Bernardo Bonanni, MD Divisione di Prevenzione e Genetica Oncologica Istituto Europeo di Oncologia

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1 Approcci innovativi nella farmacoprevenzione dei tumori ereditari della mammella Bernardo Bonanni, MD Divisione di Prevenzione e Genetica Oncologica Istituto Europeo di Oncologia

2 FAMILIAL / HEREDITARY CANCER MANAGEMENT A new field in Clinical Oncology RISK ASSESSMENT SURVEILLANCE RISK REDUCTION STRATEGIES

3 Sindrome ereditaria del carcinoma mammario e ovarico Carcinoma mammario Carcinoma ovarico 7% 10% Altri geni alta/bassa penetranza (sconosciuti) SNPs ad alto/basso rischio FGFR2 TNRC9 MAP3K1 LSP1 CASP8 (modello poligenico) CHEK2 (1100delC) ATM BRIP1 PALB2 1% PTEN 1% TP53 1% BRCA1/BRCA2 25%

Recommended management of high risk subjects: The IEO HIGH RISK CLINIC gynaecologist medical oncologist molecular oncologist breast surgeon general surgeon preventive oncologist geneticist genetic

4 Recommended management of high risk subjects: The IEO HIGH RISK CLINIC gynaecologist medical oncologist molecular oncologist breast surgeon general surgeon preventive oncologist geneticist genetic counselor Multi disciplinary panel pathologist radiologist psychologist epidemiologist endoscopist plastic surgeon IEO Clinical Genetics Meetings: clinical cases discussion and tailored prevention strategy revision of guidelines and syndromes literature reviews expert symposia

changes Chemoprevention Prophylactic surgery NB:

5 BREAST CANCER PREVENTION IN HIGH RISK SUBJECTS RISK REDUCING OPTIONS Surveillance & lifestyle changes Chemoprevention Prophylactic surgery NB: these options are often complementary / sequential!

6 STRATEGIE DI PREVENZIONE PER LA MAMMELLA: QUALI FARMACI? Tamoxifen Raloxifene Inibitori dell aromatasi Retinoidi (fenretinide) FANS, Statine, Metformina, Vit. D, TK inibitori, PARP-inibitori, ecc.

triple negative and early onset) BRCA2 ~ 80% endocrine

7 BRCA1 and BRCA2 mutations induce mostly different breast cancer phenotypes BRCA1 ~ 90% non-endocrine responsive BC (frequently triple negative and early onset) BRCA2 ~ 80% endocrine responsive and later onset Targetable by SERMs (tamoxifen, raloxifene) and AIs

8 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+?

Av Ann Rate per 1000 STAR: Study of Raloxifene and Tamoxifen (n=19747) 10 8 6 4 2 312* 68.3% vs 71.

9 Av Ann Rate per 1000 STAR: Study of Raloxifene and Tamoxifen (n=19747) * 68.3% vs 71.5% compliance Gail Model projection TAM Raloxifene # of events, median follow-up 3.9±1.6 yrs JAMA 2006; 295:2727

10 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!)

12 PARP-inhibitors in cancer prevention? Poly ADP ribose polymerase: key regulator of DNA repair process PARP inhibition and tumor-selective synthetic lethality. Several PARP-i under 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?

13 PARP-inhibitors in cancer prevention? 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)

14 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?

15 Retinoids/Rexinoids and Breast Cancer 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: LG 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 (4-hydroxiphenyl-retinamide, 4-HPR) Rather peculiar retinoid Long term results of phase III trial available (Veronesi, Ann Oncol 2006)

FENRETINIDE AND BRCA-1 MUTATED BREAST CANCER CELLS At clinically relevant doses, Fenretinide has shown to induce NO-mediated apoptosis in human and murine BRCA-1 mutated

16 FENRETINIDE AND BRCA-1 MUTATED BREAST CANCER CELLS 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 Simeone AM et al., Carcinogenesis, 2005

17 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.

18 ORIGINAL FENRETINIDE PHASE III TRIAL Excised stage I breast cancer < 10 years R Fenretinide 200mg/d Control 5 yrs 1. Sample: 2867 women aged accrued from 1987 to 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 Cumulative hazard 0.

62, 95% CI 0.46-0.83 HR=1.23, 95% CI 0.63-2.

19 INCIDENCE OF SECOND BREAST CANCER PER ARM AND MENOPAUSAL STATUS Cumulative hazard Cumulative hazard PREMENOPAUSE POSTMENOPAUSE HR=0.62, 95% CI HR=1.23, 95% CI CONTROLS FENRETINIDE FENRETINIDE CONTROLS Years Years

20 FENRETINIDE AND OVARIAN CANCER PREVENTION During intervention, 6 cases of ovarian cancer in the control arm vs 0 in the 4-HPR arm 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

21 NEW PHASE III PREVENTION TRIAL OF 4-HPR vs PLACEBO IN YOUNG HIGH-RISK SUBJECTS (PI: U. Veronesi) BRCA 1/2 carriers or >20% mut. prob. Healthy, Age R 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

22 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

23 NEW PHASE III PREVENTION TRIAL OF 4-HPR vs PLACEBO IN YOUNG HIGH-RISK SUBJECTS Critical issues/protocol amendments pregnancy contraception length of treatment (3 to 5yrs) timing of proph. salpingo-oophorectomy Enrollment started Dec at the IEO

24 Association between oral contraceptives (OC) use and breast or ovarian cancer in BRCA1/2 carriers. Iodice S. et al. EJC, 46 (2010)

25 KEY ISSUE: combined reduction of breast and ovarian cancer 4-HPR O.C. / ring Br Ca risk (premen.) Ov Ca risk (?) potential teratogenesis Ov Ca risk low to no Br Ca risk best contraception

26 Istituto Europeo di Oncologia Divisione di Prevenzione e Genetica Oncologica divisione.prevenzionegeneticaoncologica@ieo.it Numero Verde:

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