Week 9 Flashcards
Risk factors for breast cancer
Non-modifiable:
-strongest= age (peak= 50-70)
-previous breast disease (eg benign)
-family history (BRCA and other)
-hormone related factors
Modifiable:
-high socioeconomic group (obesity, alcohol, high fat diet, smoking, less pregnancies and less likely to breast feed)
Also present in men=1%
Beatson 1896
Demonstrated that bilateral overiectomy 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 eg goserelin
Oestrogen and breast cancer link
People exposed to oestrogens for longest:
-early menarche- before 12
-late menopause- 3% per year over 45
-no child or first child after 30
-parity- 7% reduction for each full term birth
-breast feeding reduces risk- 4% per 12 months
Body mass index post menopause
-as oestrogen concn in post menopausal women increases with BMI
Testing for ER
Test for oestrogen receptor positivity (ER+) in biopsied/surgcially removed primary tumour and sites of metastatic spread by immunohistochemistry IHC
Testing must be very accurate and reproducible
Testing lab must be accredited-validated against other test centres and inspected every 2 years
Deemed positive if at least 1% of cells express ER
Determines risk of recurrence and whether suitable for hormone therapy
Why do people die from breast cancer
Metastatic spread to other organs
-skeleton-bone
-liver
-lung
-brain
-skin
-ovaries (Krugenberg tumours)
-Gi system
Adjuvant systemic therapy
To reduce risk of metastatic spread
Hormone therapy:
-SERM such as tamoxifen
-aromatase inhibitor (postmenopausal)
-gonadotrophin-releasing hormone analogue (pre menopause)
Chemotherapy:
-poorly differentiate (grade 3 or higher) tumour
-lymph node involvement
-oestrogen receptor negative
Types of BCa; cell types
Luminal A
Luminal A:
-ER and PgR positive HER2 negative low proliferation (Ki-67 ‘low’) recurrence risk low
-few copy number changes
-few mutated genes >5%
-responsive to endocrine therapy
-less to chemotherapy
What is an oestrogen receptor
Protein- member of nuclear hormone superfamily
specifically binds oestrogen (17B-oestradiol)
2 forms alpha and beta (6q25.1 and 14q23.2)- multiple isoforms due to RNA splicing
Interacts with DNA -influencing gene transcription in a ligand dependent manner
5 domains:
-A/B trans activation in absence of ligand- weak
-C- binds to oestrogen response element on DNA
-D- hinge region
-E- ligand binding and co activator/repressor binding
-F- function unknown (variable in length)
Genomic action of oestrogen E2
ER located in nucleus associated with HSP90
E2= steroid passes through membrane
Causes dimerisation and phosphorylation
Increases binding of coactivators and releases corepressors
Transcriptional activator factor TAF1 and 2 regions within receptor activated
Increases transcription of genes (eg PR, IGF and TGFa)
-stimulate tumour growth
SERMs
Selective oestrogen receptor modulators eg tamoxifen
Competitive inhibitor of oestrogen, binds to ER in competition with oestrogen
Mainstay of endocrine therapy for breast cancer for last 30 years
More trial evidence on tamoxifen then any other anti cancer drug
Early breast cancer trialists collaborative group- published Cochran reports in 1998, 2007 etc
Reduces recurrence by 42% with 5 years treatment
-and improved survival 22% in early breast cancer
-reduces risk of developing contralateral primary tumour
Uses of tamoxifen
20mg per day (no benefit of increasing)
First test by IHC for presence of ER
Can be used for:
-neo-adjuvant treatment of locally advanced disease
-adjuvant systemic therapy- reduces risk of metastatic spread
-metastatic disease- 40% response rate
Often used in combination with chemotherapy- better then chemo alone
How does tamoxifen inhibit
Competes with oestrogen
In doing so it prevents the release of corepressors and prevents recruitment of coactivators and it blocks the TAF-2 region
However TAF 1 is still active -potential problem long term use increase risk of endometrial cancer
In breast cancer TAF-2 most important this stops transcription so dont get release of IFG so dont get increase in cell proliferation
It is cytostatic- does not kill cells but prevents them from carrying on proliferating
No gene transcription but perhaps increases TGFb
Treatment related complications
Menopausal symptoms such as hot flushes and sweats 40% of women
Fatigue 25%
Painful joints 25%
Nausea 20%- usually only at first
Less common- vaginal discharge/discomfort, water retention, weight gain, headaches, depression, hair thinning
Rare:
-increased risk of deep vein thrombosis, pulmonary embolism
-increased risk of endometrial cancer
Mechanisms of acquired tamoxifen resistance
Upregulation of EGFR signalling pathways leading to phosphorylation of the ER . Alternative pathway with no ER so tamoxifen ineffective
Amplification of cyclin D expression and interaction with coactivators
Aromatase inhibitors
In post menopausal women- local oestrogen levels controlled by conversion of testosterone to oestradiol in the adipose tissues by aromatase enzymes
ATAC trial
Tamoxifen v anastrozole as adjuvant therapy in early stage disease in 9366 post menopausal women
Anastrozole more likely to stop cancer recurrence with lower side effects (risk of endometrial cancer and DVT)
Conclusion: AIs preferred initial treatment for postmenopausal women with localised hormone receptor positive breast cancer
Side effects of aromatase inhibitors
Hot flushes and vaginal dryness
Nausea
Rashes
Joint stiffness
Raised cholesterol
Osteoporosis
Neurological effects on extremities
BIG 1-98
Trial looked at whether there is benefit in giving AIs instead of tamoxifen or of sequential treatments ie 5 yr tam then 5 yr AI 8000 patients
In post menopausal women with receptor positive early breast cancer
Use of AI disease reoccurrence lower
Premenopausal women oestrogen production and goserelin
Pituitary stimulated to release FSH by LHRH produced by hypothalamus
Goserelin is a drug that’s a LHRH agonist, has the 10 AA sequence , 9 same as LHRH
Allows it to bind to receptors in pituitary very strongly doesn’t get released initially stimulates FSH/LH release
However continuous exposure (within 2 weeks) results in receptors being down regulated so you get less receptors present in pituitary to be stimulated by LHRH
Therefore you are reducing FSH being released as so reduce amount of oestrogen being released
Types of BCa: luminal B
ER positive
Either HER2 positive
Or high Ki-67 and PR-ve
Often aneuploid
Mutations in cyclin D1 (56%) EGFR1 (23%) and often PIK3CA, PTEN and TP53
Responsiveness to endocrine therapy (but less then luminal A)
More sensitive to chemo
Oncotype Dx
If diagnosed with early stage ER+ve breast cancer
Hormone therapy
And chemo
But who will benefit
Over treatment v insufficient treatment
Panel of 21 genes tested
-15BCa specific. 5 reference genes
Generate “recurrence score”
Use this to decide who to give chemo to
Prostate cancer-incidence
Globally prostate cancer is:
-the 6th most common cancer
-the third most frequently diagnosed cancer in men
Primarily a disease of older men
-bigger health problem in developed countries where life expectancy is higher
In UK:
-most common form of cancer in men
-second most common cause of cancer death in men after lung cancer
