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ONCOLOGIA:
ESPERIENZE
CLINICHE
A CONFRONTO.
IL CARCINOMA
MAMMARIO
METASTATICO
CHIETI
12 NOVEMBRE 2013
SALA FONDAZIONE D’ANNUNZIO
CENTRO SCIENZE
DELL’INVECCHIAMENTO CE.S.I.
Via Colle dell’Ara 66100 - Chieti
Il trattamento della malattia metastatica
ormonoresponsiva: una visione d’insieme
Giuseppe Naso MD
Associate Professor of Medical Oncology
Head of Translational Oncology
Clinical Head of Breast Unit
Sapienza Università di Roma
Breast Cancer Epidemiology
Italy
~ 47,000 New EBC/year
~ 15,000 New MBC
~ 50.000 MBC prevalence/year
Ca Mammario Metastatico
Miglioramento della Sopravvivenza nel tempo
Cumulative survival
0.8
0.6
1995–2000
1990–1994
0.4
1985–1989
0.2
1980–1984
1974–1979
0.0
0
12
24
36
Months
Giordano S, et al. Cancer 2004
48
60
Hormone Receptor positive metastatic Breast
Cancer: a different disease
TNBC
Median Overall
Survival after
relapse
9-12 months
ER pos.ve
24-36
months
Andre F et al. JCO 2004;22:3302-3308
Management of Metastatic Breast Cancer
Diagnosis of metastatic breast cancer
Determination of sites and extent of disease
Assessment of HER2, hormonal receptor status, disease-free interval, age, and
menopausal status
No life-threatening disease
Hormone-responsive
1st-line hormonal therapy
Response
No Response
1st-line chemotherapy
Progression
2nd-line chemotherapy
Progression
2nd-line hormonal therapy
Hormone-unresponsive, or
Life-threatening disease
No Response
Response
Progression
3rd-line chemotherapy
Progression
3rd-line hormonal therapy
No Response
Supportive care
Heterogeity of Clinical Presentation
Characteristics
Treatment
Objectives
 Symptomatic/ poor PS
Palliation
 Elderly/indolent disease/poor PS
Improve TTP & QoL
 Amenable to locoregional control
Increase response rate
 Young/good PS visceral mts
Prolong survival
Stephen R.D. Johnston ASCO 2013
Tamoxifene
(SERM)
Trattamento della malattia
metastatica
Number of
patients
Effective in
Pre-MP
Post-MP
Tamoxifen
1269
Yes
Oophorectomy
3380
Yes
Progestins
3479
Yes
A.I.
1153
LH-RH analogs
293
Response rate
(%)
(range)
32
(16-52)
33
(21-41)
Yes
31
(9-67)
Yes
32
(16-43)
40
(32-45)
Yes
26
(15-38)
Yes
Yes
Estrogens
1683
Androgens
2250
Yes
Yes
21
(10-38)
Adrenalectomy
3739
Yes
Yes
32
(23-46)
Hypophysectomy
1174
Yes
Yes
36
(22-58)
MP: menopause
Adapted from Harris JR et al, 1991.
NEW
SERMS
Selective Estrogen Receptor Modulators
• First generation
– Toremifene, Droloxifene, Idoxifene
• Second /Third generation
– Raloxifene, Arzoxifene, EM-800, etc.
Status: Advantage over Tam not
shown
Aromatase Inhibitors Versus Tamoxifen as First-Line
Therapy in Metastatic Breast Cancer
Patients
No.
OR,
%
Clin.
