and why ?????????????

Breast cancer:

-in the Netherlands 10.000 new cases/year -incidence has doubled since 1940, now 1000/106 women/year-30 % of all cancers in women-life time risk is 8-12%-in 50% of women with primary tumors occult metastases occur-death rate: 40% in node-negative

70% in node-positivenearly 100% in metastatic disease

hereditary 5-10%, involvement BRCA-1, BRCA-2 and CHEK-2

in men: incidence 1% of that of women.

Hormonale behandeling bij borstkanker

Remmers van de ER werking: Anti-oestrogenen borst bot endometrium endotheel

SERM: tamoxifen – + + –

selective ER modulator raloxifen – + – –

SERD (selective ER downregulator) = full-anti-oestrogenen: ICI 182.780 (Faslodex=Fulvestrant)

doet ER afbreken.

Remmers van de oestrogeen aanmaak: Aromatase remmers

Nonsteroidale: Anastrazole (Arimidex) en Letrozole (Femara)Steroidale : Exemestane(Aromasin)

Voor & naVoor & nade menopauzede menopauze

ACTHACTH

Voor de menopauzeVoor de menopauzeLH/FSHLH/FSH

BijnierschorsBijnierschors

OestrogenenOestrogenenProgesteronProgesteron

ProgesteronProgesteron

Androgenen OestrogenenAndrogenen Oestrogenen

OmzettingOmzettingdoor aromatasedoor aromatase

OvariumOvarium

Hormonale Hormonale regulatieregulatie van de borstvan de borst

HypofyseHypofyse

Aromatase remmerAromatase remmer

Ovariële ablatieOvariële ablatie

Hormonale Hormonale interventies bij mammacarcinoominterventies bij mammacarcinoom

AntiAnti--oestrogeenoestrogeenProgestageenProgestageen

BijnierschorsBijnierschors

HypofyseHypofyse

OvariumOvarium

Enzym Enzym aromatasearomatase

LHRHLHRH--agonistagonist

Ligands and anti-estrogens

Endocrine treatment options of breast cancer

After Robertson et al, EJC, 41, 346, 2005.

ER-

ER+tamoxifen

treatmentFulvestrant,Aromatase inhibitors

100

70

effect of anti-estrogen treatment on recurrence in breast cancer

recurrences

tumor progressie veroorzaakt doorgenetische chaos

ER-DES ER- raloxifeneagonist antagonist

cofactor

FRETFluorescence Resonance

Energy Transfer

Profile of anti-estrogen sensitivity by FRET

sensitive

insensitiveresistant

Hypothetical scheme of anti-estrogenic treatment of breast cancer

ER positive tumor

truly positive tumor,ER dependent :

or not

chemotherapyPKA MAPK treatment

tamoxifen

ICI 163.384 or resveratrol

fulvestrant

raloxifene

Individual treatment based on modification of the Estrogen Receptor

Acknowledgements

Tumor BiologyAlexander GriekspoorWilbert ZwartLennert JanssenAstrid BalkenendeDesiree VerwoerdEls GroeneveldJacques NeefjesRob MichalidesClinicSabine LinnPathologyHans PeterseElly MesmanEllen RiemStatisticsHarm van Tinteren

FRETKees Jalink

MicroarrayArno FlooreArno VeldsLaura van ‘t Veer

CLSMLauran OomenLenny Brocks

FACSAnita PfauthFrank van Diepen

Monoclonal AntibodyUpstate Biotechnology Inc.

Anti-estrogensMichel Renoir, GenevaClaude Labrie, QuebecOrganonGSK