breast cancer SD Flashcards
What is tissue involution?
changes in the breast with increasing age
involutional changes are changes due to altered sex steroid levels that accopany decreasing ovarian fxn
Sx of breast disease
lumpiness
pain
palpable mass
nipple discharge
most common type of benign breast tumour
fibroadenoma
2 types of breast carcinomas
- non-invasive
- ductal carcinoma in situ DCIS
- lobular carcinoma in situ LCIS - invasive/infiltrating carcinoma
- infiltrating ductal carcinoma
- invasive lobular carcinoma
tests for metastases
- lymph node ultrasound/biopsy
- MRI scan
- CT scan
- liver ultrasound
- bone scan
stages of BC
STAGE 0: DCIS, pre-invasive BC, cancer cells are in breast ducts and have not started to spread into surrounding breast tissue
STAGE 1: cancer is small and only in breast tissue or might be in lymph nodes close to breast, early stage
STAGE 2: cancer is in breast or in nearby lymph nodes or both, early stage
STAGE 3: cancer has spread from breast to lymph nodes close to breast or to skin of breast or chest wall, locally advanced breast cancer
STAGE 4: cancer has spread to other parts of the body
How is the ER/PR/HER2 receptor status determined?
immunohistochemistry
What does triple positive BC mean?
ER +ve
PR +ve
HER2 +ve
-> no mutations, could be early stage cancer
Which ER type is in breast?
ER alpha
What type of drug is Tamoxifem?
SERM
-> doesn’t allow helix H12 to fit correctly, antagonist effect
What does tamoxifen prevent?
prevents ER gene co-activation
How does Tamoxifen work?
- binds to ER at helix H12
- masks the AF2 site
- leads to less co-activator recruitment
- partial agonist/antagonist
- activates other genes - pro-apoptotic genes, dec proliferation
2 actions of SERMs (tamoxifen and raloxifine)
- estrogenic and antiestrogenic actions depending on target tissue
- antiestrogenis in mammary tissue
- proestrogenic on uterine epithelium and bone
How can Tamoxifen resistance occur?
- loss of ER expression in patient
- activating ER mutations
- ER is hypersensitised to low oestrogen levels
- increased oestrogen levels -> competition
- pharmacologic tolerance, inc efflux OR dec influx of the drug by membrane pump glycoproteins (Tamoxifen pumped out of cell)
- R crosstalk (HER2)
How do aromatase inhibitors work?
inhibit aromatase converting androgens to oestrogens
examples of reversible aromatase inhibitors
aminoglutethimide - poor selectivity
anastrazole, Letrozole - bind to haem group of aromatase and prevents binding to steroid
example of irreversible aromatase inhibitors
Exemestane
Fulvestrant
- new ER antagonist
- brand = Faslodex
- SERD - selective ER degrader
- binds tightly to ER
- masks both AF1 & AF2 sites
- causes receptor instability
- ER is degraded by the proteome
difference between Fulvestrant and Tamoxifen
masks both AF1 and AF2 sites
doesn’t allow ER into nucleus
Tx if patient ER +ve
Tamoxifen
Tx if patient HER2 +ve
Herceptin
What can ER crosstalk with?
HER2 receptor
What family is HER2 from?
EGFR family
How do the HER activating ligands work?
HER 1, 3 and 4 require HER 2
HER 2 binds to HER 1, 3 or 4, dimerises and becomes active
normal vs malignant growth with HER2 R
- low HER 2 - weak signalling, normal growth
- high HER 2 - potent signalling, malignant growth
What type of receptor is HER2?
cell surface tyrosine kinase receptor
% of BC that overexpress HER2
20-30%
Tx to block HER2
Herceptin - Trastuzumab
MAb
well tolerated
s/e with Herceptin
CV dysfunction
monitoring for Herceptin
cardiac fxn
What protein does HER2 use to activate proliferation/attract blood vessels?
VEGF
HER2 p95 fragment
- HER2 can undergo proteolytic cleavage in overexpressing cells
- leads to extracellular domain fragment being shed
- leaves active p95 domain
- poor prognosis
6 MOA of Herceptin
- blocks cleavage, prevents autophosphorylation
- blocks dimerisation (of other HER R)
- endocytosis of HER2
- activation of antibody dependent cell mediated cytotoxicity: ADCC (immune system attack HER2)
- blocks VEGF and tumour vascularisation
- upregulates p27 to block cell cycle
How can you get Herceptin resistance?
- HER2 p95 fragment generation
- epitope masking by mucin
- epitope masking by CD44
-> Herceptin can’t bind when any of these happen
What region does Herceptin bind to on HER2?
region 4
drug for Herceptin resistance and MOA
- Pertuzumab
- binds to region 2 (not 4 - Herceptin)
- overcomes resistance by p95 clevage and masking
Where does Pertuzumab bind to on HER2?
region 2
When is Pertuzumab licenced to be given?
in combination with docetazel and trastuzumab (Herceptin)
Trastuzumab Emtansine -> Kadcyla
- antibody-drug conjugate:
- Trastuzumab linked to DM1 (microtubule inhibitor)
- effect = prevention of microtubule polymerisation and initiation of apoptosis (by DM1)
- licenced for Tx of HER2 +ve, unresectable, locally advanced/metastatic BC
- previosuly received trastuzumab + taxane (separate or combination)
- should have:
- received Tx for locally advanced/metastatic disease OR
- developed disease recurrence during/within 6mths of completing adjuvant therapy
