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“Approcci innovativi nella
farmacoprevenzione
dei tumori ereditari della mammella”
Bernardo Bonanni, MD
Divisione di Prevenzione e Genetica Oncologica
Istituto Europeo di Oncologia
FAMILIAL / HEREDITARY CANCER MANAGEMENT
A new field in Clinical Oncology
RISK REDUCTION
STRATEGIES
SURVEILLANCE
RISK ASSESSMENT
Sindrome ereditaria del carcinoma
mammario e ovarico
Carcinoma mammarioCarcinoma ovarico
7%10%
Altri geni alta/bassa
penetranza
(sconosciuti)
SNPs
ad alto/basso rischio
FGFR2
TNRC9
MAP3K1
LSP1
CASP8
(modello poligenico)
BRCA1/BRCA2
25%
TP53
1%PTEN
1%
CHEK2 (1100delC)
ATM
BRIP1
PALB2
1%
Recommended management of high risk subjects:
The IEO HIGH RISK CLINIC
IEO Clinical Genetics Meetings:
clinical cases discussion and tailored prevention strategy
revision of guidelines and syndromes
literature reviews expert symposia
endoscopist
plastic surgeon
pathologist
radiologist
psychologist
epidemiologist
breast surgeon
general surgeon
Multi
disciplinary
panel
preventive oncologist
geneticist
genetic counselor
gynaecologist
medical oncologist
molecular oncologist
BREAST CANCER PREVENTION
IN HIGH RISK SUBJECTS
RISK REDUCING
OPTIONS
Surveillance &
lifestyle changesChemoprevention
Prophylactic
surgery
NB: these options are often complementary / sequential !
FANS, Statine, Metformina, Vit. D,
TK inibitori, PARP-inibitori, ecc.
Retinoidi (fenretinide)
Inibitori dell’aromatasi
Raloxifene
Tamoxifen
STRATEGIE DI PREVENZIONE PER LA
MAMMELLA: QUALI FARMACI?
BRCA1 and BRCA2 mutations induce mostly
different breast cancer phenotypes
BRCA1~ 90% non-endocrine
responsive BC (frequently
triple negative and early onset)
~ 80% endocrine responsive
and later onset
Targetable by SERMs (tamoxifen, raloxifene) and AIs
BRCA2
TAMOXIFEN:
oggi il più efficace farmaco per la
prevenzione del carcinoma mammario
endocrinoresponsivo
Minima dose attiva (5 mg/d) e
personalizzazione (CYP2D6)
Uso nei soggetti a rischio ereditario?
BRCA2+ ?
0
2
4
6
8
10
Gail Model
projection
TAM Raloxifene
Av A
nn
Rate
per
10
00
163 168
•# of events, median follow-up 3.9±1.6 yrs
312*68.3% vs 71.5% compliance
STAR: Study of Raloxifene and
Tamoxifen (n=19747)
JAMA 2006; 295:2727
Aromatase Inhibitors:
evidence and promise
Treatment: mostly superior to tamoxifen
(lowers risk of recurrence and contralateral
BC), but only in postmenopausal pts
Prevention: benefit to be
confirmed: ongoing phase III trials
(e.g. IBIS-II); concerns about side
effects (bone metabolism!)
PARP-inhibitors in cancer prevention ?
Poly ADP ribose polymerase: key regulator of DNA repair process
PARP inhibition and tumor-selective synthetic lethality. Several PARP-iunder development.
Results in BC / OvC treatment:
- ICEBERG Trial in metastatic BC / OvC (Olaparib 400 bid better)
- BSI-201 Phase II Trial (better OS with chemo + PARP-i combo)
Clinical issues:
- Toxicities (hematologic/non hem.)
- Continuous inhibition necessary? Or intermittent?
Ongoing and future trials with PARP-i
Ongoing: Early phase P-i biomarker modulation prevention
trial (J. Garber, Dana Farber, multicentric):
BRCA+ women planning RRM
1 month treatment (4 levels of doses)
biomarkers: ALDH1+ plus others
Starting 2011: Phase I / II biomarker trial (P. Brown,
MDACC + other NCI Chemoprevention Consortium
centers incl. IEO, Bonanni):
Triple neg. BC survivors
8 weeks treatm. (various doses)
Dose finding + Biomarker modulation (gamma-H2AX)
PARP-inhibitors in cancer prevention ?
ISSUES in P-i Clinical Trials:
Continuous vs intermittent/Repeated brief vs longer
term exposure possible chromosomal instability in
the longer period (these agents disrupt the DNA-repair
mechanism)??
Maybe this may be overcome with intermittent use?
Side effects
Effects on non BRCA+ subjects?
PARP-inhibitors in cancer prevention ?
