breast cancer

Question 1

what age gp does breast cancer effect most *

Answer 1

post-menopausal women

Question 2

what do women present with *

Answer 2

lump on breast

Question 3

investigations into breast cancer *

Answer 3

consultation and clinical examination

mammography

core needle biopsyu

Question 4

what is the commonest type of breast cancer *

Answer 4

ER+ PR+ HER2- invasive ductal carcinoma

er = oestrogen receptor

pr = progesterone r

Question 5

why do you do annual surveillance mammograms for at least 5 years *

Answer 5

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

Question 6

what do you do during surgery of a tumour

Answer 6

lymph node biopsy - look for infiltrating tumour cells

Question 7

descrieb the epidemiology of breast cancer *

Answer 7

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

Question 8

describe the epidemiology of breast cancer - mortality *

Answer 8

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

Question 9

describe the normal structure of breast *

Answer 9

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

Question 10

what type of tumours are breast cancer *

Answer 10

carcinomas - tumours of the epithelial tissue

except phylodes tumour - tumour of soft tissue ie sarcoma - rare but difficult to treat

Question 11

describe the normal organisation of the mammary gland *

Answer 11

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

Question 12

re myoepithlial cells involved in cancer *

Answer 12

can be

Question 13

describe the progression from normal to malignant breast tissue *

Answer 13

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

Question 14

describe the major histological types of invasive breast cancer *

Answer 14

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

Question 15

describe how it was discovered that oestrogen is involved in breast cancer *

Answer 15

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

Question 16

what are important risk factors for breast cancer *

Answer 16

include the lifetime of exposure of oestrogen:

age of onset of menarch

age to 1st full time preg

contraceptive pills

hormone replacement therapies

Question 17

describe nuclear receptors *

Answer 17

they are a family of receptors

ligand activated

TF - bring about changes in the genes when they are bound to their ligand

Question 18

describe the oestrogen receptor and its actions *

Answer 18

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

Question 19

what is the different effect of the ER receptor in normal cells than in tumours *

Answer 19

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

Question 20

describe the oestrogen receptor in tumours *

Answer 20

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

Question 21

meaning or ER over expression for treatments *

Answer 21

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)

Question 22

what are the treatments for breast cancer &

Answer 22

surgery - mainstay - if given early it is very effective - lumpectomy/masectomy

radiation therapy, chemo and endocrine therapy are the follow up treatments

Question 23

summarise the role of endocrine therapy *

Answer 23

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

Question 24

what are the 3 types of anti-oestrogen therapy *

Answer 24

ovarian suppression - for pre-menopause

blocking oestrogen production by enzymatic inhibition (ie block the enzyme that makes oestrogen)

inhibit oestrogen responses

Question 25

descrieb the control and production of oestrogen *

Answer 25

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

Question 26

describe the conversion of androgens to oestrogens *

Answer 26

happens peripherally in fat, liver and muscle

fat important becasue breast is a fatty organ

done by aromatase (high levels in these sites)

Question 27

describe ovarian ablation *

Answer 27

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

Question 28

describe medical ablation therapy *

Answer 28

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

Question 29

describe anti-oestrogens *

Answer 29

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

Question 30

describe tamoxifen *

Answer 30

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

Question 31

importance of tamoxifem being a SERM *

Answer 31

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

Question 32

SE of tamoxifen *

Answer 32

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

Question 33

describe tomifene *

Answer 33

structural derivitive of tamoxifen - very similar properties

Question 34

describe ICI 182 780 *

Answer 34

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

Question 35

describe raloxifene *

Answer 35

is an antitumour agent in animals

agonist in bone - used to treat osteoporosis in post-menopausal women

no effect in breast/uterus

Question 36

principle of breast cancer prevention *

Answer 36

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

Question 37

describe problems associated with using tamoxifen in prevention *

Answer 37

increased incidence of endometrial cancer

stroke

dvt

cataracts

[to overcome the problems trials are being conducted with raloxifene/faslodex and aromatase inhibitors

Question 38

describe the use of aromatase inhibitors in breast cancer *

Answer 38

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

Question 39

drug that limits etrone sulfate

Answer 39

inibits estrone sulfatase

in clinical trial

Question 40

describe irreversible aromatase inhibitors *

Answer 40

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

Question 41

describe reversible aromatase inhibitors *

Answer 41

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

Question 42

what type of breast cancer is the most responsive to eostrogen therapy *

Answer 42

ER+ and PR +

this is because PR is ER mediated

indicates progesterone has a role in breast cancer

Question 43

drugs that target PR *

Answer 43

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

Question 44

problem with endocrine therapies *

Answer 44

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

Question 45

what is the solution to resistance to endocrine therapies *

Answer 45

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)

Question 46

risk factors of breast cancer *

Answer 46

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

Question 47

describe screening for breast cancer *

Answer 47

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

Question 48

clinical features of breast cancer *

Answer 48

lump

pain - especially if metastisised

Question 49

treatment for ER-ve breast cancer

Answer 49

chemo

for ErbB2+ve = herceptin

for basal like - eg lapatinib, MEK inhibitors, PI3K inhibitors - possible novel treatments