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 66100 - Chieti

Giuseppe Naso MD

Associate Professor of Medical Oncology

Head of Translational Oncology

Clinical Head of Breast Unit

Sapienza Università di Roma

Il trattamento della malattia metastatica ormonoresponsiva: una visione d’insieme

Breast Cancer Epidemiology Italy

~ 47,000 New EBC/year

~ 15,000 New MBC

~ 50.000 MBC prevalence/year

Months

60 48 36 24 12 0

Cu

mu

lati

ve s

urv

iva

l

0.8

0.6

0.4

0.2

0.0

1995–2000

1990–1994

1985–1989

1980–1984

1974–1979

Giordano S, et al. Cancer 2004

Ca Mammario Metastatico Miglioramento della Sopravvivenza nel tempo

Median Overall Survival after

relapse

TNBC

9-12 months

ER pos.ve

24-36 months

Andre F et al. JCO 2004;22:3302-3308

Hormone Receptor positive metastatic Breast Cancer: a different disease

No Response

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

Hormone-unresponsive, or

Life-threatening disease

1st-line hormonal therapy 1st-line chemotherapy

Response No Response

2nd-line hormonal therapy

2nd-line chemotherapy

Progression

Progression

Progression

Progression

3rd-line hormonal therapy

Response

No Response

3rd-line chemotherapy

Supportive care

Management of Metastatic Breast Cancer

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

Heterogeity of Clinical Presentation

Stephen R.D. Johnston ASCO 2013

Tamoxifene

(SERM)

Trattamento della malattia

metastatica

Tamoxifen 1269 Yes Yes 32

Oophorectomy 3380 Yes 33

Progestins 3479 Yes Yes 31

A.I. 1153 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)

Number of

patients

Effective in

Pre-MP Post-MP

Response rate

(%) (range)

MP: menopause Adapted from Harris JR et al, 1991.

Selective Estrogen Receptor Modulators

• First generation

–Toremifene, Droloxifene, Idoxifene

• Second /Third generation

–Raloxifene, Arzoxifene, EM-800, etc.

Status: Advantage over Tam not shown

NEW SERMS

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

182 21 vs 17 59 vs 46

p 0.0098

11 vs 6 p 0.005

11 vs 11

Bonneterre* J Clin Oncol 18:3748, 2000

ANA 340 vs

328 32 vs 32 56 vs 55 8 vs 8 56 vs 54

Mouridsen^ J Clin Oncol 21:2101, 2003;

LET 453 vs

454 30 vs 20 49 vs 38

p 0.004

9 vs 6 p <0.0001

34 vs 33

Paridaens^

J Clin Oncol 2008

EXE 182 vs

189 46 vs 31 66 vs 49 10 vs 6

p 0.028 15 vs 11

Trial design for: *equivalence, ^superiority

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

OR Rate

(%)

Clinical

Benefit (%)

AN = anastrazole TX = Tamoxifene

TTP

(month)

TTF

(month)

Pts = 353 (171 vs 182)

Pts = 668 (340 vs 328)

*

*

OR Rate

(%)

Clinical

Benefit (%)

TTP

(month)

TTF

(month)

Bonneterre et al, J Clin Oncol 2000 Nabholtz et al, J Clin Oncol 2000

Anastrozole versus Tamoxifen

60% pts included no previous Adjv ET

20% pts included previous Tam Adjv 10% pts included previous Tam Adjv

70% pts included no previous Adjv ET

Exclusion Criteria: Adjv Tam received within 12 months before study entry

Equivalence Trial

Letrozole/Exemestane vs Tamoxifene

OR Rate

(%) Clinical

Benefit

(%)

*

EX = exemestane TX = tamoxifene

TTP

(month)

TTF

(month)

*

* *

Pts = 907

OR Rate

(%) Clinical

Benefit

(%)

TTP

(month)

Pts = 371 LE = letrozole

*

*

*

Paridaens et al, JCO2008 Mouridsen et al, J Clin Oncol 2001

80% pts included no previous Adjv ET

20% pts included previous Adjv Tam

Exclusion Criteria: Adjv Tam received within 12 months before study entry

17ESTRADIOLO

AF1

AF2

TAMOXIFENE ERE

ERE

ATTIVAZIONE PARZIALE DELLA TRASCRIZIONE

(solo AF1) ANTAGONISTA

AGONISTA

INIBITORI DELLE

AROMATASI BLOCCO COMPLETO DELLA

TRASCRIZIONE, PERSISTENZA DELLA VIA RECETTORIALE ESTROGENICA

FULVESTRANT BLOCCO COMPLETO DELLA

TRASCRIZIONE, ABOLIZIONE DEL SEGNALE MITOGENICO ESTROGENO-

MEDIATO

RE

AF1

AF2

ERE

ERE

RE

AF1

AF2

RE

ERE

ERE

DIFFERENTE MECCANISMO D’AZIONE: SERM, IA, SERD

17ESTRADIOLO

17ESTRADIOLO

AF1

AF2

RE

0

10

20

30

40

50

60

70

80

90

100

1 5 10 50 100 300 1000 3000 10000

Concentrazione (nM)

