Breast Cancer Flashcards
Describe the epidemiology of breast cancer
Breast cancer is the leading female cancer, accounting for almost 1 in 5 cancer deaths among women
Breast cancer incidence is increasing while mortality is decreasing
What are some possible reasons for the changes in breast cancer incidence
Early Diagnosis
Chemo/Radiotherapies
Hormonal Therapies
Describe the development of the mammary gland
Only organ that develops post-natally
Under the control of hormones (steroids like oestrogen and progesterone)
What are the cell types in the breast that can become cancerous
Lobule
Duct
Lactiferous sinus
Fat and connective tissue stroma
What is the most common type of breast cancer
Carcinoma (cancer of epithelial cells - acini and ducts)
What are phyllodes tumours
They are of soft tissue rather than epithelium and are very aggressive but rare
Describe the structure of the mammary gland
A layer of myoepithelial cells, some of which are slightly vacuolated, is seen just around the luminal cells, making contact with the basement membrane
2 layers of epithelial cells
Describe the luminal cells of the breast
Produce milk in response to various cues (including hormones)
Have receptors for the steroid hormones (estrogen and progesterone)
How does oestrogen stimulate growth of the breast
Indirectly
Oestrogen stimulates paracrine secretions which stimulate growth in nearby cells
In cancers estrogen is often found to be stimulating growth directly: this is pathological.
Which hormone regulates breast cancer and how
Oestrogen
- Binding to oestrogen receptor -> receptor
- Gene Expression is Induced by Binding to oestrogen Response Elements
- The oestrogen-Induced Gene Products Increase Cell Proliferation, Resulting in Breast Cancer
Give examples of genes in the cell that oestrogen regulates
Cyclin D1
c-Myc
TGF-α
the progesterone receptor
In what proportion of breast cancers is the oestrogen receptor over expressed and how does this affect
70%
Increased ER -> better prognosis in women, worse in men
How does progesterone receptor expression affect breast cancer
PR expression is associated with better responses to treatment
Progestin response in the breast influences both proliferation and function
Therapy can use high dose synthetic progestins (better absorbed than progesterone) e.g. megestrol acetate
What are the major treatment approaches to breast cancer
Surgery
Radiation therapy
Chemotherapy
Endocrine therapy
How successful is surgery in treating beast cancer and what are the
Can be very successful, and is more regularly used than for many other cancers
Lumpectomy - If the tumour can be confirmed to be confined to the lump
Full mastectomy - whole breast is removed
Oophorectomy - removal of ovaries
At which levels can endocrine therapy for breast cancer be achieved
Ovarian Suppression
Blocking oestrogen production by enzymatic inhibition
Inhibiting oestrogen responses
What are the 2 mechanisms in which the body makes oestrogens
FSH + LH from pituitary -> ovary -> oestrogens, progesterone
ACTH from pituitary -> androgens from adrenals -> oestrogen
What is ovary ablation and how is it carried out
Eliminates the ovaries as a source of oestrogen using LHRH
Surgical oophorectomy
Ovarian irradiation
What are the problems with ovary ablation and how are they resolved
High morbidity and irreversibility
Luteinising hormone releasing hormone (LHRH) agonists to result in reversible ovarian suppression (pre-menopause)
Describe the actions LHRH agonists
Synthetic LHRH agonists are hyperactive compared to endogenous LHRH
Over-stimulation of the negative feedback loop
Pituitary gland’s gonadotrophs remove LHRH receptors from their cell membrane, becoming unresponsive to it. Suppressing LH and FSH release inhibits ovarian function and thus estrogen production.
Give examples of LHRH agonists
goserelin, buterelin, triptorelin, and leuprolide
What is the major source of oestrogen for postmenopausal women and hence what is the treatment for breast cancer in these individuals
Conversion of adrenal hormones (androstenedione and testosterone -> oestroen)
Aromatase inhibitors
How do aromatase inhibitors work and at what sites
Inhibits aromatase complex which converts androgens to oestrogens at extra-adrenal sites like liver, fat, and muscle
What are the types of aromatase inhibitors and give examples
Type I - “suicide inhibitors”, covalently bind to aromatase’s active site e.g. exemestane
Type II - temporary, competitive antagonists e.g. anastrozole
Describe the use of anti-oestrogens and give an example
Useful for both pre- and post-menopausal women
competitive inhibitors of oestradiol binding to the ER, blocking the action of oestrogen and causing the cell to be held at G1
e.g. Tamoxifen
What are the side effects of tamoxifen therapy
Hot flushes > Thromoembolic episodes Cataracts Endometrial thickening -> cancer Hyperplasia Fibroids
What are the desirable effects of tamoxifen treatment (besides breast cancer treatment)
ER agonist
Oestrogen effects in bone (+BMD)
Oestrogen effects in CVS
What is the best endocrine therapy for metastatic disease post-menopause and what class of drugs does it belong to
Tamoxifen
SERMs (selective estrogen receptor modulators)
Describe the use of tamoxifen prophylactically
Proven to be useful prophylactically for high risk patients (those with previous breast pathology or family history)
Reduces the incidence of contralateral breast cancer by 38% (a patient who already had breast cancer acquiring a new tumour in the other breast).
What is ICI 182,780/faslodex/fulvestrant
True anti-estrogen that binds to the ER to stop all estrogenic effects
It has side effects like osteoporosis
What can ICI 182,780/faslodex/fulvestrant be used for
Could be used as a first- line treatment for advanced breast cancer, as it decreases invasion and doesn’t stimulate endometrial hyperplasia. It could also be used as a second-line treatment in patients unresponsive to tamoxifen.
What is raloxifene
SERM
anti-estrogen activity in the breast and uterus but agonist activity in bone.
It is also used simply for post-menopausal treatment of osteoporosis
