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4/ CAN > Lecture 18 - Hormones and Cancer > Flashcards

Lecture 18 - Hormones and Cancer Flashcards

1
Q

What are the 3 most hormone responsive organs, How?

A

Breast and Endometrium
- oestrogen and progesterone produced by ovaries, repsonsbile for breast tissue development and lactation
- menstrual cycling has direct effect
- oestrogen - linear growth, bone turnover
- post-menopausally - testosterone produced by adrenal glands metabolised to oestrogen - maintaining bone strength
Prostate
- testosterone produced by testes and adrenal glands - reponsible for gonadtrophin regulation, spermatogenesis, sexual differentiation
- metabolised to dihydrotestosterone - a natural anabolic steroid (increases protein synthesis and muscle mass)

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2
Q

What are the risk factors for breast cancer?

A
  • age
  • high SES (high fat diet, high BMI, fewer children and shorter duration of breast feeding)
  • previous breast disease e.g. benign
  • family history
  • oestrogen exposure (early menarche or late menopause)
  • breast feeding and parity
  • alcohol and smoking
  • radiation exposure
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3
Q

What did Beaston show in 1896?

A
  • demonstrated that bilateral ovariectomy on a young woman with breast cancer would cause remission
  • oldest form of molecular targeted therapy
  • ovarian oblation still used for premenopausal women
  • -> surgically if carry BRCA gene
  • -> chemically via GnRH analogues e.g. Goserelin
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4
Q

What is the pathogenesis of hormones in breast cancer?

A
  • Oestrogen and progesterone receptors found in high numbers in well differentiated tumours (normally involved in growth and lactation)
  • about 70% of breast cancer express ER or PgR
  • cancers show dependence on hormones to grow
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5
Q

What is the link between OCP and breast cancer?

A
  • relative risk of 1.3 when used for 6 months or longer

- if begin before 18 and continue for more than 10 years, relative risk rises to 3.1

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6
Q

What is the link between HRT and breast cancer?

A
  • greater for lower than higher weight individuals
  • effect of HRT on mortality from BC unknown
  • comparable with delayed menopause
  • 5 years after cessation, no increased risk
  • HRT decreased risk of colorectal cancer
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7
Q

Describe the oestrogen receptor

A
  • Protein, member of nuclear hormone superfamily
  • specifically binds oestrogen (17beta-oestradiol)
  • 2 forms alpha and beta - multiple iso forms due to RNA splicing
  • interacts with DNA - influencing gene transcription in a ligand-dependent manner
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8
Q

Describe the genome action of oestrogen (E2)

A
  • ER lcatioed in nucleus associated with HSP90 (stabiliser)
  • E2 = steroid passes through membrane
  • causes dimerisation and phosphorylisation of ER
  • increases bending of co-activators and releases co-repressors
  • transcriptional activator factor regions (TAF1 and 2) with receptor activated
  • increases transcription of genes (e.g PR, IGF and TGFalpha)
  • increases proliferation
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9
Q

Where does breast cancer metastasise to?

A 
skeletal bone 
liver 
lung 
brain 
(skin, ovaries, GI)
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10
Q

Describe the indications for adjuvant chemotherapy

A
  • poorly differentiated (grade 3 or higher tumour)
  • lymph node involvement
  • oestrogen receptor negative
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11
Q

What are the 3 options for adjuvant hormone therapy?

A
  • SERM such as Tamoxifen
  • Aromatase inhibitor (post menopausal)
  • Gonadotrophin-releasing hormone analogue (premenopausal)
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12
Q

What are SERMs?

A

selective oestrogen receptor modulators e.g. Tamoxifen

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13
Q

How does Tamoxifen work?

A

Direct competitive inhibitor of oestrogen at ER receptor
Tamoxifen prevents coactivation of ER
Corepressors remain bound
Not a complete switch off - TAF2 activity blocked
TAF1 remains active - so still some transcription, implications in endometrium

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14
Q

Describe the uses of Tamoxifen

A

Can be used for
- neoadjuvant treatment of locally advanced disease
- adjuvant systemic therapy - reduced risk of metastatic spread
- metastatic disease - 40% response rate
Often used in combination with chemotherapy - better than chemo alone

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15
Q

What are the tamoxifen associated complications?

A
  • menopausal symptoms such as hot flushes and sweats
  • fatigue
  • painful joints
  • causes
    Less common = vaginal discharge, water retention, weight gain, headaches, depression, hair thinning
    Rare = increased DVT risk, PE risk, endometrial cancer risk
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16
Q

What are the pros and cons of Tamoxifen for chemoprevention?

A 
Pros = reduces cholesterol and maintains bone density 
Cons = increased risk of endometrial cancer and thormoembolic disease
17
Q

What are the two types of resistance to Tamoxifen?

A

Acquired resistance = period of initial response, then all tumours eventually become resistant
De novo resistance = no initial response seen, no effect ever

18
Q

What are some of the proposed mechanisms for Tamoxifen resistance?

A
  1. cell removes Tamoxifen - NO
  2. cells lose ER - some evidence in de novo resistance,
  3. change in CoA:CoR balance, increased CoA mean T is less able to block effects of E2
19
Q

What are the additional molecular targets for generating tamoxifen resistance?

