Download - The Breast Course Breast Cancer: Biologicals New Paradigms ---------------------------------
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The Breast CourseThe Breast Course
Breast Cancer: Breast Cancer: BiologicalsBiologicals
New ParadigmsNew Paradigms
------------------------------------------------------------------ Joseph RagazJoseph Ragaz, , DirectorDirector, , Oncology Oncology
Program McGill University Hospital Program McGill University Hospital Center Center
May 5 2006May 5 2006
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The 1979 – 2000 BrCa Mortality Trends: UK, USA, Canada
J.Ragaz, A.Coldman, ASCO 2005J.Ragaz, A.Coldman, ASCO 2005
60
70
80
90
100
110
120
1979 1984 1989 1994 1999 2004
Year
Rate
(%
)
BC
ON
PQ
Canada
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Breast Cancer: Mortality Breast Cancer: Mortality ReductionReduction
Education & screening & downstaging Education & screening & downstaging Endocrine (Tamoxifen & AIs)Endocrine (Tamoxifen & AIs)ChemotherapyChemotherapyRadiotherapyRadiotherapy
Can we cure more Can we cure more pts?pts?
Molecular Biology
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Breast Cancer: Breast Cancer: Targeted Targeted TherapyTherapy
Tumor Biology Tumor Biology BiologicalsBiologicals
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Genesis of Human Breast Genesis of Human Breast Ca:Ca:
Genes & Genetic markersGenes & Genetic markers
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Targeted TherapyTargeted Therapy
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Her-2/Her-2/NeuNeu
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erb-b1EGFRHER1
Erb-Erb-b2b2HER2/NeuHER2/Neu
Erb-b3HER3
Erb-b4HER4
TG
F
EG
F
HR
G(N
RG
1)
Ep
i
-ce
l
HB
-E
GF
Am
p
Ep
i
HB
-GF
NR
G1
NR
G2
NR
G3
NRG4
Tyrosinekinase
domain
Ligandbindingdomain
Transmembrane
Mendelsohn and Baselga. Oncogene. 2000;19:6550.Olayioye et al. EMBO J. 2000;19:3159.Prigent and Lemoine. Prog Growth Factor Res. 1992;4:1.Harari and Yarden. Oncogene. 2000;19:6102.Earp et al. Breast Cancer Res Treat. 1995;35:115.
The EGFR/HER FamilyThe EGFR/HER Family
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Her2/Neu and Breast Her2/Neu and Breast CancerCancer
Benign epithelial cellsBenign epithelial cells: 20,000 Her2 : 20,000 Her2 ReceptorsReceptors
Her2+ve BrCa cells:Her2+ve BrCa cells: 2 million2 million Her2 Her2 ReceptorsReceptors
Her2/NeuHer2/Neu expressionexpression
Breast Cancer, overall: Breast Cancer, overall: 20 – 20 – 25%25%
High Grade DCIS: High Grade DCIS: 60 - 70%60 - 70%
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Slamon et al, 1987Slamon et al, 1987
Shortened Median Shortened Median SurvivalSurvival
HER 2/Neu +ve: 3 yrsHER 2/Neu -ve 6 - 7 yrs
Her2/Neu and Breast Her2/Neu and Breast CancerCancer
HER2 protein HER2 protein OverexpressionOverexpression
HER2 geneHER2 geneAmplificationAmplification
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HER2 Protein Overexpression HER2 Protein Overexpression Associated with Poor Prognosis and Associated with Poor Prognosis and
Shortened SurvivalShortened Survival
HER2 overexpression: HER2 overexpression:
ER negative statusER negative statusHigh S-phase fraction High S-phase fraction Positive nodal statusPositive nodal statusMutated p53Mutated p53High nuclear gradeHigh nuclear grade
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HER / NEU stainingHER / NEU staining
Protein Protein expressionexpression
IHC: IHC: 1+ or 2+ or 1+ or 2+ or 3+3+
Gene Copy: Gene Copy: FISH +ve or -veFISH +ve or -ve
CISH +ve or -veCISH +ve or -ve
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Herceptin: HumanizedHerceptin: Humanized Anti-HER2 Antibody Anti-HER2 Antibody
Targets HER2 Targets HER2 oncoproteinoncoprotein
High affinity (KHigh affinity (Kdd = 0.1 = 0.1 nM) and specificitynM) and specificity
95% human, 5% murine95% human, 5% murine Decrease potential for Decrease potential for
immunogenicityimmunogenicity Increase potential for Increase potential for
recruiting immune-effector recruiting immune-effector mechanismsmechanisms
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Herceptin:Herceptin:Mode of ActionMode of Action
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Herceptin and Herceptin and ChemotherapyChemotherapy
Additive effectAdditive effectSynergistic effectSynergistic effect
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Herceptin (Trastuzumab)Herceptin (Trastuzumab) st. st. IV : IV : Response only in Response only in
Her2+ve casesHer2+ve cases Slamon et.al. , NEJM, Slamon et.al. , NEJM,
2001:2001: significant benefit significant benefit of Herceptin added to of Herceptin added to Taxol (Paclitaxel) in Taxol (Paclitaxel) in stage IV disease…stage IV disease…
QUESTION:QUESTION: Cost Cost benefit? benefit?
