Transcript Adjuvant Chemohormonal Therapy for Early Breast Carcinoma

SISSEJUHATUS
MOLEKULAARONKOLOOGIASSE
VAHUR VALVERE, MD, PhD
Onkoloogia õppetool
Kliinilise Meditsiini Instituut
MOLEKULAARMEDITSIINI DEFINITSIOON
• Molekularmeditsiin on arstiteaduse haru, mis
tegeleb molekulaartasandil haiguse
tekkepõhjuste ja patogeneesimehhanismide
uurimisega ning haiguste ennetamise-,
diagnostika- ja raviga
DIAGNOSTIKA TASANDID
•
•
•
•
Organi tasand
Koe tasand
Raku tasand
Molekulaartasand
RAKUTSÜKLI REGULATSIOON
Anti-growth factors
(e.g. TGFb)
Tubulin
WNT
Frizzled
Dishevelled
GSK-3b
TCF
APC
Cell
b-Cutenin
E-Cadherin
p16
CdC42
ECM
TGFbR
b-Cutenin:TCF
PI3K
Integrins
Rac
Cycl D:CDK+
Fak
Src
Cas
Rb
Growth factors (e.g. EGF,
amphiregulin TGFa)
Fyn
Shc
NF1
RTK
Grb2
SOS
Ras
p27
PKC
Mos
MKKs
Ral
MEK
MAPK
Survival factors
(e.g. IGF1)
G-Prol
JNKs
Ad Cycl
Rac
E2Fs
JUN
MAPK
ELK
Max:Max
MEKK
CdC42
7-TMR
Smads
HPVE7
PLC
Abl
GPCR ligands
Nuclear receptors
(e.g. oestrogen)
p15
Crk
Fos
Myc:Max
Cycl E:CDK2
Changes
in Gene
Expression
Cell
Proliferation
(cell cycle)
Surface
Ag
p21
DNA damage
sensor
p53
Rho
PKA
CREB
ARF
MDM2
Bax
NHR (e.g. ER)
PKC
RTK
P13K
Akt
NF-kB
Akka
NF-kB
Mitochondria
Stat 3.5
Bcl-2
Cell Death
(Apoptosis)
IKB
Caspase 8
FADD
Stat 3.5
?
PTEN
Caspase 9
Fap
Cytochrome C
Stat 3.5
Bcl XL
Bad
Jaks
Abnormality
sensor
Decoy R
Bcl-2
Mitochondria
Bid
Fas
Death
factors
(e.g. FasL)
Bim, etc.
Cytokine R
Cytokines
(e.g. ILs, IFNs)
Hanahan D, Weinberg RA. Cell 2000;100:57–70
ONKOLOOGIA MÕISTE
• Onkoloogia on õpetus kasvajatest((kreeka
keeles onkos=mass, kühm, kasvaja;
logos=õpetus)
• Onkoloogia on arstiteaduse haru, mis käsitleb
kasvajate põhjusi, tekkemehhanismi, liigitust,
diagnoosimist, ravi ja ennetust
ONKOLOOGIA JAOTUS
• Eksperimentaalne onkoloogia- tegeleb koe, raku
ja molekulaartasandil eeskätt vähi tekkepõhjuste ja
maligniseerumisprotsessi uurimisega; tegeleb
samuti uutele sihtmärkidele suunatud vähiravimite
väljatöötamisega
• Kliiniline onkoloogia- tegeleb eeskätt patsiendi kui
terviku tasandil vähi diagnoosimise, ravi ja
ennetustegevusega
MIS ON MOLEKULAARONKOLOOGIA?
• Molekulaaronkoloogia on täiesti uus
arstiteaduse haru, mis tegeleb
molekulaartasandil vähi tekkepõhjuste ja
malignisatsiooniprotsessi uurimisega ning vähi
preventsiooni-, diagnostika- ja raviga.
MOLEKULAARONKOLOOGIA RAKENDUSED
• Vähiriski hindamine (molekulaarepidemioloogia)
• Vähi molekulaarne diagnostika
• Molekulaarmarkerite kasutamine haiguse
prognoosi hindamisel ja võimaliku ravivastuse
prognoosimisel
• Molekulaarsetele sihtmärkidele suunatud
vähiravimite väljatöötamine
MOLEKULAARDIAGNOSTIKA UUED TEHNOLOOGIAD
RINNAVÄHI NÄITEL
21st century
19th century
1980s
2000
DNA arrays
SNP analysis
Multiplex PCR
Proteomics
Histology
Single-gene predictors
Multi-gene predictors
“MICROARRAY” EHK GEENIKIIPIDE TEHNOLOOGIA
• Simultaneous measurement of
several thousand genes in biological
specimens
• Number of human genes is around
30,000–40,000
 possible to monitor entire
genome in a tumor specimen
Genetic
probe
A technological
breakthrough in analysing
human tissues
mRNA
The chip is covered
with genetic probes.
