1. Dott.ssa Pamela Guglielmini
Prof. Francesco Boccardo

2. The dimension of the problem
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

3. Advanced Breast Cancer: Heterogeneous Population Requires Tailored Treatments
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 3

4. Is metastatic breast cancer a curable disease?

5. Metastatic breast cancer: improved survival over time
1.0
0.8
0.6
1995–2000
Cumulative survival
1990–1994
0.4
1985–1989
0.2
1980–1984
1974–1979
0.0 12 24 36 48 60
Months
Giordano, et al. Proc ASCO 2002

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

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

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

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

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

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
Pituitary
Cell LH
LHRHa
Pituitary
Cell LH 
Administration of LHRHa initially leads to occupation of a very high proportion of LHRH receptors (Figure A)
LH release is transiently increased, but the receptors disappear from the surface of the cell (Down-regulation)
As newly synthesised receptors appear on the cell surface, they are occupied by LHRHa and disappear
As a result, the continuous presence of LHRHa prevents the reappearance of sufficient numbers of LHRH receptors on the pituitary cell for the synthesis and secretion of LH (Figure B)

16. Treatment response Measurable disease Goserelin (n 29)
Ovariectomy (n 30)
Response
No. % CR 4 14 3 10 PR 5 17
Stable disease 8 28 26
Increased disease 7 24 9 30
Inadequate assessment
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
Endpoint
LHRH-agonist alone
(n=256)
LHRH-agonist + tamoxifen (n=250)
Hazard Ratio/Odds Ratio (95% CI)
Log-rank p value
Primary
median survival (yrs)
2.5
2.9
0.78
( )
0.02
Secondary
median progression-
free survival (mos)
5.4
8.7
0.70
( )
<0.001
Objective response (%)
29.7
38.8
0.67
( )
0.03
CHAT and EORTC meta-analysis, 1999

19. primary breast cancer (3). All previously treated with Z+T.
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: % OR/SD
Endocrine effects: mean E2 (pmol/L)
Z+T (pre )= 224
Z+T (6 mos)=
Z+A (3 mos)=
Z+A (6 mos)=

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

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) 20 60
240 14 93 38 21 52 68
[Stenbygaard et al, 1993]
(Phase III trial) 40 31 29 44
[Hayes et al, 1995]
200
221
212 22
Tamoxifen
215 19
Droloxifene
[Rauschning et al, 1994]
(Randomised phase II trial
100 84 88 96 30 47
TAT-59
[Tominaga, 1995]
(Randomised Phase II trail) 10 15 11 13 55
Howell A et al, 1996

23. Incidence of common side-effects with new NSAEs
Hot flushes (%)
Lassitude (%)
Nausea/vomiting (%)
Tamoxifen 30 10
Toremifene 19 8
Droloxifene 29 26
Raloxifene 43 36 14
TAT-59 3
Idoxifene
“similar to tamoxifen”
Howell A et al, 1996

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

25. Estrogen Receptor Downregulator
Faslodex
(fulvestrant)
Estrogen Receptor Downregulator OH 7 HO
(CH2)9SO(CH2)3CF2CF3
Catena laterale alchilsulfonilica

26. ER: Interazione con estradiolo
estradiolo+ER
Attivazione AF1 e AF2
Omodimerizzazione

27. ER: Interazione con Tamoxifene
Tamoxifene Dimerizzazione con solo AF1 attivato
Meccanismo d'azione di tamoxifen
Tamoxifen (T) si lega all'ER presente nel citoplasma cellulare (fase 1). Il complesso va incontro a omodimerizzazione (fase 2) e si localizza principalmente nel nucleo cellulare. Al contrario di quanto avviene per l'estradiolo, il complesso dimerico possiede una sola funzione di attivazione (AF1; la funzione AF2 non è attiva). Come risultato, un singolo coattivatore viene reclutato da AF1 e ciò implica una ridotta trascrizione ed una altrettanto ridotta divisione cellulare, in confronto a quelle ottenute dall'agonista completo, l'estradiolo.
Il risultato dell'azione di tamoxifen è una trascrizione parzialmente inattivata del DNA.
Ciò significa che tamoxifen ha ancora un parziale effetto agonista, il quale potrebbe spiegare lo sviluppo della resistenza al farmaco che si osserva in alcune pazienti affette da carcinoma mammario. Tale effetto agonista parziale può anche essere responsabile della nota incidenza di flare tumorale e di effetti tromboembolici registrata con tamoxifen, così come della stimolazione dell'endometrio che può dar luogo ad alterazioni indesiderate a carico di quest'ultimo.
Il risultato dell'azione di tamoxifen è un'inattivazione parziale della trascrizione del DNA. Ciò significa che tamoxifen ha ancora un parziale effetto agonista, il quale potrebbe spiegare il noto sviluppo di resistenza al farmaco in alcune pazienti affette da carcinoma mammario
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
Meccanismo d'azione di 'Faslodex'
F si lega inizialmente all'ER presente nel citoplasma (fase 1). Il complesso accelera la degradazione dell'ER (fase 2) e, in seguito a ciò, il tasso di omodimerizzazione e di localizzazione nucleare del complesso risulta notevolmente diminuito (fase 3). Di conseguenza, il legame del complesso all'ERE risulta ridotto ed i coattivatori rimangono inattivi. Come effetto finale, dunque, non si ha nessuna stimolazione della trascrizione dei geni estradiolo-responsivi (cioè, nessuna trascrizione del DNA) né alcuna divisione cellulare estrogeno-dipendente (fase 4). Inoltre, il complesso F-ER si degrada rapidamente, provocando la perdita della proteina ER.
Per riassumere, 'Faslodex' possiede un meccanismo d'azione esclusivo, grazie al quale blocca e degrada gli ER, come è dimostrato dalla rapida perdita di proteina ER. Tale meccanismo si differenzia nettamente da quelli delle attuali opzioni terapeutiche per il trattamento delle donne in postmenopausa con carcinoma mammario ormono-responsivo, fra cui gli inibitori dell'aromatasi quali 'Arimidex', che riducono i livelli di estradiolo, e gli antiestrogeni della classe SERM quali tamoxifen, che bloccano gli ER in modo soltanto competitivo.
'Faslodex' blocca e degrada gli ER, come è dimostrato dalla rapida perdita di proteina ER
'Faslodex' è il primo di una nuova classe di farmaci: esso è un downregulator del recettore per gli estrogeni:
 I downregulator del recettore per gli estrogeni ed i SERM differiscono nel meccanismo d'azione e negli effetti sulla via di trasduzione dell'ER.
Il meccanismo d'azione di 'Faslodex' è unico per il fatto che questo agente non dimostra alcuna attività agonista nei confronti dell'ER, producendo una completa downregulation del recettore.
Inattivazione completa della trascrizione
e inibizione alla proliferazione cellulare
Riduzione Dimerizzazione e
stimolazione alla degradazione ER

