Download models of systemic treatment in breast cancer

MODELS OF SYSTEMIC
TREATMENT IN BREAST CANCER
EMRA against cancer 1st Forum
“NGOs and cancer: Challenges and opportunities”
Marrakech, 18 - 19 June 2010
Introduction
•
Breast cancer: most common malignancy in
women .
•
Advances in clinical and translationnel
research.
•
Systemic treatment: chemotherapy, targeted
therapy, endocrine therapy
 Survival improvement
Peto Meta analysis
Peto et al, SABCS 2007
INO Recruitement: 1985 - 2006
1200
1000
800
600
400
200
Sein
Col
Poumon
Colo-rectum
20
06
20
05
20
04
20
03
20
02
20
01
20
00
19
99
19
97
19
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93
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87
19
85
0
Cavum
Breast cancer treatment

Loco-regional:
Surgery
Radiotherapy

Systemic:
 Chemotherapy
 Endocrine
therapy
 Targeted therapy
Personalize Medicine:
Right Drug to the Right Patient
Chan
ging Portraits
Concept
evolution
claudin low
Lum A Lum B Basal Her2
Biology as the Framework for
Progress
Clinical
Characteristics
Biology
Pathology
Treatment improvement
Indications of systemic
treatment
Adjuvant setting
Primary systemic therapy
Palliative chemotherapy
ADJUVANT SETTING
Adjuvant chemotherapy
Goals

Post operative

Against micrometastasic spread

Aim : Improve survival
Adjuvant chemotherapy:
Active drugs
•
•
•
•
•
Methotrexate
5 FU
Cyclophosphamide
Anthracyclines
Taxanes (paclitaxel, docetaxel)
Adjuvant chemotherapy:
Regimens
 6 FAC
 6 FEC
 4 AC 60
 4 TC
 3 FEC+ 3 Docetaxel
 4AC 60 + 12 Paclitaxel
Adjuvant Treatment and Survival
Improvement Over Past 40 Years
Peto metanalysis
EBCTCG up date 2007
Taxanes > anthra > CMF > No chemotherapy
Breast cancer mortality
50
10-y gain 4.3% (SE 1.0)
Lorank 2p < 0.00001
10-y gain 4.3% (SE 1.0)
Lorank 2p < 0.00003
Control
36.4%
40
10-y gain 5.1% (SE 1.6)
Lorank 2p < 0.00001
CMF
31.3%
Anthr.
31.0%
30
20.5
20
%
+ SE
CMF
32.2%
19.9
17.8
16.5
Anthr.
27.0%
15.3
12.8
10
Years
Years
Taxane
25.9%
Years
0
0
5
10
0
5
10
0
5
10
Peto et al, SABCS 2007
Role of taxanes:
Docetaxel Meta-analysis: Trials
Study
Nodes
GEICAM 9805
N0
ECOG 2197
N0/ N+ ≤3
USO 9735
No. Pts Regimen
1060
F/U (yr)
TAC vs FAC
5
1893/989
AT vs AC
5
N0/N+
487/529
TC vs AC
7
UK TACT
N0/N+
835/3327
FEC-T vs FEC/E-CMF
5
RAPP-01
N0/N+ ≤3
627
AT vs AC
5
FinHer
N+ (89%)
1010
T-FEC vs V-FEC
5
BCIRG001
N+
1491
TAC vs FAC
TAXIT 216
N+
972
E-T-CMF vs E-CMF
5
PACS01
N+
1999
FEC-T vs FEC
5
BIG2-98, TAX315
N+
2887
A-T (AT)-CMF vs A(C)-CMF
5
WSG/AGO
N+ ≤3
1837
EC-T vs FEC
5
HORG
N+
756
T-EC vs FEC
5
20,698 Patients
4.5
Laporte S, et al. SABCS 2009..
Docetaxel Meta-Analysis: DFS and OS
According to Nodal Status
• Overall, the pooled HR estimate [95% CI] for DFS was 0.82 [0.75;0.89]
(P<0.001) in favor of docetaxel-based chemotherapy
• The overall estimated HR for OS was 0.82 [0.74;0.91] (P<0.001)
Laporte S, et al. SABCS 2009.
Worldwide Overview: Chemotherapy vs no
chemotherapy, by age &ER, ratio of recurrence
rates in years 0-4
Age
ER-poor
ER+
<50
0.57 (0.07)
0.51 (0.06)
50-59
0.65 (0.07)
0.75 (0.05)
60-69
0.78 ( 0.08)
0.81 (0.05)
Peto et al, SABCS 2007
In summary
•
Adjuvant chemotherapy: Survival benefit in node
positive and negative breast cancer
•
Anthracyclines based regimen.
•
Anthracyclines + Taxanes
• Node positif
• High risk node negatif (SBRIII, RH-, LVI, Her3+..)
Targeted therapy

Trastuzumab.

HER2 over expressing tumor.

