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Hormkne Drivers Of Cancer Flashcards

(49 cards)

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1
Q

Hormone producing tumours

A

Cancers which due to where they arise produce hormones
Adverse effects on the body due to excessive hormone levels
E.g pituitary tumour - prolactinoma, ADH, ACTH
Pancreas insulinoma, glucagonoma

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2
Q

Hormone dependent cancers

A

Cancers which need hormone to grow

Hormones can cause certain cancers to grow more aggressively -> esp oestrogen

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3
Q

Hormone responsive organs

A

Breast and endometrium
Require oestrogen and progesterone from ovaries to develop
Menstrual cycling and lactation
Oestrogen needed for linear growth and bone development
Pre menopause oestrogen produced by ovaries
Post menopause oestrogen produced by fat and adrenal glands
Prostate
Testosterone produced by testes and adrenal glands
Responsible for gonadotropin regulation, spermatogenesis and sexual differentiation
Metabolised by dihydrotestosterone - natural anabolic steroid - increases protein synthesis and muscle mass

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4
Q

Female cancer stats more women get breast cancer than lung also women die of lung cancer more than breast cancer

A

Fewer interventions that can treat lung cancer

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5
Q

Risk factors for breast cancer

A 
Age 
High social economic group 
- fewer children 
- children at older age 
- high BMI 
- short duration breast feeding 
Previous breast cancer 
Family history - BRCA  and others 
Oestrogen exposure - early menarche, no or late child bearing
Parity 7% reduction for each child 
Breast feeding reduces 4% per 12 months 
Alcohol and smoking 
Radiation exposure
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6
Q

Breast cancer - hormone dependent cancer

A

Breast needs oestrogen and progesterone growth and lactation
Oestrogen major role in development and progression of disease
~70% of breast cancers express oestrogen or/and progesterone receptors
These can be targeted in treatment

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7
Q

Oldest form of molecular targeted therapy Beatson 1896

A

Bilateral ovariectomy on young woman with breast cancer caused breast cancer remission
Ovarian ablation still used fit premenopausal women -> remove oestrogen production of ovaries
Surgically if patient carries BRCA
Chemically via GnRH analogues

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8
Q

Oral contraceptives and breast cancers

A

Link
If taken for 6 months or longer relative risk of 1.3
Begin before 18 and continues for 10 years risk increase to 3.1
After stopping inc years decrease chance of getting BC it near never users

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9
Q

HRT and breast cancer

A

Current users increased risk
Particularly if combined oestrogen and progesterone
Greater risk for lower than higher weight individuals
5 years after cessation no sig diff
Findings should be considered in the context of benefits and other risks
Dec risk of colorectal cancer

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10
Q

What is an oestrogen receptors

A

Protein - member of nuclear hormone superfamily
Specifically binds oestrogen - 17beta-oestradiol
2 forms alpha and beta due to RNA splicing
Interacts with DNA - influencing gene transcription in a ligand dependent manner

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11
Q

Genomic interaction of oestrogen E2

A

E2 a steroid hormone passes through membrane
ER located in the nucleus and is associated with HSP90
Causes dimerisation and phosphorylation
Increases binding of co activators and release of co repressors
Transcriptional activator factor regions within receptors activated
Inc transcription of genes-IGF bind to breast cell inc proliferation

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12
Q

Why do people die from breast cancer

A

Metastatic spread to other organs

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13
Q

What types of adjuvant systemic therapy are there why are they used

A

Hormone therapy
Chemotherapy
Reduce risk of metastatic spread

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14
Q

Types of hormone therapy

A

SERM - tamoxifen
Aromatase inhibitors- post menopausal
GnRH analogue - pre menopausal

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15
Q

Chemotherapy used when

A

Poorly differentiated-grade 3 or higher tumour
Lymph node involvement
Oestrogen receptors negative

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16
Q

What are SERMs

A

Selective oestrogen receptor modulators

Tamoxifen

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17
Q

Survival with SERMs

A

Reduces reoccurrence by 42% with 5 years treatment
Improved survival 22% in early breast cancers
Reduces contra lateral primary tumour

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18
Q

How does tamoxifen inhibit

A 
Competitive inhibition to bind to ER
Reduces E2 amount that can bind 
Therefore reduces dimerisation and phosphorylation of receptors 
Reduces binding of coactivators 
Reduces the release of corepressors 
Block TAF 2activity
And prevents growth and proliferation
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19
Q

Which taf does it block which is still active

A

Taf2 blocked

TAF 1 still active

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20
Q

What possibly does TAF 1 inc

Study These Flashcards
A

TGF beta which may inc time spent in G0 phase

21
Q

How much of tamoxifen is used why is amount not increase

Study These Flashcards
A

20mg

No benefit of increasing

22
Q

What is tested for before use

Study These Flashcards
A

ER receptor

Immunohistochemistry

23
Q

What can tamoxifen be used for

Study These Flashcards
A

Neo-adjuvant treatment for locally advanced disease
Adjuvant systemic therapy reduce systemic spread
Metastatic disease-40% response rate