The mRNA binds to
the probes that hold
complementary
sequences
GEENIKIIPIDE TEHNOLOOGIA KASUTAMINE
35
ER-positive
30
25
20
ER-negative
15
42 Training Cases Profiled on Affymetrix Arrays
10
BRCA2
5
BRCA1
0
FNA 155
FNA 157
FNA 158
FNA 139
FNA 128
FNA 106
FNA 135
FNA 117
FNA 123
FNA 165
FNA 171
FNA 177
FNA 181
FNA 182
FNA 188
FNA 189
FNA 108
FNA 153
FNA 154
FNA 156
FNA 102
FNA 111
FNA 126
FNA 133
FNA 113
FNA 136
FNA 130
FNA 180
FNA 159
FNA 116
FNA 186
FNA 161
Measure ER, HER2 and
other individual markers
Pusztai L, et al. Clin Cancer Res 2003
Predict response to
paclitaxel/FAC
preoperative chemotherapy
RD 156
RD 113
RD 214
RD 181
RD 201
RD 196
RD 158
RD 106
RD 128
RD 135
RD 117
RD 182
RD 139
RD 130
RD 186
RD 121
RD 154
RD 133
RD 220
RD 189
RD 188
RD 108
RD 155
pCR 123
RD 171
RD 157
pCR 161
pCR 176
pCR 159
pCR 116
pCR 177
pCR 165
pCR 179
pCR 212
pCR 211
pCR 206
RD 126
pCR 205
pCR 199
pCR 111
pCR 180
pCR 153
pCR 136
Pusztai L, et al. ASCO 2003
Detect existing markers
Screen for BRCA
Predict response to Tx
Novel molecular classes
Predict prognosis
Predicting survival of patients
with BC
Van’t Veer L, et al. Nature 2002
Grouping BC into luminal and
basal epithelial cell types
Sorlie/Perou, et al. PNAS 2001
GEENIKIIPIDE TEHNOLOOGIA KASUTAMINE
35
ER-positive
30
25
20
ER-negative
15
42 Training Cases Profiled on Affymetrix Arrays
10
BRCA2
5
BRCA1
0
FNA 155
FNA 157
FNA 158
FNA 139
FNA 128
FNA 106
FNA 135
FNA 117
FNA 123
FNA 165
FNA 171
FNA 177
FNA 181
FNA 182
FNA 188
FNA 189
FNA 108
FNA 153
FNA 154
FNA 156
FNA 102
FNA 111
FNA 126
FNA 133
FNA 113
FNA 136
FNA 130
FNA 180
FNA 159
FNA 116
FNA 186
FNA 161
Measure ER, HER2 and
other individual markers
Pusztai L, et al. Clin Cancer Res 2003
Predict response to
paclitaxel/FAC
preoperative chemotherapy
RD 156
RD 113
RD 214
RD 181
RD 201
RD 196
RD 158
RD 106
RD 128
RD 135
RD 117
RD 182
RD 139
RD 130
RD 186
RD 121
RD 154
RD 133
RD 220
RD 189
RD 188
RD 108
RD 155
pCR 123
RD 171
RD 157
pCR 161
pCR 176
pCR 159
pCR 116
pCR 177
pCR 165
pCR 179
pCR 212
pCR 211
pCR 206
RD 126
pCR 205
pCR 199
pCR 111
pCR 180
pCR 153
pCR 136
Pusztai L, et al. ASCO 2003
Detect existing markers
Screen for BRCA
Predict response to Tx
Novel molecular classes
Predict prognosis
Predicting survival of patients
with BC
Van’t Veer L, et al. Nature 2002
Grouping BC into luminal and
basal epithelial cell types
Sorlie/Perou, et al. PNAS 2001
SOBIVUS RINNAVÄHI HORMOONRAVIKS
Hormonal receptor status (ER/PgR by IHC)
ER+
ER–
40–60% response to
anti-oestrogen therapy
NO BENEFIT from
anti-oestrogen therapy
SOBIVUS RAVIKS TRASTUZUMAB’ga
HER2 status(determined by IHC, FISH or CISH)
FISH+
IHC+
Eligible for Trastuzumab
FISH–
IHC–
No benefit from Trastuzumab
GEENIKIIPIDE TEHNOLOOGIA KASUTAMINE
42 Training Cases Profiled on Affymetrix Arrays
35
ER-positive
30
25
20
ER-negative
15
10
BRCA2
5
BRCA1
0
FNA 155
FNA 157
FNA 158
FNA 139
FNA 128
FNA 106
FNA 135
FNA 117
FNA 123
FNA 165
FNA 171
FNA 177
FNA 181
FNA 182
FNA 188
FNA 189
FNA 108
FNA 153
FNA 154
FNA 156
FNA 102
FNA 111
FNA 126
FNA 133
FNA 113
FNA 136
FNA 130
FNA 180
FNA 159
FNA 116
FNA 186
FNA 161
Measure ER, HER2 and
other individual markers
Pusztai L, et al. ASCO 2003
RD 113
RD 214
RD 181
RD 201
RD 196
RD 158
RD 106
RD 128
RD 135
RD 117
RD 182
RD 139
RD 130
RD 186
RD 121
RD 154
RD 133
RD 220
RD 189
RD 188
RD 108
RD 155
pCR 123
RD 171
RD 157
pCR 161
pCR 176
pCR 159
pCR 116
pCR 177
pCR 165
pCR 179
pCR 212
pCR 211
RD 126
pCR 206
pCR 205
pCR 199
pCR 111
pCR 180
pCR 153
pCR 136
Predict response to
paclitaxel/FAC
preoperative chemotherapy
RD 156
Pusztai L, et al. Clin Cancer Res 2003
Detect existing markers
Screen for BRCA
Predict response to Tx
Novel molecular classes
Predict prognosis
Predicting survival of patients
with BC
Van’t Veer L, et al. Nature 2002
Grouping BC into luminal and
basal epithelial cell types
Sorlie/Perou, et al. PNAS 2001
