Carcinoma della Mammella:scelte terapeutiche complesse

Discussione di un caso clinico:Paziente con comorbidità

Giorgio Mustacchi e Marina Bortul

Fellow up 2009Fellow up 2009

Programma di lavoro

• Da discutere nell’ambito dei lavori di gruppo:   – Ruolo della chirurgia nella malattia metastatica

– Approccio alla paziente con BC HER2+ e comorbidità cardiovascolare

– Scelta della terapia endocrina nella paziente con BC ER+

– Rischi e benefici della terapia con AIs (switching vs upfront)

– Scelta della terapia endocrina a ripresa di malattia

Donna di 56 anni con diabete, ipertensione e CHFMastectomia per:

CLI multifocale (N-, G3, ER+, PR-, HER2-POS)dopo 4 anni sviluppa metastasi epatiche

Donna di 56 anni, in menopausa da 5

Diabete di Tipo II (dieta e antidiabetici orali)

Ipertensione arteriosa (ACE-Inibitori + diuretici)

CHF due anni prima (LVEF 45%)

La Paziente

Giugno 2003

Mastectomia dx

CLI multifocale G3

N neg Ki67 35 %

Er 60 % PgR neg

HER2 +++

La Terapia Adiuvante scelta

CMF x 6

TAMOXIFEN

LVEF Basale : 45 %

Post CMF : 46 %

Depressione

2003: no Trastuzumab adiuvante

Aprile 2007: Intervallo libero 4 anni

• Linfonodi sopraclaveari dx• Astenia G2• Anoressia G2• Febbricola serotina• Metastasi epatiche

• PS 2• LVEF 40 %

Biopsia Linfonodo FISH pos

ER 70% PgR Neg

Scelta Terapeutica: Docetaxel e Trastuzumab

Tempo 0

Dopo 6 cicli

Il seguito della storia

• TTP: 12 mesi– (PD fegato, polmone e N s.cl)

• PS 2 (dispnea, astenia)

2° linea: – Capecitabina + Trastuzumab

PR per 7 mesi (PS1)

PD dopo 7 mesi3° linea di trattamento

• Non vuole più alopecia

• Chiede la prospettiva reale

3 linea scelta

Letrozole + Trastuzumab

SD per 4 mesi

La fine della storia

• PD con decadimento generale

• Si concorda per BSC

• Ambulatoriale per 4 mesi

• ADI 1 mese

• Decesso in Hospice dopo 1 mese

Sopravvivenza Globale : 29 mesi

Primo quesito

Ha senso fare una biopsia a progressione di malattia?

SI

NO

Secondo QuesitoRuolo della chirurgia nella

malattia metastatica

Se la metastasi era polmonare ?

Oltre l’informazione biologica, può la chirurgia dare altro?

Terzo QuesitoApproccio alla paziente con BC HER2+ e

comorbidità cardiovascolare

Opportunità di usare Trastuzumab

Cardiotossicità di Trastuzumab

Scelta dello schema chemioterapico

Monitoraggio cardiologico

Quarto QuesitoTrastuzumab beyond Progression ?

Opportunità di usare Trastuzumab

Scelta dello schema chemioterapico

Monitoraggio cardiologico

Alternative attuali al Trastuzumab

Quinto QuesitoScelta della terapia endocrina

nella paziente con BC HER2+/ER+

• Endocrino sensibilità del fenotipo

• Tipo di Endocrinoterapia

Sesto quesitoAlternative a Trastuzumab

Settimo quesitoTrastuzumab o Lapatinib ?

Ottavo QuesitoRischi e benefici della terapia con

AIs (switching vs upfront)

Back from San Antonio 2008

Highlights on

Endocrine adjuvant treatment in postmenopausal women

Primo quesito

Ha senso fare una biopsia a progressione di malattia?

SI

NO

Franco N et al. Proc ASCO 2004;Abstract 539.

