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Dott.ssa Pamela Guglielmini Prof. Francesco Boccardo.

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Presentation on theme: "Dott.ssa Pamela Guglielmini Prof. Francesco Boccardo."— Presentation transcript:

1 Dott.ssa Pamela Guglielmini Prof. Francesco Boccardo

2 USA – SEER 2008  182,000 new cases of breast cancer  83,000 women would develop metastatic disease  46,000 women would die of metastatic breast cancer The dimension of the problem

3 Advanced Breast Cancer: Heterogeneous Population Requires Tailored Treatments  Symptomatic/ poor PSPalliation  Elderly/indolent disease/poor PSImprove TTP & QoL  Amenable to locoregional control Increase response rate  Young/good PS visceral mtsProlong survival CharacteristicsTreatment Objectives

4 Is metastatic breast cancer a curable disease?

5 Metastatic breast cancer: improved survival over time Giordano, et al. Proc ASCO 2002 Months Cumulative survival – – – – –1979

6 Overall survival curves of 1,544 patients (excluding 37 patients with insufficient information to determine response status) with MBC receiving front-line chemotherapy according to response to therapy. Deaths from any cause were included. Greenberg PAC et al, 1996

7  Symptoms palliation  Quality of life improvement  Survival prolongation Objective tumor response is correlated with each of the previous one Which end points can be achieved in all other patients?

8 Proportion of patients with symptom response according to each objective response category: significant results with both CRF and QoL data., CR/PR;, SD;, PD. Geels P et al, 2000

9 Proportion of patients with symptom response according to each objective response category: significant results only QoL data. Const, constipation., CR/PR;, SD;, PD. Geels P et al, 2000

10  Hormone therapy  Chemotherapy  Biologicals  Surgery/radiotherapy  Analgesics  Bisphosphonates  Supportive care (eritropoietin) Which treatment options?

11  Patients characteristics: age/menopausal status  Tumor characteristics: DFI duration tumor burden dominant site of disease ER/PgR status previous response to endocrine therapy Which patients are best candidate to hormonetherapy?

12  Suppressive treatments Premenopause: ovariectomy, LH-RHa Postmenopause: aromatase inhibitors  Competitive treatments Pre/postmenopause: antiestrogens (TAM, TOR) steroidal antiestrogen (Faslodex) progestagens antiprogestins Hormonetherapy: which drugs? which sequences?

13 Invasive Breast Cancer by Age (Year 1998) Li CL et al. J Clin Oncol 2003, 1:28 Premenopausal ≈ 25% - 30% ER-/PR-ER+/PR+Other Premenopausal, and HR+ ≈ 60%

14 Sir G.T. BEATSON Dr E. JENSEN

15 Mechanism of action of LHRHa Figure A - Hypersecretion of LH following acute administration of LHRHa Figure B - Hyposecretion of LH following chronic administration of LHRHa LHRHa LHRHa LHRHa LHRHa LHRHa LHRHa LHRHa LHRHa LHRHa PituitaryCell LH LHRHa LHRHa LHRHa LHRHa LHRHa LHRHa LHRHa LHRHa LHRHa PituitaryCell LH 

16 Treatment response Measurable disease Goserelin (n 29)Ovariectomy (n 30) ResponseNo.% % CR PR5175 Stable disease Increased disease Inadequate assessment5175 Taylor CW et al, 1998

17 PFS by treatment arm OS by treatment arm Taylor CW et al, 1998

18 Summary of results by treatment group EndpointLHRH- agonist alone (n=256) LHRH- agonist + tamoxifen (n=250) Hazard Ratio/Odds Ratio (95% CI) Log-rank p value Primary median survival (yrs) ( ) 0.02 Secondary median progression- free survival (mos) ( ) <0.001 Objective response (%) ( ) 0.03 CHAT and EORTC meta-analysis, 1999

19 Combined use of Goserelin and Anastrozole as second- line endocrine treatment in pre menopausal women with advanced breast cancer. (Cheung et al, 2004)  16 women with M1 (13) or locally advanced primary breast cancer (3).  All previously treated with Z+T. Clinical results: 75% OR/SD Endocrine effects: mean E2 (pmol/L) Z+T (pre )= 224 Z+T (6 mos)= 24 Z+A (3 mos)= 6 Z+A (6 mos)= 5

20  Suppressive treatments Premenopause: ovariectomy, LH-RHa Postmenopause: aromatase inhibitors  Competitive treatments Pre/postmenopause: antiestrogens (TAM, TOR) steroidal antiestrogen (Faslodex) progestagens antiprogestins Hormonetherapy: which drugs? which sequences?

