12. Breast cancer Flashcards
What proportion of cancer deaths in women if caused by breast cancer?
1/5
How is breast cancer incidence and mortality changing?
- Incidence rising
* Mortality falling (early diagnosis)
What type of therapy has the biggest impact on breast cancer?
Hormonal therapies
What type of breast cancer is the most common?
Carcinoma (tumour of epithelial cells)
Which gland is the only organ to develop post-natally?
- Mammary gland
* Initially present as a rudimentary gland, then growth is driven by hormonal changes
What cells line the lumen in the mammary gland?
• Ring of epithelial cells • 2 layers • Second layer of epithelial cells = myoepithelial cells - can contract - these make contact with the BM
Which cells produce milk?
Luminal cells
Which cells make the milk-producing cells release it into the duct?
Myoepithelial cells squeeze the luminal cells to release milk
Is it harder to treat epithelial or myoepithelial tumours?
Myoepithelial
What percentage of luminal cells can respond to oestrogen?
- 10-20%
* These cells have receptors to respond to steroid hormones, particularly oestrogen
What is it called when there is a local proliferation of cells that are luminal, they don’t break away and there is no loss of myoepithelial cells?
Benign in situ carcinoma
• easily diagnosed as non-cancer
• however, it’s a precursor state for the development of cancer
What is lobular carcinoma?
- Cancer cells try to form tube-like structures, but fail
- Some indication that they try to retain the ability to behave like a normal luminal epithelial cell
- But no myoepithelial cells present
What is medullar carcinoma?
- Look nothing like breast cancer cells or epithelial cells
* Packed full of vesicles that are rich in neuro-endocrine peptides and hormones
What is a major staining method for the identification of breast cancer and what can this tell us?
- Immunohistochemical staining using antibodies against the human oestrogen receptor (ER) (using an antibody)
- Allows classification based on level of ER expression (nothing to very high)
- About 80% of breast cancers are ER positive - so 80% are treatable
What percentage of breast cancers does infiltrating ductal carcinoma (IDC) account for?
Almost 80%
What happens to breast tissue after the loss of ovarian function during menopause and how is this significant in treatment options?
• Atrophy of the breast tissue - no breast cancer
- Therefore, ovariectomy has been proposed as a treatment for breast cancer
- Ovariectomy in pre-menopausal women has resulted in disease regression
- Oestrogen on the other hand has been shown to stimulate breast cancer so this makes sense
Which lifetime oestrogen related risk factors can contribute to the risk of breast cancer?
- Age of onset of menarche (first menstrual cycle)
- Age to first full-term pregnancy (early pregnancy is protective)
- Some contraceptive pills
- Some hormone-replacement therapies
Which part of the cell is the oestrogen receptor located in?
Cytoplasm (but it is a ‘nuclear receptor’)
What is the oestrogen receptor bound to?
- Heat-shock 90 protein
- This is displaced when the oestrogen binds
- Allows the receptor to dimerise
How does the oestrogen receptor induce gene expression?
- Binds to specific DNA sequences called oestrogen response elements
- Increases cell proliferation and cell survival
Why is it so easy for oestrogen to cross the cell membrane?
Very lipophilic molecule
What type of receptor is the progesterone receptor?
Nuclear receptor
What is the relation between the progesterone receptor and oestrogen?
- The PR is a very strongly oestrogen-regulated gene in the mammary gland
- Where PR is expressed, the ER is working
- Can be used in a test to see if the ER is working in a tumour
Apart from the PR, which other genes are affected by oestrogen in breast cancer cells and what do they do?
- Cyclin d1 - regulator of the cell cycle
- C-myc - regulation of apoptosis
- TGF-alpha - GF that directly influences cellular growth
Why does high-dose therapy with synthetic oestrogens cause breast tumour regression in post-menopausal women?
• Negative feedback - less receptors
• Degradation of the receptor due to too much oestrogen
• Cells no longer express ER, so cannot be driven with oestrogen
- tumour regression
Why is the use of synthetic oestrogens not a good treatment option?
- Can lead to metastasis - tumour becomes incurable
- Resistance often follows remission
- Drugs must be given in high dose - many side effects
How responsive are ER-positive and negative cancers in the use of anti-oestrogens?
- ER +ve - 70%
* ER -ve - 5-10%
How does an increased level of ER expression affect the prognosis in male breast cancer?
Worse prognosis
What is the primary treatment option for breast cancer?
Surgery
What do surgeons also tend to remove during surgery, apart from the tumour itself?
Sentinel lymph nodes under the arm
What treatment are patients often offered before surgery?
Endocrine therapy to shrink the size of the tumour (rare now due to early detection)
(example of neo-adjuvant therapy)
When is endocrine therapy most often given?
• After surgery (adjuvant therapy)
• During surgery some cancer cells may break off and travel in the blood, or they may be left behind
- so endocrine treatment helps in this event
Which hormones regulate oestrogen production?