Perc

entu

ae d

i in

ibiz

ione

E2

Faslodex

Tam

SELETTIVITA’ DEL LEGAME 3H-ESTRADIOLO/RE

Estradiolo vs Faslodex vs Tam

Proteosome activation

PK model of plasma fulvestrant

0

5

10

15

20

25

30

35

0 28 56 84 112 140 168 196 224 252 280

Time (days)

Pla

sm

a c

oncentr

atio

n o

f fu

lvestr

ant

(ng/m

L)

Standard Dose Regimen Loading Dose Regimen High Dose Regimen

Auc=8

100nM

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

High Dose

(HD)

500 mg 500 mg 500 mg 500 mg

Day 0

Monthly

Monthly Day 14 Day 28

Fulvestrant dosing regimens

CONFIRM: Effect of Fulvestrant 500 mg vs 250 mg on Survival in Postmenopausal Women

• Baseline characteristics appeared well balanced between treatment arms

– Subsequent therapies were well balanced between arms, with approximately 60% of patients receiving subsequent chemotherapy and approximately one third receiving other hormonal therapy

Outcome

Timing of Analysis

Fulvestrant 500 mg

Fulvestrant 250 mg

HR (95% CI)

Median PFS First* 6.5 mos 5.5 mos 0.80‡ (0.68-0.94)

Median OS First* 25.1 mos 22.8 mos 0.84§ (0.69-1.03)

Median OS Final† 26.4 mos 22.3 mos 0.81¶ (0.69-0.96)

*First analysis was performed at 50% maturity. †Final analysis was performed at 75% maturity. ‡ P = .006 §P = .001 ¶P = .016

DiLeo A, et al. SABCS 2012. Abstract S1-4.

FINALMENTE LA PRIMA LINEA HA UN PADRONE !!!!!!!

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.

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;

Robertson et al. Br Cancer Res Treatm 2012;136: 503

Median TTP: 23.4 vs 13.1 months

34 % reduction in risk of progression

An impressive results! (secondary endpoint)

PHASE III TRIAL FALCON

No prior hormonal Rx

CDK4/6

Finn RS, et al. SABCS 2012. Abstract S1-6.

Aromatase Inhibitor + CDK4/6 Inhibitor

Improves PFS in ER+ MBC

0

0.2

0.4

0.6

0.8

1.0

0 6 12 10 14 Mos

16 20 22 28

PD 991 + LET (n = 84)

21 (25)

26.1

(12.7-26.1)

PF

S P

rob

ab

ilit

y

Pts at Risk, n

PD 991 + LET

LET

84

81

75

57

60

38

53

29

43

22

35

17

25

11

3

1

1

1

24 26 18 8 2 4

0.3

0.5

0.7

0.9

0.1

LET (n = 81)

40 (49)

7.5

(5.6-12.6)

18

6

15

5

14

4

9

3

5

3

Events, n (%)

Median PFS, mos

(95% CI)

HR

(95% CI)

P value

0.37

(0.21-0.63)

< .001

An impressive results! (Waiting for a phase III)

Combined Strategies in I line ER+ MBC

FACT: Phase III, Open-Label, Multicenter Trial of Combined Fulvestrant and Anastrozole Therapy

Fulvestrant im LD, 500 mg day 0, 250 mg days 14 and 28 then 250 mg monthly

+ Anastrozole po, 1 mg daily

ER+ and/or PR+,

at first relapse:

After/during TAM > 12 mo

After/during CT

After/during AI >12 mo

Postmenopausal or premenopausal rendered post-menopausal by adjuvant LHRH analogue*

R

*In these cases, the LHRH analog must be continued throughout the study period

N= 514

Bergh J et al. SABCS 2009;Abstract 23.

Anastrozole po, 1 mg daily

11,4 months

12,4 months

mOS 37,8 months

mOS 38,2 months

J Clin Oncol 30.-2012

FACT: Efficacy

F + A

(n=258)

A

(n=256)

HR (95% CI)

p-value

Best objective response1

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) 10.8 10.2

0.99 (0.81, 1.20)

p = 0.91

Overall survival

(months) 37.8 38.2

1.00 (0.76, 1.32)

p = 1.00

Bergh J et al. SABCS 2009;Abstract 23.