Adjuvant Adjuvant studiesstudies (NSABP, (NSABP, BCIRG, HERA)…BCIRG, HERA)…
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Adjuvant Trastuzumab TrialsNSABP B-NSABP B-
3131
NCCTG 9831
H…x 52
H…x 52
H…x 52
H…x 52
H…x 52
BCIRG 006BCIRG 006
H…x 1 years
H…x 2 years
No therapy
StandardChemo Rx
HERA
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NSABP B-31
NCCTG N9831
Arm 1Arm 2
Arm A
Arm B
Arm C
= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4= paclitaxel (T) 175 mg/m2 q 3 wk x 4= paclitaxel (T) 80 mg/m2/wk x 12= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51
Control: ACT
Investigational: ACT+H
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NSABP B-31: Herceptin NSABP B-31: Herceptin trial. Her2/Neu +ve casestrial. Her2/Neu +ve cases
ARM 1: AC – TaxolARM 1: AC – Taxol ARM 2: AC – Taxol + Herceptin x 1 ARM 2: AC – Taxol + Herceptin x 1
year year
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Herceptin Adjuvant trials: NSABP B-31 & NCCTG N9831, NEJM, Oct
2005 ARMS: AC-T AC-T+ H* HR p------------------------------------------------------------------• 4 DFS%: 85% 67% 0.48
p<.00001
• 4 OS%: 0.67 0.015
• CHF: 1% 4%*• < 50 vs >50 years: (2 vs
5.5%) , CHF: most reversible
* H=Herceptin
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Impact of Adjuvant Impact of Adjuvant Herceptin,Herceptin, DFS, DFS, NSABP-NCTCG analyses, NEJM Oct 2005NSABP-NCTCG analyses, NEJM Oct 2005
87%87% 8585%%
6767%
75%
AC-Taxol alone %
HR=0.48 2P=<0.000001
ACACTaxol - HerceptinTaxol - Herceptin
ACT
Years From Randomization
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Targeting “Targeted Therapy”
• Can we identify subsets who will benefit (from Herceptin) much more, and those who will benefit much less…
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HerceptinSensitivity Resistance(PTEN expression) (PTEN loss)
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Herceptin Response vs PTEN
RR% to Herceptin
• All pts (Her2+ve) N: 47 35-50%
-------------------------------------------------------------------
• High PTEN (30 pts): 65%
• Loss of PTEN: (17 pts): 10%
p = <0.01
* Nagata Y, et.al., Cancer Cell, Aug. 2004, 6: 117-127
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• Role of c-Myc
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NSABP B 31: Herceptin NSABP B 31: Herceptin subanalysis according to cMyc, subanalysis according to cMyc, S. Paik et.al.S. Paik et.al.
