breast cancer Flashcards
what age gp does breast cancer effect most *
post-menopausal women
what do women present with *
lump on breast
investigations into breast cancer *
consultation and clinical examination
mammography
core needle biopsyu
what is the commonest type of breast cancer *
ER+ PR+ HER2- invasive ductal carcinoma
er = oestrogen receptor
pr = progesterone r
why do you do annual surveillance mammograms for at least 5 years *
this is measure of curative survival
after 5yrs another tumour is just as likely to be a new tumour as a recurrance
therefore if disease free for 5 yrs - not recurred
what do you do during surgery of a tumour
lymph node biopsy - look for infiltrating tumour cells
descrieb the epidemiology of breast cancer *
in 1997 - leading female cancer - acounting for almost 1 in 5 cancer deaths amoung women- 1 in 9 women in UK, US and europe would have developed the disease at some point
now there is a frequence of 1 in 8 - incidence has increased and continues to increase, but the rate of increase has slowed - around 55000 women develop breast cancer every year in the UK
describe the epidemiology of breast cancer - mortality *
mortality is falling since 80s
there has been a 17% fall in deaths
this is because of early diagnosis - because of public health message for women to self-examine = earlier diagnosis = better curative window
better chem0/radio - radio is more focussed and effective - especially when used alongside imaging
now have hormonal therapies
describe the normal structure of breast *
organ that develops after birth (in puberty) under the influence of hormones
fatty organ - in the fatty stroma are ducts and tubules (glandular structures) that join at the nipple - these are the sites of milk production
what type of tumours are breast cancer *
carcinomas - tumours of the epithelial tissue
except phylodes tumour - tumour of soft tissue ie sarcoma - rare but difficult to treat
describe the normal organisation of the mammary gland *
tubular space
2 layers of epithelial cells
inner layer lines lumen
2nd layer are myoepithelial cells, some are slightly vaculolated, they make contact with the BM - have contractile property
the myoepithelia squeeze the luminal epithelium - so force milk out of luminal epi into lumen towards the nipple
the myoepithelial cells define the structures of the tubules
re myoepithlial cells involved in cancer *
can be
describe the progression from normal to malignant breast tissue *
have normal gland
develop into precancerous state - these are benign/in situ carcinomas; myoepithelium keeps the tubular structure but there is proliferation in the tubular network - lumenal space is invaded by the pre-cancerous cells
different cancer types can come out of this precancerous state:
- lobular carcinoma - tumour cells maintain morphology, even though there is no myoepithelium
- medullary carcinoma - dont look like normal epithelium, contain vesicles that look like neuroendocrine secretory vesicles - aggressive
- carcinoma - 80-85% of breast cancers - these are infiltrating ductal carcinoma cells
describe the major histological types of invasive breast cancer *
infiltrating ductal carcinoma (IDC) - no special type of histological structure - 80% of breast cancers
immunohistochemicak staining using Ab against the human estrogen receptor (HER) is informative - it is a pathology tool to see how many cells are making the ER - 80% of the >80% of breast cancers express ER ie are ER+ve
this allows us to make predictions of how to treat patients
describe how it was discovered that oestrogen is involved in breast cancer *
atrophy of breast followed cessation of ovarian function - therefore proposed ovariectomy as a treatment for breast cancer
ovariectomy in pre-menopausal women = regression of cancer = improved prognosis
oestrogen was discovered, discovered that it was a steroid hormone - oestrogen later show to stimulate breast cancer development and growth
therefore oestrogen was chemically synthesised and things that look and behave like oestrogen were synthesised
what are important risk factors for breast cancer *
include the lifetime of exposure of oestrogen:
age of onset of menarch
age to 1st full time preg
contraceptive pills
hormone replacement therapies
describe nuclear receptors *
they are a family of receptors
ligand activated
TF - bring about changes in the genes when they are bound to their ligand
describe the oestrogen receptor and its actions *
ER is a monomeric protein in cytoplasm, assciated when bound to hsp90 (a chaperone protein)
oestrogen hydrophobic so cross cell membrane and enter cell - binds to ER - ER loses hsp90 - ER binds to another ER becomes dimeric - goes into nucleus and binds DNA binding sites (oestrogen response elements)
this triggers activation of genes - gene expression changes in minutes
the oestrogen induced gene products increase cell proliferation = breast cancer
the regulated genes are PR, cyclin D1 (regulator of cell cycle), cMyc (stop apoptosis), TGF-a (GF)
these cause stimulation of pathways that lead to growth and pathways that lead to cell survival
what is the different effect of the ER receptor in normal cells than in tumours *
