Brystkræft

Michael AnderssonBrystkræftteamleder, overl. dr.med.

Onkologisk KlinikFinsencenterRigshospitalet

Parkin DM, et al CA Cancer J Clin 2005;55:74

Parkin DM, et al CA Cancer J Clin 2005;55:74

Parkin DM, et al CA Cancer J Clin 2005;55:74

Breast cancer incidence in European countries 2003-2005WSR per 100.000p

Czech RLithuania

Poland

CroatiaItaly

SloveniaSpain

Czech R

FranceGermany

NetherlandsSwitzerland

Croatia

SwedenIreland

UKAustria

DenmarkFinland

Norway

0 20 40 60 80 1000 20 40 60 80 100

Karim-Kos HE et al. Eur J Cancer 2008;44:1345

Breast cancer mortality in European countries 2003-2005WSR per 100.000p

Czech RLithuania

Poland

CroatiaItaly

SloveniaSpain

Czech R

FranceGermany

NetherlandsSwitzerland

Croatia

SwedenIreland

UKAustria

DenmarkFinland

Norway

0 5 10 15 20 25 300 5 10 15 20 25 30

Karim-Kos HE et al. Eur J Cancer 2008;44:1345

Number of prevalent cases with breast cancer in Denmark

45000

50000

35000

40000

45000

20000

25000

30000

10000

15000

20000

0

5000

1947-51 1952-56 1957-61 1962-66 1967-71 1972-76 1977-81 1982-86 1987-91 1992-96 1997-01 2002-7

Danish National Board of Health 2006, 2009

Prevalence of cancer, Denmark, females, 2003

0 10000 20000 30000 40000 50000

BreastOtherCervix utUterusMal melanomaColonCNSAnalOvaryUrin BladderUrin BladderLung

NORDCAN

Female breast cancer prevalence 2007, Denmark

Age group N % of cases % of l tipopulation

0-34 166 0.4 0.01435-49 3633 7.8 0.61650 64 16483 35 2 3 01950-64 16483 35.2 3.01965-79 18037 38.5 5.40180+ 8518 18.2 5.797All 4683 100 1 69All 46837 100 1.695

NORDCAN, 2010

Danish Board of Health 2009

Christensen et al. Eur J Cancer (2004) 40:1233

Survival differences between East Denmark and South Sweden 1994

Cox regression for death within 5 yearsCox regression for death within 5 years

Hazard rate-ratio DK/S

95%CI

Univariate 1.8 1.4-2.3

Christensen et al, Eur J Cancer (2006) 42:2773

Survival differences between East Denmark and South Sweden 1994

DK SDK S

1150 900n 1150 900

N+ 54% 47%

T>2 cm 48% 40%

Anaplasia 2-3 70% 63%

P<0.001 Christensen et al, Eur J Cancer (2006) 42:2773

Survival differences between East Denmark and South Sweden 1994

Cox regression for death within 5 yearsCox regression for death within 5 years

Hazard rate-ratio DK/S

95%CI

Univariate 1.8 1.4-2.3

Patho+age 1.3 1.0-1.8

Christensen et al, Eur J Cancer (2006) 42:2773

Survival differences between East Denmark and South Sweden 1994

Cox regression for death within 5 yearsCox regression for death within 5 years

Pt. delay (mths) DK S

Mammo. screen. 8% 39%

0-<3 75% 52%

3-<6 7% 4%

6+ 10% 5%

Christensen et al, Eur J Cancer (2006) 42:2773

Survival differences between East Denmark and South Sweden 1994

Cox regression for death within 5 yearsCox regression for death within 5 years

Hazard rate-ratio DK/S

95%CI

Univariate 1.8 1.4-2.3

Patho+age 1.3 1.0-1.8

Age+delay 1.2 0.9-1.6

Christensen et al, Eur J Cancer (2006) 42:2773

Survival differences between East Denmark and South Sweden 1994

Cox regression for death within 5 yearsCox regression for death within 5 years

Hazard rate-ratio DK/S

95%CI

Univariate 1.8 1.4-2.3

Patho+age 1.3 1.0-1.8

Age+delay 1.2 0.8-1.5

Patho+age+delay 1.1 0.8-1.5

Christensen et al, Eur J Cancer (2006) 42:2773

BREAST CANCERGoals of mammography screening

• Earlier diagnosis in asymptomatic individuals• Reduction of mortality due to detection at earlier y

stage

AgeAge Mortality Reduction (%)Mortality Reduction (%)

40-49 17% 15 years post-screening

50 69 25% 30% 10 12 years post screening50-69 25%-30% 10-12 years post-screening

70+ Insufficient data

PDQ: Screening for breast cancer for health professionals: http://Cancernetnci.nih.gov/. Accessed November 28, 1999.

Risk factors for breast cancer

• Breast irradiation (<40-50 years)

• Contralateral breast irradiation OR 2.5• Mantle radiation (Hodgkins) OR 39 0• Mantle radiation (Hodgkins) OR 39.0• A-bomb survivors OR 13.0

Risk factors for breast cancer• Family history

– First degree relative• Premenopausal diagnosis OR 3 0Premenopausal diagnosis OR 3.0• Bilateral disease OR 5.0• Premenopausal+bilateral OR 9.0• Postmenopausal diagnosis OR 1.2p g

– Second degree relative• Premenopausal diagnosis OR 1.2• Postmenopausal diagnosis no riskp g

• Germ line mutations• BRCA1/BRCA2 60-80% lifetime risk• P53 30-40% lifetime risk• CHEK2 OR 2.2

BUT HEREDITY ACCOUNTS FOR < 10% AND GERM LINE MUTATIONS FOR < 2% OF BREAST CANCER CASESBREAST CANCER CASES…

Risk factors for breast cancer

• Breast irradiation (<40-50 years)( y )

• Contralateral breast irradiation OR 2 5• Contralateral breast irradiation OR 2.5• Mantle radiation (Hodgkins) OR 39.0• A bomb survivors OR 13 0• A-bomb survivors OR 13.0

Risk factors for breast cancer• Family history

– First degree relativeg• Premenopausal diagnosis OR 3.0• Bilateral disease OR 5.0• Premenopausal+bilateral OR 9.0• Postmenopausal diagnosis OR 1.2

– Second degree relative• Premenopausal diagnosis OR 1.2• Postmenopausal diagnosis no risk

• Germ line mutations• BRCA1/BRCA2 60-80% lifetime risk• P53 30-40% lifetime risk• CHEK2 OR 2.2