1736 Her2+ve pts had 1736 Her2+ve pts had cMyc analysiscMyc analysis
432 (432 (3030%%)) were were Her2 + cMyc +ve
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NSABP B-31, according NSABP B-31, according to to cMyccMyc: : all are Her2+veall are Her2+ve 432 pts432 pts================================================ Recurrences:Recurrences: RR RR
ALL: 0.48ALL: 0.48--------------------------------------------------------------------------------------cMyc-: cMyc-: 0.630.63 cMyc+: cMyc+: 0.23 0.23
------------------------------------------------------------------------------------
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NSABP B-31, according NSABP B-31, according to to cMyccMyc: : all are Her2+veall are Her2+ve
cMyc-cMyc- cMyc+cMyc+ p p
1,078 4321,078 432
================================================ Deaths:Deaths: 0.99 0.99 0.360.36 0.037 0.037
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San Antonio 2005San Antonio 2005
DCIS and Her2/Neu expression
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Adjuvant Trastuzumab TrialsNSABP B-NSABP B-3131
NCCTG 9831
H…x 52
H…x 52
H…x 52
H…x 52
H…x 52
BCIRG 006BCIRG 006
H…x 1 years
H…x 2 years
No therapy
StandardChemo Rx
HERA
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4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
6 x Docetaxel and Carboplatin75 mg/m2 AUC 6
1 Year Trastuzumab
N=3,222
1 Year Trastuzumab
ACTax
ACTaxHerceptin
TaxCarboHerceptin
Her2+(Central FISH)
N+or high risk N-
4 x AC60/600 mg/m2
4 x Docetaxel100 mg/m2
Slamon D., SABCS 2005
BCIRG 006: Adj. BCIRG 006: Adj.
Stratified by Nodes and Hormonal Receptor Status
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Disease Free SurvivalDisease Free Survival%
Dis
ea
se F
ree
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5
Year from randomization
77%
86%
80%
73%
84%
80%86%
93%
91%
Patients Events
1073 147 AC->T No Herceptin1074 77 AC->TH
1075 98 TCHHR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001
HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002
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CARDIAC TOXICITYCARDIAC TOXICITY
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Clinically significant cardiac Clinically significant cardiac eventsevents
as per independent review panelas per independent review panel
P = 0.016 P = 0.11
P = 0.54
AC-TAC-T
n=1,050n=1,050AC-THAC-TH
n=1,068n=1,068TCHTCH
n=1,056n=1,056
PatientsPatients 1010 2525 1414
%%
(95% C.I.)(95% C.I.)0.95%0.95%
(0.46% - (0.46% - 1.74%)1.74%)
2.34%2.34%
(1.52% - (1.52% - 3.44%)3.44%)
1.33%1.33%
(0.73% - (0.73% - 2.21%)2.21%)
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HER2 and TOPO II in BCIRG 0062120 of 3222 patients analyzed
HER2Core region
17 q 12 17 q 21.1 17 q 21.2
1285 pts (60%)
N=2120
91 pts (4%)
Topo IINonCo-Amplified
Normal Amplified Deletion
TOPO II region
744 pts (35%)Co-Amplified
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DFS according to Topo DFS according to Topo IIII
Patients Events Topo II
744 57 Co-Amplified1376 191 Non Co-amplified
% D
isease Free
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5Year from randomization
Logrank P<0.001
Co-Amplified
Non Co-amplified
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Topo II and Human Topo II and Human BrCaBrCa
Topo II is the target for Topo II is the target for anthracyclinesanthracyclines
Topo II is associated with inferior Topo II is associated with inferior outcomeoutcome
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DFS according to Topo II: Topo II +ve
% D
ise
ase
Fre
e
Months
0.5
0.6
0.8
1.0
0 6 12 18 24 30 36 42 48 54
Patients Events Treatment
227 23 AC->T
265 13 AC->TH252 21 TCH
Logrank P= 0.24
TCH
AC->TH
AC->T
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DFS according to Topo II: Topo II - ve
% D
ise
ase
Fre
e
Months
0.0
0.6
0.8
1.0
0 6 12 18 24 30 36 42 48 54
Patients Events Treatment
458 92 AC->T472 45 AC->TH446 54 TCH
Logrank P= <0.001
TCHAC->TH
AC->T
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Conclusion: Outcome Conclusion: Outcome according to Topo IIaccording to Topo II
Among Topo II+ve (35% case): Among Topo II+ve (35% case): Herceptin + Carbo Tax is Herceptin + Carbo Tax is inferior inferior toto Herceptin + Anththracyclines Herceptin + Anththracyclines
Among Topo II-ve (65% cases):Among Topo II-ve (65% cases): Herceptin + Carbo Tax is Herceptin + Carbo Tax is samesame
as Herceptin + Anththracyclinesas Herceptin + Anththracyclines
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Might 9 weeks of Might 9 weeks of Herceptin be enough?Herceptin be enough?
