breast cancer SD Flashcards
what is the main function of the breast?
production and expression of milk
– To provide a nourishment and
immune protection for offspring
what does each lobe in the breast contain?
Each lobule consists of a variable
number of acini (glands) connecting to
the intralobular duct
what is the role of epithelial cells in the breast?
synthesise milk
what is the role of the intralobular duct?
connects with the extralobular duct
how many lobes do the mammary glands contain?
10-20
what happens to the lobes during pregnancy?
the lobules undergo controlled proliferation and enlargement in preparation for lactation.
what occurs following birth?
Following birth hormone fall and it is
prolactin that is necessary for the initiation
of lactation
what happens when breast feeding ceases?
When breastfeeding ceases there is a rapid
change to the differentiated lobular
structure, and the breast returns to the
pre-pregnancy structure.
how does a breast cancer diagnosis occur?
self examination for changes
mammography and ultrasonography
fine-needle aspiration cytology
core biopsy/ vacuum-assisted biopsy
what do benign breast tumours comprise?
– Fibroadenomas
– Duct papillomas
– Adenomas
– Connective tissue tumours
where do fibrodenomas arise from?
the breast lobule, and involve proliferation of both the connective tissue stroma and the glands
how do you classify breast carcinoma?
non- invasive
invasive (infiltrating)
other
what are the types of non-invasive carcinomas?
- Ductal Carcinoma in Situ (DCIS; Intraductal Carcinoma)
- Lobular Carcinoma in Situ (LCIS)
what are the types of invasive carcinomas?
- Infiltrating Ductal carcinoma
- Invasive Lobular Carcinoma
how do you stage breast cancer tumours?
TNM- tumour node metastasis
tumour status and lymph node status
and distant metastasis
what are the different groups of T4?
T4A- tumour has spread into chest wall
T4B- tumour has spread into the skin and the breast wall might be swollen
T4C- spread to both skin and chest wall
T4D- inflammatoru carcinoma
what are some common sites of metastases?
lymph nodes lead to distant sites
how can you test for metastases?
- Lymph node ultrasound/Biopsy
- MRI Scan
- CT Scan
- Liver Ultrasound
- Bone Scan
what is stage 0 of breast cancer?
Stage 0 is used for ductal carcinoma in situ (DCIS). It is a pre invasive breast cancer. The cancer cells are in breast ducts and have not started to spread into the surrounding breast tissue.
what is stage 1 of breast cancer?
- Stage 1 breast cancer means that the cancer is small and only in the breast tissue or it might be found in lymph nodes close to the breast. This is an early stage breast cancer.
what is stage 2 of breast cancer?
- Stage 2 breast cancer means that the cancer is either in the breast or in the nearby lymph nodes or both. This is an early stage breast cancer.
what is stage 3 of breast cancer?
- Stage 3 means that the cancer has spread from the breast to lymph nodes close to the breast or to the skin of the breast or to the chest wall. This is also called locally advanced breast cancer.
what is stage 4 of breast cancer?
Stage 4 breast cancer means that the cancer has spread to other parts of
the body.
where is ERa expressed?
uterus, ovarian cells, Leydig cells in testes,
epididymis, breast, and liver
where is ERb highly expressed?
prostate epithelium, testes, ovarian granulosa cells, bone marrow, and brain
what happens if there is a variation in AF regions?
different cofactors will bind
do ERa and ERb work the same way?
ERα and ERβ have different downstream transcriptional activities, resulting in their
tissue-specific biological actions
what bonding occurs with ER agonists such as estradiol?
alcohols groups- hydrogen bonds with 3 AA
hydrophobic skeleton- van der waals forces
this causes conformational change= activates receptor
what does tamoxifen prevent?
ER gene co-activation
how does tamoxifen prevent ER gene co-activation?
tamoxifen binds to ER
masks the AF2 site
this leads to less co-activator recruitment
partial agonist/antagonist
what is tamoxifen?
a non steroidal anti-estrogen competitive inhibitor
what kind of action do tamoxifen and raloxifen have?
both estrogenic AND antiestrogenic actions,
depending on the target tissue.
Strongly antiestrogenic on mammary epithelium
Proestrogenic on uterine epithelium and bone
how may tamoxifen resistance occur?
