Lecture 18 - Hormones and Cancer Flashcards
What are the 3 most hormone responsive organs, How?
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)
What are the risk factors for breast cancer?
- 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
What did Beaston show in 1896?
- 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
What is the pathogenesis of hormones in breast cancer?
- 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
What is the link between OCP and breast cancer?
- 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
What is the link between HRT and breast cancer?
- 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
Describe the oestrogen receptor
- 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
Describe the genome action of oestrogen (E2)
- 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
Where does breast cancer metastasise to?
skeletal bone liver lung brain (skin, ovaries, GI)
Describe the indications for adjuvant chemotherapy
- poorly differentiated (grade 3 or higher tumour)
- lymph node involvement
- oestrogen receptor negative
What are the 3 options for adjuvant hormone therapy?
- SERM such as Tamoxifen
- Aromatase inhibitor (post menopausal)
- Gonadotrophin-releasing hormone analogue (premenopausal)
What are SERMs?
selective oestrogen receptor modulators e.g. Tamoxifen
How does Tamoxifen work?
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
Describe the uses of Tamoxifen
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
What are the tamoxifen associated complications?
- 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
What are the pros and cons of Tamoxifen for chemoprevention?
Pros = reduces cholesterol and maintains bone density Cons = increased risk of endometrial cancer and thormoembolic disease
What are the two types of resistance to Tamoxifen?
Acquired resistance = period of initial response, then all tumours eventually become resistant
De novo resistance = no initial response seen, no effect ever
What are some of the proposed mechanisms for Tamoxifen resistance?
- cell removes Tamoxifen - NO
- cells lose ER - some evidence in de novo resistance,
- change in CoA:CoR balance, increased CoA mean T is less able to block effects of E2
What are the additional molecular targets for generating tamoxifen resistance?
- 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
What is the mechanism of action of aromatase inhibitors?
- 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
What did the ATAC trial show?
- 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
What are the side effects of aromatase inhibitors?
hot flushes and vaginal dryness nausea rashes joint stiffness raised cholesterol osteoporosis neurological effects on extremities
What is fulvesterant?
- Pure anti oestrogen
- mimics oestrogen ablation
- ised for 3rd line therapy when Tamoxifen and AIs fail
What is goserelin?
- 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
What is endometrial cancer stimulated by?
What are the risk factors?
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
What are the characteristics of endometrial cancer?
- bleeding after menopause
- polycystic ovaries
- early menarche and late menopause
- failure to ovulate every month
- irregular menstruation
- longer than average menstruation
What os the link between HRT and COP and endometrial cancer?
- 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
What is the link between tamoxifen and endometrial cancer?
- 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
How is endometrial cancer treated?
- 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
What is the incidence of prostate cancer?
- 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
What are the risk factors for prostate cancer?
- age
- family history, in under 45s, GSTP1, BRCA2
- high fat and meat diet
- frequency of sexual activity, increased frequency reduces risk
What are the signs and symptoms of early prostate cancer?
Tumour still confined to prostate Mainly urinary symptoms - difficult passing urine - nocturia - pain on urination - haematuria
What are the signs and symptoms of late prostate cancer?
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
How can prostate cancer be diagnosed?
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
What is the dilemma in prostate cancer?
- 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
What are the treatment options for non-metastatic prostate cacner>
- 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
When are hormone treatments for prostate cancer used?
- patient too trail for surgery/radiotherapy
- metastatic disease
- neoadjuvant - prior to definitive radiotherapy to reduce tumour bulk
What are the possible hormone therapies for prostate cancer, how and where do they act?
- Goserelin = LHRH agonist, acts at pituitary
- Orchidectomy = reduce testosterone
- Anti-androgen e.g. abiraterone