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Might 9 weeks of Herceptin Might 9 weeks of Herceptin be enough?be enough? H. Joensuu, et.al., Helsinki, H. Joensuu, et.al., Helsinki,
Abstr. #2Abstr. #2
1010 stage I-II BrCa, T>2 cm, Her2+ve1010 stage I-II BrCa, T>2 cm, Her2+ve11stst Randomization: Randomization:
ARM 1: Docetaxel 100 mg/m2 x 3 wks x 3 over 9 ARM 1: Docetaxel 100 mg/m2 x 3 wks x 3 over 9 wks followed by CEF x 3 (Cwks followed by CEF x 3 (C600600EE6060FF600600) )
ARM 2: NavelbineARM 2: Navelbine 25 25 mg/m2 weekly x 8 over 9 mg/m2 weekly x 8 over 9 weeks followed by CEF x 3 (Cweeks followed by CEF x 3 (C600600EE6060FF600600) )
22ndnd Randomization (232 CISH +ve pts): Randomization (232 CISH +ve pts):
ARM1: ARM1: HerceptinHerceptin weekly x 9 weeks weekly x 9 weeks ARM 2: ARM 2: No HerceptinNo Herceptin
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Might 9 weeks of Herceptin Might 9 weeks of Herceptin be enough?be enough? H. Joensuu, et.al., Helsinki, H. Joensuu, et.al., Helsinki,
Abstr. #2Abstr. #2
Herceptin vs notHerceptin vs not
HR pHR p
==============================================Any recurrence: 0.46* 0.008Any recurrence: 0.46* 0.008Distant DFS: 0.43 0.008 Distant DFS: 0.43 0.008 Overall Survival: 0.43* 0.08Overall Survival: 0.43* 0.08
* * 54% reduction of recurrences due to 54% reduction of recurrences due to HerceptinHerceptin
* 57% reduction of mortality due to Herceptin* 57% reduction of mortality due to Herceptin
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10. Cost & Benefit Of Adjuvant Herceptin / 1000 newly diagnosed (15% of all pts. treated); RR=0.5
Underlying recurrence rate: 60%.
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12. Cost Benefit of Adjuvant Herceptin: Dollars spent vs
Recurrences avoided(15% of all pts. treated; underlying recurrence rate: 60%)
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13. Cost Benefit of Adjuvant Herceptin: therapy according to
the “PTEN” statusTreated are only Her2+ve PTEN cMyc +ve (9% of newly 1,000 dg)
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Elligibility for adjuvant Herceptin: Detemination of Her2/Neu status
Protein: Immunohistochemistry (IHC): simpler, cheaper than FISH, 1st screening test
Gene: Fluorescence in situ Hybridization============================================================
• IHC: –ve, 1+: No Herceptin: • IHC 2+ : Possible Herceptin: FISH retesting: 20-30% are FISH +ve• IHC 3+: Herceptin indicated (n.b. FISH retesting, 10-15% are FISH –ve)
The 2006 guidelines: FISH required for all IHC 2+ and 3+
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Tissue Micro-Arrays:
• Validation of new genes & proteins ...
• Stains of archival (paraffin embedded) tumor samples:
• 300 pts / 1 plattform / long f/up….
Kononen J, Bubendorf L, Kallioniemi A, et al: Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nature Medicine 4:844-7, 1998
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Her2/Neu: FISH , presently “Gold Standard”….
• the red dots are her2/neu gene copies.