BUT HEREDITY ACCOUNTS FOR < 10% AND GERM LINE MUTATIONS FOR < 2% OF BREAST CANCER CASES…

Risk factors for breast cancer

• Reproductive factors• Reproductive factors

M h 16 OR 1 2• Menarche < 16 y OR 1.2• Menopause > 50 y OR 1.5• Nulliparity OR 2 0Nulliparity OR 2.0• Age at first birth < 25y decreased risk• Further births < 25y decreased risk• Age at first birth > 30y increased risk• Further births > 30y increased risk

B t f di 4 3% d d i k/• Breast-feeding 4.3% decreased risk/y

Risk factors for breast cancer

• Lifestyle

• Low fat, vegetables decreased risk• Physical activity decreased risk• Smoking no effect• Alcohol increased risk• Alcohol increased risk

Hamajima N et al Br J Cancer 2002;87:1234

Hamajima N et al Br J Cancer 2002;87:1234

Risk factors for breast cancer

• Lifestyle

• Low fat, vegetables decreased risk, g• Physical activity decreased risk• Smoking no effectg• Alcohol increased risk• Hormonal replacementHormonal replacement

therapy increased risk

WHI, JAMA 2002;288:321

Ravdin NEJM 2007; 356:1670

Ravdin NEJM 2007; 356:1670

Fisher B J Natl Cancer Inst 2005;97:1652

Fisher B J Natl Cancer Inst 2005;97:1652

Population Attributable Risk for Breast Cancer. Estrogen/progestin replacement therapy, alcohol,

h i l i d b t f di d tiphysical exercise and breast-feeding duration

• Using population based survey and cancer registry data from California, USA, population attributable risk percents were calculated.

• Out of annually 13 019 diagnosed cases with breast cancer• Out of annually 13,019 diagnosed cases with breast cancer attributable cases:

EPRT 10.9%

Al h l 20 0%Alcohol 20.0%Physical activity 15.0%Breast feeding 11 0%Breast feeding 11.0%

Total 56.9

Clarke BMC Cancer 2006;6:170

Risk factors for breast cancer

• Prior breast cancer

Kurian AW et al. J Natl Cancer Inst 2009;101:1059

BREAST CANCERSigns and symptoms at presentation

Mass or painMass or painin the axillain the axillain the axillain the axilla

P l blP l bl Palpable massPalpable mass ThickeningThickening PainPain

Nipple dischargeNipple discharge Nipple retractionNipple retraction

Edema or erythemaEdema or erythemaof the skinof the skin

Breast cancerat presentationat presentation

• Early (90-95%)Locally advanced (5%)Locally advanced (5%)Primarily disseminated (3-4%)

(significance of tumour cells in blood and bone marrow– (significance of tumour cells in blood and bone marrow uncertain at present)

• But 20%-50% develop distant recurrence after shorter or longer disease free intervalshorter or longer disease free interval

• Metastatic breast cancer considered non curable• Metastatic breast cancer considered non-curable. Median survival ∼ 3 years

• DK 2002-6 mortality/incidence ratio 26%

Breast cancer• Malignant tumor arising in breast tissue• Histology:• Histology:

-DCIS frequency depending on -LCIS mammography screeningLCIS mammography screening-ductal 80% (grade I, II, III)-lobular 10% (grade I, II, III)lobular 10% (grade I, II, III)-medullary 5%-mucinous 2%-tubular 3%-mixed 2%-other 8% (sarcoma, metast.,

lymphoma, other)

Brenton JD et al. JCO 2005;23:7350

Brenton JD et al.JCO 2005;23:7350

Sotiriou C et al. NEJM 2009;360:790

Primary surgical therapy

Modified radical Lumpectomy (DK mastectomy (DK 35%)-removal of corpus

p y (60%)-removal of tumor

mammae-axillary lymph node

dissection level I-II-axillary lymph node dissection level I-II

(sentinel node)-(primary reconstruction)

(sentinel node)-radiotherapy

E l b tEarly breast cancerNon-surgical (neo-) adjuvant therapies

• Radiotherapy• Chemotherapy• HER2 targeted• HER2-targeted• Hormonal

E l b tEarly breast cancerNon-surgical (neo-) adjuvant therapies

• Radiotherapy• Chemotherapy• HER2 targeted• HER2-targeted• Hormonal

DBCG recommendationsDBCG recommendations adjuvant radiotherapyj py

• Lumpectomyid l b t (if N i l L h-residual breast. (if N+: incl. reg. Lymph

nodes) M t kt• Mastektomy-N+, T>5 cm, -radical op.: chest wall + reg. L h dLymph nodes

• 50 Gy/25 F 5F/W (BCS: boost age 40-49: 10 Gy/5F; age<40: 16Gy/8F; margen<2 mm: 16Gy/8F)

DBCG adjuvant systemic treatment recommendations for high-risk patients 2007

Chemotherapy (E90C600 x 3 Docetaxel100 x 3 q 3w)-Chemotherapy (E90C600 x 3 – Docetaxel100 x 3 q 3w)

if ER+: Endocrine therapy 5 years (after CT)-if ER+: Endocrine therapy 5 years (after CT)

(if ER+ and age >59: no chemotherapy)(if ER+ and age >59: no chemotherapy)

If HER2+ d CT T t b 12 th ( ft CT)If HER2+ and CT: Trastuzumab 12 months (after CT)

Prognostic stratification-DBCGadjuvant systemic therapyadjuvant systemic therapy

• Low risk (15%): survival expectancy as general population• High risk (85%): systemic antineoplastic therapy recommended

if any of:y

-node+ (mikro+makro)tumor>20 mm-tumor>20 mm

-grade II-III (duktal carcinoma, appr. 80%)-grade III (lobular carcinoma, appr. 10%)-ER- and PgR- (appr. 20%)-HER2+ (appr. 15%)age<40-age<40

-(TOP2A)

E l b tEarly breast cancerNon-surgical (neo-) adjuvant therapies

• Radiotherapy• Chemotherapy• HER2 targeted• HER2-targeted• Hormonal

DBCG adjuvant systemic treatment recommendations for high-risk patients 2007

Chemotherapy (E90C600 x 3 Docetaxel100 x 3 q 3w)-Chemotherapy (E90C600 x 3 – Docetaxel100 x 3 q 3w)

if ER+: Endocrine therapy 5 years (after CT)-if ER+: Endocrine therapy 5 years (after CT)

(if ER+ and age >59: no chemotherapy)(if ER+ and age >59: no chemotherapy)

If HER2+ d CT T t b 12 th ( ft CT)If HER2+ and CT: Trastuzumab 12 months (after CT)

Adjuvant chemotherapyj py

1970-1985 1986-97 1998-

CMF-type regimens

Anthracycline-based regimens

Taxane-based regimens

DBCG 77B DBCG 89D BIG02-98Oral Adriamycin PaclitacxelIV Epirubicin Docetaxel6 months Low dose1 year High dose+/- vincristine +/- 5-FU/ /+/- prednisone