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)

Treatment until disease progression

Stratified by previous adjuvant tamoxifen

Women with progression

encouraged to cross over to

receive fulvestrant

Mehta RS, et al. SABCS 2011. Abstract S1-1.

SWOG S0226: Study Design Primary endpoint: PFS

Secondary endpoints: OS, Safety

FACT SWOG

Previous AdjEsTx 69% 40%

ORR% 31,8 NR

TTP mo 10.8 15 No previous adjuvant tamoxifen -

17.0 (n = 414)

Previous adjuvant tamoxifen -

13.5 (n = 280)

OS mo 37.8 47.7 No previous adjuvant tamoxifen -

47.7 (n = 414)

Previous adjuvant tamoxifen -

49.6 (n = 280)

Diagnosis of MBC 7% <1yr 39%

Visceral disease 50% 50%

Cross-talk between different signal transduction

pathways is the best studied cause of resistance

Johnston S R Clin Cancer Res 2010;16:1979-1987

pTEN cbl

LTED (Long term estrogen deprivation)

mTOR is Activated by Estrogen Deprivation

56

mTOR Inhibition Combines Effectively With

Hormonal Therapy in BC

4-HT, 4-hydroxytamoxifen.

Yamnik RL et al. J Biol Chem. 2009;284(10):6361-6369; Johnston SR. Clin Cancer Res. 2005;11(2 Pt 2):889S-899S.

Interaction between mTOR and ERa

S6K1

mTOR

Growth factors

ERα

P

Ser167

Transcription

ER-Responsive Element

E

Cell proliferation *P < 0.05, 2-tailed paired Student t test.

Cell

pro

lifera

tion (

absorb

ance 5

40 n

m)

MDA-MB-

231

MCF7 ZR-75-1 T47D

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

* *

Control

Rapamycin

0.1μM 4-HT

0.1μM 4-HT+ rapamycin

Co-Targeting mTOR and HR in HR+/HER2-ve ABC

TAMRAD1

( prior AI)

BOLERO 22,3

(prior Let or Ana)

TAM TAM +

everolimus

EXA +

placebo

EXA +

everolimus

57 54 239 485

CBR % 42.1 61.1 p 0.045 25.5 50.5 p < 0.0001

Median PFS (m) 4.5 8.6 HR 0.54

p 0.002 4.1 11

HR 0.44

p<1x10-16

Median OS (m) 24 NR HR 0.45

p 0.007

NR

NR

1Bachelet T et al, SABCS 2010; 2 Baselga J et al, NEJM 2011; 3Hortobagyi GN et al, SABCS 2011

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)

Treatment until disease progression or unacceptable toxicity

Randomized 2:1; stratified by sensitivity to previous hormonal therapy, presence of

visceral metastases

*> 50% of patients in each arm with ≥ 3 previous therapies

BOLERO-2: Study Design

• Primary endpoint: PFS (investigator assessment)

• Secondary endpoints: OS, ORR, clinical benefit rate, safety, bone markers, PK

•

BOLERO-2: ORR and CBR by Local Assessment

• Significantly improved ORR and CBR in the everolimus +

exemestane group compared with the placebo + exemestane group

Everolimus + exemestane

Placebo + exemestane

p<0.0001

p<0.0001

7.1-months median follow-up 12.5-months median follow-up

p<0.0001

p<0.0001

ORR ORR CBR CBR

Re

spo

nse r

ate

by loca

l asse

ssm

en

t (%

)

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 (0.27–0.47) 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: 0.28–0.45) p<1x10–16

Everolimus + exemestane: 11.0 months Placebo + exemestane: 4.1 months

Time (weeks)

Pro

bab

ility

of

even

t (%

) P

rob

abili

ty o

f ev

ent

(%)

HDAC Inhibitors Mechanism of Action

HDAC inhibitors relax the structure of DNA making it more

accessible to RNA polymerases

40. Pathiraja TN, et al. J Mam Gland Biol Neoplasia. 2010;15:35-47.

Closed chromatin = genes off

Histone acetyltransferases

(HATs)

Histone deacetylases (HDACs)

Open chromatin = genes on

HDAC inhibitors

AC

AC AC

AC AC

AC

AC AC

AC

AC AC

AC AC

AC

AC AC

AC

AC AC

AC AC

AC

AC AC

AC

AC AC

AC AC

AC

AC AC

MPFS Everolimus +exemestane:11.0 months

Stephen R.D. Johnston ASCO 2013

Personalmente (con i dati attualmente disponibili)

FIRST LINE:

1)Fulvestrant+/- A.I

SECOND LINE:

3) Inibitore (Exemestane ?) + Everolimus

In SO-CALLED LUMINAL A tumor

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)

GRAZIE PER LA VOSTRA PAZIENZA