Wk 14: Breast cancer Flashcards
What happens to the breast tissues with increasing age?
Involution changes due to altered sex steroid levels + decreasing ovarian function
What do the benign breast tumours comprise of?
- Fibroadenomas (most common - proliferation of connective tissue stroma + glands in breast lobule)
- Duct papillomas
- Adenomas
- Connective tissue tumours
Give examples of non-invasive carcinomas
- Ductal carcinoma in situ (DCSI)
- Lobular carcinoma in situ (LCIS)
Give examples of invasive carcinoma
- Infiltrating ductal carcinoma
- Invasive lobular carcinoma
What are the tests for metastases?
- Lymph node ultrasound/biopsy
- MRI scan
- CT scan
- Liver ultrasound
- Bone scan
How is ER, PR + HER2 identified?
- Immunohistochemistry
- If bound to enzyme, clear -> brown
What is tamoxifen?
- SERM
- Competitive inhibitor
- Binds to ER + masks AF2 site -> less coactivator recruitment
What is a SERM? give examples
- Selective estrogen receptor modulator
- Tamoxifen + raloxifene
- Antiestrogenic: mammary epithelium
- Proestrogenic: uterine epithelium + bone
How does tamoxifen resistance occur?
- Loss of ER expression
- Activating ER mutation
- ER hypersensitivity to low oestrogen
- Inc oestrogen
What is used in 2nd line treatment in oestrogen dependant breast cancer that are tamoxifen resistent?
Aromatase inhibitors
Give examples of reversible aromatase inhibitors
- Aminoglutethimide - reversible, poor selectivity
- Anastrozole + letrozole - binds to haem of aromatase + prevents steroid binding
Give an example of an irreversible aromatase enzyme inhibitors
Exemestane (lowers circulating oestrogens)
What is the latest generation of ER antagonist?
- Fulvestrant
- Selective estrogen receptor degrader (SERD)
- Binds tightly to ER
- Masks both AF1 + AF2 -= receptor instability
- ER degraded by proteome
What is herceptin associated with?
Cardiovascular dysfunction - monitor cardiac function
What happens to HER2 in overexpressing cells?
- HER2 receptor undergo proteolytic cleavage
- Leads to ECD fragment being shed + activates p95 domain
- Poor prognosis
What is the mechanism of action of herceptin?
- Blocks cleavage
- Blocks dimerization
- Endocytosis
- Activation of antibody dependent cell mediated cytotoxicity (ADCC)
- Blocks VEGF + tumour vascularisation
- Upregulates p27
How does herceptin illicit an immune response?
- ADCC
- Fc domain of herceptin binds to natural killer cells w/ Fc gamma receptor
- Flags cells for immune attack
- Tumour cell lysis occurs
How does herceptin resistance occur?
Unable to bind to region 4 due to:
- HER p95 fragment generation
- Epitope masking by mucin
- Epitope masking by CD44
What is used in herceptin resistance?
Pertuzumab + trastuzumab emtansine
What does pertuzumab do?
- Binds to HER2 at region distinct from trastuzumab
- Overcomes p95 cleavage + masking resistance
What is trastuzumab emtansine (kadcyla)?
- Trastuzumab linked to DM1 (microtubule inhibitor)
- For: HER2 positive, unresectable, locally advance or metastatic breast cancer
When do you give trastuzumab emtansine (kadcyla)?
- Received prior therapy for locally advanced or metastatic disease
- Developed disease recurrence during/w/in 6 months of completing adjuvant therapy
What is the mechanism of action of trastuzumab emtansine (kadcyla)?
- HER2 binding
- Prevents dimerization
- Prevents HER2 ECD cleavage ->p95
- Blocks downstream signalling
- ADCC
- Prevents microtubule polymerisation
- Initiates apoptosis
What is used to target HER2 in tamoxifen resistant tumours?
Herceptin
