tumorbiologi 19.01.10 [kompatibilitetstilstand] - · pdf fileparkin dm, et al ca cancer j clin...
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![Page 1: Tumorbiologi 19.01.10 [Kompatibilitetstilstand] - · PDF fileParkin 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](https://reader033.vdocuments.pub/reader033/viewer/2022051523/5a75be977f8b9aea3e8cbd33/html5/thumbnails/1.jpg)
Brystkræft
Michael AnderssonBrystkræftteamleder, overl. dr.med.
Onkologisk KlinikFinsencenterRigshospitalet
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Parkin DM, et al CA Cancer J Clin 2005;55:74
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Parkin DM, et al CA Cancer J Clin 2005;55:74
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Parkin DM, et al CA Cancer J Clin 2005;55:74
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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
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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
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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
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Prevalence of cancer, Denmark, females, 2003
0 10000 20000 30000 40000 50000
BreastOtherCervix utUterusMal melanomaColonCNSAnalOvaryUrin BladderUrin BladderLung
NORDCAN
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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
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Danish Board of Health 2009
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Christensen et al. Eur J Cancer (2004) 40:1233
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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
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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
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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
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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
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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
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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
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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.
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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
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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…
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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
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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…
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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
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Risk factors for breast cancer
• Lifestyle
• Low fat, vegetables decreased risk• Physical activity decreased risk• Smoking no effect• Alcohol increased risk• Alcohol increased risk
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Hamajima N et al Br J Cancer 2002;87:1234
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Hamajima N et al Br J Cancer 2002;87:1234
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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
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WHI, JAMA 2002;288:321
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Ravdin NEJM 2007; 356:1670
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Ravdin NEJM 2007; 356:1670
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Fisher B J Natl Cancer Inst 2005;97:1652
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Fisher B J Natl Cancer Inst 2005;97:1652
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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
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Risk factors for breast cancer
• Prior breast cancer
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Kurian AW et al. J Natl Cancer Inst 2009;101:1059
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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
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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%
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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)
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Brenton JD et al. JCO 2005;23:7350
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Brenton JD et al.JCO 2005;23:7350
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Sotiriou C et al. NEJM 2009;360:790
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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
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E l b tEarly breast cancerNon-surgical (neo-) adjuvant therapies
• Radiotherapy• Chemotherapy• HER2 targeted• HER2-targeted• Hormonal
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E l b tEarly breast cancerNon-surgical (neo-) adjuvant therapies
• Radiotherapy• Chemotherapy• HER2 targeted• HER2-targeted• Hormonal
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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)
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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)
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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)
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E l b tEarly breast cancerNon-surgical (neo-) adjuvant therapies
• Radiotherapy• Chemotherapy• HER2 targeted• HER2-targeted• Hormonal
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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)
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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
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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
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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
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E l b tEarly breast cancerNon-surgical (neo-) adjuvant therapies
• Radiotherapy• Chemotherapy• HER2 targeted• HER2-targeted• Hormonal
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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)
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Hanahan Weinberg Cell 2000; 100: 57
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Hanahan Weinberg Cell 2000; 100: 57
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• 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
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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
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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
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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)
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Burstein NEJM 2005; 353:1652
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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
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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.
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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.
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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
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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
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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
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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
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E l b tEarly breast cancerNon-surgical (neo-) adjuvant therapies
• Radiotherapy• Chemotherapy• HER2 targeted• HER2-targeted• Hormonal
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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)
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Hanahan Weinberg Cell 2000; 100: 57
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Hanahan Weinberg Cell 2000; 100: 57
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Phase II trial - oophorectomy
Premenopausal LABC ER+
N 2N=2
RR=100%RR 100%
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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
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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
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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
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~5 years Tamoxifen vs not
RECURRENCERECURRENCEER-poor disease
ER+ diseaseER+ disease
Peto SABCS 2007
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~5 years tamoxifen vs. Not, ER+ only BREAST CANCER
MORTALITY
Peto SABCS 2007
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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
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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
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Sites of peripheral aromatisation
BreastBreasttumourtumour
MuscleMuscle FatFat LiverLiver
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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®)
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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
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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
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Proportional risk reduction 22% p<.00001) Proportional risk reduction 11%
Dowset JCO 2009 Published ahead of prin
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Dowset JCO 2009
Published ahead of print
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Proportional risk reduction 29% p<.00001 Proportional risk reduction 22% p=.02
Dowset JCO 2009
Published ahead of print
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Dowset JCO 2009
Published ahead of print
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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
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• What is MBC?t t t id b t h t llmetastases outside breast, chest wall,
axillary, retrosternal and clavicular lymph nodesnodes
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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
!!!!!!
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• 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
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• 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?
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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
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• 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?
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Demicheli R et al. Breast Cancer Res Treat 53: 209-215, 1999.
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Jatoi, JCO 2007;25
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• 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
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What is the purpose with treatment of MBC?of MBC?
• Cure?b bl t (b t b t il!)probably not (but remember tail!)
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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.
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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.
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Mauri D, JNCI 2006;98:1285
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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
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Cold et al Eur J Cancer 29A: 1146 1152 1993Cold et al. Eur J Cancer 29A: 1146-1152, 1993
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Giordano
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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
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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
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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
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MBC – treatment options
• Endocrine therapy
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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)
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MBC – treatment options
• Endocrine therapy • Chemotherapy
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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
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MBC – chemotherapy
• Combinations better than sequential? (RR and TTP superior, OS similar, toxicity increased)y )
• Anthracyclines and taxanes the most activeactive
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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
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MBC – treatment options
• Endocrine therapy• Chemotherapy• Biological therapy = targeted therapy• Biological therapy = targeted therapy
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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
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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)
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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®
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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.
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Seidman JCO 2008;26:1642
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Metastatic HER2+ breast cancer
• Trastuzumab combined with CT• Trastuzumab combined with ET (ER+)• Lapatinib combined with capecitabine• Lapatinib combined with capecitabine
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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
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Di Leo ASCO 2007
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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
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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
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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
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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
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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
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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
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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
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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
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Hanahan Weinberg Cell 2000; 100: 57
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• 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
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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
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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
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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)
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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)
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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)
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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)
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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)
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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)
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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
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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.
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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