Benefit
%
TTP
mo
ER
unknown
%
ANA
170 vs
182
21 vs 17
59 vs 46
11 vs 6
p 0.0098
p 0.005
11 vs 11
Bonneterre*
ANA
340 vs
328
32 vs 32
56 vs 55
8 vs 8
56 vs 54
Mouridsen^
LET
453 vs
454
30 vs 20
49 vs 38
9 vs 6
p 0.004
p <0.0001
34 vs 33
EXE
182 vs
189
46 vs 31
66 vs 49
Nabholtz*
J Clin Oncol 18:3758, 2000
J Clin Oncol 18:3748, 2000
J Clin Oncol 21:2101,
2003;
Paridaens^
J Clin Oncol 2008
Trial design for: *equivalence, ^superiority
10 vs 6
p 0.028
15 vs 11
Anastrozole versus Tamoxifen
Exclusion Criteria: Adjv Tam received within 12 months before study entry
70
Pts = 353 (171 vs 182)
60
50
40
30
60
0
AN = anastrazole
TX = Tamoxifene
Pts = 668 (340 vs 328)
50
*
60% pts included no previous Adjv ET
70% pts included no previous Adjv ET
40
20% pts included previous Tam Adjv
20
10
70
30
10% pts included previous Tam Adjv
20
*
OR Rate Clinical
TTP
TTF
(%) Benefit (%) (month) (month)
10
0
OR Rate Clinical
TTP
TTF
(%) Benefit (%) (month) (month)
Equivalence Trial
Nabholtz et al, J Clin Oncol 2000
Bonneterre et al, J Clin Oncol 2000
Letrozole/Exemestane vs Tamoxifene
Exclusion Criteria: Adjv Tam received within 12 months before study entry
EX = exemestane
TX = tamoxifene
LE = letrozole
Pts = 907
Pts = 371
*
80% pts included no previous Adjv ET
*
*
20% pts included previous Adjv Tam
*
*
*
OR Rate Clinical TTP
TTF
(%)
Benefit (month) (month)
(%)
Mouridsen et al, J Clin Oncol 2001
*
OR Rate Clinical
TTP
(%)
Benefit (month)
(%)
Paridaens et al, JCO2008
DIFFERENTE MECCANISMO D’AZIONE:
SERM, IA, SERD
AGONISTA
AF1
AF1
TAMOXIFENE
17ESTRADIOLO
RE
RE ANTAGONISTA
AF2
AF2
INIBITORI DELLE
AROMATASI
17ESTRADIOLO
ATTIVAZIONE PARZIALE
DELLA TRASCRIZIONE
(solo AF1)
ERE
AF1
ERE
AF2
ERE
RE
FULVESTRANT
17ESTRADIOLO
ERE
AF1
ERE
AF2
ERE
RE
BLOCCO COMPLETO DELLA
TRASCRIZIONE, PERSISTENZA DELLA
VIA RECETTORIALE ESTROGENICA
BLOCCO COMPLETO DELLA
TRASCRIZIONE, ABOLIZIONE DEL
SEGNALE MITOGENICO ESTROGENOMEDIATO
SELETTIVITA’ DEL LEGAME 3H-ESTRADIOLO/RE
Estradiolo vs Faslodex vs Tam
Percentuae di inibizione
100
90
80
70
E2
60
Faslodex
50
Tam
40
30
20
10
0
1
5
10
50
100
300
1000
Concentrazione (nM)
3000
10000
Proteosome activation
PK model of plasma fulvestrant
35
Standard Dose Regimen
Loading Dose Regimen
High Dose Regimen
Plasma concentration of fulvestrant
(ng/mL)
30
25
20
15
10
100nM
5
0
0
28
56
84
112
140
Time (days)
Auc=8
168
196
224
252
280
Fulvestrant dosing regimens
Approved Dose
(AD)
Loading Dose
(LD)
High Dose
(HD)
250 mg
250 mg
250 mg
Day 0
Day 28
Monthly
500 mg
250 mg
250 mg
250 mg
Day 0
Day 14
Day 28
Monthly
500 mg
500 mg
500 mg
500 mg
Day 0
Day 14
Day 28
Monthly
CONFIRM: Effect of Fulvestrant 500 mg vs
250 mg on Survival in Postmenopausal Women
•
Baseline characteristics appeared well balanced between treatment arms
Timing of
Analysis
Fulvestrant
500 mg
Fulvestrant
250 mg
HR (95% CI)
Median PFS
First*
6.5 mos
5.5 mos
0.80‡ (0.68-0.94)
Median OS
First*
25.1 mos
22.8 mos
0.84§ (0.69-1.03)
Median OS
Final†
26.4 mos
22.3 mos
0.81¶ (0.69-0.96)
Outcome
*First analysis was performed at 50% maturity.
†Final analysis was performed at 75% maturity.
‡ P = .006
§P = .001
¶P = .016
– Subsequent therapies were well balanced between arms, with approximately
60% of patients receiving subsequent chemotherapy and approximately one
third receiving other hormonal therapy
DiLeo A, et al. SABCS 2012. Abstract S1-4.
FINALMENTE LA PRIMA LINEA HA UN PADRONE !!!!!!!
FIRST: Study Design
• Randomized, open-label phase II trial
– Primary endpoint: CBR, defined as CR, PR, or SD
for ≥ 24 wks
Postmenopausal
women with
previously untreated
hormone receptor–
positive advanced
breast cancer
(N = 205)
Robertson JFR, et al.