PREDISPOSITSIOON RINNAVÄHILE
5–10%
BRCA1 (52%)
Teisd geenid(16%)
BRCA2 (32%)
Sporaadiline
Pärilik
Ford D, et al. Am J Hum Genet 1998;62:676–89
GEENIKIIPIDE TEHNOLOOGIA KASUTAMINE
42 Training Cases Profiled on Affymetrix Arrays
35
ER-positive
30
25
20
ER-negative
15
10
BRCA2
5
BRCA1
0
FNA 155
FNA 157
FNA 158
FNA 139
FNA 128
FNA 106
FNA 135
FNA 117
FNA 123
FNA 165
FNA 171
FNA 177
FNA 181
FNA 182
FNA 188
FNA 189
FNA 108
FNA 153
FNA 154
FNA 156
FNA 102
FNA 111
FNA 126
FNA 133
FNA 113
FNA 136
FNA 130
FNA 180
FNA 159
FNA 116
FNA 186
FNA 161
Measure ER, HER2 and
other individual markers
Pusztai L, et al. ASCO 2003
RD 113
RD 214
RD 181
RD 201
RD 196
RD 158
RD 106
RD 128
RD 135
RD 117
RD 182
RD 139
RD 130
RD 186
RD 121
RD 154
RD 133
RD 220
RD 189
RD 188
RD 108
RD 155
pCR 123
RD 171
RD 157
pCR 161
pCR 176
pCR 159
pCR 116
pCR 177
pCR 165
pCR 179
pCR 212
pCR 211
RD 126
pCR 206
pCR 205
pCR 199
pCR 111
pCR 180
pCR 153
pCR 136
Predict response to
paclitaxel/FAC
preoperative chemotherapy
RD 156
Pusztai L, et al. Clin Cancer Res 2003
Detect existing markers
Screen for BRCA
Predict response to Tx
Novel molecular classes
Predict prognosis
Predicting survival of patients
with BC
Van’t Veer L, et al. Nature 2002
Grouping BC into luminal and
basal epithelial cell types
Sorlie/Perou, et al. PNAS 2001
RINNAVÄHI MOLEKULAARNE KLASSIFIKATSIOON
ER–
Basallike
ER+
HER2
+++
Mostly grade 3
Basal
characteristics
 Keratin 5/6/14
ER: oestrogen receptor.
Luminal
A
Mostly
grade 1
Luminal
B
Luminal
C
Mostly grade 3
Luminal characteristics
 Keratin 8/18/19
RINNAVÄHI RAVI SÕLTUVALT
MOLEKULAARSEST ALATÜÜBIST
Subtype
Pts
%
Clinical Course
15–25 highly aggressive
(basal-like: HER 2-/
(visceral mets)
HT
Triple Negative
+++
NA
ER-/PgR-)
HER2+/ER-/PgR(HER2+)
HER2-/ER &/or
PgR+
CT
CDDP/
Carbo
+
Taksaa
n
Cetuximab+
Carbo
Avastin
Dasatinib?
8–10 highly aggressive
(visceral/CNS inv.)
NA +++ Herceptin
Lapatinib
30–38 indolent
(bone/soft tissue)
++
+
+
Hormone
ChemoR
x
15–24 aggressive
(visceral inv.)
++
++
Herceptin
Lapatinib
(luminal A)
HER2+/ER &/or
PgR+ (luminal B)
Targeted
Rx
GEENIKIIPIDE TEHNOLOOGIA KASUTAMINE
42 Training Cases Profiled on Affymetrix Arrays
35
ER-positive
30
25
20
ER-negative
15
10
BRCA2
5
BRCA1
0
FNA 155
FNA 157
FNA 158
FNA 139
FNA 128
FNA 106
FNA 135
FNA 117
FNA 123
FNA 165
FNA 171
FNA 177
FNA 181
FNA 182
FNA 188
FNA 189
FNA 108
FNA 153
FNA 154
FNA 156
FNA 102
FNA 111
FNA 126
FNA 133
FNA 113
FNA 136
FNA 130
FNA 180
FNA 159
FNA 116
FNA 186
FNA 161
Measure ER, HER2 and
other individual markers
Pusztai L, et al. ASCO 2003
RD 113
RD 214
RD 181
RD 201
RD 196
RD 158
RD 106
RD 128
RD 135
RD 117
RD 182
RD 139
RD 130
RD 186
RD 121
RD 154
RD 133
RD 220
RD 189
RD 188
RD 108
RD 155
pCR 123
RD 171
RD 157
pCR 161
pCR 176
pCR 159
pCR 116
pCR 177
pCR 165
pCR 179
pCR 212
pCR 211
RD 126
pCR 206
pCR 205
pCR 199
pCR 111
pCR 180
pCR 153
pCR 136
Predict response to
paclitaxel/FAC
preoperative chemotherapy
RD 156
Pusztai L, et al. Clin Cancer Res 2003
Detect existing markers
Screen for BRCA
Predict response to Tx
Novel molecular classes
Predict prognosis
Predicting survival of patients
with BC
Van’t Veer L, et al. Nature 2002
Grouping BC into luminal and
basal epithelial cell types
Sorlie/Perou, et al. PNAS 2001
KASVAJA GEENIEKSPRESSIOONI
PROFIIL MÄÄRAB PROGNOOSI
Geeniekspressiooni profiil määrab:
•
Haiguse lokaalse taastekke riski
•
Metastaseerumise riski
•
Ravimärklaudade olemasolu
•
Võimaliku ravivastuse
•
Elulemuse
van`t Veer, JCO 23: 1631, 2005
TSIRKULEERIVAD VÄHIRAKUD
• Peripheral blood epithelial cells shed from tumor
surface of cancer patients
– Defined by phenotypic characteristics
– Expression of cytokeratin or mucin markers such
as CK18, CK19, and MUC-1
• Phenotypically similar to primary and/or metastatic
tumour cells
Cell Search System
Fehm T, et al. Clin Cancer Res. 2002;8:2073-2084.
