12: Breast Cancer Flashcards
Summarise the epidemiology of breast cancer
Mainly: post-menopausal women
- 1/5 of all female cancer deaths
- 1/9 of women will get breast cancer
- increasing incidence but decreasing mortality
What is the trend of the incidence in breast cancer in the UK?
The incidence is increasing
What is the trend of the mortality rates in breast cancer?
Why?
The mortality is decreasing due to
- Early Diagnosis
- Better therapies
- Chemo/Radiotherapies
- Hormonal Therapies
What kind of tumors are most breast cancers?
Normally Carcinomas! (epithelial tissues of ducts)
but might be:
- e.g. Sarcoma of fatty tissue (rare but agressive)
Explain the strucutre of the ductural epithelium in the mamillary gland
The ductural epithelium surrounds the ducts consisting of 2 layers
- Luminal epithelium (inner layer)
- Outer Myopithelial cells
- contract during milk ejection
Which cells are the main site of development of a Mamma Ca?
The luminla (inner layer) epithelial cells
How do you call the pre-cancerous state in “breast cancer”?
What are its characteristics?
It is called “carcinoma in situ”
- pre-invasive
- often: the characterisitcs of individual cells are normal but they have an abnormal growth pattern
Picture: carcinomal im situ of luminal epitheilal cells
What are the differnet forms of cancer that can develop from a mamillary carcinoma in situ?
What is the most common one?
Carcinoma in situ can go on and develop differnt types of cancer– >originate in terminal duct lobular unit
- Lubular carcinoma (10-15%)
-
Infiltrating Ductal Carcinoma, not otherwise specified
- 80%!
- Medullary carcinoma, rare, agressive
How do you asses if a Mamma Ca is oestrogen positive or negative?
How many carcinomas show each characteristic?
It is done by histological staining with antibodies against human Estrogen Receptor (ER)
- 80% of IDCs (infiltrating ductal carcinomas) are ER positive!
Explain the location, activation and effect of the Estrogen Receptor and ER activation
It is an steroid (intracellular) receptor
- Estrogen binds to it and releases hsp90
- Causing dimerisation of ER
- Travel into cell and alter DNA transcription
Which molecules get expressed via the activation of an Estrogen Receptor?
Normally upregulates pro- proliferative and anti-apoptotic factors
- upregulation of Progesterone Receptor (PR)
- Cyclin D1
- c-myc
- TGF-a
Explain the usuall treatment approach for Breast Cancer
Normally
- Surgery
- remove the tumor
- Adjuvant therapy –> kill everything that is left behind)
- radiotherapy
- chemotherapy
- endocrine therapy
What is the normal response to Estrogen stimmulation in normal breast cells and in cancerous cells
Though activation of ER leads to increased expression of pro-proliferative and anti-apoptotic signals,
- Normal cells: don’t proliferate/grow themselves but signal adjacent cells to grow (e.g. via TGF)
- In tumor cells: drives tumor growth
What is the main rationale behind endocrine therapy in breast cancer?
What are the different approaches used?
RAtionale: To reduce Estrogen and therefore growth and proliferation of the tumor
- In pre-menopausal women: ovarian supression
- Blocking estrogen production by enzymatic inhibition
- Inhibiting estrogen responses
When would you chosse to treat breast cancer via ovarian supression?
Which strategies do you have?
Aim: to reduce Estrogen production in pre-menopausal women
- Ovarin ablation
- surgical oophorectomy
- Ovarian Irradiation
- Supress production of LH/FSH
Explain the process of ovarian ablation in the treatment of breast cancer
What are the disadvantages
Reduce estrogen production in pre-menopausal women
- Surgical removal
- ovarina irradiation (destruction via radiation)
–> Steps are irreversible and lead to infertility, increased morbidity due to risk of procedures
Explain the process of hormonal supression in the treatment of breast cancer
LHRH Agonist used to supress the production of LH/FSH
- overstimmulation of LHRH-receptor leads to its downregulation –> less/no response to LHRH
- reduced Estrogen production
Explain the MOA of antiestrogens in breast cancer
ER antagonists
- negate the stimulatory effects of estrogen by blocking the ER, causing the cell to be held at the G1 phase of the cell cycle.
Name an example of an anti-estrogenic drug and its clinical use
e.g. Tamoxifen
- used as adjuvant therapy in Breast cancer
- metastatic disease in postmenopausal patients –> effective and few side effects
Also use as HRT in poastmenopause
Explain the effects of Tamoxifan and its use
It is a Selective-Estrogen Receptor Modulator (SERM)
- anti-estrogenic in breast tissue –> blocks growth of cancer cells
- pro-estrogenic in bone + CVS
- prevents osteoporosis + enhances estrogenic CVS protection
What are the main side-effects of the use of Tamoxifen?
- It increases the riks of thrombosis/embolisms
- It stimmulates growh of the endometrium –> endrometrial cancer
- increased frequency of cataracts
What are the effects of tamoxifen in contalateral breast cancer/ prevention
Reduces the incidence of contralateral breast cancer of 30% –> might be considered as preventative treatement for high risk patients
Where does the peripheral enzymatic conversion of androgens to estrogens mainly occur?
Mainly in fatty tissue –> breast is a fatty tissue
But also in
- liver
- muscle
Explain the role of the Progesterone receptor in cancer treatement
In advanced cases
- Progesterone Receptor positive diseases were a lot more likely to respond to treatment
- Can be used as a target in Breast cancer treatment
Which other receptor/Hormone could you use to treat breast cancer?
Progesterone Receptors
- use progestin in breast cancer –> high dose to cause downregulation of receptors and therefore low responses to treatment
- used in uterine and breast cancer
- for breast cancer: 2nd/ 3rd line therapy in metastatic disease
- (megestrol acetate)
What is the main issue with endocrine treatments in breast cancer?
Resistance
- expecially in metastatic disease, all patients become resistant
- But still express ER and are driven by estrogen –> switch from tamoxifen to aromatase inhibitors
–> Use endocrine treatments as long as possible but after that: additional treatment required
What are risk factors for developing breast cancer?
Mainly: Exposuter to estrogen
- early onset of menstruation, late menopause
- age at first full-term pregnancy
- Forms of contraceptive pill
- HRT
- obesity (aromatase in fatty tissue)
- lDiet, physical activity, height, medication (Aspirin)
