L18 - Hormone driven cancers Flashcards
What are the main horome responsive organs?
The breast and endometrium are infuenced by oestrogen and progesterone.
The prostate is influenced by testosterone.
What are the main risk factors for breast cancer?
- Age
- Oestrogen exposure is main risk factor
- High fat diet
- Family history
- Nulliparity
- Alcohol and smoking
What was the oldest form of molecular targeted cancer therapy?
Found in 1800s that bilateral ovariectomy in a young women with breast cancer would cause remission.
Why would an overiectomy not be a suitable treatment in someone with a BRCA mutation? what would be a good alternative?
As it is not the oestrogen causing the cancer as the cells are mutated so don’t properly repair DNA. This means that surgical removal would be a better option.
What percentage of breast tumours show oestrogen and progesterone receptors?
About 70% this means that lots of tumours rely on hormones to grow.
What are the cancer risks of contraceptive pill and HRT?
Minimal with oral contraceptives and slightly higher with HRT
What types of women are at higher risk of cancer from HRT?
Women of lower body mass are at higher risk of it because more obese women produce higher levels of oestrogen naturally. So they will be more used to it.
How does oestrogen bind to its receptor and what is the effect of this?
Oestrogen binds to its intracellular receptor on the nucleus. As it is a lipid hormone it can pass through the cell membrane and bind to the receptor. The receptor dimerises and becomes phosphorylated upon binding. This causes coactivators to be activated that have a DNA binding sequence. TAF 1 and 2 (transcription activating factors) bind and influence transcription. This causes transcription of proteins such as TGF alpha which then act on the cell to cause further growth. This is in an autocrine loop.
Why do people die from breast cancer?
Through metastatic spread to other parts of the body such as the brain, lungs, liver and bone
What adjuvant systemic therapies can be used to reduce the metastatic spread of breast cancer?
Hormone therapies: - SERM (systemic estrogen receptor modulator) such as tamoxifen -aromatase inhibitors (post menopausal) -GnRH analogues (pre menopausal) Chemotherapy
How does tamoxifen work and what are its side effects?
Tamoxifen works by competitively inhibiting oestrogen at the receptor. This actively blocks TAF2 which reduces gene transcription however it does not block TAF1 so does not completely block it. Its side effects include menopausal symptoms, fatigue and joint pain (effectively the symptoms of low oestrogen)
What are the two types of resistance that can occur to hormone therapies?
De novo resistance - cells may mutate or change their oestrogen receptor which causes resistance early on
Aquired resistance - occurs over 2 - 5 years.
Can have increased activity of coactivators that prevent tamoxifen from being as effective or the cancer cells can use different pathways to get same effect.
How do aromatase inhibitors work?
Aromatase is the enzyme in adipose tissue that converts testosterone to oestrogen. Aromatase inhibitors stop this from working hence reduce the amount of oestrogen being produced.
What order of treatments tend to be used depending on the stage of breast cancer?
For early breast cancer tamoxifen tends to be used and then aromatase inhibitors when this becomes resistant. Gives longer using one after the other before the patient is resistant to both. If late stage cancer then aromatase inhibitors are often used first.
How does goserelin (GnRH analogue) work?
It initially causes an increase in the amount of FSH and LH being produced but through continous exposure it causes downregulation of receptors on pituitary so causes lower production. This is typically used for pre menopausal women.