21 Structures of non-steroidal anti-oestrogens clinically available or in clinical trials. Howell A et al, 1996

22 Results of studies using newer non-steroidal anti-oestrogens as first-line endocrine therapy for advanced breast cancer Drug Dose (mg/day) No. of patients Response CR/PR (%) Toremifene [Valavaara, 1990] (Phase II trials summarised) Toremifene [Stenbygaard et al, 1993] (Phase III trial) Toremifene [Hayes et al, 1995] Tamoxifen (Phase III trial) Droloxifene [Rauschning et al, 1994] (Randomised phase II trial TAT-59 [Tominaga, 1995] (Randomised Phase II trail) Howell A et al, 1996

23 Incidence of common side-effects with new NSAEs Hot flushes (%) Lassitude (%) Nausea/vomiting (%) Tamoxifen3010 Toremifene19108 Droloxifene Raloxifene TAT Idoxifene“similar to tamoxifen” Howell A et al, 1996

24  Suppressive treatments Premenopause: ovariectomy, LH-RHa Postmenopause: aromatase inhibitors  Competitive treatments Pre/postmenopause: antiestrogens (TAM, TOR) steroidal antiestrogen (Faslodex) progestagens antiprogestins Hormonetherapy: which drugs? which sequences?

25 Faslodex (fulvestrant) Estrogen Receptor Downregulator Faslodex (fulvestrant) Estrogen Receptor Downregulator m Catena laterale alchilsulfonilica OH HO(CH 2 ) 9 SO(CH 2 ) 3 CF 2 CF 3 7

26 ER: Interazione con estradiolo estradioloestradiolo+ER Attivazione AF1 e AF2Omodimerizzazione

27 ER: Interazione con Tamoxifene Tamoxifene Dimerizzazione con solo AF1 attivato Parziale trascrizione e legame con un solo coattivatore Legame con RNA Pol.II e parziale trascrizione con riduzione prolif.cellulare

28 ER: Interazione con Fulvesrant Fulvestrant Fulvestrant+ER AF1 e AF2 inattivi Riduzione Dimerizzazione e stimolazione alla degradazione ER Inattivazione completa della trascrizione e inibizione alla proliferazione cellulare

29 Howell A et al. Lancet 1995; 345: 29–30. ICI 182,780 (‘Faslodex’): Phase II Results Clinical Efficacy - Response Rate Response n % Complete response00 Partial response737 Stable disease632 Progression } 69 69% of patients achieved OR or SD  24 weeks

30 2 nd line Phase III Trial Designs Postmenopausal women with advanced breast cancer. Prior HT for early or advanced breast cancer Anastrozole 1mg daily orally Trial 20: n=229 Trial 21: n=194 Fulvestrant 250mg i.m. once monthly Trial 20: 1 x 5ml (n=222) Trial 21: 2 x 2.5ml (n=206) Analysis after 340 events (progression or death prior to progression) Analysis of TTD performed after >75% of patients dead Trial 20Trial 21

31 TTP mediano (mesi) 5,5 5,1 5,4 3,4 Risposta Obiettiva*20,7%15,7% 17,5%17,5% Durata mediana della Risposta Obiettiva (mesi)14,314,0 19,3 10,5 Beneficio Clinico Obiettivo**44,6%45,0% 42,2% 36,1% Durata mediana del Benefico Clinico Obiettivo (mesi) 11,811,4 12,8 10,8 *Risposta Obiettiva = RC + RP **Beneficio Clinico Obiettivo = RC+RP+MS >24 settimane Studi Numero pazienti FxAx Fx Ax Efficacia clinica Follow-up mediano a 15.1 mesi

32  Suppressive treatments Premenopause: ovariectomy, LH-RHa Postmenopause: aromatase inhibitors  Competitive treatments Pre/postmenopause: antiestrogens (TAM, TOR) steroidal antiestrogen (Faslodex) progestagens antiprogestins Hormonetherapy: which drugs? which sequences?

