Hormkne Drivers Of Cancer Flashcards
Hormone producing tumours
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
Hormone dependent cancers
Cancers which need hormone to grow
Hormones can cause certain cancers to grow more aggressively -> esp oestrogen
Hormone responsive organs
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
Female cancer stats more women get breast cancer than lung also women die of lung cancer more than breast cancer
Fewer interventions that can treat lung cancer
Risk factors for breast cancer
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
Breast cancer - hormone dependent cancer
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
Oldest form of molecular targeted therapy Beatson 1896
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
Oral contraceptives and breast cancers
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
HRT and breast cancer
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
What is an oestrogen receptors
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
Genomic interaction of oestrogen E2
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
Why do people die from breast cancer
Metastatic spread to other organs
What types of adjuvant systemic therapy are there why are they used
Hormone therapy
Chemotherapy
Reduce risk of metastatic spread
Types of hormone therapy
SERM - tamoxifen
Aromatase inhibitors- post menopausal
GnRH analogue - pre menopausal
Chemotherapy used when
Poorly differentiated-grade 3 or higher tumour
Lymph node involvement
Oestrogen receptors negative
What are SERMs
Selective oestrogen receptor modulators
Tamoxifen
Survival with SERMs
Reduces reoccurrence by 42% with 5 years treatment
Improved survival 22% in early breast cancers
Reduces contra lateral primary tumour
How does tamoxifen inhibit
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
Which taf does it block which is still active
Taf2 blocked
TAF 1 still active
What possibly does TAF 1 inc
TGF beta which may inc time spent in G0 phase
How much of tamoxifen is used why is amount not increase
20mg
No benefit of increasing
What is tested for before use
ER receptor
Immunohistochemistry
What can tamoxifen be used for
Neo-adjuvant treatment for locally advanced disease
Adjuvant systemic therapy reduce systemic spread
Metastatic disease-40% response rate
Used in combination with chemotherapy-
Better than chemo alone
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
Tamoxifen resistance
Few de novo resistance
Most after response, resistance is acquired
All tumors will eventually become resistant
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
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
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
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
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
What does aromatase enzymes do
Block action of aromatase
Reduce amount of oestrogen produced by fat cells
Trial tamoxifen vs AI
AI more likely to stop recurrence than tamoxifen
AI preferred in post menopausal women
Side effects of AI
Hot flushes and vaginal dryness Nausea Rashes Joint stiffness Raised cholesterol Osteoporosis Neurological effects on the extremities
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
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
Who is goserelin used to treat
Pre menopausal women not many SE
Also used to treat prostate cancer
How is goserelin given
Injection once a month
How is tamoxifen given
Tablet daily
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
Risk factors for endometrial cancer
Bleeding after menopause PCOS Early menarche Late menopause Failure to ovulate every month Irregular menstruation Longer than average menstruation
Treatment endometrial cancer
Hysterectomy and chemotherapy
HRT and pill and endometrial cancer
Inc risk HRT if oestrogen only
Pill combined or progesterone only so normally ok
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
Treatment
Usually early presentation
Cure rates 85% +
Treatment surgery (hysterectomy and bilateral oophrectomy)
Combined with chemo and radio if high risk
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
Cause
Age Family history Under 45s stronger genetic basis GSTP1 BRCA2 High fat and meat diet Frequency of sexual activity
Diagnosis
PSA
DRE
Transrectal ultrasound
Biopsy
Treatment
Nonmet
Surveillance
Radical prostatectomy
Radiotherapy
Hormone treatment if not strong enough for surgery
Neoadjuvant - prior to definitive radiotherapy to reduce tumour bulk
