Cancer as a Disease - Breast Cancer Flashcards
Three things that need to occur before oncologists can diagnose breast cancer
Consultation and clinical examination
Mammography
Core needle biopsy
Leading cause of female cancer?
Breast
% of women that will develop breast cancer in life
12.5% , 1 in 8
Breast cancer incidence change over time?
Been increasing
Breast cancer mortality change over time?
Falling
Reasons for breast cancer mortality fall ? (3)
early diagnosis, chemo/radiotherapies, hormonal therapies
X gland is the only one which develops post-Nataly
mammary glands
What signals mammary gland growth
Puberty
- The breast is a fatty organ with a X which comes together at the nipple
Ductal network
Around the ductal network of the breast is X
Fatty stroma
the vast majority of breast cancers are …
carcinomas of the epithelial cells of the ductal network
How many epithelial tissue layers are there in the breast? What are they called?
2 layers of epithelial cells An inner layer of luminal epithelial cells and a second layer of myoepithlial cell
Purpose of the myoepithelial cells?
can constrict/contract and are important to the development of the mammary gland, this helps move milk to the nipple
Most types of breast cancer arise from which layer of epithelium?
- Most types of breast cancer arise from the luminal epithelial cells, but some are myoepithelial and they are more difficult to treat
Which type of epithelium has oestrogen receptors
Luminal epithelium
Describe the progression from a normal to malignant breast (KW: benign in situ carcinoma, lobular, medullary)
- Local proliferation of luminal cells occurs without breaking away from the tube and without loss of the myoepithelial cells
- This is benign in situ carcinoma – this is not dangerous and there’s no intervention, it’s a watching and waiting kind of situation
- We believe this is a precursor state for the development of cancer/tumour cells
- From benign in situ carcinoma we can get lobular carcinoma (cells retain some ability to behave normally, they adopt a tubular arrangement but there are no more myoepithelial cells ) or medullary carcinoma (cells are very different to normal epithelial cells)
What 2 things can a benign in situ carcinoma develop into
lobular carcinoma (cells retain some ability to behave normally, they adopt a tubular arrangement but there are no more myoepithelial cells ) or medullary carcinoma (cells are very different to normal epithelial cells)
What is a lobular carcinoma
cells retain some ability to behave normally, they adopt a tubular arrangement but there are no more myoepithelial cells
What is a medullary carcinoma
cells are very different to normal epithelial cells
XXX many of which feature no special type of histological structure, account for almost 80% of breast cancers
- Infiltrating ductal carcinoma (IDC)
Example of a biomarker test for breast cancer
- Oestrogen Receptor test is a biomarker test that is super useful
- About 80% of breast cancers are XXX, these are the ones that grow in response to oestrogen
oestrogen-receptor positive
BREAST CANCER GROWTH IS X REGULATED
Oestrogen
Risk factors for breast cancer? (7)
lifetime of exposure to oestrogens:
- Early age of onset of menarche (start of periods)
- age to first full-term pregnancy (early age is a protective factor)
- Some contraceptive pills
- Some hormone-replacement therapies
- Obesity
- Diet, physical activity, height, medication (Aspirin)
Following menopause the breast undergoes X
atrophy
How does the oestrogen receptor lead to breast cancer (what is the name of the gene sequence it activates)
- Activated upon binding oestrogen
- Oestrogen being a steroid hormone is able to cross the cell membrane very easily
- Gene Expression is Induced by Binding to Specific DNA Sequences called Oestrogen Response Elements
- The Oestrogen-Induced Gene Products Increase Cell Proliferation, Resulting in Breast Cancer
What is the oestrogen receptor usually bound to
HSP90
Oestrogen binding allows the receptor to detach from X and Y
HSP90
dimerise
We call the proteins that are able to bind to ligands and activate transcription ….
Nuclear activators
Nuclear activators are…
the proteins that are able to bind to ligands and activate transcription
Which gene products are heavily oestrogen regulated (4)
Progesterone receptor
Cyclin D1
C-Myc
TGF-alpha
- 1/3 of premenopausal women with advanced breast cancer will respond to ….
oophorectomy (surgical removal of both ovaries
What is used to treat premenopausal women normal breast cancer
Oophorectomy
How do we treat normal breast cancer in postmenopausal some and why does this work
With high-dose therapy of synthetic oestrogens, this regress because of overstimulation of the oestrogen receptor leading to the cell degrading that receptor
Peak af problem synthetic oestrogen therapy can cause if not careful, and less peak problems?
Metastatic disease and bare side effects
Difference in prognosis between men and women in ER overexpression
Better for women worse for men
How to treat BC with overexpressed oestrogen receptors?