Perchè la biopsia?Discordance in ER and PR Status

Between Primary and Metastatic Breast Cancer: A Meta-Analysis

Receptor change

ER, n=658

Risk ratio(95% CI)

PR, n=418

Risk ratio(95% CI)

Positive to negative 0.22 (0.17-0.30) 0.20 (0.12-0.33)

Negative to positive 0.11 (0.06-0.22) 0.15 (0.08-0.28)

Total discordance 0.29 (0.18-0.47) 0.27 (0.20-0.36)

Perchè la biopsia?Discordance in HER2 Testing

Secondo QuesitoRuolo della chirurgia nella

malattia metastatica

Se la metastasi era polmonare ?

Oltre l’informazione biologica, può la chirurgia dare altro?

Terzo QuesitoApproccio alla paziente con BC HER2+ e

comorbidità cardiovascolare

Opportunità di usare Trastuzumab

Cardiotossicità di Trastuzumab

Scelta dello schema chemioterapico

Monitoraggio cardiologico

NR

Months

60483624120

Su

rviv

al

100%

80%

60%

40%

20%

0%

NR

PR

CR

4landmark

P<.0001, logrank test

>12 months

16.2 28.8

Response and survival

(Bruzzi, Del Mastro, JNCI 2004)

Prognosis of women withStage IV breast cancer byHER2 status and trastuzumab treatment.

S.Dawood et alASCO 2008 Abs #1018

2091 patients1782 HER2 Negative118 HER2 Positive NO Trastuzumab191 HER2 Positive Trastuzumab

Clinical benefits of trastuzumab plus taxanes

1Slamon DJ, et al. N Engl J Med 2001;344:783–922Baselga J. Oncology 2001;61(Suppl. 2):14–21

3Marty et al. J Clin Oncol. 2005

H0648g (IHC 3+)1,2 M770013

Outcome

H + P (n=68)

P (n=77)

H + D (n=92)

D (n=94)

ORR (%) 49 17 61 34

TTP (months) 7.1 3.0 10.6 6.1

OS (months) 24.8 17.9 27.7 18.3

No Difference in OSPolyCT NO better in PFS, ORRPolyCT better toxicity profile due to lower docetaxel dose

No Difference in OSPolyCT better in PFS, ORRPolyCT slightly worse toxicity profile

Poly vs monochemotherapy

Comorbidity is a Key Factor

Age-comorbidity Score n

Actual 10 year Survival (%)

0-1 369 97-992 136 873 109 794 42 475 29 34

Charlson, J Chron Dis 40:373, 1987

Cardiac events

Cardiac Dysfunction Outcomes (CREC)

H + AC AC H + T T

Cardiac dysfunction events, n (%) 39 (27) 11 (8) 12 (13) 1 (1)

NYHA class III/IV heart failure, % 16 4 2 1

Deaths, n 4 1 1 2

• MBC 4 0 0 2

• Cardiac 0 1 0 0

• Pneumonia 0 0 1 0

CREC; Cardiac Review and Evaluation Committee

Seidman A et al. J Clin Oncol 2002; 20: 1215-1221

Trastuzumab plus chemotherapy in MBC patients - other trials

Cardiac Dysfunction Outcomes (CREC)

