Il trattamento della malattia metastatica ormonoresponsiva: una visione d insieme. Sapienza Università di Roma
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1 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 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
2 Breast Cancer Epidemiology Italy ~ 47,000 New EBC/year ~ 15,000 New MBC ~ MBC prevalence/year
3 Cumulative survival Ca Mammario Metastatico Miglioramento della Sopravvivenza nel tempo Months Giordano S, et al. Cancer 2004
4 Hormone Receptor positive metastatic Breast Cancer: a different disease TNBC Median Overall Survival after relapse 9-12 months ER pos.ve months Andre F et al. JCO 2004;22:
5 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 Hormone-unresponsive, or Life-threatening disease 1st-line chemotherapy Response Progression 2nd-line hormonal therapy Response Progression 3rd-line hormonal therapy No Response No Response No Response Progression 2nd-line chemotherapy Progression 3rd-line chemotherapy Supportive care
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8 Heterogeity of Clinical Presentation Characteristics Symptomatic/ poor PS Elderly/indolent disease/poor PS Amenable to locoregional control Young/good PS visceral mts Treatment Objectives Palliation Improve TTP & QoL Increase response rate Prolong survival
9 Stephen R.D. Johnston ASCO 2013
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12 Tamoxifene (SERM)
13 Trattamento della malattia metastatica Number of patients Effective in Pre-MP Post-MP Response rate (%) (range) Tamoxifen 1269 Yes Yes 32 Oophorectomy 3380 Yes 33 Progestins 3479 Yes Yes 31 A.I Yes 32 LH-RH analogs 293 Yes 40 Estrogens 1683 Yes 26 Androgens 2250 Yes Yes 21 Adrenalectomy 3739 Yes Yes 32 Hypophysectomy 1174 Yes Yes 36 (16-52) (21-41) (9-67) (16-43) (32-45) (15-38) (10-38) (23-46) (22-58) MP: menopause Adapted from Harris JR et al, 1991.
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15 Selective Estrogen Receptor Modulators First generation NEW SERMS Toremifene, Droloxifene, Idoxifene Second /Third generation Raloxifene, Arzoxifene, EM-800, etc. Status: Advantage over Tam not shown
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17 Aromatase Inhibitors Versus Tamoxifen as First-Line Therapy in Metastatic Breast Cancer Patients No. OR, % Clin. Benefit % TTP mo ER unknown % Nabholtz* J Clin Oncol 18:3758, 2000 ANA 170 vs vs vs 46 p vs 6 p vs 11 Bonneterre* J Clin Oncol 18:3748, 2000 ANA 340 vs vs vs 55 8 vs 8 56 vs 54 Mouridsen^ J Clin Oncol 21:2101, 2003; LET 453 vs vs vs 38 p vs 6 p < vs 33 Paridaens^ J Clin Oncol 2008 EXE 182 vs vs vs vs 6 p vs 11 Trial design for: *equivalence, ^superiority
18 Anastrozole versus Tamoxifen Exclusion Criteria: Adjv Tam received within 12 months before study entry 70 Pts = 353 (171 vs 182) 70 AN = anastrazole TX = Tamoxifene Pts = 668 (340 vs 328) * 60% pts included no previous Adjv ET % pts included no previous Adjv ET 20% pts included previous Tam Adjv 10% pts included previous Tam Adjv 10 * 10 0 OR Rate (%) Clinical Benefit (%) TTP (month) TTF (month) 0 OR Rate (%) Clinical Benefit (%) TTP (month) TTF (month) Equivalence Trial Nabholtz et al, J Clin Oncol 2000 Bonneterre et al, J Clin Oncol 2000
