CasaD - Breast Cancer Flashcards
Although the incidence of BC is increasing, mortality is decreasing - why is this?
Due to
• early diagnosis
• chemo
• hormonal therapies
What is unique about breast cancer?
ONLY organ to develop AFTER birth
• hence EVERY part of the gland (all cells) can have a type of cancer
Where does most breast cancer originate in?
Luminal epithelium
Explain mammary gland organisation
Between the tubules are fatty stromal cells
There are two layers of epithelial cells:
• Luminal epithelial cells
• Myoepithelial cells – contractile cells
Where can oestrogen receptors be found?
ONLY expressed by luminal epithelial cells
• BUT NOT all the luminal cells express the receptor
Explain the oestrogen receptor response in a NORMAL vs. BC state
NORMAL response to oestrogen
• stimulate growth via production of GFs by the luminal cells expressing receptors (not the cells themselves)
Breast cancer response
• REVERSAL
• oestrogen-responsive cells directly respond to oestrogen as a GF and stimulate their own growth.
Schematic diagram of the progression of normal to malignant breast tissue?
Benign/carcinoma-in-situ
• proliferation of luminal cells but the myoepithelium is still around it
Lobular carcinoma
• resemblance of the architecture of the gland.
Medullary carcinoma
• no resemblance to the gland.
• majority of cancers are not either lobular or medullary so are just called breast carcinomas.
What is the major histological type of invasive BC?
IDC - infiltrating ductal carcinoma
Feature NO special histological features
• 80% of BCs are ‘OR’ +VE
OR
Positive (immunohistochemically staining)
How is staining carried out for BCs?
Immunohistochemically staining
• using ABs against the human ‘OR’ (oestrogen receptor) is informative
• This stain marks the nucleus as ‘OR’ is a steroid receptor.
> 80% of breast cancers are OR+.
RFs for BC?
- Early menstruation
- Late menopause
- HRT
- Contraceptive pill
- Pregnancy
Explain how the ‘OR’ is activated
Inside the cell, the OR is bound to a heatshock protein to form a dimer
• Oestrogen (lipophilic) then passes through the membrane
• it binds to the OR and displaces the heatshock protein –> 2 ORs then dimerise
Dimerised ORs enter the nucleus and bind to the DNA response elements
• pull them together (response elements are also in two halves and need a dimer to activate them)
What are some important oestrogen regulated genes
- Progesterone receptor (PR)
- Cyclin D1
- C-myc
- TGF-alpha
Oestrogen can also affect some BCs like it affects the normal breast - explain this
Approx 1/3 of PRE-MENOPAUSAL women will respond to an oophorectomy
Paradoxically, breast cancer in POST-MENOPAUSAL women respond to high-dose oestrogen therapy
• due to downregulation of ORs as there is a high concentration of oestrogen
OR is over-expressed in around 70% of BCs - explain this
Presence is indicative of a BETTER prognosis
OR+ cases can have
• oestrogen withdrawn OR antagonised with anti-oestrogens
to result in ~70% response in OR+ cancers and 10-15% in OR- cancers.
Prognosis if OR expression in females vs. males
Females = GOOD prognosis
Males = BAD prognosis
Major treatment approaches for BC?
- Surgery
- Radiation therapy
- Chemotherapy
- Endocrine therapy
What is the gold-standard/cornerstone treatment for BC?
Endocrine therapy - includes:
• Ovarian supression
• Blocking oestrogen production via. enzymatic inhibition
• Inhibition of oestrogen responses
2 types of therapy that can be used which targets the ovaries?
Ovarian ablation (surgical)
vs.
Suppression (endocrine)
Why is Ovarian Ablation carried out?
The ovary is the major source of oestrogens and so ablation aims to eliminate this source. This is done via:
o Surgical oophorectomy
o Ovarian irradiation
The major problems with this is
• morbidity & irreversibility
so there are more medical suppression techniques
Explain Ovarian Suppression
Reversible/reliable medical ovarian ablation is achieved with
• LHRH (LH-Releasing Hormone) agonists!!
These bind in the pituitary gland:
• down-regulate & suppress LH release
• inhibit ovarian function (including oestrogen production)
Examples of LHRH?
LH-Releasing Hormone
- Goserelin
- Buserelin
- Leuprolide
- Triptorelin
What are the hormonal targets for BC?