in normal cells - the cells activated by oestrogen dont grow, but the cells around that dont express ER them do grow
in tumour - oestrogen drives the growth of the tumour cells
describe the oestrogen receptor in tumours *
some breast cancers are sensitive to effects of oestrogen
ER is overexpressed in 70% of breast cancers - presence suggests better prognosis
oestrogen regulates the expression of genes in cell prolif = leading to breast c
an increased level of ER is better prognosis in female breast c but worse in male - because androgne driven and act more like ER -ve breast cancers
meaning or ER over expression for treatments *
1/3 of premenopausal women with advanced breast cancer will respond to oophorectomy (removal of ovaries)
in post-menopausal women cancer responds to high dose oestrogen therapy - overstimulates ER so it shuts down = tumour regression - problem was there was relapse with metastatic disease
oestrogen withdrawal/competition for binding sites results in response from 70% of ER +ve cancers and 5-10% of ER-ve (because the ER cant always be detected fully)
what are the treatments for breast cancer &
surgery - mainstay - if given early it is very effective - lumpectomy/masectomy
radiation therapy, chemo and endocrine therapy are the follow up treatments
summarise the role of endocrine therapy *
adjuvant treatment - after surgery to make sure you have killed off all the other cells that have broken from the mass (either on their own or because of the force of surgery) which could lead to a secondary tumour
sometimes given as neoadjuvant treatment - if tumour is so large that you have to shrink the tumour before surgery - this is less common because people are better at spotting small tumours/lumps now
what are the 3 types of anti-oestrogen therapy *
ovarian suppression - for pre-menopause
blocking oestrogen production by enzymatic inhibition (ie block the enzyme that makes oestrogen)
inhibit oestrogen responses
descrieb the control and production of oestrogen *
LHRH (peptide hormone) is produced from the hypothalamus and acts on the pituitary gland
pit gland makes lh and fsh (peptide hormones) - act on ovary = production of progesterone and oestrogen
pit gland also makes ACTH - act on adrenal medulla - produces androgens - androgens are converted to oestrogen by the peripheral converion
describe the conversion of androgens to oestrogens *
happens peripherally in fat, liver and muscle
fat important becasue breast is a fatty organ
done by aromatase (high levels in these sites)
describe ovarian ablation *
only in pre-menopausal women (no use in post-men - ovaries are not making oestrogen)
the ovary is the main site of oestrogen synth
ovarian ablation eliminates this source
can be done by surgical oophorectomy, or ovarian radiation
problems with this are comorbidities and irreversibility - irreversible means people of reproductive age are infertile
to avoid this, medical ablation therapy has been produced
describe medical ablation therapy *
reversible and reliable
using LHRH agonists - block to stop the signal going to the ovary
teh agonist stimulates the pituitary at high activity = overstimulation of the pituitary gland - through feedback cycle = down regulation of the surface receptors for LHRH = suppression of LH release and inhibition of ovarian function, including oestrogen production
when the medicine is stopped - oestrogen is produced - can have children then you can go back onto the treatment after pregnancy
describe anti-oestrogens *
tamoxifen and ICI 182 780
ICI 182 780 has a very similar structure to oestrogen but the side chain makes it different - ER binds to it = cant cause transcription = block ER function because ER can’t differentiate ot from E
tamoxifen - different structure to oestrogen but also cannot be differentiated by the receptor so binds but cant act like oestrogen = cant alter gene expression = stop effects of oestrogen
describe tamoxifen *
anti-oestrogen
competitive inhibitor of oestradiol binding to oestrogen
negates the negative stimulatory effects of oestrogen by blocking the ER - causing cell to be held at G1 - eventually the cells will die
treatment for met breast c in post-menopausal women - approx 1/3 of women respond to it
few SE - hot flush (29%) is most commonly reported
it is a selective oestrogen receptor modulator
importance of tamoxifem being a SERM *
osteoporosis
- oestrogen is important in pre-menopausal women to maintain bone (after menopause can get oestrogen therapy)
- long term therapy on anti-oestrogen could cause premature osteoporosis
- howeveer tamoxifen has oestrogenic effects in bone - ie is an oestrogen agonist
atherosclerosis
- oestrogen lowers LDL and raises HDL
- after menopause women are at same CHD risk as men
- long term anti-oestrogen could cause increased risk of CHD
- but - tamoxifen has oestrogenic effects in cvs
SE of tamoxifen *
thrombolytic episodes - not frequent
endometrial thickening, hyperplasia, polyps and vaginal discharge and fibroids after several years of therapy - risk of endometrial cancer
affects hypothalamus - increases vasomotor symptoms
causes cataracts - can be treated
describe tomifene *
structural derivitive of tamoxifen - very similar properties