Taxane vs no chemo(i) age <50

Years 0-4 rate ratios (SE)Recurrence Breast ca

mortality

Years 0-4, rate ratios (SE)

mortality

CMF vs no chem 0.56 (0.05) 0.68 (0.05)Anthr. vs CMF 0.84 (0.05) 0.81 (0.05) Taxane vs Anthr. 0.84 (0.04) 0.86 (0.05)( ) ( )

Taxane vs no chem 0.38 (0.07) 0.46 (0.08)Taxane vs no chem 0.38 (0.07) 0.46 (0.08) (multiplying 3 RRs) 2p<0.00001 2p<0.00001

Taxane vs no chemo(ii) age 50-69

Years 0-4 rate ratios (SE)Recurrence Breast ca

Years 0-4, rate ratios (SE)

mortality

CMF vs no chem 0.75 (0.03) 0.91 (0.03)Anthr. vs CMF 0.89 (0.06) 0.90 (0.06) Taxane vs Anthr 0.82 (0.04) 0.84 (0.05)Taxane vs Anthr 0.82 (0.04) 0.84 (0.05)

Taxane vs no chem 0.52 (0.07) 0.66 (0.08) (multiplying 3 RRs) 2p<0.00001 2p=0.00002

E l b tEarly breast cancerNon-surgical (neo-) adjuvant therapies

• Radiotherapy• Chemotherapy• HER2 targeted• HER2-targeted• Hormonal

DBCG adjuvant systemic treatment recommendations for high-risk patients 2007

Chemotherapy (E90C600 x 3 Docetaxel100 x 3 q 3w)-Chemotherapy (E90C600 x 3 – Docetaxel100 x 3 q 3w)

if ER+: Endocrine therapy 5 years (after CT)-if ER+: Endocrine therapy 5 years (after CT)

(if ER+ and age >59: no chemotherapy)(if ER+ and age >59: no chemotherapy)

If HER2+ d CT T t b 12 th ( ft CT)If HER2+ and CT: Trastuzumab 12 months (after CT)

Hanahan Weinberg Cell 2000; 100: 57

Hanahan Weinberg Cell 2000; 100: 57

• The HER2 gene is l li d tlocalized to chromosome 17q

• HER2 is a tyrosine ykinase transmembrane growth factorgrowth factor receptor

Fernandes et al, Fernandes et al, Cancer LettCancer Lett 1999; Moghal et al, 1999; Moghal et al, Curr Opin Cell BiolCurr Opin Cell Biol 1999; Yarden et al, 1999; Yarden et al, Nat Rev Mol Cell BiolNat Rev Mol Cell Biol 20012001

HER2 receptor dimer transmembrane signal transduction pathway

Growth factor

Binding site

Growth factor

Plasmamembrane

Signaltransductionto nucleus

Tyrosinekinase activity

membrane

to nucleus

NucleusCytoplasm NucleusCytoplasm

Gene activation CELLGene activation DIVISION

Indicators of increased HER2 productionNormal Amplification/OverexpressionNormal Amplification/Overexpression

HER2 receptorprotein 3HER2mRNA

1

2

4

CytoplasmNucleus

HER2 DNA

4

1 = gene copy number2 = mRNA transcription

Cytoplasmicmembrane

Nucleus

3 = cell surface receptor protein expression4 = release of receptor extracellular domain

Role of HER2 in breast cancer

• HER2 gene amplification or receptor g p poverexpression occurs in approximately 15% of breast cancers

• HER2-positive tumours are associated with poor prognosis and shortened disease-poor prognosis and shortened diseasefree/overall survival

• HER2 receptor provides an extracellular targetfor novel and specific anticancer treatment(monoclonal antibodies)(monoclonal antibodies)

Burstein NEJM 2005; 353:1652

Adjuvant Herceptin trials:j p>13,000 patients treated

HERA (ex-USA) BCIRG 006 (global)HERA (ex USA) BCIRG 006 (global)

IHC / FISH (n=5090)

Observation

1 year FISH(n=3222) 1(n 5090)

2 years(n 3222)

1 year

1 year

NCCTG N9831 (USA) NSABP B-31 (USA)

IHC / FISH IHC / FISHIHC / FISH (n=3505)

1 year

1 year

IHC / FISH (n=2030)

1 year

DocetaxelDocetaxel + carboplatin

Doxorubicin + cyclophosphamide Herceptin

Standard chemotherapy Paclitaxel

Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2006FISH, fluorescence in situ hybridisation

HERA NSABP B-31/NCCTG N9831

BCIRG 006 FinHer PASC0431/NCCTG N9831

Randomization 2001–2005 2000–2005 2001–2004 2000–2003 2000–2004

Number of patients 3387 3351/3969 3222 232 528

Design After standard chemotherapy randomization to T1 (1 year every 3 weeks)

ACP2

vs. ACP +T (1 year every week after chemotherapy or in combination with P)

(1) ACP vs.(2) ACP + T (1 year every week in combination with P)

V/DCEF4

vs.V/D+T (9 weeks)CEF

FE100C vs. E75,D75 randomization to T (1 year every 3 weeks)

combination with P) P) vs.(3) DCT3

Age < 50 years, % 51 51 52 50 49/48

Node+, % 68 94 71 84 100/100

Hormone receptor+, % 50 52 54 54 61/58

Median follow-up, months 48 39 36 62 48

1T: trastuzumab 2ACP: doxorubicin + cyclophosphamide 4 cycles – paclitaxel 4 cycles. 3DCT: docetaxel + carboplatin 6 cycles + trastuzumab 1 year weekly given in combination with DC 4V/DCEF: vinorelbine or docetaxel 3 cycles (9 weeks) –cyclophosphamide + epirubicin + fluorouracil 3 cycles.

