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).
what are the normal effects of oestrogen on bone?
helps maintain bone
what are the normal effects of oestrogen on the CVS?
lowers LDL
increases HDL
therefore cardiprotective by preventing atherosclerosis
what effect does menopause have on the CVD risk in women?
with the decrease in oestrogen, the CVS protective effects are lost and their risk then equals to that of men
what are some other drugs that be used to target tissues?
Toremifene = analogue of tamoxifen.
Faslodex = no oestrogen-like activity but effective at controlling oestrogen-stimulated growth.
Raloxifene = anti-tumour agent in animals.
what does faslodex do?
o Pure anti-oestrogen.
o Decreases tumour cell invasion and the stimulation of occult endometrial carcinoma.
what effects does raloxifene have?
o Oestrogenic in bone.
o No activity in breast or uterus.
o Treats osteoporosis.
arguably better than tamoxifen as it doesn’t mess the uterus and Bress
what effect does tamoxifen have on the contralateral breast?
Tamoxifen reduces the incidence of contralateral breast cancer by a third.
what are the issues with using tamoxifen as prophylaxis?
o Endometrial cancer (oestrogenic effects on uterus)
o Stroke.(thromboembolism)
o DVT. (thromboembolism)
o Cataracts.
trials with other drugs and aromatase inhibitors are being done for prevention measures
what is the main source of oestrogen in post-menopausal women?
the main source of oestrogen is from the CONVERSION of the adrenal hormones androstenedione and testosterone (less) to oestrone rather from the ovaries directly
where does androgen conversion to oestrogen take place? what catalyses this reaction?
extra-adrenal or peripheral sites – liver, fat and muscle.
aromatase enzyme complex.
what makes up the aromatase complex?
Cytochrome P450 haem containing protein.
Flavoprotein NADPH CYP450 reductase.
what are the specific actions of aromatase?
o Aromatase catalyses 3 steroid hydroxylations involved in conversion of androstenedione to oestrone.
o Aromatase can also metabolise androstenedione to produce oestrone sulphate (circulates in plasma).
what are aromatase inhibitors?
block off oestrogen production
two types:
type 1- irreversible
type 2- reversible
name a type 1 aromatase inhibitor
Exemestane
name a type 2 aromatase inhibitor
Anastrozole (reversible)
what does Exemestane do?
competitive antagonist:
Competes with androstenedione and testosterone for binding to aromatase.
Enzyme acts on the inhibitor to create reactive alkylating species which covalently bond the active site of the enzyme so are irreversibly inactivated.
what does Anastrozole do?
Binds reversibly to aromatase
type 2 aromatase inhibitor
what is the main progestin?
progesterone
what are the use of synthetic progestrone in breast cancer?
o Endocrine treatment of uterine and breast cancers with proven antineoplastic properties.
o Metastatic breast cancer as a 2nd or 3rd line therapy (e.g. Megestrol acetate).
what occurs with long term endocrine therapy?
patients become resistant but therapy is continued as responses don’t fade despite dome regulation of receptors
, additional oestrogen inhibitors are used
describe normal breast tissue
single layer of myoepithelial cells with normal contact with a basement membrane
how does the normal breast tissue structure change into a benign/in-situ carcinoma?
- development of multiple layers
- originates in terminal duct lobular unit
- develops into invasive ductal carcinoma or invasive lobular carcinoma
what are the 2 types of benign carcinoma of the breast ?
invasive ductal carcinoma (80%)
invasive lobular carcinoma (5-15%)
what type of carcinoma are most cases?
invasive ductal carcinoma
- show no special histological features
- easily metastasise to axillary lymph nodes –> poor prognosis
which lymph nodes can invasive ductal carcinomas metastasise to?
axillary lymph nodes
leads to poor prognosis
describe the breast lump
- usually painless (pain in only 10%)
- firm
- irregular
- fixed to surroundings
ductal carcinoma is impalpable
what is the presentation of Breast cancer?
breast features:
- breast lump
- breast shape change (e.g. dimpling, swelling)
- nipple discharge (possibly bloody)
- breast/nipple pain
- nipple inversion or retraction
skin:
- peau d’orange (orange skin)
- redness
- skin tethering
- skin ulceration
- skin texture change
- axillary lump (lymph node changes)
- malignancy symptoms [3]
what are the symptoms of malignancy of breast tumour?