29. 69% of patients achieved OR or SD  24 weeks
ICI 182,780 (‘Faslodex’): Phase II Results Clinical Efficacy - Response Rate
Response n %
Complete response 0 0
Partial response 7 37
Stable disease 6 32
Progression 6 31
19 100 } 69
69% of patients achieved OR or SD  24 weeks
Howell A et al. Lancet 1995; 345: 29–30.

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

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

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

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

35. Front-line Therapy With Aromatase Inhibitors
ANA vs TAM1
(1 mg)
ANA vs TAM2
LTZ vs TAM3
No. of patients
171/182
340/328
453/454
Response rate
(CR + PR) %
21/17
33/32
30/20 (0.006)
Clinical benefit
(CR + PR + SD>24 wks) %
59/45
56/55
49/38 (0.001)
Median TTP, mos
11.1/5.6 (0.005)
8.2/8.3 (8.9/7.8)
10.1/6.2 (0.0001)
Median TTF, mos
7.6/5.4
7.3/6.3 (6.2/6.0)
10/6.1 (0.001)
Median OS, mos
-/-
Edema (weight gain)
2.9/1.1
1.8/1.8
Hot flashes
36.5/24.2
20.5/20.7
18/15
Thromboembolic disease
4.1/8.2
4.8/7.3
Nausea
30.6/34.1
12.5/13.4
15/16
Vomiting
14.7/12.1
3.9/4.3
Asthenia
31.8/35.5
8.6/4.9
11/10
Pain
25.3/26.4
6.3/6.1
20/18
1Nabholtz JM, 2000; 2Bonneterre J, 2000; 3Mouridsen H, 2001

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

37. 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. 37

38. Ormonoterapia – Pre-menopausa
AIOM 2009

39. Ormonoterapia – Post-menopausa
AIOM 2009

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

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

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

43. 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
Ellis MJ, SABCS 2008

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

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

47. FASLODEX EXEMESTANE OR (CR+PR) CBR (CR+PR+SD>24WS) 20/270 [7.4%]
18/270 [6.7%]
CBR
(CR+PR+SD>24WS)
87/270 [32.2%]
85/270 [31.5%]

48. Fulvestrant plus letrozole is more active than either agent alone in tumour xenografts
Change of mean tumour volume (%)
Time (weeks)
100
200
300
400
500
600
700
800 6 12 18 24 30 36
Control
Letrozole (10 µg/day)
Fulvestrant (1 mg/day) + letrozole (10 µg/day)
Fulvestrant (1 mg/day)
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’

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 250
Median Duration CB (mos) vs
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

55. Clinical Evidence for Co-Targeting Growth Factor Receptors in ER+ MBC
Trial
Regimen
Population
No. of patients
Median PFS, mo
Endocrine therapy alone
Endocrine therapy + anti-ErbB
TAnDEM 1
Phase III
Anastrozole +/- trastuzumab
HER2+
208
2.4 *
4.8 *
Osborne et al2
Randomized, placebo-controlled phase II
Tamoxifen +/- gefitinib
ITT
HER2+ subset
206† 37
8.8
5.8
10.9
6.7
Cristofanilli et al3
Anastrozole +/- gefitinib 93
8.2
14.5
TAnDEM trial serves as proof of concept in HER2+
1Mackey J, et al. Breast Cancer Res Treat. 2006;100. Abstract 3; 2Osborne K, et al. Breast Cancer Res Treat. 2007;106. Abstract 2067; 3Cristofanilli M, et al. J Clin Oncol. 2008;26(No 15S). Abstract 1012. 55 55

56. In newly diagnosed MBC or had completed adj Tam > 1 yrs:
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
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

57. 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). 5%
12%
PFS: A+G = mos
A+P = 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….”
Cristofanilli M et al ASCO 2008

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
HER-2+

61. (p=0.019), with an improvement in median PFS from 3.0 to 8.2 months
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

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

65. 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….”
Baselga J, et al. Breast Cancer Res Treat, 2005
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..”
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).