• Peptide gonadotrophin hormones FSH + LH
- from pituitary gland
• Pituitary is regulated by GnRH
- from hypothalamus
• Androgenic steroids can be converted to oestrogens (aromatisation)
- in pre/post-menopausal women
What is ovarian ablation?
- Suppression of ovaries to stop them from producing oestrogen
- Surgical oophorectomy - removal
- Ovarian irradiation - destroy thecal cells
What are the problems with ovarian ablation?
- Morbidity and irreversibility
* Lost fertility
How can the problems of ovarian ablation be overcome
- Medical ovarian ablation using LHRH agonists
- Bind to LHRH receptors in the pituitary
- Leads to LHRH receptor down-regulation and suppression of LH release
- This causes inhibition of ovarian function
Are the effects of medical ovarian ablation with LHRH agonists reversible?
Yes, ovarian function and fertility is restored when coming off treatment
Can women have children during treatment with LHRH agonists?
Yes
What can we prescribe to block the effect of oestrogen on cancer in post-menopausal women?
- Aromatase inhibitors
* Anti-oestrogens
What does tamoxifen do?
- Anti-oestrogen
- SERM - selective oestrogen receptor modulator
- Competitive inhibitor oestradiol binding to the ER
- Causes the cell to be held at G1 - cell will die
- Endocrine treatment of choice for metastatic disease in post-menopausal patients
- 1/3 respond
- Few side effects
What is the effect of tamoxifen on bone?
- Oestrogenic effects
* Therefore it doesn’t cause osteoporosis like most long-term anti-oestrogens
What effect does oestrogen have on cholesterol and why is this significant for post-menopausal women?
- Lowers LDL
- Raises HDL
- Removal of this effect causes post-menopausal women to be at the same risk for CHD as men
What is the effect of tamoxifen on the CVS?
- Oestrogenic effects
* Therefore it doesn’t increase the CV effects like most long-term anti-oestrogens
What is a SERM?
- Selective oestrogen receptor modulator
- Acts different on different oestrogen receptors
- Some can only target the mammary gland to effect the tumour
What are the unwanted effects of tamoxifen?
- Association with thromboembolic episodes
- Endometrial thickening (risk of cancer)
- Hyperplasia
- Fibrosis
What are the advantages and disadvantages of Fulvestrant (anti-oestrogen)?
- Pure anti-oestrogenic - many side effects
* However, it decreases tumour cell invasion well and decreases the stimulation of endometrial carcinoma
What is raloxifene?
- Anti-tumour agent
- SERM - acts in the bone
- Used in the treatment of osteoporosis in post-menopausal women
How useful has tamoxifen been in breast cancer prevention?
- 38% decrease in incidence
- No effect on ER negative incidence
- No association between prevention and age
Therefore, it promotes prevention
Give 4 problems associated with the use of tamoxifen in prevention
- Endometrial cancer risk
- Stroke
- DVT
- Cataracts
What has been done to overcome the problems associated with the use of tamoxifen in prevention?
Trials being conducted with
• Raloxifene/Faslodex (SERM)
• Aromatase inhibitors
What is, and describe, the major source of oestrogen in post-menopausal women?
- Conversion of adrenal hormones Androstenedione (and testosterone to a lessor extent)
- Occurs at extra-adrenal or peripheral sites e.g. fat, muscle and liver
- Catalysed by the aromatase enzyme complex
What does aromatase consist of?
- Complex containing a CYP450 heme containing protein
* Also flavoprotein NADPH CYP450 reductase
What type of reactions and how many reactions does aromatase catalyse?
Three separate hydroxylations involved in the conversion of androstenedione to oestrone
Where is androstenedione produced?
Adrenal glands
Oestrone sulphate is produced by the metabolism of what?
Androstenedione by aromatase
What 2 types of drugs can inhibit the activity of aromatase?
- Type I - mechanisms-based, or suicide, inhibitors - irreversible
- Type II - competitive inhibitors - reversible
Describe type I aromatase inhibitors
- Initially compete with the natural substrate for binding to the active site
- The enzymes then acts on the inhibitor to yield reactive alkylating species
- These form covalent bonds at/near the active site
Describe type II aromatase inhibitors
- Bind reversibly to the active site of the enzyme
* Prevent product formation only as long as the inhibitor occupies the catalytic site
How are progestins useful in cancer treatment?
• Response in the breast is complex, but it influences proliferation and differentiation function
• Used in endocrine treatment of uterine and breast cancer - anti-neoplastic properties
• Second/third-line therapy for metastatic breast cancer
e.g. megestrol acetate
What type of treatment do all patients with metastatic disease become resistant to?
Endocrine therapy
How do ER-positive tumours become resistant to endocrine therapy and how can this be overcome?
- Mutation of ER
* Continue with this therapy, but with additional therapeutic agents
What the the UK breast-cancer screening programme involve?
- Mammography for women between 50-60yrs who are registered with a GP
- Age being extended to 70
- Attendance every 3 years
- More than 90% are spotted by women themselves