Duration : 1 year.
Trastuzumab trials
Rôle des sécrétions hormonales dans la prolifération
therapy
tumorale etEndocrine
site d’action des
Tt anti hormonaux
Aromatase inhibitors
Hypothalamus
LHRH
Antagonist
Adrenal gland
breast
Fat
TAMOXIFEN
H
Hypophyse
FULVESTRANT
RH
FSH
LH
Cancerous cell
Ovary
CASTRATION
Endocrine therapy: in summary
 RH:
positive (≥1%)
 Premenopausal
 Post
women : Tamoxifen
menopausal women: Aromatase
inhibitors
5
years
Indications

Prognostic factors

Predictive factors
First « generation » factors





Age
Grade
Histological type
RE/RP, HER2
Vascular invasion
« 2d generation » factors
•Proliferation index
• UPA, PAI-1
• Micrometastasis
•Alpha II Topoisomerase
« 3d generation » factors:
Multigenic signatures:
Oncotype Dx
Mammaprint
Genomic grade
T
N
M
Indications: adjuvant chemotherapy
Anthracycline regimens: all patients
Anthracyclines + Taxanes
o Node positif
o High risk node negatif (SBRIII, RH-, LVI, Her3+..)
o
Trastuzumab: Her 2 neu +++:
HR +: endocrine therapy (pre vs post-menopausal)
Indications : Consensus conferences
•
NCCN 2010
•
St Gallen 2009
•
St Paul de vence
Goldhirsch, Ann Oncol 2009
Primary systemic Therapy
Primary systemic Therapy:
Goals
• Induction therapy, preoperative systemic therapy, neo-adjuvant
chemotherapy.
• Down staging
• Breast-conservative surgery
• Treat early micro metastases
• Study of predictive factors
• Assess chemo sensitivity
Primary systemic therapy: anthracyclines
NSABP B-18 , N: 1,523
Wolmark NSABP B18 , JNCI 2001
NSABP B18 update ( 2007)
Tumor response
Overall Survival
Nodal response
Disease Free Survival
NSABP B18 update ( 2007)
DFS and pCR
OS and pCR
OS and PFS benefit correlated to pCR
Wolmark, NCI Meeting March 2007
Taxanes: neo-adjuvant setting
•
Slide Aberdeen trial
Aberdeen, TAX 301
Taxanes: neo-adjuvant setting
Pathologic Complete Responses
% pCR
CVAP x 4
-->
34
Doc x 4
16
CVAP x 8
0
10
20
30
40
Aberdeen, TAX 301
Taxanes: neo-adjuvant setting
Pathologic Complete Responses
Disease Free Survival
Overall Survival
1.0
Follow Up medio: 104 Settimane
( Range 13 - 187)
% Libere da Malattia
Risposta iniziale 
Randomizzate a
Docetaxel
p=0.022
Risposta iniziale 
Randomizzate a CVAP
Survival probability
docetaxel
.9
Docetaxel  DFS and OS
CVAP
.8
Log Rank Test
Nessuna Risposta
iniziale  Trattate tutte
con Docetaxel
Tempo (settimane)
p=0.05
.7
0
10
20
30
40
time (months)
50
Smith, JCO 2002
Hutcheon, 3rd EBCC 2002
60
SCHEDULES
• Sequentiel anthracyclines and Taxanes.
• Increase rate of pCR / successful breast conservation
surgery / node negative patients by 50%.
• Trastuzumab is indicated for Her 2-neu +++ patients, to
be continued in adjuvant setting .
For whom?
• Inoperable breast cancer:
o Inflammatory breast cancer.
o Locally advanced breast cancer (T4Nx, TxN2-3)
• Operable breast cancer:
o Conservative surgery
METASTATIC SETTING
METASTATIC SETTING
•
Goals of therapy in MBC:
– Improve survival
– Delay time to disease progression
– Palliate symptoms
SCHEDULES

Monochemotherapy :










Doxorubicin
Epirubicin
Liposomal Doxorubicin
Paclitaxel
Docetaxel
Gemcitabine
Vinorelbine
Capecitabine
Cisplatine
Carboplatin
• Targeted therapy
•Trastuzumab
•Lapatinib
•Bevacizumab
Monochemotherapy:
Fumoleau IGR 2006
Targeted therapy
SCHEDULES
• Polychemotherapy (Her2 neu -):
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
FAC
FEC
AC 60
AT
AP
Docetaxel + capécitabine
Paclitaxel + gemcitabine
Docetaxel + gemcitabine
Capecitabine + Vinorelbine
Capecitabine + Vinorelbine
Ixabepilone + Capécitabine
Bevacizumab + Paclitaxel
Etoposide + Cisplatine
Gemcitabine + Cisplatine
Gemcitabine + Oxaliplatine
Paclitaxel + Carboplatine
Polychemotherapy versus
monochemotherapy: Meta-analysis
Fossati JCO 1998
Polychemotherapy = sequentiel
monochemotherapy
ECOG 1193, Sledge 2003
SCHEDULES in Her2 neu positive disease
Trastuzumab + Docetaxel
 Trastuzumab + Paclitaxel
 Trastuzumab + Vinorelbine
 Trastuzumab + Capécitabine
 Lapatinib + Capécitabine

