Cancer 12: breast cancer Flashcards
What is the 5 year curative window for breast cancer?
Means that cancer hasnt reoocured for cancer
after 5 year, as likely to be a new tumour than the same that came back –> pretty low
Describe the epidiemology of breast cancer?
Incidence has been rising year on year
BUT mortality rate is falling->thanks to earlier tumour detection and better drugs (chemo + radio)
55000 cases in UK each year- one every 10 mins
self examination has been very positive
Describe general physiology of the mammary gland?
Only organ to FULLY develop post-birth (under hormone)
Network of ducts and tubules that join up at nipple-ducts, lobules, tubules
Main cells-epithelium, fibroblasts, soft tissue
Meaning many types of breast cancer-sarcomas, carcinomas,
But was majority of cancer are from tubules-tubular carcinoma
tubules-lumen with 2 LAYERS-rare epithelial cells lining them-second layer called myoepithelium (can contract to squeeze milk out)
How is the breast lumen epithelial organised
tubules-lumen with 2 LAYERS-rare epithelial cells lining them-second layer called myoepithelium (can contract to squeeze milk out)
Myoephithelium also decide the architecture of the tubules
How does normal breast tubules develop to a cancerous state?
Epithelium (tubulalr cell) with myoepithelum
Can reach a point of pre carcinoma where the tubular cells have grown and obstructed to block tubule–
But doesnt alwyas give rise to same cancer
Lobular carcinoma-keep sort of organisation
Medullary carcinoma-completely undifferentiated-looks nothing like epithelium-tends to be very agressive
middle ground is undifferentiated breast cancer-85% of BC present wit
=> means that histology isnt very useful if not combined with AB measurement (especially for oestrogen receptor)->on that basis
What cancer can give good indication of treatments for breast cancer?
as most are undistinct cell histologocally, use AB vs oestrogen receptor-
This tells how many cells are overexpressing it
gives a big clue about how to treat and how well they will repsond to certain drugs
means 2 types sorta-estrogen positive and estrogen negative
What receptor does estrogen bind? What genes does it express? What about in cancer?
Estrogen receptor exist as monomer bound to Hsp90
Estrogen enters cytosol and cause release of receptor-forms a dimer of active receptor
this dimer acts as a transcription factor for Estrogen Response Elements
eg genes-Progesterone receptor, Cyclin D1, c-myc, TGF-a
These can lead to cell proliferation-why its so important in breast cancer
In normal breast, estrogen receptor expressing cells then produce factors for other cells (which dont bind estrogen) to grow
But in cancer, 70% of the cell are esteogen sensitive-megagrow
Why does over-active estrogen like compounds can treat breast tumours- IN THEORY? What was a better idea in reality?
In theory, over activation of the receptors cause the downregulation of the receptors-through feedback loops
IN REALITY-cause relapse after a bit can cause deadly metastatic diseases
In reality-using competitive inhbitors of esteogen-70% ER positive cancer response, even 15% in ER negative
for male cancers-usually driven by androgen-Estrogen competitors are very meh
What are the 4 treatment modalities for breast cancer?
Surgery-very effective
Radioation therapy
Chemotherapy
Endocrine therapy-adjuvent-once remove tumour w/ surgery-kill of what ever cells left –even used rarely as neoadjuvent-before surgery-less common because tumours picked up early
How does endocrine therapy supress breast cancer?
Supress estrogen
Ovarian supression
Blocking estrogen production by enzymatic inhbit
Inhbiting estrogen receptors
How is estrogen production regulated
GnRH to Pit gland -produce LH+FSH -> ovary -> estrogen +progesterone
also ACTH from pit -> Adrenal-> androgens->Estrogens (peripherally in fatty tissue by aromatase (LIKE BREAST)-target
What is ovarian ablation and how does it help with breast cancer?
ONLY GOOD IN PRE-MENOPAUSAL-reduce biosynthesis of estrogen
Either surgical or ovarian irradiation
Irreversible and morbidity-> what causes development of pharma alternative
Blocking FSH and LH via GnRH agonist –mimics GnRH => feedback loop downregulates GnRH receptor-> reduce LH and FSH -> but can also be reversible->
eg: Goserelin
What are the 2 startegies to inhbit estrogen production?
GnRH agonist-
Blocking FSH and LH via GnRH agonist –mimics GnRH => feedback loop downregulates GnRH receptor-> reduce LH and FSH -> but can also be reversible->
eg: Goserelin
Aromatase inhbitors–in post menopausal women-adrenals make most androgens. Conversion to Estroen (E2) happens in fatty tissue to Estroen sulphate-how it moves around. In target tissue remove sulphate and acts
Aromatase is cytP450 heme and NADPH cyt450 reductase
-catalyse three seperate steroid hydroxylation makin estrone
Can have either reversible (competitive) type 2 or irrevesible- (binds forever) type 1
Irreversible-names
reversible-names
=> work even in post menauposal women
antiestrogens-
How do anti-estrogen receptors function? What are the side effects?
very similar structure to estrogen-binds the receptor but goes make it active-blocks the activity of the receptor
eg: Tamoxifen -
called SERM-selective estrogen receptor modulators
Tamoxifen also doesnt cause oesteoporosis-acts as agonist in bones!
Also doesnt cause artherosclerosis-cardio-protective
also fine in liver
=> also reduce chance of contralateral breast cancer
undesirable effect-rare embolism, growing endometrium (can lead to cancer), cataract,
but tamoxifen is pretty much the only SERM-and it was discovered by chance
falsodex-pure anti-estrogen-anti estrogen all over body-cause osteoporosis-
Raloxifen-good for oestoporosis, less for BC
What is the role of progesterone in breast cancer treatment?
progetstin therapy-influence proliferation and differentiation
3rd line for metastastic breast cancer-