describe ICI 182 780 *
called faslodex or fulvestrant
exhibits no oestrogenic effects
controls oestrogen stimulated growth
faslodex is a pure antioestrogen - causes osteoporosis, CVS disease - therefore needs to be carefully managed
may be clinically advantagous to tamoxifen by reducing tumour cell invasion and stimulation of occult endometrial cancer
could have a role for 1st line when advanced breast cancer, and second line when primary tamoxifen fails
describe raloxifene *
is an antitumour agent in animals
agonist in bone - used to treat osteoporosis in post-menopausal women
no effect in breast/uterus
principle of breast cancer prevention *
tamoxifen reduces incidence of contralateral breast cancer that isnt a result of the 1st by 1/3
this led to trials for breast c prevention
trials have focussed on high risk pts - previous benign breast path on last 5 yrs, previous fam history not due to BRCA 1/2
there is a reduction in breast cancer incidence
no effect on ER-ve brest cancer incidenc
no association between prevention and age
describe problems associated with using tamoxifen in prevention *
increased incidence of endometrial cancer
stroke
dvt
cataracts
[to overcome the problems trials are being conducted with raloxifene/faslodex and aromatase inhibitors
describe the use of aromatase inhibitors in breast cancer *
in post-menopausal women major oestrogen source is conversion of androstenedione (and testosterone to lesser extent) to estroen (E2) in mammary gland
this occurs at extra-adrenal/peripheral sites such as fat, liver and muscle
this is catalysed by the aromatase enzyme complex
adrenal glands produce androstenedione that ends up in plasma - taken into fatty tissue and converted into estrone sulfate (main form of circulating oestrogen) - estrone sulfate is taken up by tissues that want to use oestrogen- sulfate removed by estrone sulfatase
aromatase is a complex containing a cytochrome p450 heme containing protein as well as flavoprotein NADPH cytochrome p450 reductase
it catalyses 3 steroid hydroxylations involved in conversion of androstenedione to estrone sulfate
drugs bind to the AS of aromatase itself - inhibit conversion of androgen to oestrogen
drug that limits etrone sulfate
inibits estrone sulfatase
in clinical trial
describe irreversible aromatase inhibitors *
compete with androstenedione and testosterone for AS
the enzyme acts on the inhibitor to get reactive alkylating species - form covalent bonds at or near AS - irreversibly inhibit enzyme - enzyme broken down
they are type 1 - ie mechanism based inhibitors
eg exmestane - single dose = major reduction in oestrogen - SE mild = hot flushes, nausea nad fatigue
describe reversible aromatase inhibitors *
type 2 - competative inhibitors
bind reversibly to AS of enzyme and prevent product formation - only as long as in AS
eg anastrozole (arimidex) - suppress oestrogen levels approaching the level of assay sensitivity
what type of breast cancer is the most responsive to eostrogen therapy *
ER+ and PR +
this is because PR is ER mediated
indicates progesterone has a role in breast cancer
drugs that target PR *
progesterone is the dominant naturally occuring progestin
progestin is an agonist - overstimulate the progestin receptors - suppressed in tumour cells
progestin response in the human breast is complex and influences proliferation and differentiated function
they are used in the treatment of uterine and breast cancer - clinically proven anti-neoplastic properties
progestin therapy for metastatic breast cancer has been used as a 2nd/3rd line therapy following selective oestrogen
the principle progestin for met breast c is megastrol acetate
problem with endocrine therapies *
a significant proportion of patients presenting with breast cancer and all patients with met disease become resistant to endocrine therapies - develop metastasis that is resistant
however most cases continue to demonstrate oestrogen responses and contain oestrogen receptor
in treatment >60% ERa+ve cancers respond to anti-oestrogens or exomestane
but resistance means there is eventual relapse - tumours have mutated ER
what is the solution to resistance to endocrine therapies *
continue use as it is successful
but need additional therapeutic agents/strategies for endocrine resistant, metastatic disease new targets that inhibit cdk
order of treatment currently - ovarian ablation and tamoxifen, tehn aromatase inhibitors then flasodex (not ovarian ablation in post-menopausal)
risk factors of breast cancer *
early age of onset of menarche
late age to menopause
age at full term preg
some forms of the pill
HRT
obestity - more aromatase
diet, physical inactivity, height, medication - aspirin
describe screening for breast cancer *
mammography to screen all women between 50-64 - being extended to 70 - attend every 3yrs
>70% of women attend screening appointments
only 6 out of 100 are asked to go back for more tests
more than 90% of cancers are spotted by women themselves
clinical features of breast cancer *
lump
pain - especially if metastisised
treatment for ER-ve breast cancer
chemo
for ErbB2+ve = herceptin
for basal like - eg lapatinib, MEK inhibitors, PI3K inhibitors - possible novel treatments