HERA NSABP B-31/NCCTG N9831

BCIRG 006 FinHer PASC04

Randomization 2001–2005 2000–2005 2001–2004 2000–2003 2000–2004

Number of patients 3387 3351/3969 3222 232 528

Design After standard chemotherapy randomization to T1 (1 year every 3 weeks)

ACP2

vs. ACP +T (1 year every week after

(1) ACP vs.(2) ACP + T (1 year every week in

V/DCEF4

vs.V/D+T (9 weeks)CEF

FE100C vs. E75,D75 randomization to T (1 year every 3 weeks)

chemotherapy or in combination with P)

combination with P) vs.(3) DCT3

Disease free survival:

Hazard ratio, 95 % Confidence interval (CI)

0.64 (0.54–0.76)

0.48 (0.41-0.57)

(1) vs. (2): 0.61 (0.48–0.76)

(1) vs. (3): 0.67

0.65 (0.30–1.12)

0.86 (0.61–1.22)

(0.54–0.83)

3 years disease-free survival, % 81 vs. 74 88 vs. 78 (2): 87 vs. (3): 86 vs. (1): 81

90 vs. 78 Not reported

Overall survival:Overall survival:

Hazard ratio, 95 % CI 0.66 (0.47–0.91)

0.65(0.51-0.84)

(1) vs. (2): 0.59 (0.42–0.85)

(1) vs (3): 0 66

0.55 (0.27–1.11)

1.27 (0.68–2.38)

(1) vs. (3): 0.66 (0.47–0.93)

3 years overall survival, % 95 vs. 90 95 vs. 93 (2): 97 vs. (3): 95 vs. (1): 93

96 vs. 91 Not reported

1T: trastuzumab 2ACP: doxorubicin + cyclophosphamide 4 cycles – paclitaxel 4 cycles. 3DCT: docetaxel + carboplatin 6 cycles + trastuzumab 1 year weekly given in combination with DC 4V/DCEF: vinorelbine or docetaxel 3 cycles (9 weeks) – cyclophosphamide + epirubicin + fluorouracil 3 cycles.

Disease-free survival (ITT)

100Patients 1 year trastuzumab

Median FU 2 yrs

80(%)

1 year trastuzumab

Observation 6.3%

60

403-year

40

20

Events HR 95% CI p value

0.64 0.54, 0.76 <0.0001

DFS

80.674 3

218321

012 360 186 24 30

74.3321

1703 1591 1434 1127 742 383 1401698 1535 1330 984 639 334 127

Months from randomisation

No. at risk 1698 1535 1330 984 639 334 127at risk

Overall survival (ITT)

100Patients 1 year trastuzumabMedian FU 2 yrs

80(%)

Observation2.7%

60

403-year

40

20

Events HR 95% CI p value

0.66 0.47, 0.91 0.0115

OS

92.489 7

5990

089.7

12 360 186 24 30

90

1703 1627 1498 1190 794 407 146

Months from randomisation

No. at risk 1698 1608 1453 1097 711 366 139at risk 1698 1608 1453 1097 711 366 139

HERA NSABP B-31/NCCTG N9831

BCIRG 006 FinHer PASC04

Randomization 2001–2005 2000–2005 2001–2004 2000–2003 2000–2004

Number of patients 3387 3351/3969 3222 232 528

Design After standard chemotherapy randomization to T1 (1 year every 3 weeks)

ACP2

vs. ACP +T (1 year every week after

(1) ACP vs.(2) ACP + T (1 year every week in

V/DCEF4

vs.V/D+T (9 weeks)CEF

FE100C vs. E75,D75 randomization to T (1 year every 3 weeks)

chemotherapy or in combination with P)

combination with P) vs.(3) DCT3

Cardiotoxicity

Cardiac death 0 0 0 0 0

Congestive hearth failure, % 0.6 4.1 (in combination with P)

(2): 1.9 (3): 0.3 0 1.7with P)

Discontinuation of T due to cardiac stopping rules, %

4.3 18 Not reported Not reported 16

Adjuvant trastuzumab• Based on interim analyses of two American

studies and the HERA trial DBCGstudies and the HERA trial DBCG recommends (June 2005) to the National Cancer Steering Committe that all patients inCancer Steering Committe that all patients in Denmark with HER2-positive early breast cancer are offered one year of adjuvant y jtherapy with trastuzumab given i.v. q 3 weeks sequentially to adjuvant chemotherapy and

i d i dj hconcomittant to endocrine adjuvant therapy.• Estimated yearly cost to medicine: 20 mio EU

E l b tEarly breast cancerNon-surgical (neo-) adjuvant therapies

• Radiotherapy• Chemotherapy• HER2 targeted• HER2-targeted• Hormonal

DBCG adjuvant systemic treatment recommendations for high-risk patients 2007

Chemotherapy (E90C600 x 3 Docetaxel100 x 3 q 3w)-Chemotherapy (E90C600 x 3 – Docetaxel100 x 3 q 3w)

if ER+: Endocrine therapy 5 years (after CT)-if ER+: Endocrine therapy 5 years (after CT)

(if ER+ and age >59: no chemotherapy)(if ER+ and age >59: no chemotherapy)

If HER2+ d CT T t b 12 th ( ft CT)If HER2+ and CT: Trastuzumab 12 months (after CT)

Hanahan Weinberg Cell 2000; 100: 57

Hanahan Weinberg Cell 2000; 100: 57

Phase II trial - oophorectomy

Premenopausal LABC ER+

N 2N=2

RR=100%RR 100%

100 years in the development of endocrine therapy

Date of the first publication Type of therapy Principal author189619221939

OophorectomyOvarian irradiationAndrogens

BeatsonCourmellesUlrich

194419511952

gSynthetic oestrogensProgestinsPituitary irradiation

HaddowEsherDouglas1952

195319531971

Pituitary irradiationAdrenalectomyHypophysectomyAntioestrogens

DouglasHugginsLuftCole1971

197319821987

AntioestrogensAromatase inhibitorsLHRH agonistsA ti ti

ColeGriffithsKlijnR i1987

1993Antiprogestins‘Pure’ antioestrogens

RomieuHowell

Reference: Howell, AReference: Howell, A. . et al. Reviews on Endocrineet al. Reviews on Endocrine--related Cancer. 1993; 43: 5related Cancer. 1993; 43: 5--2121

Mode of Action of Estradiol andMode of Action of Estradiol and TamoxifenAF2EstradiolEstradiol

EREE

E+ AF1 + AF2

ACTIVEReceptor

FULLY ACTIVATEDTRANSCRIPTION(tumor cell

AF2EstradiolEstradiol

TamoxifenPARTIALLY

AF1 ACTIVEpdimerization (tumor cell

division)AF1

AF1

ER+PARTIALLY INACTIVATEDTRANSCRIPTION(reduced rate of

ll

T TT

AF1 ACTIVE

NOAF1 + AF2

FulvestrantER+F F F

tumor celldivision)AF1

Nodimerization

TRANSCRIPTION(no tumor celldivision)

AF1 + AF2INACTIVE

AF1

ACCELERATED RECEPTOR DEGRADATION

Adapted from: Wakeling AE. EndocrAdapted from: Wakeling AE. Endocr--Relat Cancer 2000; 7: 17Relat Cancer 2000; 7: 17––28.28.