Fulvestrant 500 mg by intramuscular injection
Days 0, 14, 28, and every 28 days thereafter
(n = 102)
Anastrozole 1 mg/day orally
(n = 103)
Until disease
progression or
other event
requiring
discontinuation
FIRST Trial: efficacy Analysis
Primary EndPoint: Clinical Benefit Rate
CBRs of 72.5% and 67.0%, respectively
(odds ratio, 1.30; 95% CI, 0.72 to 2.38; P .386;
Median TTP: 23.4 vs 13.1 months
PHASE III TRIAL
34 % reduction in risk of progression
FALCON
An impressive results!
No prior hormonal Rx
(secondary endpoint)
Robertson et al. Br Cancer Res Treatm 2012;136: 503
CDK4/6
PFS Probability
Aromatase Inhibitor + CDK4/6 Inhibitor
Improves PFS in ER+ MBC
Events, n (%)
Median PFS, mos
(95% CI)
HR
(95% CI)
P value
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
PD 991 + LET (n = 84) LET (n = 81)
21 (25)
40 (49)
26.1
7.5
(12.7-26.1)
(5.6-12.6)
0.37
(0.21-0.63)
< .001
An impressive results!
(Waiting for a phase III)
0
Pts at Risk, n
PD 991 + LET84
LET
81
2
4
6
8
10
12
75
57
60
38
53
29
43
22
35
17
25
11
Finn RS, et al. SABCS 2012. Abstract S1-6.
14 16
Mos
18
6
15
5
18
20
22
24
26
14
4
9
3
5
3
3
1
1
1
28
Combined Strategies in I line ER+ MBC
FACT: Phase III, Open-Label, Multicenter Trial
of Combined Fulvestrant and Anastrozole
Therapy
ER+ and/or PR+,
at first relapse:

After/during TAM > 12 mo

After/during CT

After/during AI >12 mo
Postmenopausal or
premenopausal
rendered postmenopausal by
adjuvant LHRH
analogue*
R
N= 514
Fulvestrant im LD, 500 mg day 0,
250 mg days 14 and 28
then 250 mg monthly
+
Anastrozole po, 1 mg daily
Anastrozole po, 1 mg daily
*In these cases, the LHRH analog
must be continued throughout the
study period
Bergh J et al. SABCS 2009;Abstract 23.
12,4 months
11,4 months
J Clin Oncol 30.-2012
mOS 38,2 months
mOS 37,8 months
FACT: Efficacy
F+A
(n=258)
A
(n=256)
1.6%
1.6%
14.3%
13.3%
39.1%
40.2%
HR (95% CI)
p-value
Best objective response1
Complete response (CR)
Partial response (PR)
Stable disease (SD) ≥ 24 weeks
Median time to progression
(months)
Overall survival
(months)
10.8
37.8
10.2
38.2
—
0.99 (0.81, 1.20)
p = 0.91
1.00 (0.76, 1.32)
p = 1.00
Bergh J et al. SABCS 2009;Abstract 23.
SWOG S0226: Study Design


Primary endpoint: PFS
Secondary endpoints: OS, Safety
Stratified by previous
adjuvant tamoxifen
Postmenopausal
women with ER+ MBC:
Previous TAM
Previous AIs or CT
> 12 months
(N = 707)
Treatment until disease
progression
Anastrozole 1 mg/day PO +
Fulvestrant LD 500 mg on Day 1,
250 mg on Days 14 and 28,
250 mg every 28 days
(n = 355)
Anastrozole 1 mg/day PO
(n = 352)
Women with
progression
encouraged to
cross over to
receive
fulvestrant
Mehta RS, et al. SABCS 2011. Abstract S1-1.
FACT
SWOG
Previous AdjEsTx
69%
40%
ORR%
31,8
NR
TTP mo
10.8
15
No previous
adjuvant tamoxifen
-
Previous adjuvant
tamoxifen
-
OS mo
37.8
17.0
(n = 414)
13.5
(n = 280)
47.7
No previous
adjuvant tamoxifen
-
Previous adjuvant
tamoxifen
-
Diagnosis of MBC
7% <1yr
39%
50%
50%
Visceral disease
47.7
(n = 414)
49.6
(n = 280)
Cross-talk between different signal transduction
pathways is the best studied cause of resistance
pTEN
cbl
Johnston S R Clin Cancer Res 2010;16:1979-1987
LTED
(Long term estrogen deprivation)
mTOR is Activated by Estrogen Deprivation
Cell proliferation (absorbance 540 nm)
mTOR Inhibition Combines Effectively With
Hormonal Therapy in BC
Interaction between mTOR and ERa
0.7
Growth factors
0.6
0.5
mTOR
0.4
0.3
S6K1
0.2
0.1
Ser167
*
*
P
E
ERα
0
MDA-MB231
T47D
Control
Rapamycin
MCF7
Transcription
ZR-75-1
ER-Responsive Element
0.1μM 4-HT
0.1μM 4-HT+ rapamycin
Cell proliferation
*P < 0.05, 2-tailed paired Student t test.