• greenish small dots are the cept 17/ chr
D.Huntsman, L.Brown, BCCA
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Her-2/Neu testing: FISHHer-2/Neu testing: FISH ADVANTAGES:ADVANTAGES:
Close to 100% specificClose to 100% specific
96.5% sensitive96.5% sensitive
Low inter-laboratory variationLow inter-laboratory variation
DIS-ADVANTAGES:DIS-ADVANTAGES:
High Cost and specialised equipmentHigh Cost and specialised equipment
(Florescent microscopy)(Florescent microscopy)
Limited availability to communityLimited availability to community
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Chromogenic in-situ hybridization
CISH: advantages over FISH
• Light microscope• Availability in the communities• Permanent stains (FISH stain fades
after a few weeks)• Lower cost…
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Her2/Neu: CISH amplification
WEAK:< 6 signals per nucleus - minimal clumping
STRONG: >6 Large
clumped signals per
nucleus
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HER2 / Neu: IHC 3+ (Expressors) vs <3+ (Non-
Expressors)
* Event: Breast Ca Death
RR: 1.62 (1.3, 2.01)
p<0.005
J.Ragaz, M v de Rijn,, BrCa Res Treat;
2002; 76: S29
Year
Sur
viva
l (%
)
0 5 10 15 20 25
020
4060
8010
0
Aug 02 IHC - Disease-Specific Survival (n= 841)
Survival and 95%CI
Time HER2 -ve HER2 +ve
5 yr:
10 yr:
15 yr:
20 yr:
72 (69, 76)
59 (55, 63)
50 (46, 54)
46 (41, 50)
49 (42, 57)
40 (33, 48)
35 (29, 44)
34 (27, 43)
HER2 -ve (n=670, O=324, O/E=0.91)HER2 +ve (n=171, O=108, O/E=1.46)
p-value = 1e-005 RR: 1.62 (1.3, 2.01)
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CISH vs FISH: Event- BrCa Deaths
• CISH RR: 1.54 p=0.0004
• FISH RR: 1.64 p= 0.0002
J. Ragaz, K.Bauer, et.al., SABC 2005Year
Su
rviv
al (
%)
0 5 10 15 20 25
02
04
06
08
01
00
Aug 02 FISH - Disease-Specific Survival (n= 521)
Survival and 95%CI
Time HER2 -ve HER2 +ve
5 yr:
10 yr:
15 yr:
20 yr:
72 (68, 77)
59 (54, 64)
49 (44, 55)
46 (41, 52)
50 (41, 59)
40 (32, 50)
34 (27, 45)
33 (25, 43)
HER2 -ve (n=401, O=195, O/E=0.89)HER2 +ve (n=120, O=77, O/E=1.46)
p-value = 0.0002 RR: 1.64 (1.26, 2.14)
Years
Sur
viva
l (%
)
0 5 10 15 20 25
020
4060
8010
0
Nov 02 CISH / All Patients / Disease-Specific Survival (n= 626)
Survival and 95%CI
Time negative positive
5 yr:
10 yr:
15 yr:
20 yr:
73 (69, 77)
60 (56, 65)
52 (47, 57)
47 (42, 52)
53 (46, 61)
42 (34, 50)
37 (30, 45)
37 (30, 45)
negative (n=472, O=226, O/E=0.9)positive (n=154, O=96, O/E=1.38)
p-value = 0.0004 RR: 1.54 (1.21, 1.96)
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San Antonio 2006San Antonio 2006
Avastin
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VEGF and Targeted Therapy:VEGF and Targeted Therapy:
AVASTINAVASTIN
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IntroductionIntroductionSeveral prior studiesSeveral prior studies have shown have shown
association of association of VVascular ascular EEndothelial ndothelial GGrowth rowth FFactor (actor (VEGFVEGF) )
with with human Breast Cahuman Breast Ca.. However, only a few past studies had a However, only a few past studies had a sample sample
size to measure outcome with sufficient size to measure outcome with sufficient powerpower, or availability of multiple , or availability of multiple other other markersmarkers..
In this study, In this study, impact of VEGFimpact of VEGF is correlated with is correlated with the outcome in a the outcome in a large cohort of BrCa ptslarge cohort of BrCa pts (N:871) diagnosed between 1978-1990 .(N:871) diagnosed between 1978-1990 .
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VEGF- HISTORYVEGF- HISTORY 1960’s:1960’s: J.Folkman, Neovascularization of J.Folkman, Neovascularization of
malignant tumorsmalignant tumors Late 1980Late 1980:: VEGF was co-discovered (separately) VEGF was co-discovered (separately)
by Hal Dvorak (who called it Vascular by Hal Dvorak (who called it Vascular Permeability Factor) and Napoleone Ferrara.Permeability Factor) and Napoleone Ferrara.
Late 1980sLate 1980s: VEGF described as both an : VEGF described as both an endothelial cell proliferative factor and as a endothelial cell proliferative factor and as a compund increasing vascular permeabilitycompund increasing vascular permeability
Early 1990’sEarly 1990’s:: It was subsequently also found to It was subsequently also found to be an important anti-apoptotic agent (G. Sledge be an important anti-apoptotic agent (G. Sledge et.al.).et.al.).