• LHRH agonists
• Aromatase inhibitors
- prevent conversion of androgens –> osterogens
• Antioestrogens
Main Anti-Oestrogen drug that can be used?
Tamoxifen
What is Tamoxifen
OR-blocker
OR
a SERM (selective oestrogen receptor modulator)
It is a competitive inhibitior!
How does Tamoxifen work?
Negates the effects of oestrogens
• so the cell is arrested at the G1 phase
Also has oestrogenic effects in the BONE & CVS
• so decreases risk of oestoporosis & atherosclerosis
When is Tamoxifen normally used?
It is the endocrine treatment for metastatic disease in POST-menopausal patients
• around 1/3 patients respond
What are some side-effects associated with Tamoxifen?
Hot flushes
Increased risk of
• thromboembolic events
AND
• can cause endometrial hyperplasia (endometrial cancer possibility)
Desirable effects of oestrogen vs. negative effects?
Brain
• +VE = improves cognitive function
Breast
• +VE = programs glands to produce milk
• -VE = promotes breast cancer
Liver & Heart
• +VE = lowers cholesterol, reduces atherosclerosis and HAs
• -VE = increases thromboembolism in LIVER
Uterus
• +VE = programs uterus to nourish a foetus
• -VE = promotes endometrial cancer
Bone
• +VE = maintains density to help prevent bone loss
ONENOTE!!
Toremifene?
Analogue of Tamoxifen
Faslodex?
NO oestrogen-like activity
BUT
Effective at controlling oestrogen-stimulated growth
- pure anti-oestrogen
- decreases tumour cell invasion & stimulation of occult endometrial carcinoma
Raloxifene?
Anti-tumour agent
- osterogenic in bones
- no activity in breast OR uterus
- treats osteoporosis
What has Tamoxifen trials shown?
Tamoxifen reduces the incidence of contralateral breast cancer by a third
Tamoxifen trials have shown:
o 38% reduction in overall breast cancer incidence
o No effect on OR- breast cancer incidence
o No association between prevention and patient age
Problems associated with Tamoxifen as a PROPHYLACTIC drug?
- Endometrial cancer
- Stroke
- DVT
- Cataracts
Due to these, prevention trials are being conducted with Raloxifene/Faslodex (SERMs) and aromatase inhibitiors
In POST-menopausal women, what is their main source of oestrogen?
From the CONVERSION of the adrenal hormones androstenedione and testosterone (to a lesser extent) to oestrone (O2/E2), rather than from the ovaries directly
o This conversion occurs at the extra-adrenal or peripheral sites – liver, fat and muscle.
o Catalysed by the aromatase enzyme complex
Explain Aromatase
Aromatase is a complex with:
• Cytochrome P450 haem containing protein
• Flavoprotein NADPH CYP450 reductase
Aromatase catalyses 3 steroid hydroxylations involved in conversion of androstenedione to oestrone
• Aromatase can also metabolise androstenedione to produce oestrone sulphate (circulates in plasma)
What are the 2 types of Aromatase inhibitors
Suicide inhibitors: Exemestane
• Competitive 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 –> irreversibly inactivated
Competitive inhibitors: Anastrozole
• Binds reversibly to aromatase
Drugs associated with the main 2 types of aromatase inhibitors?
Suicide inhibitors
• Exemestane
Competitive inhibitors
• Anastrozole
Main progestin in the body?
Progesterone
Issues with the main progestin in the body and its uses?
Due to the POOR ABSORPTION of synthetic progesterone, synthetic derivatives have been made
Uses:
o Endocrine treatment of uterine and breast cancers with proven anti-neoplastic properties
o Metastatic breast cancer as a 2nd or 3rd line therapy (e.g. Megestrol acetate)
What eventually happens to patients with BC and all patients with metastatic disease?
Become RESISTANT to endocrine therapies
• however, most cases continue to demonstrate oestrogen responses & contains ORs (which we can then inhibit)
As patients become resistance to endocrine therapy & inhibitors of oestrogen synthesis, what is the solution?
Endocrine therapy - anti-oestrogens (Tamoxifen)
Inhibitors of oestrogen synthesis - (Exemestane)
Solution is to CONTINUE therapy and add:
• ADDITIONAL inhibitors of oestrogen action
