Breast Cancer Flashcards
what are the changes in breast cancer incidence and mortality?
cancer incidence is increasing mortality is falling
1 in 5 cancer deaths in women
what are the reasons for the changes in breast cancer mortality?
- early diagnosis
- better treatment:
- chemo/ radio therapies
- (endocrine) hormonal therapies
- TAC, Herceptin
what part of the breast can develop cancer?
every part of the glands can have a type of cancer
most originate from the luminal epithelium of the tubules
describe the structure of breast tissue relevant to cancer formation
tubules are surrounded by fatty stromal cells.
tubules are aligned by two layers of epithelium: luminal epithelia and myoepithelia (contractile)
which cells express oestrogen receptors (ER)?
luminal epithelial cells (not all)
what is the normal response to oestrogen?
it stimulates growth via production of growth factors by the luminal cells expressing receptors (not the cells themselves)
what is the abnormal response to oestrogen seen in breast cancer?
Oestrogen seen as a GF:
oestrogen-responsive cells directly respond to oestrogen as a GF and stimulate their own growth.
what is the precancerous stage in the breast? how is it different to cancer?
benign/carcinoma in-situ
there is proliferation of cells but invasion has not occurred so there is still myoepithelium surrounding it
what are is the difference between a lobular breast cancer and medullary breast carcinoma?
lobular has resemblance of the gland while the medullary has no resemblance
ie. medullary is poorly differentiated
what are majority of breast cancers?
carcinomas
what are infiltrating ductal carcinomas?
have no special histological features
80% of breast cancers are like this
how are breast cancer samples stained?
Immunohistochemically staining using ABs against the human OR (oestrogen receptor) marking the nucleus as OR is a steroid receptor
what proportion of cancers are oestrogen positive?
> 80%
what are the risk factors for breast cancer?
involved lifetime exposure to oestrogens:
- Early menstruation (age of menarche)
- Late menopause
- HRT
- Contraceptive pills
- age to full term pregnancy
- obesity
how is the OR found in the cell?
bound to a heatshock protein therefore in a dimer
what property allows oestrogen to bind to the OR?
the lipophilic oestrogen can pass the membrane and bind
what happens when oestrogen binds to the OR?
the heatshock protein is displaced and then 2 ORs dimerise
the dimerised ORs can enter the nucleus and bind to oestrogen response elements on the DNA to dimerise them aswell (pull them together)
has a growth factor effect
what are some oestrogen regulated genes?
o Progesterone receptor (PR).
o Cyclin D1.
o C-myc.
o TGF-alpha
what is done in pre-menopausal women with breast cancer to reduce oestrogen effects?
oophorectomy (a third of PreM women respond)
what is done in post-menopausal women with breast cancer to reduce oestrogen effects?
paradoxically respond to high dose oestrogen therapy
ORs are downregulated as a result of high oestrogen conc
what is the prognosis like in OR+ women?
better prognosis as overexpression can be treated with oestrogen withdrawal or antagonism with anti-oestrogens
(70% response in OR+ compared to 10-15% in OR-)
how is the prognosis for OR+ in men?
bad,
androgens drive breast cancer in men
what are the major treatment options for breast cancer?
o Surgery.
o Radiation therapy.
o Chemotherapy.
o Endocrine therapy – the gold-standard or cornerstone treatment:
what is involved in endocrine therapy?
Ovarian suppression.
Blocking oestrogen production by enzymatic inhibition.
Inhibition of oestrogen responses.
what is ovarian ablation?
removal (surgical) of a source of oestrogens i.e. ovaries via oophorectomy or ovarian irradiation
why is ovarian ablation not always favoured?
what is preferred instead?
morbidity and irreversibility
suppression techniques are preferred (endocrine)
how can ovarian suppression be mediated?
by using Luteinising Hormone Releasing Hormone agonists
these have reversible effects
what effect to LHRH agonists have?
binds to pituitary and down regulates LH release (enhancing the -ve FB loop on LH), downregulates LHRH receptors and inhibits ovarian function i.e. oestrogen, FSH and LH production
same process for prostate cancer treatment
examples of LHRH agonists
Goserelin
Buserelin,
Leuprolide
Triptorelin.
what are some hormonal targets for therapy?
LHRH agonists.
Aromatase inhibitors – prevent conversion.
Antioestrogens.
when is endocrine therapy used?
as an adjuvant therapy to eliminate any remaining cancer cells to prevent any secondary tumours forming
what is tamoxifen?
OR-blocker/ Selective ER modulator (SERM)
competitive inhibitor
high efficacy with low side effects
can be used in metastatic breast cancer in post-menopausal women
what are anti-oestrogens?
structurally similar to oestrogens but can’t be differentiated by the OR and therefore will block the receptor
what effect does tamoxifen have on cells?
arrests them at G1 so negates oestrogen’s effects
what are the positive of tamoxifen?
have oestrogenic effects on the bone and CVS by decreasing risk of osteoporosis and atherosclerosis
what are the risks with using tamoxifen?
increased risk of thromboembolic events and can cause endometrial hyperplasia (cancer possibility).