Late 1990s:Late 1990s: K. Miller/ G. Sledge: Monoclonal K. Miller/ G. Sledge: Monoclonal antibody (bevacizumab/Avastin) went through antibody (bevacizumab/Avastin) went through Phase I testing.Phase I testing.
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Key Factors in AngiogenesisKey Factors in Angiogenesis
• Endothelial cell proliferation and migration
• Capillary formation
1
VEGF-A, B, C, D, E, binds to members of the family of VEGF receptors: VEGFR1, VEGFR2, VEGFR3)
4
•Neovascularization•Tumor growth
5
2
Tumor cells release angiogenic factors
P P
P P
Signal transduction
3
VEGFreceptor
Gene expression
Surroundingbloodvessel
VEGF-A
VEGF-B
VEGF-C
VEGF-D VEGF-E
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VEGF and Neo-VEGF and Neo-VascularizationVascularization
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VEGF and Neo-VEGF and Neo-VascularizationVascularization
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VEGF, Neo-Vascularization, VEGF, Neo-Vascularization, DisseminationDissemination
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VEGF, Neo-Vascularization, VEGF, Neo-Vascularization, DisseminationDissemination
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OS Impact of OS Impact of VEGF: 4 VEGF: 4 groupsgroups
J.Ragaz, K.Miller, G.Sledge, et.al., ASCO 2004J.Ragaz, K.Miller, G.Sledge, et.al., ASCO 2004 N: N:
871 pts871 pts
Median Median (years)(years)
VEGF GroupsVEGF Groups 0 (248 pts):0 (248 pts): 10.7 10.7
1+ (190 pts): 1+ (190 pts): 10.110.1 2+(394 pts): 2+(394 pts): 8.18.1 3+ (39 pts): 3+ (39 pts): 3.93.9
pp= 0.001= 0.001
Groups Groups 3+ vs 0, 1+, p<0.0013+ vs 0, 1+, p<0.001
3 +vs 2+, p=0.033 +vs 2+, p=0.03 2 +vs 0, p=0.082 +vs 0, p=0.08 1+ vs 0 p=0.61+ vs 0 p=0.6
Time (years)
201612840
Over
all S
urviv
al
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
No staining
2+
p-value =0.001 3+
1+
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PivotalPivotal Phase III Trial AVF2107g in Phase III Trial AVF2107g in Metastatatic Colorectal CaMetastatatic Colorectal Ca
• ** Patients receiving Avastin could continue therapy ** Patients receiving Avastin could continue therapy past disease progression in combination with second past disease progression in combination with second line therapy, no cross-over was permittedline therapy, no cross-over was permitted
Hurwitz et al. NEJM 2004
Previously untreated mCRC
(n=923)
PD
PD**
PD**
IFL + Placebon=411
5-FU/LV + Bevacizumab
(5 mg/kg, q2w) n=110
IFL + Bevacizumab(5 mg/kg, q2w)
n=402
Primary Endpoint:
Survival
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Hurwitz et al. NEJM 2004Stage IV, colorectal caStage IV, colorectal ca
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A randomised trial of A randomised trial of paclitaxel versus paclitaxel paclitaxel versus paclitaxel
plus plus bevacizumab bevacizumab ((AVASTINAVASTIN)), as first-line , as first-line
therapy for stage IV Breast therapy for stage IV Breast CaCa
KD Miller et.al, for ECOG 21000KD Miller et.al, for ECOG 21000
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RANDOMISE
Paclitaxel + bevacizumab
Paclitaxel 28-day cyclePaclitaxel 90mg/m2 days1, 8 and 15Bevacizumab 10mg/kg day1 and 15
KD Miller et.al, stage IV BrCa KD Miller et.al, stage IV BrCa for ECOG 21000for ECOG 21000
StratifyStratify DFI <24 months versus >24 months; <3 versus >3 metastatic DFI <24 months versus >24 months; <3 versus >3 metastatic
sitessites