MOLEKULAARDIAGNOSTIKA JA RAVI
OPTIMEERIMINE
•
Molekulaarsed markerid haiguse prognoosi hindamiseks
•
Prognostilised molekulaarsed markerid spetsiifilise ravi suhtes
•
Prognostilisd markerid ravi toksilisuse suhtes
•
Raviskeemi ja ravidoosi optimeerimine vastavalt molekulaarsetele
markeritele
Muuta ravi efektiivsust, ohutust, elukvaliteeti ja hinna/kvaliteedi suhet
MOLEKULAARSETELE SIHTMÄRKIDELE SUUNATUD
EHK
INNOVATIIVNE VÄHIRAVI
INNOVATIIVSE VÄHIRAVI SIHTMÄRGID
Growth factor receptors
and signal transduction
Improved
genetic and
molecular
techniques
Tumour suppressor genes
and oncogenes
Angiogenesis
and metastasis
Apoptosis and
cell cycle control
Targets
Innovative
cancer
therapies
MOLEKULAARSETELE SIHTMÄRKIDELE
SUUNATUD UUED RAVIMID
Anti-HER2
MAbs TM
®
Herceptin , Omnitarg
Farnesyl-transferase
inhibitors
R115777, SCH66336,
BMS 214662
Tumour-activated
chemotherapy
®
Xeloda
HER signalling
Ras
signalling
HER tyrosinekinaseTM
inhibitors
Tarceva , gefitinib
TP
Apoptosis
VEGF
signalling
Anti-VEGF MAbs
TM
Avastin
Apoptotic agents
RINNAVÄHI TÜVIRAKKUDELE SUUNATUD RAVI
Normal stem cell
CSC
Dead CSC
Differentiated cell
Dead cell
Tumor
regrowth
Tumor shrinkage
CSC targeted
therapies
Conventional
therapies
Elimination
Elimination
of tumor
of CSCs
Differentiation
of CSCs
Elimination
of tumor
Korkaya H, et al. BioDrugs. 2007;21:299-310.
RINNANÄÄRME TÜVIRAKKUDE MALIIGNE
TRANSFORMATSIOON
Wnt/b-catenin
Notch, Hedgehog
Bmi-1
Self renewal
HER2
PI3-K/Akt
SC
SCSC
PTEN
Cancer stem cell
p53
SC
Mutations,
deregulation of pathways
Early progenitor cells
Cancer stem cell
ER+
Progenitor cells
Differentiation
Myoepithelial cells
Alveolar epithelial cells
Ductal epithelial cells
RINNAVÄHI TÜVIRAKKUDELE SUUNATUD RAVI
Normal stem cell
CSC
Dead CSC
Differentiated cell
Dead cell
Tumor
regrowth
Tumor shrinkage
CSC targeted
therapies
Conventional
therapies
Elimination
Elimination
of tumor
of CSCs
Differentiation
of CSCs
Elimination
of tumor
Korkaya H, et al. BioDrugs. 2007;21:299-310.
RINNAVÄHI DIAGNOSTIKA JA RAVI
TULEVIKUPERSPEKTIIV
Histological
confirmation,
ER, PR, HER2, Ki67
CURED
DIAGNOSIS
Serum is normal
Molecular subtype
Low risk
Risk of relapse
Gene signature:
High risk
- 70-gene MammaPrint
- 21-gene Oncotype DX
- 76-gene VDX2 array
NEOADJUVANT
CHEMOTHERAPY
New biomarkers
Standard CT
Optimal chemo
regimen
Clinical trial
S
U
R
G
E
R
Y
B
L
O
O
D
T
E
S
T
Serum is cancer-like
POSTOPERATIVE
THERAPY
Improved cure rates
RINNAVÄHK- JUHTIV VÄHIPAIGE NAISTEL
Maailmas:
1,150,000 esmajuhtu aastas
410,000 vähisurma aastas
Euroopas:
350,000 esmajuhtu aastas
130,000 vähisurma aastas
Eestis:
ca 600 esmajuhtu aastas
ca 250 vähisurma aastas
2000.a. hinnang. Globocan 2002. Ferlay et al, 2004.