ACCELERATED RECEPTOR DEGRADATION

Mode of Action of Estradiol andMode of Action of Estradiol and TamoxifenAF2EstradiolEstradiol

EREE

E+ AF1 + AF2

ACTIVEReceptor

FULLY ACTIVATEDTRANSCRIPTION(tumor cell

AF2EstradiolEstradiol

TamoxifenPARTIALLY

AF1 ACTIVEpdimerization (tumor cell

division)AF1

AF1

ER+PARTIALLY INACTIVATEDTRANSCRIPTION(reduced rate of

ll

T TT

AF1 ACTIVE

NOAF1 + AF2

FulvestrantER+F F F

tumor celldivision)AF1

Nodimerization

TRANSCRIPTION(no tumor celldivision)

AF1 + AF2INACTIVE

AF1

ACCELERATED RECEPTOR DEGRADATION

Adapted from: Wakeling AE. EndocrAdapted from: Wakeling AE. Endocr--Relat Cancer 2000; 7: 17Relat Cancer 2000; 7: 17––28.28.

ACCELERATED RECEPTOR DEGRADATION

~5 years Tamoxifen vs not

RECURRENCERECURRENCEER-poor disease

ER+ diseaseER+ disease

Peto SABCS 2007

~5 years tamoxifen vs. Not, ER+ only BREAST CANCER

MORTALITY

Peto SABCS 2007

Hormones affecting the breast

GonadotrophinsGonadotrophins(FSH LH)(FSH LH)

OestrogensOestrogens

PremenopausalPremenopausal

(FSH + LH)(FSH + LH) ProgesteroneProgesterone

OvaryOvary

ProlactinProlactin

yy

LHRHLHRH // AdrenalAdrenalPituitary glandPituitary gland

Growth hormoneGrowth hormone

CorticosteroidsCorticosteroidsLHRHLHRH

(hypothalamus)(hypothalamus)Pre/postPre/post--

menopausalmenopausal

Ad ti t hiAd ti t hi

AdrenalAdrenalglandsglands

Androgens OestrogensAndrogens OestrogensAdrenocorticotrophicAdrenocorticotrophic

hormonehormone(ACTH)(ACTH)

ProgesteroneProgesterone

Peripheral conversionPeripheral conversionPeripheral conversionPeripheral conversion

Biosynthesis of OestrogensBiosynthesis of OestrogensPotential Sites of Action of Selective† and Non-Selective*

Aromatase InhibitorsAromatase Inhibitors

20,22-Lyase*Cholesterol (intermediate)

17-

17,20 Lyase*Pregnenolone17-Hydroxylase*

Dehydroepiandrosterone

(i t di t )

Hydroxypregnenolone

Progesterone

y y

21-Hydroxylase*TestosteroneAndrostenedione

aromatase* †

(intermediate)17-Hydroxyprogesterone

11-Hydroxylase*

Pharmacological Target

11-Deoxycorticosterone

Corticosterone

11-Deoxycortisol

Cortisol

Oestrone Oestradiol

18-Hydroxylase*

Pharmacological TargetCorticosterone

Aldosterone

Sites of peripheral aromatisation

BreastBreasttumourtumour

MuscleMuscle FatFat LiverLiver

Aromatase inhibitors/inactivators in breast cancer

Non-steroidalinhibitors

Steroidalinacti atorsinhibitors inactivators

1. generation Aminogluthetimide

2. generation Fadrozole Formestane

Vorozole

3 generation Anastrozole Exemestane3. generation Anastrozole(Arimidex®)

Exemestane(Aromasin®)

LetrozoleLetrozole(Femara®)

Trial Strategies in Adjuvant Therapy: Aromatase Inhibitors

Early Adjuvant setting Extended Adjuvant setting

ATAC

0 – 5 years0 – 5 years 5 – 10 years5 – 10 years

ARNO / ITATAMOXIFEN

ANASTROZOLE

LETROZOLEBIG 1-98

(BIG FEMTA)

LETROZOLE

PLACEBOEXEMESTANE

MA-17

ICCG Study 96CCG Study 96

TEAM

NSABP B33

EXEM 027

NSABP B33

N FU (mo) HR DFS Abs. Red (%) HR OS

EBCTCG 2005 5 yrs TAM vs noneTamoxifen 15 000 180 0 61 12 0 68Tamoxifen 15,000 180 0.61 12

(15 yrs)0.68

Head to head 5 yrs TAM vs 5 yrs AIAnastro ole 6241 100 0 90 2 8 1 00 nsAnastrozole 6241 100 0.90 2.8 1.00 ns

Letrozole 4922 76 0.88 3.0 0.87 ns

Sequential short 5 yrs AI vs 2 yrs TAM + 3 yrs AI

Letrozole 6182 71 1.05 ns 1.7 1.13 nsLetrozole 6182 71 1.05 ns 1.7(5 years)

1.13 ns

Exemestane 9775 27 0,89 ns <1% -

Sequential short 5 yrs TAM vs 2 yrs TAM+ 3 yrs AI

Exemestane 5742 31 0.68 4.7(3 )

0.88 ns(3 yrs)

Anastrozole 3224 28 0.60 3.1(3 yrs)

0.76 ns

Sequential long 5 yrs TAM + 5 yrs placebo vs 5 yrs AI

Letrozole 5157 28 0.57 6.0(4 yrs)

0.76 ns

Proportional risk reduction 22% p<.00001) Proportional risk reduction 11%

Dowset JCO 2009 Published ahead of prin

Dowset JCO 2009

Published ahead of print

Proportional risk reduction 29% p<.00001 Proportional risk reduction 22% p=.02

Dowset JCO 2009

Published ahead of print

Dowset JCO 2009

Published ahead of print

DBCG d tiDBCG recommendations February 2009

• Premenopausal: 5 yrs tamoxifen• Postmenopausal: 5 yrs letrozole• Postmenopausal: 5 yrs letrozole

-Pts on tamoxifen: switch to letrozole• N+ pts 5 yrs on tamoxifen: 2 5 yrs Letrozole (or• N+ pts 5 yrs on tamoxifen: 2.5 yrs Letrozole (or

longer) if postmenopausal before chemotherapy

• What is MBC?t t t id b t h t llmetastases outside breast, chest wall,

axillary, retrosternal and clavicular lymph nodesnodes

Diagnostic work-up at time of recurrence and progression at Rigshospitalet Dpt. Oncology

• X-ray chestX ray chest• Bone scintigraphy (with x-ray of pathologic foci)• Liver function tests• Liver function tests

!!!!!!

• What is MBC?t t t id b t h t llmetastases outside breast, chest wall,

axillary, retrosternal and clavicular lymph nodesnodes

• How many gets MBC?-approximately 5% at diagnosis, pp y g30%-50% after a recurrence free interval

• What is MBC?t t t id b t h t llmetastases outside breast, chest wall,

axillary, retrosternal and clavicular lymph nodesnodes

• How many gets MBC?-approximately 5% at diagnosis, pp y g30%-50% after a recurrence free interval

• Where is the MBC?

