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

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

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

Breast Cancer: Breast Cancer: Targeted Targeted TherapyTherapy

Tumor Biology Tumor Biology BiologicalsBiologicals

Genesis of Human Breast Genesis of Human Breast Ca:Ca:

Genes & Genetic markersGenes & Genetic markers

Targeted TherapyTargeted Therapy

Her-2/Her-2/NeuNeu

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

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%

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

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

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

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

Herceptin:Herceptin:Mode of ActionMode of Action

Herceptin and Herceptin and ChemotherapyChemotherapy

Additive effectAdditive effectSynergistic effectSynergistic effect

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)…

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

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

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

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

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

Targeting “Targeted Therapy”

• Can we identify subsets who will benefit (from Herceptin) much more, and those who will benefit much less…

HerceptinSensitivity Resistance(PTEN expression) (PTEN loss)

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

• Role of c-Myc

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

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

------------------------------------------------------------------------------------

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

San Antonio 2005San Antonio 2005

DCIS and Her2/Neu expression

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

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

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

CARDIAC TOXICITYCARDIAC TOXICITY

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%)

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

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

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

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

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

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

Might 9 weeks of Might 9 weeks of Herceptin be enough?Herceptin be enough?

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

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

10. Cost & Benefit Of Adjuvant Herceptin / 1000 newly diagnosed (15% of all pts. treated); RR=0.5

Underlying recurrence rate: 60%.

12. Cost Benefit of Adjuvant Herceptin: Dollars spent vs

Recurrences avoided(15% of all pts. treated; underlying recurrence rate: 60%)

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)

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+

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

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

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

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…

Her2/Neu: CISH amplification

WEAK:< 6 signals per nucleus - minimal clumping

STRONG: >6 Large

clumped signals per

nucleus

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)

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)

San Antonio 2006San Antonio 2006

Avastin

VEGF and Targeted Therapy:VEGF and Targeted Therapy:

AVASTINAVASTIN

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 .

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.

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

VEGF and Neo-VEGF and Neo-VascularizationVascularization

VEGF and Neo-VEGF and Neo-VascularizationVascularization

VEGF, Neo-Vascularization, VEGF, Neo-Vascularization, DisseminationDissemination

VEGF, Neo-Vascularization, VEGF, Neo-Vascularization, DisseminationDissemination

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+

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

Hurwitz et al. NEJM 2004Stage IV, colorectal caStage IV, colorectal ca

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

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

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

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

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

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

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

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

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

2121

Thank You

Joseph Ragaz Tel.: (514) 843 - 1527 Joseph.ragaz@mcgill.ca