RINNAVÄHI SUREMUSE
LANGUSTRENDID
Rinnavähi suremuse langus alates 1990
Annual mortality per
100,000 women ages 35-69
–33%
–10%
–25%
80 -
80 -
80 -
70 -
70 -
70 -
60 -
60 -
60 -
50 -
50 -
50 -
40 -
40 -
40 -
30 -
30 -
30 -
20 -
20 -
20 -
10 -
10 -
10 -
01950
01960
1970
1980
1990
2000
UK
Breast
Lung
2010
1950
01960
1970
1980
1990
2000
2010
1950
1960
1970
France
Colon & rectum
Uterus
1980
1990
USA
Stomach
2000
2010
RINNAVÄHI BIOLOOGIA
KASVAJA BIOLOOGILISE EHITUSE
MUUTUMINE
160 tumor blocks with adequate tissue:
– 115 (72%): no changes in ER/PR or HER2 status
• Of the 45 (28%) tumors with changes in receptor status:
– 11 went from ER/PR+ to ER/PR– 14 went from ER/PR- to ER/PR+
– 3 went from HER2- to HER2+
– 6 went from HER2+ to HER2-
Summary:
• Biopsies of relapsed/metastatic breast cancer should be performed
routinely because of changes in ER/PR or HER2 receptor status
MacFarlane R, et al. ASCO 2008. Abstract 1000.
KASVAJA TAASTEKKE RISK
The risk of relapse
diminishes with time
but never resolves
completely; hormone
receptor negative
and HER-2 positive
tumours tend to
relapse earlier and
hormone receptor
positive later
Jatoi I, et al. Breast Cancer Res Treat 89: 173, 2005
TSIRKULEERIVAD VÄHIRAKUD
• Peripheral blood epithelial cells shed from tumor
surface of cancer patients
– Defined by phenotypic characteristics
– Expression of cytokeratin or mucin markers such
as CK18, CK19, and MUC-1
• Phenotypically similar to primary and/or metastatic
tumour cells
Cell Search System
Fehm T, et al. Clin Cancer Res. 2002;8:2073-2084.
Probability of
Progression-Free Survival
TSIRKULEERIVATE VÄHIRAKKUDE
PROGNOSTILINE VÄÄRTUS
Log rank
P < .0001
100%
90%
< 5 CTCs / 7.5 mL
n = 90 (51%)
80%
70%
60%
21.9 months
50%
10.9
months
40%
30%
≥ 5 CTCs / 7.5 mL
n = 87 (49%)
20%
10%
0%
0
2
4
6
8
10 12 14 16 18
20 22 24 26 28 30
Time From Baseline (Months)
Cristofanilli M, et al. N Engl J Med. 2004;351:781-791.
TSIRKULEERIVATE VÄHIRAKKUDE PROGNOSTILINE
VÄÄRTUS RAVI AJAL
1
2
3
4
Probability of Survival
100%
90%
<5 CTCs at all time points
83 (47%)
38 (21%)
> 5 at baseline and < 5 CTC at last draw
< 5 at Early Draw and > 5 CTC at last draw 17 (10%)
> 5 CTCs at all time points
9 (22%)
1 vs 2 P = .3188
1 vs 3 P = .0014
1 vs 4 P < .0001
80%
70%
60%
50%
2
1
40%
2 vs 3 P = .0397
30%
20%
10%
0%
2 vs 4
3 vs 4
0
2
4
P < .0001
P = .0051
6
8
10
4
12 14
16 18
20 22 24 26
Time From Baseline (Months)
Cristofanilli M, et al. ASCO 2005. Abstract 524.
3
28
30
RINNAVÄHI DIAGNOSTIKA JA RAVI
TULEVIKUPERSPEKTIIV
Histological
confirmation,
ER, PR, HER2, Ki67
CURED
DIAGNOSIS
Serum is normal
Molecular subtype
Low risk
Risk of relapse
Gene signature:
High risk
- 70-gene MammaPrint
- 21-gene Oncotype DX
- 76-gene VDX2 array
NEOADJUVANT
CHEMOTHERAPY
New biomarkers
Standard CT
Optimal chemo
regimen
Clinical trial
S
U
R
G
E
R
Y
B
L
O
O
D
T
E
S
T
Serum is cancer-like
POSTOPERATIVE
THERAPY
Improved cure rates
METASTAATILISE
RINNAVÄHI
FARMAKOTERAAPIA
HETKESEIS