SITES OF FIRST RECURRENCE

BrainBrain 4%

SkinSkin

PleuraPleura

LungLung

Lymph nodesLymph nodes12%

19%29%

39%

Contralateral breast5%

LiverLiver

LungLung 19%

9%

BoneBone31%

From Kamby 1992, mean values compiled from 37 studies

• What is MBC?t t t id b t h t llmetastases outside breast, chest wall,

axillary, retrosternal and clavicular lymph nodesnodes

• How many gets MBC?-approximately 5% at diagnosis, pp y g30%-50% after a recurrence free interval

• Where is the MBC?• When will the recurrence come?

Demicheli R et al. Breast Cancer Res Treat 53: 209-215, 1999.

Jatoi, JCO 2007;25

• What is MBC?t t t id b t h t llmetastases outside breast, chest wall,

aksillary, retrosternal and clavicular lymph nodeslymph nodes

• How many gets MBC?-approximately 5% at diagnosis, pp y g30%-50% after a recurrence free interval

• Where is the MBC?• When will the recurrence come? • How many are alive with MBC?

at least 10% of prevalent BC patients-at least 10% of prevalent BC patients

What is the purpose with treatment of MBC?of MBC?

• Cure?b bl t (b t b t il!)probably not (but remember tail!)

What is the purpose with treatment of MBC?of MBC?

• Cure?probably not (but remember tail!)probably not (but remember tail!)

• Prolongation of life?-no randomised evidence – but indirect: several studies showindirect: several studies show survival differences.

Trials with a survival benefit in MBCAnastrozole > MGAExemestane > MGADocetaxel > paclitaxel Docetaxel > mitomycin/vinblastineVinorelbine > melphalan Oral CMF > IV CMFFAC > CMFDoxorubicin/paclitaxel > FACDocetaxel/doxorubicin > FACD t l/ it bi d t lDocetaxel/capecitabine > docetaxel AC or paclitaxel/trastuzumab > chemotherapyDocetaxel/trastuzumab > docetaxelDocetaxel/trastuzumab > docetaxel

Buzdar et al Cancer 1998, Kaufmann et al J Clin Oncol 2000, Jones et al J Clin Oncol 2005, Nabholtz et al. J Clin Oncol 1999; 17:1413-1424, Jones et al. J Clin Oncol 1995; 13:2567-2574, Engelsman et al. Eur J Cancer 1991; 21:966-970, Stewart et al. J Clin Oncol 1997; 15:1897-1905, Jassem et al. J Clin Oncol 2001; 19:1707-1715, Bontenbal et al. ECCO 2003; abstract #671, O’Shaughnessy et al. J Clin Oncol 2002; 20:2812-2823, Slamon et al. NEJM 2001; 344:783-792, Marty et al. J Clin Oncol 23:19, July 1st, 2005.

Mauri D, JNCI 2006;98:1285

What is the purpose with treatment of MBC?of MBC?

• Cure?probably not (but remember tail!)probably not (but remember tail!)

• Prolongation of life?-no randomised evidence – but indirect: several studies showindirect: several studies show survival differences. Some studies show differences over timeshow differences over time

Cold et al Eur J Cancer 29A: 1146 1152 1993Cold et al. Eur J Cancer 29A: 1146-1152, 1993

Giordano

What is the purpose with treatment of MBC?of MBC?

• Cure?probably not (but remember tail!)probably not (but remember tail!)

• Prolongation of life?-no randomised evidence – but indirect: several studies show survival differences. differences over time

• Palliation?-several studies show relation between tumor remission and quality of lifetu o e ss o a d qua ty o e

What is the purpose with treatment of MBC?of MBC?

• Cure?probably not (but remember tail!)p y ( )

• Prolongation of life?-no randomised evidence – but indirect: several studies show survival differences. differences over timePalliation?• Palliation?-several studies show relation between tumor remission and quality of lifetumor remission and quality of life

• Test of new treatments for possible preop or adjuvant usep eop o adju a t use

Advanced Breast Cancer:Advanced Breast Cancer:TREATMENT OPTIONS

Systemic antineoplastic:chemotherapy, targeted therapies

(endocrine, trastuzumab, bevacizumab, lapatinib), , p ),bisphosphonates

Local:surgery radiotherapysurgery, radiotherapySupportive:analgetics, hematopoietic growth g p g

factors, nutrition, rehabilitation

MBC – treatment options

• Endocrine therapy

Advanced Breast CancerTREATMENT STRATEGY

ER+ and indolent disease:

Premenopausal:

i i ( i l ti i l LH RHovarian suppression (surgical, actinical, LH-RH analogue)

Postmenopausal:Postmenopausal:

1. line: letrozole/anastrozole e et o o e/a ast o o e- if clinical benefit:

2. line: tamoxifen- if clinical benefit;

3. line: MA/exemestane/fulvestrant?If PD or rapidly progressing disease or HER2+:

consider chemotherapy (HER2+: +trastuzumab)

MBC – treatment options

• Endocrine therapy • Chemotherapy

MBC – active CT drugsMBC active CT drugs• docetaxel• paclitaxel (nab-)• ixebepilone• vinorelbine• vinorelbine• epirubicin• doxorubicin (liposomal)• cyclophosphamide• methotrexate• fluorouracilefluorouracile• gemcitabine• capecitabine

i l ti• cisplatinum• carboplatinum• and others

MBC – chemotherapy

• Combinations better than sequential? (RR and TTP superior, OS similar, toxicity increased)y )

• Anthracyclines and taxanes the most activeactive

MBC chemotherapyMBC – chemotherapyCurrent strategy at Finsen Center

Endocrine non-respondentEndocrine non respondent

• 1. line Taxotere (or weekly Taxol). On PD:

• 2 line epirubicin (if not treated with epi2. line epirubicin (if not treated with epi before) . On PD (perhaps)3 li i lbi CMF X l d• 3. line vinorelbine, CMF, Xeloda, Gemzar – if relevant

MBC – treatment options

• Endocrine therapy• Chemotherapy• Biological therapy = targeted therapy• Biological therapy = targeted therapy

Pivotal trastuzumab combination therapy trial (H0648g)(H0648g)

Design and enrolment

Metastatic breast cancer HER2 overexpressionEli ibl ti t ( 469) HER2 overexpression No prior CT for MBC Measurable disease KPS 60%

Eligible patients (n=469)

No prior anthracyclines Prior anthracyclinesNo prior anthracyclines Prior anthracyclines

Paclitaxel(n=96)

trastuzumab + paclitaxel(n=92)

AC(n=138)

trastuzumab + AC(n=143)

AC = doxorubicin/epirubicin + cyclophosphamide, CT = chemotherapy, MBC = metastatic breast cancer

Trastuzumab plus paclitaxel:as u u ab p us pac a e39% increase in survival (IHC 3+)