Cardiac disfunction NYHA Class III-IV CHF

Study Treatment No. pts % No. pts %

H0551g

H0552g

H0649g

H0650

H0659g

H0693g

H alone

H+cisplatinum

H alone

H alone

H other CT

H other CT

3

1

11

3

16

15

7

3

5

3

6

4

2

1

8

2

8

10

4

3

4

2

3

3

Seidman A et al. J Clin Oncol 2002; 20: 1215-1221

Francesco Perrone

Unità Sperimentazioni Cliniche

Istituto Nazionale Tumori di Napoli

Cardiosafety with trastuzumab in metastatic

breast cancer

CHF fromTrastuzumab is not associated with ultrastructural changes

Ewer MS et al., JCO 2005, 23: 7820-7826

Chia, S. et al. J Clin Oncol; 24:2773-2778 2006

Pegylated Liposomial Doxo + Trastuzumab

LVEF over timeCHF : 0

Cardiotoxicity

Without CHF

10 %

Peg Liposomial Doxo + TrastuzumabEfficacy

RR % (N = 29) 52

Median PFS mos 12

Median OS mos not reached

2 yrs Survival % 77

Chia, S. et al. J Clin Oncol; 24:2773-2778 2006

30 1st line M1 BC ptsLVEF > 55 %

G3 PPE : 30 %G3 Neutropenia : 23 %

Italic denotes studies for which the extended paper is not yet in our hand

MBC: Trastuzumab + PaclitaxelCardiotoxicity

Italic denotes studies for which the extended paper is not yet in our hand

MBC: Trastuzumab + DocetaxelCardiotoxicity

Italic denotes studies for which the extended paper is not yet in our hand

MBC: Trastuzumab + VinorelbineCardiotoxicity

Quarto QuesitoTrastuzumab beyond Progression ?

Opportunità di usare Trastuzumab

Scelta dello schema chemioterapico

Monitoraggio cardiologico

Alternative attuali al Trastuzumab

Two trials evaluating anti-HER-2 therapy after progression to trastuzumab-based

chemotherapy

Trial Study design

No. pts RR% Median TTP, mos

Median OS, mos

X 78 27 5.6 20.4

German1

X+T 78 48 8.2 25.5

X 161 17 4.4 13.7

GSK2

X+L 160 29 8.4 NR

X, capecitabine; T, trastuzumab; L, lapatinib

1 Von Minckwitz G et al. Proc SABCS 2008, 2 Geyer C et al. New Engl J Med 2006

Gelmon et al. Clin Breast Cancer. 2004;5:52-58.

Similar ORR in first and second Trastuzumab treatment

45

40

35

30

25

20

15

10

5

0

Monotherapy Plus taxane

Plus vinorelbine Total

Ob

ject

ive

resp

on

se (

CR

+P

R)

(% o

f p

atie

nts

)

1st regimen 2nd regimen(Trastuzumab retreatment)

ND

Trastuzumab Beyond Progression:Multinational Study of 105 Patients

Trastuzumab Beyond Progression:Multinational Study of 105 Patients

0

5

10

15

20

25

30

35

1st Line 2nd Line

Median TTP

H Mono

H + Tax

H + Vnr

Similar TTP in first and second Trastuzumab treatment

Gelmon et al. Clin Breast Cancer. 2004;5:52-58

Trastuzumab treatment beyond PDThe German experience

Jackisch, SABCS 2007

Prosecution of trastuzumab influences the outcome more than response does

Menard, ASCO 2008

440 metastatic pts registered in the DEMETRA study

Continuation of Herceptin prolongs median TTP in the GBG-26 study

+

+++

+++++

++

+++

++

+

+

++

+++

400

0.0

0.2

1.0

0.8

0.6

0.4

Time from 1st progression (months)

10 20 30

Probability

7477

4055

1529

812

54

33

21

11

11

HR=0.69 (2-sided p=0.034;1-sided p=0.015)

8.2a5.6a

Herceptin + Xeloda (n=78)Xeloda (n=78)

von Minckwitz , ASCO 2008

Continuation of Herceptin probably improves OS

in the GBG-26 study

7477

6668

5059

3347

2127

1015

86

31

21

+

20.4a

++++

++++

400

0.0

0.2

1.0

0.8

0.6

0.4

Time from 1st progression (months)

10 20 30

Probability

HR=0.76 (2-sided p=0.26;1-sided p=0.13)

+++++

+

+++++++

+++

+++ ++++++++++++

++++++

+++++++

++++++++++++

++++++++++

Herceptin + Xeloda (n=78)Xeloda (n=78)

