Dott.ssa Pamela Guglielmini Prof. Francesco Boccardo.

Dott.ssa Pamela GuglielminiDott.ssa Pamela Guglielmini

Prof. Francesco BoccardoProf. Francesco Boccardo

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

Advanced Breast Cancer: Heterogeneous Population Requires Tailored Treatments

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

Characteristics Treatment Objectives

Is metastatic breast cancer a

curable disease?

Metastatic breast cancer:improved survival over time

Giordano, et al. Proc ASCO 2002

Months60483624120

Cu

mu

lati

ve s

urv

ival

1.0

0.8

0.6

0.4

0.2

0.0

1995–2000

1990–1994

1985–1989

1980–1984

1974–1979

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

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?

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

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

Hormone therapy Chemotherapy Biologicals Surgery/radiotherapy Analgesics Bisphosphonates Supportive care

(eritropoietin)

Which treatment options?

Patients characteristics: age/menopausal status Tumor characteristics:

DFI durationtumor burdendominant site of diseaseER/PgR statusprevious response to

endocrine therapy

Which patients are best candidate to

hormonetherapy?

Suppressive treatments Premenopause: ovariectomy, LH-

RHa Postmenopause: aromatase

inhibitors Competitive treatments Pre/postmenopause:

antiestrogens (TAM, TOR)

steroidal antiestrogen (Faslodex)

progestagensantiprogestins

Hormonetherapy: which drugs?

which sequences?

Invasive Breast Cancer by Age Invasive Breast Cancer by Age (Year 1998)(Year 1998)

Li CL et al. J Clin Oncol 2003,

1:28

5,8

18,3

23,421,0 21,0

10,3

0,0

5,0

10,0

15,0

20,0

25,0

20-39 40-49 50-59 60-69 70-79 80+

Premenopausal ≈ 25% - 30%

0

10

20

30

40

50

60

70

20-39 40-49 50-59 60-69 70-79 80+

ER-/PR-ER+/PR+ Other

Premenopausal, and HR+ ≈ 60%

Sir G.T. BEATSON Dr E. JENSEN

Mechanism of action of LHRHaMechanism of action of LHRHaFigure AFigure A- Hypersecretion of LH - Hypersecretion of LH

following acute following acute administration of LHRHaadministration of LHRHa

Figure BFigure B- Hyposecretion of LH - Hyposecretion of LH

following chronic following chronic administration of LHRHaadministration of LHRHa

LHRH

a

LHRH

a

LHRHaLHRHa

LHRHa

LHRHa

LH

RH

aL

HR

HaL

HR

Ha

LH

RH

a

LHRHa

LHRHa

LHRHaLHRHa

LHR

Ha

LHR

Ha

LH

RH

aL

HR

Ha

PituitaryPituitaryCellCell LHLH

LHR

Ha

LHR

Ha

LH

RH

a

LH

RH

a

LHRHaLHRHa

LHRHaLHRHa

LHRHa

LHRHa

LH

RH

aL

HR

Ha

LHRHaLHRHa

LHRH

a

LHRH

a

LHR

Ha

LHR

Ha

PituitaryPituitaryCellCell LHLH

Treatment response

Measurable diseaseGoserelin (n

29)Ovariectomy (n

30)Response No. % No. %CR 4 14 3 10PR 5 17 5 17Stable disease 8 28 8 26Increased disease 7 24 9 30Inadequate assessment

5 17 5 17

Taylor CW et al, 1998

PFS by treatment arm OS by treatment armTaylor CW et al, 1998

Summary of results by treatment group

Endpoint LHRH-agonist alone

(n=256)

LHRH-agonist + tamoxifen (n=250)

Hazard Ratio/Odd

s Ratio (95% CI)

Log-rank p value

Primary median survival (yrs)

2.5 2.9 0.78(0.63-0.96)

0.02

Secondary median progression- free survival (mos)

5.4 8.7 0.70(0.58-0.85)

<0.001

Objective response (%)

29.7 38.8 0.67(0.46-0.96)

0.03

CHAT and EORTC meta-analysis, 1999

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








which sequences?