RINNAVÄHI FARMAKOTERAAPIA
KAASAEGSED VÕIMALUSED
KEMOTERAAPIA
HORMOONRAVI
Oral capecitabine, vincas,
taxanes, anthracyclines,
liposomal preparations,
nanoparticle preparations,
ixabepilone
Tamoxifen, AIs,
fulvestrant
BIOTERAAPIA
Trastuzumab, bevacizumab,
lapatinib, sunitinib,
KEMOTERAAPIA JA
BIOLOOGILISE RAVI ARENGUD
1970
•
1980
•
1990
•
2000
•
•
•
•
Enne antratsükliine
– CMFVP, CMF
Antratsükliinidega
– Kombinatsioonid (AC, CAF, FAC, EC, CEF,
FEC, CMF-A)
– Ravi intensiivistamine (HD-CT)
Taksaanid(DjaP) ja Vinorelbine
– Järjestikune kasutamine( AC D või P )
– Kombinatsioonid(AT, TAC, G+P, G+D, X+D)
Bioloogilised ravimid(MA + TKI)
– Trastuzumab ja Lapatinib
– Sunitinib
– Bevacizumab
Capecitabine
Liposomaalne doxorubicin
Ixabepilone
HORMOONRAVI ARENGUD
1970
• Antiöstrogeenid
– Tamoksifeen
1980
1990
• Mitte-selektiivsed aromataasi
inhibiitorid
– Aminoglutetemiid
• LHRH agonistid
– Gosereliin
• Selektiivsed aromataasi inhibiitorid
2000
– Mittesteroidsed (anastrosool, letrosool)
– Steroidsed (eksemestaan)
• “Puhtad” antiöstrogeenid
(fulvestrant)
ERINEVATE RAVISKEEMIDE
EFEKTIIVSUSE VÕRDLUS
•
•
•
•
•
•
•
•
•
•
•
•
Oral cCMF > IV CMF 1
Vinorelbine > melphalan 2
FAC > CMF 3
Docetaxel > mitomycin/vinblastine 4
AC or paclitaxel/trastuzumab > chemotherapy5
Doxorubicin/paclitaxel > FAC 6
Docetaxel/capecitabine > docetaxel 7
Doxorubicin/docetaxel > FAC 8
Docetaxel > paclitaxel 9
Docetaxel/trastuzumab > docetaxel 10
Docetaxel/doxorubicin > FAC11
Gemcitabine/ paclitaxel > paclitaxel12
1. Engelsman et al. Eur J Cancer 1991; 2. Jones et al. J Clin Oncol 1995; 3. Stewart et al. J Clin Oncol 1997;
4. Nabholtz et al. J Clin Oncol 1999; 5. Slamon et al. NEJM 2001; 6. Jassem et al. J Clin Oncol 2001;.
7. O’Shaughnessy et al. J Clin Oncol 2002; 8. Bontenbal et al. ECCO 2003; 9. Ravdin et al. ECCO 2003;
10. Extra et al. ECCO 2003; 11. Bontenbal et al J Clin Oncol 2005 12. K Albain ASCO 2004.
METASTAATILINE RINNAVÄHI RAVISTRATEEGIAD
Kemoteraapia
+/- Trastuzumab*
Hormoonravi
+/- Trastuzumab*
+/-Kiiritusravi
• Haiguse kiire
progressioon
• ER +
• Vistseraalsed
metastaasid
• ER +/-
• Pehmete kudede/luude
metastaasid
• Pikk retsidiivivaba
periood
• Hormooresistentne
kasvaja
• Indolentsed/aeglaselt
progresseeruvad kasvajad
* HER-2 +
(+/- bisfosfonaadid)
AEGLASELT PROGRESSEERUVA ER+ RINNAVÄHI
RAVIALGORITM
ER+
Endocrine 1
Endocrine 2
ER-
Chemo 1
Chemo 2
Chemo 3
Chemo 4
AGRESSIIVSE ER+ RINNAVÄHI RAVIALGORITM
Chemo 1
ER +ve
induction
Endocrine 1
maintenance
Chemo 2
Endocrine 2
Chemo 3
Chemo 4
RINNAVÄHI RAVI SÕLTUVALT
MOLEKULAARSEST ALATÜÜBIST
Subtype
Pts
%
Clinical Course
15–25 highly aggressive
(basal-like: HER 2-/
(visceral mets)
HT
Triple Negative
+++
NA
ER-/PgR-)
HER2+/ER-/PgR(HER2+)
HER2-/ER &/or
PgR+
CT
CDDP/
Carbo
+
Taksaa
n
Cetuximab+
Carbo
Avastin
Dasatinib?
8–10 highly aggressive
(visceral/CNS inv.)
NA +++ Herceptin
Lapatinib
30–38 indolent
(bone/soft tissue)
++
+
+
Hormone
ChemoR
x
15–24 aggressive
(visceral inv.)