4-HT, 4-hydroxytamoxifen.
Yamnik RL et al. J Biol Chem. 2009;284(10):6361-6369; Johnston SR. Clin Cancer Res. 2005;11(2 Pt 2):889S-899S.
56
Co-Targeting mTOR and HR in HR+/HER2-ve ABC
TAMRAD1
BOLERO 22,3
( prior AI)
(prior Let or Ana)
TAM
TAM +
everolimus
EXA +
placebo
EXA +
everolimus
57
54
239
485
CBR %
42.1
61.1
p 0.045
25.5
50.5
p < 0.0001
Median PFS (m)
4.5
8.6
HR 0.54
p 0.002
4.1
11
HR 0.44
p<1x10-16
Median OS (m)
24
NR
HR 0.45
p 0.007
NR
NR
1Bachelet
T et al, SABCS 2010; 2 Baselga J et al, NEJM 2011; 3Hortobagyi GN et al, SABCS 2011
BOLERO-2: Study Design
•
•
•
Primary endpoint: PFS (investigator assessment)
Secondary endpoints: OS, ORR, clinical benefit rate, safety, bone markers, PK
Randomized 2:1; stratified by sensitivity to
previous hormonal therapy, presence of
visceral metastases
Postmenopausal women with
ER-positive advanced breast
cancer who progressed on
previous nonsteroidal AI
therapy*
(N = 724)
Treatment until disease progression
or unacceptable toxicity
Exemestane 25 mg/day +
Everolimus 10 mg/day
(n = 485)
Exemestane 25 mg/day +
Placebo
(n = 239)
*> 50% of patients in each arm with ≥ 3 previous therapies
BOLERO-2: ORR and CBR by Local Assessment
• Significantly improved ORR and CBR in the everolimus +
exemestane group compared with the placebo + exemestane group
Response rate by local assessment (%)
p<0.0001
p<0.0001
p<0.0001
p<0.0001
Everolimus + exemestane
Placebo + exemestane
ORR
CBR
7.1-months median follow-up
ORR
CBR
12.5-months median follow-up
BOLERO-2: PFS Central Assessment
Significantly improved PFS for everolimus + exemestane group compared with the
placebo + exemestane group
Probability of event (%)
7.1-months median follow-up
HR=0.36, 95% CI (0.27–0.47)
Log-rank p=3.3x10–15
Everolimus + exemestane: 10.6 months
Placebo + exemestane: 4.1 months
12.5-months median follow-up
HR=0.36 (95% CI: 0.28–0.45)
p<1x10–16
Everolimus + exemestane: 11.0 months
Placebo + exemestane: 4.1 months
Probability of event (%)
•
Time (weeks)
HDAC Inhibitors Mechanism of Action
 HDAC inhibitors relax the structure of DNA making it more
accessible to RNA polymerases
Closed chromatin = genes off
HDAC inhibitors
Histone
acetyltransferases
(HATs)
AC
AC
AC
AC
Histone deacetylases
(HDACs)
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
AC
40. Pathiraja TN, et al. J Mam Gland Biol Neoplasia. 2010;15:35-47.
AC
Open chromatin =
genes on
MPFS Everolimus
+exemestane:11.0
months
Stephen R.D. Johnston ASCO 2013
In SO-CALLED LUMINAL A tumor
Personalmente (con i dati attualmente disponibili)
FIRST LINE:
1) Fulvestrant+/- A.I
SECOND LINE:
3) Inibitore (Exemestane ?) + Everolimus
Personalmente (con i dati attualmente disponibili)
Se resistenza durante adiuvante
FIRST LINE:
Inibitore (Exemestane ?) + Everolimus
Or
CHT
SECOND LINE:
FULVESTRANT??? CHT??? (AT PRESENT NO DATA)
???? (only God knows)
GRAZIE PER LA VOSTRA PAZIENZA

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