Retinoids/Rexinoids and Breast Cancer
Fenretinide (4-hydroxiphenyl-retinamide, 4-HPR)• Rather peculiar retinoid
• Long term results of phase III trial available
(Veronesi, Ann Oncol 2006)
Bexarotene• RXR selective ligand with promising preclinical background of
efficacy and an interesting risk-benefit ratio (Li and Brown, Eur J Cancer Prev 2007)
• Tested in BRCA mutation carriers in a phase II trial: reduction of
Cyclin D1 (postmenopausal women) but not Ki-67(Brown, SABCS 2007)
New rexinoid: LG100268• It affects angiogenesis in vitro and in vivo
(Sogno, FCPR, Philadelphia, 2007)
• In the animal model, is highly synergistic action in combination with
either arzoxifene or acolbifene, two new SERMs
(Liby, Clin Cancer Res 2006)
FENRETINIDE AND BRCA-1
MUTATED BREAST CANCER CELLS
Simeone AM et al., Carcinogenesis, 2005
At clinically relevant doses,
Fenretinide has shown to induce
NO-mediated apoptosis in human
and murine BRCA-1 mutated cancer
cells
In this ability Fenretinide was the
most potent of the phenylretinamide
analogues against BRCA-1 mutated
breast cancer cells
Fenretinide e Prevenzione
del Tumore Ovarico
La 4-HPR modula l’ espressione genica nelle cellule ovariche:
sovraregolazione dell’espressione genica proapoptotica nelle OVCA433 cells.
sottoregolazione nelle mutazioni BRCA nelle IOSE (precancerose) e OVCA433 cells.
Ciò suggerisce un effetto preventivo nelle lesioni precancerose e un effetto di trattamento sulle cellule tumorali.
Brewer M et al, Int J Cancer 2006
ORIGINAL FENRETINIDE PHASE III TRIAL
Excised stage I
breast cancer
< 10 years
R
Fenretinide
200mg/d
Control
5 yrs
1. Sample: 2867 women aged 30-70 accrued from 1987 to 1993
2. Primary endpoint: contralateral breast cancer (8/1000 year)
3. Secondary endpoint: ipsilateral breast cancer reappearance
4. Setting: national multicentric trial, 10 centres
INCIDENCE OF SECOND BREAST CANCER
PER ARM AND MENOPAUSAL STATUS
Years
Cumulative
haz
ard
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
0.0
0.1
0.2
0.3
0.4
Years
Cumulative
haz
ard
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
0.0
0.1
0.2
0.3
0.4
CONTROLS
FENRETINIDE CONTROLS
FENRETINIDE
PREMENOPAUSE POSTMENOPAUSE
HR=0.62, 95% CI 0.46-0.83 HR=1.23, 95% CI 0.63-2.40
FENRETINIDE AND
OVARIAN CANCER PREVENTION
At 10 years of follow-up, 10
cases in the control group and 6
in the fenretinide group
De Palo et al., Gynecol Oncol 2002
During intervention,
6 cases of ovarian cancer
in the control arm vs 0 in the
4-HPR arm
NEW PHASE III PREVENTION TRIAL OF 4-HPR
vs PLACEBO IN YOUNG HIGH-RISK SUBJECTS (PI: U. Veronesi)
BRCA 1/2 carriersor >20% mut. prob.
Healthy, Age 25-44
Fenretinide
200mg/d
Placebo
5 yrs
1. Primary endpoint: Incidence of breast cancer (ER+
and ER-) and DCIS
2. Secondary endpoints: ovarian ca, biomarkers of ca
risk
3. Sample size: 748 subjects
4. Follow-up: 10 yrs
5. Setting: national, multicenter
R
NUOVO TRIAL HPR:
17 CENTRI PARTECIPANTI
1. Prevenzione e Genetica Oncologica, IEO, Milano
2. Ginecologia e Ostetricia, Ospedale Mauriziano, Torino
3. Oncologia, AO Universitaria e Università di Pisa
4. Istituto Nazionale Tumori “Fondazione G. Pascale”, Napoli
5. Oncologia Medica, EO. Ospedali Galliera, Genova
6. Hereditary Breast and Ovarian Cancer Study Centre, Policlinico di Modena
7. Medicina Sperimentale, Università La Sapienza, Roma
8. Oncologia Medica, AO S. Andrea, Roma
9. Clinica Endocrinologica Molecolare e Oncologia Policlinico Federico II, Napoli
10. Istituto Nazionale dei Tumori, Milano
11. Oncologia Medica, Ospedale S. Salvatore, Università di L’Aquila
12. Senologia e Prevenzione Chirurgica, Istituto Tumori , Bari
13. Istituto Scientifico per la Prevenzione Oncologica, Firenze
14. Prevenzione Oncologica, Centro di Riferimento Oncologico, Aviano
15. Oncologia, Ospedale Busonera, Università di Padova
16. Oncologia Medica, Ospedale S. Bortolo, Vicenza
17. Policlinico S. Matteo, Pavia
Critical issues/protocol amendments
pregnancy
contraception
length of treatment (3 to 5yrs)
timing of proph. salpingo-oophorectomy
Enrollment started Dec. 2009 at the IEO
NEW PHASE III PREVENTION TRIAL OF 4-HPR
vs PLACEBO IN YOUNG HIGH-RISK SUBJECTS
Association between oral contraceptives (OC) use
and breast or ovarian cancer in BRCA1/2 carriers.
Iodice S. et al. EJC, 46 (2010) 2275 –2284
KEY ISSUE: combined reduction of
breast and ovarian cancer
4-HPR
Br Ca risk (premen.) Ov Ca risk (?) potential teratogenesis
O.C. / ring
Ov Ca risk low to no Br Ca risk best contraception
Istituto Europeo di Oncologia
Divisione di Prevenzione e Genetica Oncologica
email:
Numero Verde: 800 831 233