33

34 Second-line therapy with aromatase inhibitors Goss PE & Strasser K, 2001

35 Front-line Therapy With Aromatase Inhibitors ANA vs TAM 1 (1 mg) ANA vs TAM 2 (1 mg) LTZ vs TAM 3 (1 mg) No. of patients171/182340/328453/454 Response rate (CR + PR) % 21/1733/3230/20 (0.006) Clinical benefit (CR + PR + SD>24 wks) % 59/4556/5549/38 (0.001) Median TTP, mos11.1/5.6 (0.005)8.2/8.3 (8.9/7.8)10.1/6.2 (0.0001) Median TTF, mos7.6/5.47.3/6.3 (6.2/6.0)10/6.1 (0.001) Median OS, mos-/- Edema (weight gain)2.9/1.11.8/1.8 Hot flashes36.5/ /20.718/15 Thromboembolic disease4.1/8.24.8/7.3-/- Nausea30.6/ /13.415/16 Vomiting14.7/ /4.3-/- Asthenia31.8/ /4.911/10 Pain25.3/ /6.120/18 1 Nabholtz JM, 2000; 2 Bonneterre J, 2000; 3 Mouridsen H, 2001

36  Suppressive treatments Premenopause: ovariectomy, LH-RHa Postmenopause: aromatase inhibitors  Competitive treatments Pre/postmenopause: antiestrogens (TAM, TOR) steroidal antiestrogen (Faslodex) progestagens antiprogestins Hormonetherapy: which drugs? which sequences?

37 Many premenopausal and postmenopausal women with hormoneresponsive breast cancer benefit from sequential use of endocrine therapies at the time of disease progression.Many premenopausal and postmenopausal women with hormoneresponsive breast cancer benefit from sequential use of endocrine therapies at the time of disease progression. Therefore, women whose breast cancers respond to an endocrine manouvre with either shrinkage of the tumor or long-term disease stabilization (clinical benefit) should receive additional endocrine therapy at the time of disease progression.Therefore, women whose breast cancers respond to an endocrine manouvre with either shrinkage of the tumor or long-term disease stabilization (clinical benefit) should receive additional endocrine therapy at the time of disease progression.

38 Ormonoterapia – Pre-menopausa AIOM 2009

39 Ormonoterapia – Post-menopausa AIOM 2009

40 The action and reaction model Normanno et al JNCI 2005 Dependence on multiple different estrogen independent pathways

41 CAUSES OF ENDOCRINE-RESISTANCE AROMATASE INHIBITORS Hypersensitivity Increased cross-talk between the growth factor signalling pathways and ER – ER remains an integral part of signalling Hypersensitivity Increased cross-talk between the growth factor signalling pathways and ER – ER remains an integral part of signalling

42 Tumor cell adaptation:effects of long-term estrogen deprivation

43 Ellis MJ, SABCS 2008 A Randomized phase 2 trial of Low Dose (6 mg Daily) versus High Dose (30 mg Daily) Estradiol for Patients with Estrogen Receptor Positive AI- Resistant ABC

44

45 CAUSES OF ENDOCRINE-RESISTANCE AROMATASE INHIBITORS Hypersensitivity Increased cross-talk between the growth factor signalling pathways and ER – ER remains an integral part of signalling Hypersensitivity Increased cross-talk between the growth factor signalling pathways and ER – ER remains an integral part of signalling

46 Possible approaches to overcoming endocrine resistance: Maximal blockade of ER signaling Co-targeting ERand HER family signalling Co-targeting IGF-1 system Targeting downstream signalling Maximal blockade of ER signaling Co-targeting ERand HER family signalling Co-targeting IGF-1 system Targeting downstream signalling

47 FASLODE X EXEMESTAN E OR (CR+PR ) 20/270 [7.4%] 18/270 [6.7%] CBR (CR+PR+SD>2 4WS ) 87/270 [32.2%] 85/270 [31.5%]

48 Fulvestrant plus letrozole is more active than either agent alone in tumour xenografts Jelovac et al. Cancer Res 2005; 65: 5439–5444

49 Fulvestrant combination trials with AIs SWOG S0226 –‘Faslodex’ + ‘Arimidex’ versus ‘Arimidex’ FACT –‘Faslodex’ and ‘Arimidex’ in Clinical Trial SOFEA –Study Of ‘Faslodex’, Exemestane and ‘Arimidex’

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52 CONFIRM Phase III Trial: 500 vs 250 mgs Fulvestrant Nr 362 vs 374 Responders to previuos HT 63.3 vs 66.6 % Median TTP (mos) 500 Vs Median Duration CB (mos) 16.6 vs 13.9 Angelo Di Leo, Abs 25

53 Cross-talk and endocrine resistance Increased EGFR and HER2 signalling is associated with the development of resistance to endocrine agents Targeting both the ER with endocrine agents and the EGFR with anti EGFR agents delays the onset of resistance in pre-clinical models

54 Possible approaches to overcoming endocrine resistance: Maximal blockade of ER signaling Co-targeting ERand HER family signalling Co-targeting IGF-1 system Targeting downstream signalling Maximal blockade of ER signaling Co-targeting ERand HER family signalling Co-targeting IGF-1 system Targeting downstream signalling