– Loss of ER expression in patient
– Activating ER mutations
– ER receptor is hypersensitised to low oestrogen levels
– Increased oestrogen levels – competition
– Altered co-regulators
– Pharmacologic tolerance – increased efflux OR decreased influx of
the drug by membrane pump glycoproteins
– Endocrine adaption and receptor crosstalk (
why were aromatase inhibitors used?
upon development of resistance of tamoxifen
when are aromatase inhibitors used?
2nd line treatment in oestrogen dependant breast cancer that have become Tamoxifen resistant
what does the aromatase enzyme inhibitor comprised of?
– Cytochrome P450 (CYP19A1)
– Reductase enzyme that uses NADH as a cofactor
what are the two clinically used aromtase enzyme inhibitors?
reversible competitive inhibitor
irreversible inhibitors
give an example of a reversible aromatase enzyme inhibitor and how it binds
Anastrazole and Letrozole – binds to
haem group of aromatase and prevents
binding to steroid
how do irreversible aromatase enzyme inhibitors work?
- More selective that reversible inhibitors
- Act as “suicide” substrate as they
permanently inactivate aromatase
inhibitor - Exemestane mimics androstenedione
but binds irreversibly - Overall effect is to lower circulating
oestrogens
what is SERD? how does it work?
Brand name Faslodex (Astra Zeneca)
* Selective Estrogen Receptor Degrader (SERD)
* Tightly binds to ER
* Masks both AF1 and AF2 sites
* Causes receptor instability
* ER is then DEGRADED by the proteome
what is ER+ve?
use drugs that block estrogen producing or estrogen signalling
what is HER2 +ve?
eg herceptin
use drugs to target HER2 signalling
what is triple negative?
use other more generalised, more toxic drugs as blocking estrogen/HER2 wont be effective
what have mutations that lead to EGFR overexpression been associated with?
Adenocarcinoma of the lung (40% of cases),
* Rectal cancers
* Glioblastoma (50%)
* Epithelian tumors of the head and neck (80-100%).
what is HER2?
HER (Human Epidermal Growth Factor Receptor)
– The HER2 gene amplified in 20-30% of breast cancers
– HER2 is a receptor tyrosine kinase - undergoes dimerization and
autophosphorylation
what happens with low HER2 and high HER2?
low- normal growth
high=malignant growth
what is HER2 amplification/ overexpression associated with?
– accelerated cell growth and proliferation
– increased risk of disease recurrence
– shortened overall patient survival.
where is HER2 found?
Found on the surface of normal breast cells
* Some breast cancer cells have a very high number of HER2 receptors
what is trastuzumab?
Trastuzumab is a humanized antibody that blocks the HER-2 receptor
what monitoring is required with herceptin?
– Associated with cardiovascular dysfunction
– Monitoring of cardiac function required
what happens to HER2 p95 fragment?
HER2 receptor undergoes proteolytic cleavage in overexpressing cells
* Leads to the ECD fragment being shed and an active “p95” domain
* Function not fully characterised
* Associated with poor prognosis for patients
how does herceptin illicint an immune response?
- Antibody Dependent Cellular Cytotoxity (ADCC)
- The Fc domain of Herceptin binds to Natural Killer cells with Fc gamma receptor
- Herceptin binding not only triggers all previous events but also flags the cells for immune attack
- Tumour cell lysis occurs
what doe herceptin do?
Blocks VEGF and Tumour
Vascularisation
why does herceptin upregulate?
upregulated p27 to block cell cycle
how does herceptin resistance occur?
Her2 p95 fragment generation
Epitope masking by Mucin
Epitope masking by CD44
how does pertuzumab work?
- Binds to HER-2 at a region distinct from trastuzumab (domain II not IV)
- Overcomes resistance by p95 cleavage and masking
- UK license for use in combination with docetaxal and trastuzumab
who is kadcyla licensed for?
- Licensed for treatment of patients with HER2-positive,
unresectable, locally advanced or metastatic breast cancer
– Previously received trastuzumab and a taxane, separately or in
combination.
what should patients starting on kadcyla should have recieved?
– Received prior therapy for locally advanced or metastatic disease, or
– Developed disease recurrence during or within six months of
completing adjuvant therapy
what effects does herceptin have?
- HER2 binding
- Prevents dimerization
- Prevents Her2 ECD
cleavage p95 - Blocks down stream
signalling - ADCC