Structures of non-steroidal anti-oestrogens clinically available or in clinical trials.

Howell A et al, 1996

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)

2060

240

149338

215268

Toremifene [Stenbygaard et al,

1993] (Phase III trial)

24040

3131

2944

Toremifene [Hayes et al, 1995]

60200

221212

2122

Tamoxifen (Phase III trial)

20 215 19

Droloxifene [Rauschning et al,

1994] (Randomised phase

II trial

2040

100

848896

304744

TAT-59 [Tominaga, 1995] (Randomised Phase II trail)

102040

151113

155531


Incidence of common side-effects with new NSAEs

Hot flushes

(%)

Lassitude (%)

Nausea/vomiting (%)

Tamoxifen

30 10 10

Toremifene

19 10 8

Droloxifene

29 26 29

Raloxifene

43 36 14

TAT-59 10 3 3Idoxifene “similar to tamoxifen”









which sequences?

Faslodex(fulvestrant)

Estrogen Receptor Downregulator

Faslodex(fulvestrant)

Estrogen Receptor Downregulator

Catena laterale alchilsulfonilica Catena laterale alchilsulfonilica

OH

HO (CH2)9SO(CH2)3CF2CF3

7

ER: Interazione con estradiolo

estradiolo estradiolo+ER

Attivazione AF1 e AF2 Omodimerizzazione

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

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

Howell A et al. Lancet 1995; 345: 29–30.

ICI 182,780 (‘Faslodex’): Phase II Results

Clinical Efficacy - Response RateResponse n %

Complete response 0 0Partial response 7 37Stable disease 6 32Progression 6 31

19 100

}69

69% of patients achieved OR or SD 24 weeks

2nd line Phase III Trial Designs Postmenopausal women with advanced breast cancer.

Prior HT for early or advanced breast cancer

Anastrozole 1mg daily orallyTrial 20: n=229Trial 21: n=194

Fulvestrant 250mg i.m. once monthlyTrial 20: 1 x 5ml (n=222)

Trial 21: 2 x 2.5ml (n=206)

Analysis after 340 eventsAnalysis after 340 events(progression or death prior to progression)(progression or death prior to progression)

Analysis of TTD performed after >75% of patients deadAnalysis of TTD performed after >75% of patients dead

Trial 20 Trial 21

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) 14,3 14,0 19,3 10,5

Beneficio Clinico Obiettivo** 44,6% 45,0% 42,2% 36,1%

Durata mediana delBenefico Clinico Obiettivo (mesi) 11,8 11,4 12,8 10,8*Risposta Obiettiva = RC + RP**Beneficio Clinico Obiettivo = RC+RP+MS >24

settimane

Studi

Numero pazienti 222 229 206 194

0020

0021

Fx Ax Fx Ax

Efficacia clinicaFollow-up mediano a 15.1 mesi








which sequences?

Second-line therapy with aromatase inhibitors

Goss PE & Strasser K, 2001

Front-line Therapy With Aromatase Inhibitors ANA vs TAM1

(1 mg)ANA vs TAM2

(1 mg)LTZ vs TAM3

(1 mg)No. of patients 171/182 340/328 453/454Response 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 18/15Thromboembolic disease 4.1/8.2 4.8/7.3 -/-Nausea 30.6/34.1 12.5/13.4 15/16Vomiting 14.7/12.1 3.9/4.3 -/-Asthenia 31.8/35.5 8.6/4.9 11/10Pain 25.3/26.4 6.3/6.1 20/18

1Nabholtz JM, 2000; 2Bonneterre J, 2000; 3Mouridsen H, 2001








which sequences?

