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CAN > Hormkne Drivers Of Cancer > Flashcards

Hormkne Drivers Of Cancer Flashcards

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

A

TGF beta which may inc time spent in G0 phase

21
Q

How much of tamoxifen is used why is amount not increase

A

20mg

No benefit of increasing

22
Q

What is tested for before use

A

ER receptor

Immunohistochemistry

23
Q

What can tamoxifen be used for

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-

A

Better than chemo alone

25
Q

Treatment related complications

A

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
Q

Tamoxifen resistance

A

Few de novo resistance
Most after response, resistance is acquired
All tumors will eventually become resistant

27
Q

Mechanisms proposed - to do with the pathway itself

A

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
Q

Additional molecular targets - other pathways which circumvent tamoxifens effects

A

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
Q

What impact does erk1/2 phosphorylating ER directly have

A

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
Q

Inhibition of growth factor pathways

A

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
Q

Aromatase inhibitors used in who and why

A

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
Q

What does aromatase enzymes do

A

Block action of aromatase

Reduce amount of oestrogen produced by fat cells

33
Q

Trial tamoxifen vs AI

A

AI more likely to stop recurrence than tamoxifen

AI preferred in post menopausal women

34
Q

Side effects of AI

A 
Hot flushes and vaginal dryness 
Nausea
Rashes
Joint stiffness 
Raised cholesterol 
Osteoporosis
Neurological effects on the extremities
35
Q

What is fulvestrant

A

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
Q

What is goserelin

A

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
Q

Who is goserelin used to treat

A

Pre menopausal women not many SE

Also used to treat prostate cancer

38
Q

How is goserelin given

A

Injection once a month

39
Q

How is tamoxifen given

A

Tablet daily

40
Q

What is endometrial cancer stimulated by

A

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
Q

Risk factors for endometrial cancer

A 
Bleeding after menopause 
PCOS
Early menarche 
Late menopause 
Failure to ovulate every month 
Irregular menstruation
Longer than average menstruation
42
Q

Treatment endometrial cancer

A

Hysterectomy and chemotherapy

43
Q

HRT and pill and endometrial cancer

A

Inc risk HRT if oestrogen only

Pill combined or progesterone only so normally ok

44
Q

Tamoxifen properties and problems

A

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
Q

Treatment

A

Usually early presentation
Cure rates 85% +
Treatment surgery (hysterectomy and bilateral oophrectomy)
Combined with chemo and radio if high risk

46
Q

Prostate cancer incidence

A 
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
Q

Cause

A 
Age 
Family history 
Under 45s stronger genetic basis 
GSTP1 
BRCA2 
High fat and meat diet 
Frequency of sexual activity
48
Q

Diagnosis

A

PSA
DRE
Transrectal ultrasound
Biopsy

49
Q

Treatment

A

Nonmet
Surveillance
Radical prostatectomy
Radiotherapy
Hormone treatment if not strong enough for surgery
Neoadjuvant - prior to definitive radiotherapy to reduce tumour bulk

CAN (21 decks)

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