25.5a

von Minckwitz , ASCO 2008

Quinto QuesitoScelta della terapia endocrina

nella paziente con BC HER2+/ER+

• Endocrino sensibilità del fenotipo

• Tipo di Endocrinoterapia

Metastatic Breast CancerHormone Responsiveness

ER/PgR

HER2 &

Tamoxifen

DFS in tamoxifen-

treated patients

Arpino, G. et al. J Natl Cancer Inst 2005;97:1254-1261

ER+/PR+

ER+/PR+

ER+/PR-

ER+/PR-

Her2+ Better Her2+ worse

OverallOverall 1.441.44 (1.34 – 1.56)(1.34 – 1.56)

EllegdeEllegde 1.211.21 (0.87 – 1.69)(0.87 – 1.69)

HayesHayes 1.061.06 (0.47 – 2.38) (0.47 – 2.38)

HoustonHouston 2.072.07 (1.57 – 2.73)(1.57 – 2.73)

Lipton 1stLipton 1st 1.421.42 (1.24 – 1.63)(1.24 – 1.63)

WillsherWillsher 1.331.33 (0.56 – 3.16) (0.56 – 3.16)

WrightWright 1.541.54 (0.86 – 3.74)(0.86 – 3.74)

YamauchiYamauchi 1.661.66 (1.05 – 2.64)(1.05 – 2.64)

HER2 and Endocrine Therapy - MetanalysisER+ Patients (N=1195)

Relative Risk

0,2 0,5 1 2 5

Lipton 2ndLipton 2nd 1.401.40 (1.25 – 1.56)(1.25 – 1.56)

Relative Risk of Treatment Failure (95%CI)

p<0.00001

Test for Heterogeneity: p=0.26

De Laurentiis, Clin Cancer Res 2005;11:4741-4748

Tamoxifen in HER2+ Disease

Tam vs AI in HER2+ tumorsNeoadjuvant setting

Author Nr Study arms Results subgroup HER2 and ER+

% pts HER2 +

Ellis

JCO 2001

250 TAM

vs

Letrozole

RR

21% vs 88%

P=0.0004

14

IMPACT trial

BCRT 2004

abs

330 TAM

vs

Anastrozole

vs

Combination

CR 22%

vs

58%

vs

31%

14

OverallOverall 1.421.42 (1.24 – 1.63)(1.24 – 1.63)

Effect by Type of TherapyLipton Study (N=566)

Her2+ Better Her2+ worse

Relative Risk

0,2 0,5 1 2 5

LetrozoleLetrozole 1.531.53 (1.24 – 1.88)(1.24 – 1.88)

TamoxifenTamoxifen 1.341.34 (1.12 – 1.60)(1.12 – 1.60)

Relative Risk of Treatment Failure (95%CI)

Relative Risk of Treatment Failure (95%CI)

TransATAC: adjuvant HT & HER2Time To Recurrence

(Dowsett, SABCS 2008)

Actually, endocrine resistance!

TanDEM: Response and clinical benefit rates

0

10

20

30

40

50

60

PR SD PD Missing Clinicalbenefit

Pat

ien

ts (

%)

A + H (n=74)

A (n=73)A + H (n=103)

A (n=104)

p=0.026

p=0.018

PR, partial response; SD, stable disease; PD, progressive disease

17

7

43

28

TanDEM: Anastrazole +/- Trastuzumab Progression-free survival

103 48 31 17 14 13 11 9 4 1 1 0 0A + HNo. at risk

104 36 22 9 5 4 2 1 0 0 0 0 0A

Pro

bab

ilit

y1.0

0.8

0.6

0.4

0.2

0 5 10 15 20 25 30 35 40 45 50 55 60Months

95% CI

3.7, 7.02.0, 4.6

p value

0.0016

Median PFS

4.8 months2.4 months

Events

8799

Baselga 2006

Luminal B Tumors are quite endocrine-resistant

TTP is usually much longer

Nabholtz, J. M. et al. J Clin Oncol; 18:3758-3767 2000

Sesto quesitoAlternative a Trastuzumab

EGF100151

Lapatinib Mechanism of Action

• Binds to intracellular ATP binding site of EGFR (ErbB-1) and HER2 (ErbB-2) preventing phosphorylation and activation