Trastuzumab in Her2 neu positive disease
prognosis
Trastuzumab in Her2 positive disease = Her 2-
Endocrine therapy

Premenopausel women:



Tamoxifene + castration
Adjuvant Tamoxifene : no standard, recommendation : ovarien
ablation± AI
Menopausel women:

Not pretreated by AI:




Standard : 3d generation AI (anastrozole, létrozole)
Exemestane
Option : fulvestrant
Pretreated by non stéroïdiens AI


No standard
Option : Fulvestrant, Exemestane, Tamoxifene
INDICATIONS

According to :

Hormonal status

Her2 status

Disease agressiveness:

Agressive disease : symptomatic disease, multiple metastatic
sites, visceral metastases, high tumor burden, relapse interval<
2years

Non agressive disease : asymptomatic, relapse interval >
2years (5years ?), low tumor burden, few metastatic sites, slow
evolutive disease
Treatment criteria choice
Prognostic factors
Favorable
Unfavorable
PS
Good
poor
Sites of disease
Bone, soft, tissue
Viscera
N°sites disease
Oligo
Multiple
HR status
Positive
Negative
Her-2/Neu
Negative
Positive
Disease free interval
>2 years
< 2 years
Prior adjuvant therapy
NO
Yes
Prior therapy MBC
NO
YES
Beslija, Ann oncol 2007
In summary
Her2+
Agressive
Non agressive
Her2Agressive
Non
agressive
Hormono
RH+
Trastuzumab Trastuzumab +
+ CT
Hormono
PolyCT
RH-
Trastuzumab
+ CT
PolyCT
Trastuzumab
+/- CT
Sequentiel
MonoCT,
PolyCT?
Conclusion
Many therapeutic options  real survival
improvement
Area of targeted therapy and molecular
profiling: right drug to the right patient
Morrocco: recommendations in accordance
with literature
Morrocan chemotherapy guide
Chimiothérapie adjuvante (60% des patients):
Pour les patientes Her 2-neu - :
3cycles de FEC (Epirubicine 100mg/m2, 5 Fluorouracile 500mg/m2,
cyclophosphamide 500mg/m2) + 3 cycles de docétaxel 100mg/m2
Pour les patientes Her 2-neu + (20% des cas):
3cycles de FEC (Epirubicine 100mg/m2, 5 Fluorouracile 500mg/m2,
cyclophosphamide 500mg/m2) + 3 cycles de docétaxel 100mg/m2
+ Trastuzumab 8mg/Kg puis 6mg/Kg (tous les 21 jours), pendant une année
Chimiothérapie de première ligne métastatique (40% des patients):
Moyens multiples: chimiothérapie, hormonothérapie, thérapeutiques ciblées
Monochimiothérapie versus polychimiothérapie ?
Indication dépend de plusieurs facteurs :
Age, co-morbidités (OMS), vécu et préférence du patient
Niveau d’agressivité de la tumeur : volume tumoral, nombre de sites
métastatiques, présence d’envahissement viscéral, cinétique tumorale,
intervalle libre de rechute.
Profil biologique de la tumeur : RH et Her 2 +++
Expositions aux thérapeutiques antérieures (adjuvant ou néo-adjuvant)
Difficile d’élaborer un seul protocole
Chimiothérapie de première ligne métastatique (40% des patients):
On distingue les patientes HER 2 +++ (20% des patientes):
Patientes ayant déjà reçu taxanes : Trastuzumab 8mg/Kg puis 6mg/Kg (tous
les 21 jours) + vinorelbine 25mg/m2 j1j8 (tous les 21 jours)
Patientes n'ayant pas reçu de taxanes: Trastuzumab 8mg/Kg puis 6mg/Kg +
docetaxel 100mg/m2 J1 (tous les 21 jours)
Chimiothérapie de première ligne métastatique (40% des patients):
Pour les patientes Her2-:
Patientes n’ayant reçu ni taxanes ni anthracyclines:
Si Monochimiothérapie : Doxorubicine, Docetaxel
Si polychimiothérapie :
AT : Doxorubicine + Docetaxel
Ou séquentiel programmé : 4 FEC + 4 Docetaxel
Patientes n'ayant pas reçu de taxanes (pré-traitées par anthracyclines) :
Si Monochimiothérapie : Docetaxel
Si polychimiothérapie : Docetaxel + capécitabine
Patientes ayant déjà reçu anthracyclines et taxanes:
Si Monochimiothérapie : Vinorelbine ou Capécitabine
Si polychimiothérapie : Capécitabine + Vinorelbine