19 Letrozole/Exemestane vs Tamoxifene Exclusion Criteria: Adjv Tam received within 12 months before study entry Pts = 907 EX = exemestane TX = tamoxifene LE = letrozole Pts = % pts included no previous Adjv ET * * * * 20% pts included previous Adjv Tam * * * OR Rate (%) Clinical Benefit (%) TTP (month) TTF (month) OR Rate (%) Clinical Benefit (%) TTP (month) Mouridsen et al, J Clin Oncol 2001 Paridaens et al, JCO2008
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21 DIFFERENTE MECCANISMO D AZIONE: SERM, IA, SERD AGONISTA TAMOXIFENE 17 ESTRADIOLO RE AF1 ANTAGONISTA AF2 ERE ERE ATTIVAZIONE PARZIALE DELLA TRASCRIZIONE (solo AF1) INIBITORI DELLE AROMATASI 17 ESTRADIOLO RE AF1 ERE BLOCCO COMPLETO DELLA TRASCRIZIONE, PERSISTENZA DELLA VIA RECETTORIALE ESTROGENICA AF2 ERE FULVESTRANT 17 ESTRADIOLO RE AF1 AF2 ERE ERE BLOCCO COMPLETO DELLA TRASCRIZIONE, ABOLIZIONE DEL SEGNALE MITOGENICO ESTROGENO- MEDIATO
22 Percentuae di inibizione SELETTIVITA DEL LEGAME 3H-ESTRADIOLO/RE Estradiolo vs Faslodex vs Tam E2 Faslodex Tam Concentrazione (nm)
23 Proteosome activation
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25 Plasma concentration of fulvestrant (ng/ml) PK model of plasma fulvestrant Standard Dose Regimen Loading Dose Regimen High Dose Regimen nM Auc=8 Time (days)
26 Fulvestrant dosing regimens Approved Dose (AD) 250 mg 250 mg 250 mg Day 0 Day 28 Monthly Loading Dose (LD) 500 mg 250 mg 250 mg 250 mg Day 0 Day 14 Day 28 Monthly High Dose (HD) 500 mg 500 mg 500 mg 500 mg Day 0 Day 14 Day 28 Monthly
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28 CONFIRM: Effect of Fulvestrant 500 mg vs 250 mg on Survival in Postmenopausal Women Baseline characteristics appeared well balanced between treatment arms Outcome Timing of Analysis Fulvestrant 500 mg Fulvestrant 250 mg HR (95% CI) Median PFS First* 6.5 mos 5.5 mos 0.80 ( ) Median OS First* 25.1 mos 22.8 mos 0.84 ( ) Median OS Final 26.4 mos 22.3 mos 0.81 ( ) *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 Abstract S1-4.
29 FINALMENTE LA PRIMA LINEA HA UN PADRONE!!!!!!!
30 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) 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 Robertson JFR, et al.
31 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;
32 Robertson et al. Br Cancer Res Treatm 2012;136: 503 PHASE III TRIAL FALCON No prior hormonal Rx Median TTP: 23.4 vs 13.1 months 34 % reduction in risk of progression An impressive results! (secondary endpoint)
33 CDK4/6
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36 PFS Probability Aromatase Inhibitor + CDK4/6 Inhibitor Improves PFS in ER+ MBC Pts at Risk, n Mos PD LET LET Finn RS, et al. SABCS Abstract S1-6. Events, n (%) Median PFS, mos (95% CI) HR (95% CI) P value PD LET (n = 84) 21 (25) 26.1 ( ) ( ) < LET (n = 81) 40 (49) 7.5 ( ) An impressive results! (Waiting for a phase III)
37 Combined Strategies in I line ER+ MBC
38 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.
39 12,4 months 11,4 months
40 J Clin Oncol mos 38,2 months mos 37,8 months
41 FACT: Efficacy F + A A HR (95% CI) (n=258) (n=256) p-value Best objective response 1 Complete response (CR) Partial response (PR) Stable disease (SD) 24 weeks 1.6% 14.3% 39.1% 1.6% 13.3% 40.2% Median time to progression (months) Overall survival (months) (0.81, 1.20) p = (0.76, 1.32) p = 1.00 Bergh J et al. SABCS 2009;Abstract 23.