• Blocks downstream signaling through homodimers and heterodimers of EGFR (ErbB-1) and HER2 (ErbB-2)

• Dual blockade of signaling may be more effective than the single-target inhibition provided by agents such as trastuzumab

1+1 2+2 1+2

Lapatinib

Downstream signaling cascade

Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. Oncogene 2002;21:6255-6263;Konecny et al. Cancer Res. 2006;66:1630-1639

EGF100151

Study Design

• Progressive, HER2+ MBC or LABC

• Previously treated with anthracycline, taxane and trastuzumab*

• No prior capecitabine

Lapatinib 1250 mg po qd continuously +

Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk

Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk

Patients on treatment until progression or unacceptable toxicity, then followed for survival

Stratification:• Disease sites• Stage of disease

RANDOMIZE

*Trastuzumab must have been administered for metastatic disease

N=528

EGF100151

Response Rate - ITT Population

Lapatinib + Capecitabine(n=160)

Capecitabine(n=161)

Complete response 1 (< 1%) 0 (0%)

Partial response 35 (22%) 23 (14%)

Overall response rate* (95% CI)

22.5% (16.3 - 29.8)

14.3%(9.3 - 20.7)

*P-value (Fisher’s exact, 2-sided) = 0.113

EGF100151

Time (weeks)0 10 20 30 40 50 60 70

Cu

mu

lati

ve P

rog

ress

ion

-Fre

e S

urv

ival

, %

0

10

20

30

40

50

60

70

80

90

100

Progression-Free Survival - ITT Population

0.000045P-value (log-rank, 1-sided)

73 (45%)45 (28%)Progressed or died

0.48 (0.33, 0.70)Hazard ratio (95% CI)

17.936.9Median PFS, wk

161160No. of pts

CapecitabineLapatinib +

capecitabine

EGF100151

Mean LVEF at Scheduled Assessments

Week 12 Week 18 Week 24 Week 36 Week 48Week 6Screening

Assessment

Lapatinib + Capecitabine

Capecitabine

Mea

n L

VE

F (

%)

80

75

70

65

60

55

50

n=160 n=160

n=108

n=92

n=84 n=67

n=63n=37

n=37 n=26

n=15n=9

n=7n=1

Trastuzumab plus lapatinib

• Synergistic drug interactions were observed in HER2-overexpressing cell lines1

• Phase I: MBC, 94% progressed on prior trastuzumab 1CR, 6PRs in 27 patients (26%)2

Humanized monoclonal antibody directed against HER2

Trastuzumab

Lapatinib Dual-specific TK inhibitor against EGFR and HER2

1Konecny et al. Cancer Res 2006; 2 Storniolo et al. Breast Cancer Res Treat 2005

EGF104900: PFS and OS

Settimo quesitoTrastuzumab o Lapatinib ?

HER2 signalling pathway: the role of PTEN

HER2

Shc

GRB2

PI3K p85

c-myc

AKT

GSK3

HRG

PTEN

Ras

MAPK

Cell survival Cell proliferation

HER3

mTOR

PI3K p85

IGF-1R

The traslational Neoadjuvant Study

Jenny Chang, SABCS 2008

Low PTEN/PI3KA-mut

Jenny Chamg, SABCS 2008

Conclusions

Jenny Chamg, SABCS 2008

PK interaction between Tamoxifen and Lapatinib

TAM induces hepatic CYP3A, the primary route of LAP elimination

So LAP plasma levels are reduced.This important information may impact in ongoing adjuvant

lapatinib studies

parameter (units) LAP LAP+TAMDecrease in LAP+TAM vs LAP

LAP AUC tau (h*mg/L)

25.2 (16.3-39.0) 17.9 (12.8-24.9) 0.71 (0.64-0.79)

LAP Cmax (mg/L) 1.73 (1.26-2.38) 1.20 (0.91-1.59) 0.69 (0.62-0.78)

