L22: Hormone Driven Cancers Flashcards by selcan icli

What are the risk factors for breast cancer

Age 
High fat diet 
High BMI 
Shorter duration of breastfeeding 
Previous breast disease
Family history 
Oestrogen exposure 
Early menarche 
Late menopause 
No children 
Alcohol smoking 
Radiation

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How can you have exposure to oestrogen

Oral contraceptive pill

Hormonal replacement therapy

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What happens to the risk of breast cancer when you stop taking OCPs/HRT

Decreases

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What is the treatment for local disease

Lumpectomy
Mastectomy
Adjuvant radiotherapy
Adjuvant systemic therapy

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What is the treatment for invasive breast cancer

Wide local excision with lymph nodes
Radiotherapy
Neo adjuvant chemotherapy
Adjuvant systemic therapy

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What is the purpose of systemic therapy

Prevent metastasis to other organs

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What does the systemic therapy depend on

The nature of cancer:

I.e if hormone dependent or not

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If the cancer is oestrogen dependent what therapy can we use

Taxomifen
Aromatase inhibitors
Gonodotrophin releasing hormone analogue

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Who is aramotase inhibitors used on

Post menopausal woman

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Who is gonodotrophin releasing hormone used on

Pre menopausal woman

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If the cancer is not hormone dependent i.e oestrogen dependent what therapy would we use

Chemotherapy

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When we take the tumour out via surgery what is done to the lump

Histology

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What is luminal a breast cancer

Oestrogen receptor positive
Progesterone positive
HER2 negative

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Where is oestrogen receptor present

In the nucleus

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What bins to oestrogen receptors

Oestrogen

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What is oestrogen receptor in the nucleus stabilised by

HSP90

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What happens to oestrogen receptor (ER) when oestrogen binds to it

Dimerises and phosphorylated

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What happens to HSP90 protein when oestrogen binds to ER

Loses its effect

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When we have dimerised ER what bind to it

Co activator molecules in

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What does the co-activator bound form of ER have exposed

Transcriptional actor factor - TAF 1+2

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What is the role of TAF 1 & 2

Binds to DNA and causes the transcription of genes of progesterone receptor, IGF, TGF-alpha

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What happens to IGF and TGF-alpha that is released

Binds to insulin growth receptors (IGF) and TGF-alpha receptors on the surface of the cell in a autocrine fashion

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What type of receptor is TGF-alpha receptor

Tyrosine kinase receptor

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When the receptors are activated what pathway becomes activated

MAP pathway

PI-3 kinase pathway

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What does the MAP and PI-3 Kinase pathway result in

Proliferation | Cell growth

Name an example of a selective oestrogen receptor modulator (SERM)

Tamoxifen

How does tamoxifen work

1) It binds to oestrogen receptors 2) ER cannot be dimerised and become phosphorylated 3) this stop co-activator molecules from binding 4) TAF 2 regions are blocked so transcription of IGF and TGF-alpha are decreased 5) TAF1 is still active

How can tamoxifen be used

Neo-adjuvant- to reduce the size of the tumour Adjuvant systemic therapy- to reduce risk of metastasis In combination with chemotherapy

What are the side effects of tamoxifen

Menopausal symptoms of hot flushes, sweats Deep vein thrombosis Increased risk of endometrial cancer

What can develop when we use tamoxifen long term

Resistance

What are the 2 types of tamoxifen resistance that can occur

De novo: despite ER present there are mutation in the epigenetic region Acquired resistance

What are the resistance mechanism for tamoxifen

- change in balance of corepressor and co-activators (more present) which increases gene transcription - mutated ER - tamoxifen removed from the cells

What are the other pathways involved apart from oestrogen that can activate ER

1) EGF can activate the MAP and PI-3 kinase pathway by binding to EGFR 2) In the MAP pathway, ERK1/2 moves to the nucleus to directly phosphorylate ER on serine 118 3) therefore ER is activated without the binding of oestrogen i.e tamoxifen has no effect 4) in the PI-3 kinase pathway, AKT, can phosphorylate ER

Name a drug that is an aromatase inhibitor

Letrozole

What is the normal role of aramatase enzyme

Covert testosterone into oestrogen (2-cell hypothesis)

What is the role of aromatase enzymes

Inhibit the production of oestrogen

Why is aromatase enzyme used in post menopausal woman

Because oestrogen is not released in the ovaries, it is made in the local tissue by testosterone conversion

What are the side effects of aromatase inhibitors

``` Hot flushes Vagina dryness Nausea Rashes Osteoporosis ```

What can happen if you use letrozole long term

Resistance

If you develop resistance with both tamoxifen and letrozole what is the 3rd line of therapy

Fulvesterant

What is fulvesterant

A pure anti-oestrogen

Name a gonodotrophin releasing hormone analogue used in pre-menopausal woman

Goserelin

Describe how goserelin works

1) goserelin is an analogue of Luteinising hormone releasing hormone receptor (LHRHR) in the pituitary gland 2) this stimulates the LH/FSH release in the short term 3) a continuing exposure causes the down regulation of receptors so FSH production is decreased via a feedback loop 4) less stimulation to the ovaries via FSH 5) less oestrogen is produced

What is luminal b breast cancer criteria

ER positive | Either HER2 Positive or high Ki-67+ progesterone negative

What mutations are present in luminal b

``` Cyclin d EGFR PI-3 kinase PTEN Tp53 ```

Are luminal b breast cancer responsive to endocrine therapy

Yes more aggressive form so chemotherapy may be required

How do we decide if we should add chemotherapy

Oncotype DX: a pool of genes identified to be associated with progressive disease e.g luminal B cancer. There are 15 genes associated with breast cancer you can look for the 15 genes and generate a score and give chemotherapy to high scorers.

What are the other types of breast cancer

HER2 over expressing | Basal like

What is HER2 breast cancer

When HER2 is overexpresed

What is the treatment for HER2 over expressing breast cancer

Herceptin

What is basal like breast cancer

ER negative PR negative HER2 negative Associated with BRAC1

What is the treatment for basal like breast cancer

Chemotherapy | PARP inhibitors

What is the role of BRCA1 and BRCA2

DNA repair

What type of penetrance does BRCA1/2 have

High penetrance

What are the other genes that can be associated with basal like breast cancer

``` Tp53 ATM Chek2 Palb2 RAD51 ```

What are the risk factors for endometrial cancer

``` Bleeding after menopause Early menarche Late menopause Irregular menstruaton HRT ```

What is endometrial cancer stimulated by

Unopposed oestrogen i.e if you have oestrogen but not progesterone

Why is tamoxifen a risk factor for endometrial cancer

1) tamoxifen blocks TAF2 but TAF1 is active | 2) the uterus is sensitive to TAF1 receptor stimulation

What is the treatment for endometrial cancer

Hysterectomy

What are the risk factors for prostate cancer

Age Family history- BRCA2 High fat and diet

What are the early signs and symptoms of prostate cancer

Difficulty to pass urine Nocturia Pain in urination Blood in urine

What are the advanced symptoms of prostate cancer

``` Impotence Tiredness Loss of appetite Pain in hips and spine- due to bone metastasis Spinal nerve compression ```

How is prostate cancer diagnosed

PSA test Digital rectal examination Transrectal biopsy

What are the treatment options for prostate cancer

Active survelliance- regular psa and biopsy to see if cancer is advancing Radical prostectomy- surgery Radiotherapy: external bias or brachytherapy (planting radiation near prostate) Hormone treatment- for metastatic disease

What are the hormone treatments for prostate cancer

Goserelin Anti-androgen e.g abireterone Orchidectomy