42 SWOG S0226: Study Design Primary endpoint: PFS Secondary endpoints: OS, Safety Stratified by previous adjuvant tamoxifen Treatment until disease progression Postmenopausal women with ER+ MBC: Previous TAM Previous AIs or CT > 12 months (N = 707) 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 Abstract S1-1.
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49 FACT SWOG Previous AdjEsTx 69% 40% ORR% 31,8 NR TTP mo No previous adjuvant tamoxifen - Previous adjuvant tamoxifen (n = 414) 13.5 (n = 280) OS mo No previous adjuvant tamoxifen - Previous adjuvant tamoxifen (n = 414) 49.6 (n = 280) Diagnosis of MBC 7% <1yr 39% Visceral disease 50% 50%
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51 Cross-talk between different signal transduction pathways is the best studied cause of resistance pten cbl Johnston S R Clin Cancer Res 2010;16:
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53 LTED (Long term estrogen deprivation)
54 mtor is Activated by Estrogen Deprivation
55 Cell proliferation (absorbance 540 nm) mtor Inhibition Combines Effectively With Hormonal Therapy in BC Interaction between mtor and ERa Growth factors mtor S6K MDA-MB- 231 T47D * MCF7 * ZR-75-1 E Ser 167 P ERα Transcription ER-Responsive Element Control 0.1μM 4-HT Rapamycin 0.1μM 4-HT+ rapamycin *P < 0.05, 2-tailed paired Student t test. Cell proliferation 4-HT, 4-hydroxytamoxifen. Yamnik RL et al. J Biol Chem. 2009;284(10): ; Johnston SR. Clin Cancer Res. 2005;11(2 Pt 2):889S-899S. 56
56 Co-Targeting mtor and HR in HR+/HER2-ve ABC TAMRAD 1 ( prior AI) BOLERO 2 2,3 (prior Let or Ana) TAM TAM + everolimus EXA + placebo EXA + everolimus CBR % p p < Median PFS (m) HR 0.54 p HR 0.44 p<1x10-16 Median OS (m) 24 NR HR 0.45 p NR NR 1 Bachelet T et al, SABCS 2010; 2 Baselga J et al, NEJM 2011; 3 Hortobagyi GN et al, SABCS 2011
57 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 Treatment until disease progression or unacceptable toxicity Postmenopausal women with ER-positive advanced breast cancer who progressed on previous nonsteroidal AI therapy* (N = 724) 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
58 Response rate by local assessment (%) BOLERO-2: ORR and CBR by Local Assessment Significantly improved ORR and CBR in the everolimus + exemestane group compared with the placebo + exemestane group p< p< p< ORR CBR 7.1-months median follow-up p< ORR CBR 12.5-months median follow-up Everolimus + exemestane Placebo + exemestane
59 Probability of event (%) Probability of event (%) BOLERO-2: PFS Central Assessment Significantly improved PFS for everolimus + exemestane group compared with the placebo + exemestane group 7.1-months median follow-up HR=0.36, 95% CI ( ) 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: ) p<1x10 16 Everolimus + exemestane: 11.0 months Placebo + exemestane: 4.1 months Time (weeks)
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62 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 AC AC Histone acetyltransferases (HATs) AC AC AC AC AC AC AC AC AC AC AC Histone deacetylases (HDACs) AC AC AC AC AC AC AC Open chromatin = genes on 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.
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65 MPFS Everolimus +exemestane:11.0 months Stephen R.D. Johnston ASCO 2013
66 In SO-CALLED LUMINAL A tumor Personalmente (con i dati attualmente disponibili) FIRST LINE: 1) Fulvestrant+/- A.I SECOND LINE: 3) Inibitore (Exemestane?) + Everolimus
67 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)
68 GRAZIE PER LA VOSTRA PAZIENZA
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