24
Q

Used in combination with chemotherapy-

Study These Flashcards
A

Better than chemo alone

25
Treatment related complications
40% of women menopausal symptoms hot flushes - more tolerable than chemo symptoms, som have to stop as can't cope with the SE 25% fatigue 25% painful joints 20% nausea usually only at first Lesson common, vaginal discharge, discomfort, water retention, weight gain, headaches, depression, hair thinning Rare inc risk DVT, PE Inc risk endometrial cancer
26
Tamoxifen resistance
Few de novo resistance Most after response, resistance is acquired All tumors will eventually become resistant
27
Mechanisms proposed - to do with the pathway itself
Change in corepressor coactivator balance Less corepressors more coactivators Tamoxifen less effective more gene transcription more tumour growth Some cells can remove tamoxifen from in them Some cells lose/ change/ mutate their oestrogen receptors So are less sensitive to tamoxifen
28
Additional molecular targets - other pathways which circumvent tamoxifens effects
PI3K pathway overexpression Causes increased phosphorylation so cells less sensitive to tamoxifen Treat with herceptin, EGF receptor inhibitor EGF and heregulin present in BC cells In E2 pos cancer these play a minor role but if ER are blocked then these become more active Heregulin inc phosphorylation of BRCA1 through AKT in breast cancer cells EGF pathways causes an increase in activity of ERK1/2 Erk1/2 move to the nucleus cause cell proliferation and direct phosphorylation of ER
29
What impact does erk1/2 phosphorylating ER directly have
Means that tamoxifen no longer needs to outcompete oestrogen as the receptor is no longer needing oestrogen to work as erk1/2 can activate the receptor hence proliferation
30
Inhibition of growth factor pathways
Iressa gefitinib Binds to the ATP binding site of EGFR Has proven to ineffective in breast cancer trials Herceptin transuzumab Ab to HER2 Work in BC
31
Aromatase inhibitors used in who and why
Post menopausal women Aromatase converts testosterone into oestrogen in adipose tissue In post menopausal women get their oestrogen from as ovaries no longer produce oestrogen
32
What does aromatase enzymes do
Block action of aromatase | Reduce amount of oestrogen produced by fat cells
33
Trial tamoxifen vs AI
AI more likely to stop recurrence than tamoxifen | AI preferred in post menopausal women
34
Side effects of AI
``` Hot flushes and vaginal dryness Nausea Rashes Joint stiffness Raised cholesterol Osteoporosis Neurological effects on the extremities ```
35
What is fulvestrant
Treat BC that has spread in women who have had their menopause Works in 2 ways Anti-oestrogen drug fits into ER blocks E2 Reduce no of ER
36
What is goserelin
Structure similar to LHRH Binds to LHRH receptor in pituitary initially stimulating FSH/LH Continuous overstimulation of LHRH causes down regulation of receptors lowers FSH production
37
Who is goserelin used to treat
Pre menopausal women not many SE | Also used to treat prostate cancer
38
How is goserelin given
Injection once a month
39
How is tamoxifen given
Tablet daily
40
What is endometrial cancer stimulated by
High levels of unopposed oestrogen - when oestrogen present and progesterone is not Usually post menopausal women stop making progesterone Obese 3x more likely to get it Insulin resistance linked Pregnancy reduces exposure and lowers risk it increases risk if pregnancy no. Greater than 4
41
Risk factors for endometrial cancer
``` Bleeding after menopause PCOS Early menarche Late menopause Failure to ovulate every month Irregular menstruation Longer than average menstruation ```
42
Treatment endometrial cancer
Hysterectomy and chemotherapy
43
HRT and pill and endometrial cancer
Inc risk HRT if oestrogen only | Pill combined or progesterone only so normally ok
44
Tamoxifen properties and problems
It is not a pure anti oestrogen Only partial particularly in the uterus Endometrium sensitive to taf1 Oestrogen response without progesterone can increase risk of endometrial cancer
45
Treatment
Usually early presentation Cure rates 85% + Treatment surgery (hysterectomy and bilateral oophrectomy) Combined with chemo and radio if high risk
46
Prostate cancer incidence
``` 6th most common 3rd most frequently diagnosed in cancer Primarily disease of old men U.K. Most common cancer in men Second most common cause of death in men after lung cancer ```
47
Cause
``` Age Family history Under 45s stronger genetic basis GSTP1 BRCA2 High fat and meat diet Frequency of sexual activity ```
48
Diagnosis
PSA DRE Transrectal ultrasound Biopsy
49
Treatment
Nonmet Surveillance Radical prostatectomy Radiotherapy Hormone treatment if not strong enough for surgery Neoadjuvant - prior to definitive radiotherapy to reduce tumour bulk

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