55 TrialRegimenPopulation No. of patients Median PFS, mo Endocrine therapy alone Endocrine therapy + anti-ErbB TAnDEM 1 Phase III Anastrozole +/- trastuzumab HER *4.8 * Osborne et al 2 Randomized, placebo-controlled phase II Tamoxifen +/- gefitinib ITT HER2+ subset 206 † Cristofanilli et al 3 Randomized, placebo-controlled phase II Anastrozole +/- gefitinib ITT Clinical Evidence for Co-Targeting Growth Factor Receptors in ER+ MBC 1 Mackey J, et al. Breast Cancer Res Treat. 2006;100. Abstract 3; 2 Osborne K, et al. Breast Cancer Res Treat. 2007;106. Abstract 2067; 3 Cristofanilli M, et al. J Clin Oncol. 2008;26(No 15S). Abstract 1012.

56 In newly diagnosed MBC or had completed adj Tam > 1 yrs: PFS (ITT): T+G= 10.9 mos T+P = 8.8 mos HR: 0.84, 95% CI Randomized Phase II study of gefitinib or placebo in combination with tamoxifen in pts with hormone receptor positive metastatic breast cancer Osborne CK,SABCC 2007

57 PFS: A+G = 14.5 mos A+P = 8.2 mos HR: 0.55, 95% CI Conclusions:”…..A+G well tolerated and associated with a marked advantage in PFS versus A+P in postmenopausal women with newly diagnosed HR+ MBC….” A phase II multicenter, randomized trial to compare anastrozole plus Gefitinib with anastrozole plus placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer (MBC). Cristofanilli M et al ASCO %5%

58 Zac-FasT Trial (Zactima Faslodex Trial): a randomised, double-blind, parallel-group, multicentre, phase II study to evaluate the safety and pharmacological activity of the combination of a new TKI Vandetanib (100 or 300 mg/daily or placebo) with Fulvestrant (loading dose), in postmenopausal advanced breast cancer patients. Primary endpoint:EFS Main Secondary endpoints: - Success rate at 6 months - Objective tumor response rate - Time to Progression - Progression-free survival - Overall survival - Safety and tolerability of the combination

59 All

60 HER-2+ Median OS 33 m

61 Efficacy Summary In postmenopausal women with HR+, HER2+ MBC the combination of letrozole and lapatinib showed: - 29% reduction in risk of disease progression (p=0.019), with an improvement in median PFS from 3.0 to 8.2 months - Significant improvement in clinical benefit rate (29% to 48%; p=0.003) In postmenopausal women with HR+, HER2- ve MBC: –No significant treatment benefit on PFS [HR 0.90 (0.77, 1.05; p=0.188)] –23% reduction in risk of disease progression by preplanned Cox analysis [adjusted treatment HR 0.77 (0.64, 0.94; p=0.010)] Prior tamoxifen exposure was a significant covariate Biomarker studies ongoing

62 Possible approaches to overcoming endocrine resistance: Maximal blockade of ER signaling Co-targeting ERand HER family signalling Co-targeting IGF-1 system Targeting downstream signalling Maximal blockade of ER signaling Co-targeting ERand HER family signalling Co-targeting IGF-1 system Targeting downstream signalling

63 TCD Study: Multicenter, randomized, open label study evaluating an anti Insulin-like Growth Factor-1 Receptor (IGF-1R/CD221) monoclonal antibody, AVE1642, administered every 4 weeks in combination with Faslodex® in postmenopausal patients with advanced hormono-dependent breast cancer (in I or II line) Primary endpoint : Clinical Benefit (CB) Main Secondary endpoints : - Progression Free Survival Rate (PFSR) at 6 months - Progression Free Survival (PFS) - Safety

64 Possible approaches to overcoming endocrine resistance: Maximal blockade of ER signaling Co-targeting ERand HER family signalling Co-targeting IGF-1 system Targeting downstream signalling Maximal blockade of ER signaling Co-targeting ERand HER family signalling Co-targeting IGF-1 system Targeting downstream signalling

65 1.Treatment of postmenopausal women with LABC or MBC with Let alone or in combination with Tensirolimus: a randomized, 3-arm, phase 2 study: “…Combination well tolerated, longer PFS….” 2. Phase 3 study of tensirolimus plus Let vs Let alone in postmenopausal women with LABC or MBC:”… No improvement in PFS was seen in the overall population..” Baselga J, et al. Breast Cancer Res Treat, 2005 Chow LWC, et al. Breast Cancer Res Treat, 2006

66 Tailor treatment according to disease characteristics and patients expectations! A negligible achievement to the physician might be terribly important to the patient (… and viceversa).


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