• Many premenopausal and postmenopausal women Many premenopausal and postmenopausal women with hormoneresponsive breast cancer benefit with hormoneresponsive breast cancer benefit from sequential use of endocrine therapies from sequential use of endocrine therapies at the at the time of disease progressiontime of disease progression. .

• Therefore, women whose breast cancers respond Therefore, women whose breast cancers respond to an endocrine manouvre with either shrinkage of to an endocrine manouvre with either shrinkage of the tumor or long-term disease stabilization the tumor or long-term disease stabilization (clinical benefit) should receive additional (clinical benefit) should receive additional endocrine therapy endocrine therapy at the timeat the time of disease of disease progressionprogression. .

Ormonoterapia – Pre-Ormonoterapia – Pre-menopausamenopausa

AIOM 2009

Ormonoterapia – Post-menopausaOrmonoterapia – Post-menopausa

AIOM 2009

The action and reaction modelThe action and reaction model

Normanno et al JNCI 2005

Dependence on multiple different estrogen independent pathways

CAUSES OF ENDOCRINE-RESISTANCECAUSES OF ENDOCRINE-RESISTANCEAROMATASE INHIBITORSAROMATASE INHIBITORS


• Hypersensitivity

• Increased cross-talk between the growth factor signalling pathways and ER

– ER remains an integral part of signalling




Tumor cell adaptation:effects of long-term estrogen deprivation

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

Possible approaches to overcoming Possible approaches to overcoming endocrine resistance:endocrine resistance:

• Maximal blockade of ER signaling

• Co-targeting ERand HER family signalling

• Co-targeting IGF-1 system

• Targeting downstream signalling





FASLODEX

EXEMESTANE

OR(CR+PR)

20/270 [7.4%]

18/270 [6.7%]

CBR(CR+PR+SD>

24WS)

87/270 [32.2%]

85/270 [31.5%]

Fulvestrant plus letrozole is more active thaneither agent alone in tumour xenografts

Jelovac et al. Cancer Res 2005; 65: 5439–5444

Changeof meantumourvolume(%)

Time (weeks)0

0

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)

Fulvestrant Fulvestrant combination trials with AIscombination trials with AIs

• SWOG S0226 – ‘Faslodex’ + ‘Arimidex’ versus ‘Arimidex’

• FACT – ‘Faslodex’ and ‘Arimidex’ in Clinical Trial

• SOFEA – Study Of ‘Faslodex’, Exemestane and ‘Arimidex’

CONFIRM Phase III Trial: 500 vs 250 mgs Fulvestrant

• Nr 362 vs 374

• Responders to previuos HT 63.3 vs 66.6 %

0102030405060708090

100

%

ORR PR SD CBR

250500

Median TTP (mos) 500 Vs 250 6.5 5.5

Median Duration CB (mos)

16.6 vs 13.9

Angelo Di Leo, Abs 25

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 andthe EGFR with anti EGFR agents delays the onset of resistance in pre-clinical models

Trial Regimen PopulationNo. of

patients

Median PFS, mo

Endocrine therapy alone

Endocrine therapy + anti-ErbB

TAnDEM 1

Phase IIIAnastrozole +/-

trastuzumabHER2+ 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

Randomized, placebo-controlled phase II

Anastrozole +/- gefitinib

ITT 93 8.2 14.5

Clinical Evidence for Co-TargetingGrowth Factor Receptors in ER+

MBC

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.

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 0.59-1.18

Randomized Phase II study of gefitinib or placebo in combination with tamoxifen in pts with hormone receptor positive metastatic breast cancerOsborne CK,SABCC 2007

PFS: A+G = 14.5 mos A+P = 8.2 mos HR: 0.55, 95% CI 0.32-0.94

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 plusGefitinib with anastrozole plus placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer (MBC).

Cristofanilli M et al ASCO 2008

12%5%

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:EFSMain 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

HER-2+

HER-2+ Median OS 33 m

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

TCD 10631 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

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

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

Dott.ssa Pamela Guglielmini Prof. Francesco Boccardo.

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