++
++
Herceptin
Lapatinib
(luminal A)
HER2+/ER &/or
PgR+ (luminal B)
Targeted
Rx
HORMOONREFRAKTAARSE RINNAVÄHI
RETSIDIIVIDE RAVI
Adjuvant
Treatment
No Anthracycline
Anthracycline
Anthra+Taxanes
1st line
Anthracycline
Regimens
Anthracyclines +
taxanes
Weekly paclitaxel
Pac/Gemcitabine
Doc/Capecitabine
Pac/Bevacizumab
Capecitabine/
ixabepilone
Navelbine/
Gemcitabine
2nd line
Wkly taxanes
Pac/Gemcitabine
Doc/Capecitabine
Pac/Bevacizumab
Cape/ixabepilone
Navelbine/Gem
Cape/ixabepilone
Gemcitabine
Navelbine
Antimetabolite 2
Ixabepilone
3rd line
Cape/ixabepilone
Gemcitabine
Navelbine
Antimetabolite 2
Ixabepilone
Ixabepilone
4th line
Ixabepilone
Single agents may be preferable in HR+ tumors after several lines of endocrine agents
Rechallenge an option when TFI > 1yr
RCTs -yellow Phase II trials -red
UUED UURINGUD
San Antonio Breast Cancer
Symposium, Dec. 10-14, 2008
BCIRG 005: Study Design
HER2 normal
(FISH)
N= 3298
Stratification:
• Nodes:
1-3
4+
• HR+/• Center
4 x AC 4 x Docetaxel
60/600 mg/m2
R
Endpoints:
• Primary: DFS
• Secondary: OS, safety
100 mg/m2
6 x TAC
75 / 50 / 500 mg/m2
Dexamethasone premedication, 8 mg bid, 3 days
Prophylactic ciprofloxacin 500 mg bid, day 5-14
BCIRG 005: DFS
(Primary Endpoint)
1.0
0.9
78.9%
Disease free probability
0.8
78.6%
0.7
0.6
TAC
0.5
AC
T
Total
Patients
Events
1649
352
1649
356
3298
708
24
36
Logrank
p=0.98
HR = 1.002
(95% CI, 0.86-1.16)
0.4
0
12
48
Months
60
72
84
96
BCIRG 005: OS
(Secondary endpoint)
1.0
88.9%
0.9
88.1%
Survival probability
0.8
0.7
0.6
TAC
AC
0.5
T
Total
Patients
Events
1649
202
1649
187
3298
389
Logrank
p=0.37
HR = 0.91
(95% CI, 0.75-1.11)
0.4
0
12
24
36
48
Months
60
72
84
96
BCIRG 005:
Selected Adverse Events
TAC
n=1635
AC-T
n=1634
%
%
p-value
17.9
8.3
<0.0001
2.5
1.3
27.5
42.8
<0.0001
0.3
1.5
0.0004
Nail Changes (all grades)
22.1
44.5
<0.0001
Myalgia (all grades)
35.8
50.9
<0.0001
0.9
4.9
<0.0001
Arthralgia (Gr 3/4)
0.9
2.4
0.001
Fluid Retention (Gr 3/4)
1.3
2.8
0.011
0
1.8
<0.0001
Febrile neutropenia
Thrombocytopenia (Gr 3/4)
Neuropathy-Sensory (all grades)
Neuropathy-Sensory (Gr 3/4)
Myalgia (Gr 3/4)
Hand Foot Syndrome (Gr 3/4)
0.01
JÄRELDUSED
• HER2-negat. ja N+ patsientidel on retsidiivivaba
perioodi suhtes adjuvantne TAC(6 tsüklit)
ekvivalentne AC-T skeemiga(8 tsüklit)
• Võrreldes AC-T skeemiga TAC-ga kaasnes:
 Rohkem febriilset neutropeeniat ja kasvufaktori
kasutamist, aga mitte suuremat infektsioonide arvu
 Vähem sensoorset neuropaatiat, küünte muutusi,
müalgiat ja artralgiat
FinXX Design
R
D80
D80
D80
C600
A
N
n=
1,500
RT
E75
AI*/Tam
for 5yrs
F600
(ER +ve)
D
O
D60
D60
D60
RT
C600
M
Stratify:
-Center
-No. of +ve
nodes
-HER2 status
AI*/Tam
for 5yrs
E75
(ER +ve)
X900
X900
X900
X900
X900
X900
0
3
6
9
12
15
weeks
Xeloda dose: 900 mg/m2 twice daily, days 1–14, every 21
days
Recurrence-free survival
%
100
92.5%
80
88.9%
TX / CEX
T / CEF
60
40
HR = 0.66 (95% CI: 0.47 – 0.94)
20
P = 0.020
0
0
12
24
36
48
60 Months
Overall survival
%
95.6%
100
TX / CEX
94.9%
80
T / CEF
60
HR = 0.66 (95% CI: 0.40 – 1.07)
40
P = 0.089
20
0
0
12
24
36
48
60 Months
OLULISEMAD TOKSILISED REAKTSIOONID(gr. III-IV)
Event
Neutropenia
Amenorrhea
Fatigue
Infection with neutropenia
Hand-foot syndrome
Febrile neutropenia
Myalgia
Pain
Diarrhea
Nail changes
Infection, no neutropenia
Stomatitis
Dyspnea
Vomiting
T/CEF (%)
97.9
87.3
14.3
12.4
0.3
8.8
8.0
5.5
3.4
0.5
5.1
1.6
4.2
2.2
TX/CEX (%)
86.0
81.5
13.5
5.8
11.1
4.4
1.9
7.3
6.2
4.7
4.4
4.2
3.0
1.5
P
<0.0001
0.0025
0.79
<0.0001
<0.0001
0.0008
<0.0001
0.20
0.011
<0.0001
0.55
0.0048
0.26
0.44
*classified according to CTCAEv3.0
JÄRELDUSED
• TX/CEX pikendab statistiliselt retsidiivivaba
perioodi võrreldes T/CEF skeemiga vaatamata
madalamale Docetaxel’i doosile TX/CEX
skeemis
• TX/CEX põhjustab enam ravikatkestusi
