI
Età mediana
Precedente chemio.Solo adiuvanteadiuvante + ABCsolo ABC
Precedente AIadiuvante ABC
Precedente tamoxifensolo adiuvanteadiuvante + ABC ABC
n=77 n (%)
(29–89)
(27)(18)(14)
(1)(99)
(44)(4)(25)
68
211411
176
343
19
Ingle JN et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S38, abs 409
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ONCO
Sopravvivenza mediana: 21 mesi
– 1-anno survival rate: 70.4% (95% CI 60.5–82.0)
EFFICACIA
PR
SD 6 months
CB rate
10% (13)*
15% (19)
32%
Totale(n=77)
* Durata mediana di 10 mesi (range 2-20 mesi)
Ingle JN et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S38, abs 409
5% (24)*
6% (29)
52%
AI (n=21)
5% (9)*
9% (16)
25%
AI + tamoxifene(n=56)
PRECEDENTE TRATTAMENTO
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ONCOTOLLERABILITA’*
FatigueVampate di caloreNauseaAnoressiaArtralgiaAlopecia
%2517131188
n=76
* all NCI-CTC grado 1-3
Ingle JN et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S38, abs 409
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ONCO
CB 41%1CB 41%1
CB 50%2
FulvestrantFulvestrantFulvestrantFulvestrant
AI nsAI ns(n=46)(n=46)AI nsAI ns
(n=46)(n=46)
AI nsAI ns(n=22)(n=22)AI nsAI ns
(n=22)(n=22)
CB = clinical benefitCB = clinical benefit
2 Howell A, Robertson J. Ann Oncol 2002; 13 (Suppl 5): 48, Abstr 173P.
1 Vergote I et al, Breast Cancer Res Treat 2003; 79: 207–211.
EFFICACIA DELLA TERAPIA ENDOCRINA DOPO PROGRESSIONE DA
FULVESTRANT
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ONCO
• Fulvestrant è efficace nelle pazienti resistenti al
tamoxifene
• Fulvestrant o Exemestane sono efficaci in pazienti
che progrediscono da inibitori dell’aromatasi non
steroidei
• Pazienti che rispondono a Fulvestrant risultano
essere sensibili ad una successiva terapia endocrina
CONCLUSIONE