- Oestrogen withdrawal or competition for binding to the ER using anti-estrogens results in a response in about 70% of ER-positive cancers (5-10% of ER-negative also respond)
Primary therapy for BC
Surgery
Types of surgery for BC? (3)
Oophorectomy, complete mastectomy or smaller lumpectomies
What is removed post tumour removal in BC and why?
remove sentinel lymph nodes to check for indications of metastasis
Main treatments for BC?
- Surgery
- Radiation therapy
- Chemotherapy
- Endocrine therapy
When does endocrine therapy take place
Usually post surgery as an adjuvant, can be pre too as a neoadjuvant to shrink tumour
Why is endocrine therapy used adjuvantly
- In accessing the tumour, you liberate tumour cells, so in order to stop these from forming new tumours, we use endocrine therapy
Aim of endocrine therapy?
INHIBITING OESTROGEN ACTION IN BREAST CANCE
Three levels of endocrine therapy?
- Ovarian suppression – STOP OVARIES MAKING OESTROGEN
- Blocking oestrogen production by enzymatic inhibition
- Inhibiting oestrogen responses
Where produces oestrogens
Peripheral conversion of androgens to oestrogens
And ovary obvs
2 ways of carrying out physical ovarian ablation?
- Surgical oophorectomy
- Ovarian Irradiation
Problems with ovarian ablation
morbidity and irreversibility
Reversible and reliable medical ovarian ablation can be achieved using Luteinising Hormone Releasing Hormone (LHRH) agonists
in Y women
premenopausal
Goserelin, Buserelin, Leuprolide, Triptorelin are examples of
LHRH agonists
How do LHRH agonists work
- LHRH agonists bind to LHRH receptors in the pituitary leading to receptor down-regulation and suppression of LH release and inhibition of ovarian function, including oestrogen production
3 pharmacological ways to decrease oestrogen in women
LHRH agonists
Aromatase inhibitors
Antiestrogens
examples of SERM
- Tamoxifen looks like oestrogen to the ER
What is tamoxifen
- Tamoxifen is a selective estrogen receptor modulators (SERMs)
Its a competitive inhibitor of oestradiol binding to the ER
What does an antiestrogen like tamoxifen cause
- Anti-oestrogens negate the stimulatory effects of oestrogen by blocking the ER, causing the cell to be held at the G1 phase of the cell cycle
Why is tamoxifen particularly good
NOTE: Tamoxifen has oestrogenic effects on bone (rather than anti-oestrogenic), so it does not cause osteoporosis as someone might hypothesise
NOTE2: Similarly, in atherosclerosis, oestrogen is protective due to influences on cholesterol levels, and tamoxifen has oestrogenic CVS effects (so it doesn’t cause CVS problems like one might hypothesise)
Side effects of tamoxifen in treatment
- Tamoxifen for advanced breast cancer has been associated with subsequent thromboembolic episodes
- Tamoxifen is known to produce endometrial thickening, hyperplasia, and fibroids following several years of therapy
What are the 2 uses of tamoxifen
Breast cancer prevention and therapy
Side effects of tamoxifen in prevention
- Increase incidence of endometrial cancer
- Stroke
- Deep Vein Thrombosis
- Cataracts
In postmenopausal women, the major source of oestrogen come from …
conversion of the adrenal hormones Androstenedione (A) and (to a lesser extent) Testosterone, to Oestrone (E2)
The peripheral conversion of androstenedione and testosterone is catalysed by ..
aromatase enzyme complex
The peripheral conversion of androstenedione and testosterone happens in …
sites such as fat, liver, and muscle
What molecules are converted into oestrogen by aromatase
Androstenedione
Testosterone
What does aromatase consist of
NADPH, cytochrome P450 reductase and cytochrome P450
What number and type of reaction converts Androstenedione to oestrogen
3 hydroxylations
What else can aromatase do to Androstenedione bar convert to oestrogen
metabolise to Oestrone Sulphate
Difference between the 2 types of aromatase inhibitors?
T1 irreversible
T2 reversible
Progestin response in the human breast causes …
Proliferation and differentiation
How does progestin help with breast cancer
Overstimulation of the progesterone receptor leads to downregulating receptor
2 treatment methods targeting ER in BC?
Anti-oestrogens e.g. tamoxifen
Inhibitors of estrogen synthesis e.g. exomestane
Clinical problem with targeting ER in BC?
- Initial response but eventual relapse
- Relapse due to resistance during prolonged endocrine therapy
- NOT due to tumours becoming ER-independent
- Recent data shows that resistant tumours have mutated ER
Solution to the problem of relapse with ER treatment?
- Continue use endocrine therapies as these are successful
- But, require additional therapeutic agents/ strategies for endocrine resistant, metastatic disease
Age for BC screening?
all women between 50 and 64y/o who are registered to a UK GP (this is being extended to 70y/o)
- Patients asked to attend once every 3 years
Recommended treatment for ER -ve tumours?
Chemo