A
  • tamoxifen normally prevents phosphorylation of ER
  • EGF alternative pathway phosphorylates ER, tamoxifen cannot inhibit this –> treatment is redundant
  • heregulain, PI3-K hijacked to phosphorylate ER
20
Q

What is the mechanism of action of aromatase inhibitors?

A
  • in pist menopausal women - local oestrogen levels controlled by conversion of testosterone to estradiol in the adipose tissues by aromatase enzymes
  • aromatase inhibitors block this conversion so there is less oestrogen in the serum
21
Q

What did the ATAC trial show?

A
  • compared aromatase inhibitor and tamoxifen and them combined
  • shows AI’s preferred initial treatment for postmenopausal women with localised hormone receptor positive breast cancer
  • more effective and fewer side effects
22
Q

What are the side effects of aromatase inhibitors?

A 
hot flushes and vaginal dryness
nausea 
rashes
joint stiffness 
raised cholesterol 
osteoporosis 
neurological effects on extremities
23
Q

What is fulvesterant?

A
  • Pure anti oestrogen
  • mimics oestrogen ablation
  • ised for 3rd line therapy when Tamoxifen and AIs fail
24
Q

What is goserelin?

A
  • one amino acid changed from LHRH dedapeptide
  • bind to LHRH receptors in the pituitary, initially stimulating FSH/LH release –> tumour false
  • continous exposure causes down-regulation of receptors and lowers FSH production (within 2 weeks)
  • less oestrogen –> artificial menopause
25
Q

What is endometrial cancer stimulated by?

What are the risk factors?

A

high unopposed oestrogen

  • usually in postmenopausal women as stop making progesterone
  • obese women more likely ti get ut
  • insulin resistance
  • pregnancy reduces exposure to oestrogen and lower risk but risk increased if number of pregnancies >4
26
Q

What are the characteristics of endometrial cancer?

A
  • bleeding after menopause
  • polycystic ovaries
  • early menarche and late menopause
  • failure to ovulate every month
  • irregular menstruation
  • longer than average menstruation
27
Q

What os the link between HRT and COP and endometrial cancer?

A
  • HRT does increase risk of endometrial cancer - oestrogen only varieties normally only be prescribed for women who have had a hysterectomy
  • contraceptive pill usually combined or progesterone only so ok
28
Q

What is the link between tamoxifen and endometrial cancer?

A
  • tamoxifen isn’t a pure antioestrgen
  • it also has partial agonist properties, particularly in the uterus
  • increases risk of endometrial cancer, women should be moinitered after 2yrs
  • tower mortality from endometrial cancer only 0.4% whereas reduction in breast cancer mortality is 2.8% –> acceptable risk
29
Q

How is endometrial cancer treated?

A
  • as symptoms early, often detected at stage I so cure rates in excess of 85%
  • treatment = surgery (hysterectomy and bilateral oophorectomy)
  • combined with radiotherapy or chemotherapy if high risk
30
Q

What is the incidence of prostate cancer?

A
  • globally = 6th most common cancer, 3rd most frequently diagnosed cancer in men
    Primary a disease of older men
  • UK = most common form of cancer in men, second most common cause of cancer death in men after lung cancer
31
Q

What are the risk factors for prostate cancer?

A
  • age
  • family history, in under 45s, GSTP1, BRCA2
  • high fat and meat diet
  • frequency of sexual activity, increased frequency reduces risk
32
Q

What are the signs and symptoms of early prostate cancer?

A 
Tumour still confined to prostate 
Mainly urinary symptoms 
- difficult passing urine 
- nocturia
- pain on urination 
- haematuria
33
Q

What are the signs and symptoms of late prostate cancer?

A 
Signs and symptoms 
- impotence 
- tiredness
- general feelings of unwellness 
- loss of appetite 
Bone metastases can cause:
- pain in the hips and spine 
- increased fractures 
Spinal nerve compression 
- paraesthia or weakness 
- incontinence
34
Q

How can prostate cancer be diagnosed?

A

PSA test
- very sensitive but NOT specific for prostate cancer
- up to 2/3rd of men with moderately raised PSA will NOT have prostate cancer
- 20% of paints with prostate cancer will NOT have raised PSA
Digital rectal examination and transrectal biopsy

35
Q

What is the dilemma in prostate cancer?

A
  • increased proportion of population over 70, so increasing incidence
  • increased PSA testing - greater diagnostic rate
  • now over 90% of PCs detected early
    BUT
  • mortality rates stable
  • problem of over treatment of indolent disease
36
Q

What are the treatment options for non-metastatic prostate cacner>

A
  • deferred treatement/active surveillance, PSA every three months and repeat biopsy after 2y
  • radical prostatectomy if localised to gland
  • radiotherapy if disease in pelvis or higher PSA
37
Q

When are hormone treatments for prostate cancer used?

A
  • patient too trail for surgery/radiotherapy
  • metastatic disease
  • neoadjuvant - prior to definitive radiotherapy to reduce tumour bulk
38
Q

What are the possible hormone therapies for prostate cancer, how and where do they act?

A
  • Goserelin = LHRH agonist, acts at pituitary
  • Orchidectomy = reduce testosterone
  • Anti-androgen e.g. abiraterone

4/ CAN (39 decks)

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