LAP Cmin (mg/L) 0.56 (0.32-0.99) 0.33 (0.22-0.48) 0.58 (0.47-0.72)

Cardoso, SABCS 2008, Poster 2073

Trastuzumab and Letrozole

Letrozole+Lapatinib in MBC

Response Rate (HER2 pos, n=219)

S. Johnston, SABCS 2008

PFS : HER2 pos pts

S. Johnston, SABCS 2008

Ottavo QuesitoRischi e benefici della terapia con

AIs (switching vs upfront)

Back from San Antonio 2008

Highlights on

Endocrine adjuvant treatment in postmenopausal women

Start AI After 2–3 Years of TAM:Randomization/Analysis Upfront or at Switch

0

4

8

12

16

0 2 4 6 8 10

An

nu

al r

ecu

rren

ce r

ate

(%)

Time (years)

BIG 1-98

IES, ITA, ARNO/ABCSG

TEAM

TAMAI

Node+

Node–

Update of Houghton. J Clin Oncol. 2005;23(16S):24s. Abstract 582; Untch and Jackisch. Onkologie. 2007;30:55.

R Randomization

R

R

R

Switch metanalysis

TAM vs AI

5 yrs AI vs TAM (ER+): DFS

TAM 2-3 yr AI 2-3 yr

Conclusioni

DFS : AI > TAM in ogni caso

Upfront: + 4 % a 8 anni– effetto presente fino alla fine del trattamento

Switch: + 3.5 % a 6 anni– Effetto presente fino a 2-3 anni, poi modesto (???)

Buon profilo di sicurezza

BIG 1-98

BIG 1-98 Study Design

BIG 1-98: monotherapy update

BIG 1-98: BC Events TamLet vs Let

BIG 1-98: BC Events LetTam vs Let

BIG 1-98 Central Review (Median Follow-up of 51 mo) DFS Benefit of Letrozole Observed Irrespective of PgR or HER2 Status

Viale et al. J Clin Oncol. 2007;25:3846; Rasmussen et al. J Clin Oncol. 2007;25(18S):12s. Abstract 538.

100

DF

S (

%)

90

807060

50

40

3020

100

0 1 2 3 4 5D

FS

(%

)

10090

807060

50

40

3020

100

0 1 2 3 4 5Years Since RandomizationYears Since Randomization

DFS by PgR status DFS by HER2 status

N Events 4-y DFS% (SE)

PgR-absent tamoxifen 185 41 79 (3)

PgR-absent letrozole 191 37 81 (3)

PgR-present tamoxifen 1553 228 86 (1)

PgR-present letrozole 1580 167 90 (1)

N Events 4-y DFS% (SE)

HER2- tamoxifen 1646 240 86 (1)

HER2- letrozole 1647 178 90 (1)

HER2+ tamoxifen 105 32 70 (5)

HER2+ letrozole 134 28 79 (4)

ABCSG 8 Trial

ABCSG 8 Trial : RFS

ABCSG 8 Trial : OS

The TEAM STUDY

TEAM Trial: revised design 2004

TEAM: DFS at 2.75 years (ITT)

TEAM: Time to Distant Metastases

DFS: On-Study Drug and Pre-Switch(96 never treatet pts excluded)

TEAM : conclusions

Sommario “Mustacchi”su HT adiuvante in menopausa (2008)

Argomento ormai abusato

AI > TAM sempre (ma non così tanto)

1 cp Tam 0.40 €; 1 cp AI 5.30 €

Possibili usi: – AI 5 anni (tutti), TAMAI (ANA,Exe), LETTAM (?)

Scelta: in base al profilo di tossicità e dati disponibili

Tam rimane accettabile scelta per basso rischio, cardiopatiche, etc etc

•Tante opzioni possibili = miglior “tayloring”•Se “Sequenziale +/- = Upfront”, meno tossicità (?) e ½ costo

That ‘s not the last song