Adjuvant chemotherapy yes versus no; ER+ versus ER– versus ER Adjuvant chemotherapy yes versus no; ER+ versus ER– versus ER unknownunknown
DFI = disease-free intervalER = oestrogen receptor
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KD Miller et.al, stage IV BrCa for ECOG KD Miller et.al, stage IV BrCa for ECOG 2100021000
ResponseResponsePaclitaxel
Paclitaxel + bevacizumab
316 330
28.2%
14.2%
p<0.0001
All patients
Overa
ll re
sponse
rate
40
30
20
10
0
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Hazard ratio = 0.498 (0.401–0.618)
Log rank test p<0.001
Months
Pro
gre
ssio
n-f
ree s
urv
ival
pro
port
ion
0 10 20 30
Paclitaxel + bevacizumab: 10.97 months
Paclitaxel: 6.11 months
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
KD Miller et.al, stage IV BrCa for ECOG KD Miller et.al, stage IV BrCa for ECOG
2100021000 Progression-free Progression-free survivalsurvival
6.11
10.97
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Months
OS P
roport
ion
0 10 20 40
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
KD Miller et.al, stage IV BrCa for ECOG KD Miller et.al, stage IV BrCa for ECOG
2100021000 Overall survivalOverall survival
Hazard ratio = 0.674 (0.495–0.917)Log rank test p=0.01
30
Paclitaxel + bevacizumab
Paclitaxel
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Bevacizumab toxicitiesBevacizumab toxicitiesNCI-CTC grade 3 and 4NCI-CTC grade 3 and 4
PaclitaxelPaclitaxel(n=330)(n=330)
Paclitaxel + Paclitaxel + bevacizumab bevacizumab
(n=342)(n=342)
Grade 3Grade 3 Grade 4Grade 4 Grade 3Grade 3 Grade 4Grade 4
HTN* (%)HTN* (%) 00 00 1313 0.30.3Thromboembolic Thromboembolic (%)(%) 0.30.3 0.90.9 1.21.2 00
Bleeding (%)Bleeding (%) 00 00 0.60.6 0.30.3
Proteinuria** Proteinuria** (%)(%) 00 00 0.90.9 1.51.5
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Other ToxicitiesOther ToxicitiesNCI-CTC Grade 3 and 4NCI-CTC Grade 3 and 4
PaclitaxelPaclitaxel(n=330)(n=330)
Paclitaxel + Paclitaxel + bevacizumab bevacizumab
(n=342)(n=342)Grade 3Grade 3 Grade 4Grade 4 Grade 3Grade 3 Grade 4Grade 4
Neuropathy* Neuropathy* (%)(%) 13.613.6 0.60.6 19.919.9 0.60.6
Fatigue (%)Fatigue (%) 2.72.7 00 4.74.7 0.30.3
Neutropenia Neutropenia (%)(%) 00 33 0.90.9 4.44.4
LVEF (%)LVEF (%) 00 00 0.30.3 00LVEF = left ventricular ejection fraction
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Adjuvant BrCa study: Phase I Adjuvant BrCa study: Phase I feasibility E2104 schemafeasibility E2104 schema
REGISTER
Doxorubicin 60mg/m2 plus cyclophosphamide 600mg/m2 bevacizumab 10mg/kgevery 14 days x 4
Arm A: ddBAC >BT >B
Arm B: ddAC >BT >B
Doxorubicin 60mg/m2 plus cyclophosphamide 600mg/m2 every 14 days x 4
Paclitaxel 175mg/m2 bevacizumab 10mg/kg every 14 days x 4
Paclitaxel 175mg/m2 bevacizumab 10mg/kg every 14 days x 4
Bevacizumab 10mg/kg every 14 days x 18
Bevacizumab 10mg/kg every 14 days x 22
*Hormone therapy and radiation per standard caredd = dose density; B = bevacizumab; A = doxorubicin; C = cyclophosphamide; T = paclitaxel
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Breast Ca: Mortality Breast Ca: Mortality vs Interventionsvs Interventions
1. Chemotherapy, Tam start1. Chemotherapy, Tam start
2. Education + Start of Scr. 2. Education + Start of Scr. Mammograms Mammograms
3. More of anthr.CT, Tam, 3. More of anthr.CT, Tam, RT, ScreeningRT, Screening
4. Much more of 1-3,4. Much more of 1-3,
start of start of biologicalsbiologicals
1 2 3 4
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2121