1 01.0

0.8al trastuzumab + paclitaxel

0.6f sur

viva

pPaclitaxel

0.4

abili

ty o

f

0.2Prob

a

39%0

0 5 10 15 20 25 30 35 40 45 50

17.9 24.839%

Smith IE. Anticancer Drugs 2001;12:S3–10

Time (months)

M77001: trial designM77001: trial design

HER2-positive MBC (IHC 3+/FISH+) n=188

T ti t did tTwo patients did notreceive study medication

Docetaxel*100mg/m2 q3w x6

Docetaxel100mg/m2 q3w x6

+trastuzumab

4mg/kg i v then

+4mg/kg i.v. then

2mg/kg/week until disease progression

*Patients progressing on docetaxel alone could crossover to receive trastuzumab®

Trastuzumab plus docetaxel: %38% increase in survival

1.0 trastuzumab + docetaxelDocetaxel alone

0.8

0 6surv

ival Docetaxel alone

0.6

0.4bilit

y of

0.2Prob

a

p=0.006238%

00 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

22.1 30.5

Time (months)Intent-to-treat population, 12-month cut-offDocumented crossover = 48% Marty M, et al. J Clin Oncol 23 2005.

Seidman JCO 2008;26:1642

Metastatic HER2+ breast cancer

• Trastuzumab combined with CT• Trastuzumab combined with ET (ER+)• Lapatinib combined with capecitabine• Lapatinib combined with capecitabine

Targeting EGF+HER2 tyrosine kinase GW572016 (Lapatinib)GW572016 (Lapatinib)

Fernandes et al, Fernandes et al, Cancer LettCancer Lett 1999; Moghal et al, 1999; Moghal et al, Curr Opin Cell BiolCurr Opin Cell Biol 1999; Yarden et al, 1999; Yarden et al, Nat Rev Mol Cell BiolNat Rev Mol Cell Biol 20012001

Di Leo ASCO 2007

Study Design

• Progressive HER2+Progressive, HER2+ MBC or LABC

• Previously treated Lapatinib 1250 mg po qd

continuously +RAy

with anthracycline, taxane and t t b*

continuously + Capecitabine 2000 mg/m2/d

po days 1-14 q 3 wk

AND

trastuzumab*• No prior

capecitabine Capecitabine 2500 mg/m2/d

OMIcapecitabine Capecitabine 2500 mg/m /d

po days 1-14 q 3 wkStratification:• Disease sites

IZE Patients on treatment until

progression or unacceptable toxicity, then followed for survival

Disease sites• Stage of disease

E

N=528 y,

*Trastuzumab must have been administered for metastatic disease

Time to Progression – ITT Populaation

100Capecitabine

Lapatinib + Capecitabine

8090

10069 (43%)45 (28%)Progressed or died*

19.736.9Median TTP, wk

161160No. of pts

gres

sion

*

6070

0.00016P-value (log-rank, 1-sided)0.51 (0.35, 0.74)Hazard ratio (95% CI)

from

pro

g

304050

nts

free

f

10

20

30

% o

f pat

ie

700

10 20 30 40 50 600Time (weeks)

%

* Censors 4 patients who died due to causes other than breast cancer

Response Rate - ITT Population p p

Lapatinib + Capecitabine( 160)

Capecitabine( 161)(n=160) (n=161)

Complete response 1 (< 1%) 0 (0%)

Partial response 35 (22%) 23 (14%)

Overall response rate* 22.5% 14.3%p(95% CI) (16.3 - 29.8) (9.3 - 20.7)

*P-value (Fisher’s exact, 2-sided) = 0.113

Overall Survival - ITT Population 100

%

80

90

Surv

ival

%

60

70

161160No. of ptsulat

ive

S

40

50Capecitabine

Lapatinib + Capecitabine

29 (18%)29 (18%)Deaths

0.93 (0.55, 1.59)Hazard ratio (95% CI)

NRNRMedian OS

p

Cum

u

20

30

0.800P value (log-rank, 2-sided)( , )( )

0 10 20 30 40 50 70 900

10

60 80Time (weeks)

0 10 20 30 40 50 70 9060 80

B i M t t Sit f P iBrain Metastases as Site of Progression

Lapatinib + Capecitabine

Capecitabine(n 161)Capecitabine

(n=160)(n=161)

Patients with CNS metastases at baseline

2 2

Patients with CNS relapse* 4 11

Patients with CNS as only site of relapse

3 10

*P-value (Fisher’s exact, 2-sided) = 0.110

Most Frequent Adverse Events All G dAll Grades

100

SeverityGr 480

90

Gr 3Gr 2Gr 1ie

nts

L+C60

70

1 Gr 1

% o

f Pat

L+CL+CCC40

50

19

121

6

% CC

20

30

26

19

15

11

28 20

513

2.5

11

7

Di h R h d/PPE

10

0

26

13 9 919

12

11

Diarrhea Rash and/or Skin Reaction

PPE0

L = lapatinib; C = capecitabine

Lapatinib

• Approved by EMEA and FDA for advanced HER2+ breast ca treated with anthracyclines, taxanes and y ,trastuzumab

• DK: used on the same indication• DK: used on the same indication

ALTTO

Locally-determined HER2-positive invasive breast cancer

Centrally-determined HER2+; ER and PgR

Surgery, complete (neo)adjuvant anthracycline-based chemotherapy (selected from an approved list)

LVEF 50%Max 12 w

Trastuzumab3-weekly

(For 52 weeks)

Lapatinib

(For 52 weeks)

Trastuzumab Weekly

(For 12 weeks)

Lapatinib

+Trastuzumab Washout (6 weeks)

P ti t ith ER P R iti t i d i th l t d di l t l t t d i th ill b

3-weekly(For 52 weeks)

Washout (6 weeks)

Lapatinib (34 weeks)

• Patients with ER or PgR-positive tumours receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started after the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 years

• Radiotherapy if indicated

Hanahan Weinberg Cell 2000; 100: 57

• VEGF key mediator of tumour angiogenesis and thus of tumour de elopment and metastasisdevelopment and metastasis

• VEGF limited role in normal adult physiology and thus tumour-derived VEGF can be inhibited with minor effects in adults

• VEGF expression is increased in breast cancerVEGF expression is increased in breast cancer

• Anti-VEGF treatment inhibits growth of human breast tumour xenografts in animalsxenografts in animals

• Increased VEGF levels in breast cancer mean poor clinical outcome, i l di ti t i lincluding patient survival

