Date post: | 01-May-2015 |
Category: |
Documents |
Upload: | enrico-nardi |
View: | 218 times |
Download: | 0 times |
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