võrreldes T/CEF skeemiga ja omab erinevat
toksiliste reaktsioonide profiili
1De
53
Laurentiis et al. J Clin Oncol. 2008;26:44-
NOAH: Phase III, open-label trial of neoadjuvant
Herceptin
HER2-positive LABC
(IHC 3+ or FISH+)
n=115
HER2-negative LABC
(IHC 0/1+)
n=113
n=99
H + AT
q3w x 3 cycles
AT
q3w x 3 cycles
AT
q3w x 3 cycles
H+T
q3w x 4 cycles
T
q3w x 4 cycles
T
q3w x 4 cycles
H q3w x 4 cycles
+ CMF q4w x 3 cycles
CMF
q4w x 3 cycles
CMF
q4w x 3 cycles
Surgery followed by
radiotherapya
Surgery followed by
radiotherapya
Surgery followed by
radiotherapya
H continued q3w
to Week 52
19 patients crossed
over to Herceptin
aHormone
receptor-positive patients will receive adjuvant tamoxifen
Event-free survival:
HER2-positive population
Probability1.00
, eventfree
survival 0.75
0.50
3-year
Events EFS HR
0.25
H + CTx
CTx
95% CI p valuea
70.1 0.56 0.36, 0.85 0.006
53.3
36
52
0.00
0
6
12
18
24
30
36
42
Months
Median follow-up = 3 years
aUnadjusted for stratification variables: adjusted HR=0.55, p=0.0062
Gianni et al, SABCS 2008
Overall survival:
HER2-positive population
Probability1.00
, overall
survival
0.75
0.50
0.25
Events
HR
95% CI
p value
17
22
0.65
0.34, 1.23
0.18
H + CTx
CTx
0.00
0
6
12
18
24
30
36
42
Months
Median follow-up = 3 years; data not yet mature
Gianni et al, SABCS 2008
JÄRELDUS
• Herceptin’i lisamine neoadjuvantravile ja
selle jätkamine operatsioonijärgses
adjuvantravis pikendab tõepäraselt
retsidiivivaba perioodi pikkust HER2positiivsete lokaalselt levinud rinnavähiga
patsientide grupis
VASTUSETA KÜSIMUSED
• Optimaalne ravi pikkus?
• Optimaalne Herceptin’i manustamise skeem?
– Järjestikune või paralleelne?
– Kas Herceptin’i peaks kasutama primaarse
süteemravina või adjuvandis?
• Kas uute ravimite kasutamine koos Herceptin’ga
võiks anda paremaid tulemusi?
RINNAVÄHI ONKOTERAAPIA VÕIMALUSED
2008 JA TAOTLUSED 2009
KEMOTERAAPIA JA BIOLOOGILISE
RAVI VÕIMALUSED 2008
1970

1980

1990

2000




Enne antratsükliine
– CMFVP, CMF
Antratsükliinidega
– Kombinatsioonid (AC, CAF, FAC, EC, CEF,
FEC, CMF-A)
– Ravi intensiivistamine (HD-CT)
Taksaanid(DjaP) ja Vinorelbine
– Järjestikune kasutamine( AC D või P )
– Kombinatsioonid(AT, TAC, G+P, G+D, X+D)
Bioloogilised ravimid(MA + TKI)
– Trastuzumab ja Lapatinib
– Sunitinib
– Bevacizumab
Capecitabine
Liposomaalne doxorubicin
Ixabepilone
HORMOONRAVI VÕIMALUSED 2008
1970

Antiöstrogeenid
– Tamoksifeen
1980
1990

Mitte-selektiivsed aromataasi
inhibiitorid
– Aminoglutetemiid

LHRH agonistid
– Gosereliin

2000
Selektiivsed aromataasi inhibiitorid
– Mittesteroidsed (anastrosool, letrosool)
– Steroidsed (eksemestaan)

“Puhtad” antiöstrogeenid
(fulvestrant)
RINNVÄHI KOMPLEKSHIND
(kood 314 R)
Hetkel rinnavähi komplekshind- 17 779. Onkoteraapia Ühingu(Dr.Padrik) uus taotlus23 911. Uus taotlus peaks katma

- taksaanid adjuvantravis(aluseks TAC-skeem)
- Bevacizumab + taksaanid metastaatilise
rinnavähi ravis(aluseks Paclitaxel + Avastin skeem)
- Taxotere + Xeloda kombinatsioon metastaatilise
rinnavähi ravis
PACLITAXEL + BEVACIZUMAB
(Ravivastus)
Paclitaxel
p<0.0001
Overall response rate
40
28.2%
30
20
14.2%
10
316
0
330
All patients
Paclitaxel + bevacizumab
Progression-free survival proportion
PACLITAXEL + BEVACIZUMAB
(Progressioonivaba perioodi pikkus)
1.0
Paclitaxel + bevacizumab: 10.97 months
0.9
Paclitaxel:
6.11 months
0.8
0.7
0.6
Hazard ratio = 0.498 (0.401–0.618)
Log rank test p<0.001
0.5
0.4
0.3
0.2
0.1
0
6.11
0
10.97
10
Months
20
30
PACLITAXEL + BEVACIZUMAB
(Üldine elulemus)
1.0
Paclitaxel + bevacizumab
0.9
Paclitaxel
OS Proportion
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Hazard ratio = 0.674 (0.495–0.917)
Log rank test p=0.01
0.1
0
0
10
20 Months
30
40
ALBERT EINSTEIN
“Intellektuaalid tegelevad probleemide
lahendamisega, geeniused aga probleemide
ennetamisega”