• Bevacizumab is a monoclonal antibody directed against VEGF

• FDA and EMEA approved for treatment of MBC

Bevacizumab has both early and continued ff t t l teffects on tumour vasculature

EARLY EFFECTS CONTINUED EFFECTS

1 2 3

Regression of some tumour vasculature1–2

Normalisation of surviving

Inhibition of new and recurrent vessel growth3–4

1

2

3

Normalisation of surviving tumour vasculature1,4,5

2

1. Willet et, al. Nat Med 2004; 2. Baluk, et al. Curr Opin Genet Dev 2005; 3. Inai, et al. Am J Pathol 2004; 4. Gerber, et al. Cancer Res 2005; 5. Jain, et al. Science 2005

E2100: paclitaxel +/ bevacizumabE2100: paclitaxel +/- bevacizumabPaclitaxel Treat to disease

Previously untreated locally

Paclitaxel(n=354)

Treat to disease progression*

*No cross over permittedy

recurrent or mBC(n=722)

Paclitaxel + bevacizumab

10mg/kg every Treat to disease 10mg/kg every2 weeks(n=368)

progressionPaclitaxel:90mg/m2 qw for 3 weeks of a 4-week cycle

• Primary endpoint: progression-free survival • Other endpoints: overall response rate, overall survival, quality p p , , q y

of life

Miller, et al. SABCS 2005

Progression free survivale

99% increase in median PFSPaclitaxel (n=354)

Avastin + paclitaxel (n=368)

Progression-free survival

80

100

estim

ate

HR=0.48; p<0.0001 13,3

in median PFS

S (m

onth

s)

15

10

Paclitaxel (n=354)

60

80

surv

ival

6,7

Med

ian

PFS

5

40

sion

-free

0 Avastin +paclitaxel

Paclitaxel

0

20

Pro

gres

s

6.7 13.3

Months0 10 20 30 40

HR = hazard ratio; Avastin Summary of Product Characteristics (SmPC)

Phase III trial of Avastin in first-line MBC (E2100): overall survival

1.0

(E2100): overall survival

Avastin + paclitaxeltio

n

0.9

0.8

Avastin + paclitaxel

Paclitaxel

al p

ropo

rt 0.7

0.6

ll su

rviv

a 0.5

0.4

Ove

ra 0.3

0.2

0 1HR=0.674 (0.495–0.917) L k 0 01

0 10 20 40

0.1

0

Log-rank test p=0.01

30Months

Miller ASCO 2005

ECCO 2005-update:HR 0.84 (0.64-1.05, p=0.12)

AVADO DesignDocetaxel* 100mg/m2

+ placebo q3w

AVADO – Design1. linie lokal avanceret eller

t t ti k b tk ft + placebo q3w

Docetaxel* + Avastin

Alle patienterfik mulighed

for at få

metastatisk brystkræft (n=705)

Stratificeringsfaktorer:i

Behandlingmed

placebo/7.5mg/kg q3w Avastin med

2. liniekemoterapi

• region• tidligere taxan / tid til

relaps siden adjuverende kemoterapi

ålb d

pAvastin

til sygdoms-progression

Docetaxel* + Avastin15mg/kg q3w

•*Docetaxel blev administreret i maximum 9 serier, tidligere seponering tilladt

• målbar sygdom• hormon receptor status

• Primært endepunkt: Progressionsfri overlevelse (PFS)

• Sekundære endepunkter: respons rate (ORR), varighed af respons, tid til behandlingssvigt (TTF), overlevelse (OS), safety, Livskvalitet (QoL)

Miles DW et al ASCO 2008 (Abstract LBA 1011)Miles, DW et al. ASCO 2008 (Abstract LBA 1011)

AVADO – Progressionsfri overlevelse (PFS)Avastin 7.5† +

docetaxel (n=248)Placebo +

docetaxel (n=241)Avastin 15† +

docetaxel (n=247)Placebo +

docetaxel (n=241)

HR + 95% CI (ustratificeret)

HR + 95% CI (stratificeret*) 0.69 (0.54–0.89)p=0.0035

0.79 (0.63–0.98)p=0.0318

HR + 95% CI (stratificeret*) 0.61 (0.48–0.78)p<0.0001

0.72 (0.57–0.90)p=0.0099

HR + 95% CI (ustratificeret)

1.0 1.0

Median 8.78.0 Median 8.88.0

0.8

0.6

estim

at

estim

at

0.8

0.6

0.4

0.2

PFS

e

PFS

e

0.4

0 2

*Data censurreret for non-protokol behandling inden sygdomsprogression

0.2

0.0Måneder0 6 12 18 Måneder

0.2

0.0

†mg/kg q3w0 6 12 18

Miles DW et al ASCO 2008 (Abstract LBA 1011) Data censurreret for non-protokol behandling inden sygdomsprogression†mg/kg q3wMiles, DW et al. ASCO 2008 (Abstract LBA 1011)

AVADO – Respons rate (ORR)

Placebo + docetaxel (n=207)

Avastin 7.5†

+ docetaxel (n=201)Avastin 15†

+ docetaxel (n=206)

Respons ratep værdi (vs kontrol)

44–

550.0295

630.0001

Bedste responspCRPRSDPD

1443912

352355

162254PD 12 5 4

†mg/kg q3w

Miles DW et al ASCO 2008 (Abstract LBA 1011)Miles, DW et al. ASCO 2008 (Abstract LBA 1011)

AVADO – Overlevelse* (OS)

Placebo Avastin 7 5† Avastin 15†Placebo + docetaxel

(n=241)

Avastin 7.5+ docetaxel

(n=248)

Avastin 15+ docetaxel

(n=247)

Dødsfald n (%) 50 (21) 49 (20) 37 (15)Dødsfald, n (%) 50 (21) 49 (20) 37 (15)

Median overlevelse, månederhazard ratio

NR–

NR0.92

NR0.68

(95% CI) (0.62–1.37) (0.45–1.04)

1-års overlevelse, %patienter i risiko n

7363

7873

8379

*Ustratificeret analyse; †mg/kg q3w; NR = ikke nået

patienter i risiko, n 63 73 79

Cut-off for endelig overlevelsesanalyse 24 måneder efter sidste patient rekrutteret (april 2009)Miles DW et al ASCO 2008 (Abstract LBA 1011)Miles, DW et al. ASCO 2008 (Abstract LBA 1011)

Anti-VEGF in MBC

Bevazizumab FDA and EMEA approved• Bevazizumab FDA and EMEA approved for 1. Line therapy in combination with CT

• Several anti-VEGF-r TKI in clinical test

Relative 5-years survival

80

85

70

75

cent

60

65perc

50

55

1960 1965 1970 1975 1980 1985

Denmark Sweden Norway Finland

Engeland, Acta Oncol 37: 49, 1998.

R l ti i l f D i h b tRelative survival of Danish breast cancer patients (data based on hospital reporting)

100

801-year

40

60 3-year5-year

2010-year

0

1994 1996 1998 2000 2002 2004

National Board of Health 2006