- weight loss
- bone pain
- paraneoplastic syndrome
what makes up the triple assessment for breast cancer diagnosis?
1) clinical exam
2) imaging
3) tissue diagnosis
what imaging [2] is done to assess for breast cancer?
1) ultrasound (<35yr)
2) mammogram [xray] (>35yr)
- screening begins after 50
what are the tissue sampling used to assess for breast cancer?
1) fine needle aspiration
- 4 hours for results to come back
2) core biopsy
- takes a day for results to come back
what are the 2 subtypes of cancer based on receptor?
oestrogen receptor negative
oestrogen receptor positive
which subtype of breast cancer is more prominent?
oestrogen receptor positive (80%)
requires endocrine therapy
what subtype of oestrogen receptor negative cancer is the main one?
Erb2 +ve (aka HER2)
this is a tyrosine kinase receptor
treated with Herceptin e.g. trastuzumab
describe the oestrogen receptor
- type
- responds to
- regulates
- intracellular
- respond to oestrogen (a steroid hormone)
- regulates genes: Cyclin D, cMyc and progesterone receptor
what are the surgical options?
- mastectomy (sometimes prophylactic)
- lumpectomy
- reconstructive
- oophorectomy
what is the purpose of an oophorectomy?
remove the source of oestrogen
how can a oophorectomy be done?
surgically or by irradiation
what is the setback of an oophorectomy?
associated morbidity
irreversibility
what is the purpose of endocrine treatment?
1) ovarian suppression
2) blocking oestrogen production
3) antagonising oestrogen
what is used to suppress the ovaries?
how does it do so?
- use of LHRH (GnRH agonist)
- causes down regulation of LHRH receptors due to overstimulation
- this means less LH is produced
- leads to ovarian supression
think about prostate cancer and how that is androgen dependent like breast cancer is oestrogen dependent : makes use of LHRH agonist as well
examples of LHRH agonists used in endocrine therapy
goserelin
buserelin
how is oestrogen production blocked?
using aromatase inhibitors
what is the major source of oestrogen in post-menopausal women?
the adrenals
what do the adrenals produce to lead to oestrogen production?
adrenals produce the precursors androstenedione/testosterone
which then is converted to oestrone (oestrogen)
what converts androstenedione into oestrogen?
aromatase
how do type 1 aromatase inhibitors interact with aromatase?
- bind to the active site of aromatase
- generates a reactive species
- irreversibly binds to enzyme
how do type 2 aromatase inhibitors interact with aromatase?
- bind reversibly to aromatase’s active site
what is used to antagonise oestrogen?
SERMs
Selective Estrogen Receptor Modulators
- used in third of patients with metastatic disease
also used in osteoporosis as oestrogen has effects on the bone
examples of SERMs
tamoxifen
raloxifene
N.b. used in osteoporosis aswell
what are SERMs?
what effect does it have on the cell?
competitive antagonists of oestrogen receptor hence selective estrogen receptor modulators
halts the cell at G1
what are the side effects of SERMS?
- hot flushes
- agonist of endometrium (BUT raloxifene is not)
- thromboembolic episodes (also risk in osteoporosis treatment)
- cataracts risk
how efficacious are SERMs?
- recurrence
- mortality
- woman (age)
- contralateral breast
- overall incidence
- reduces recurrence by nearly half
- reduces mortality by a third
- equal in pre- and post-menopausal women
- reduced contralateral breast cancer by a third
- overall reduction in incidence (38%)
why does the response to oestrogen therapy not fade even though resistance has been developed?
the receptor is still expressed so therapy must go on
here, when oestrogen receptor expression is lost, other drugs are considered to be given in addition
