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
Aetiology prostate cancer
Age
Family history:
-in under 45s stronger genetic basis
-GSTP1
-BRCA2
High fat and meat diet
Signs and symptoms
Early disease: 90%
-tumour still confined to prostate symptoms limited as tumour so small
-difficulty passing urine
-nocturia
-pain on urination
-haematuria
Advanced disease:
-impotence
-tiredness
-general feelings of unwellness
-loss of appetite
Bone metastasis can cause:
-pain in the hips and spine
-increased fractures
Spinal nerve compression:
-paraethesia or weakness
-incontinence
Diagnosis prostate cancer
Prostate specific antigen (mis named)
-gamma seminoprotein or kallikrein-3
-very sensitive but not specific for prostate cancer distinct from benign hypoplasia
-up to 2/3rds of men with modestly raised PSA will not have prostate cancer
-and 20% of patients with prostate cancer wont have raised PSA
Digital rectal examination and transrectal biopsy (unless typical symptoms of bone metastases)
Dilemma prostate cancer
Increased proportion of population over 70- so increasing incidence
Increased prostate specific antigen PSA testing- greater diagnostic rate
Now over 90% of PCa detected early
But mortality rates stable
Problem of over treatment of indolent disease
Treatment options
Treatment options for non metastatic prostate cancer include:
-deferred treatment/active surveillance: (low grade tumours + PSA <10ng/ml): PSA every 3 months and repeat biopsy after 2year
-radical prostatectomy: tumour localised to gland
-radiotherapy (disease in pelvis or higher PSA):
—external beam (intensity modulated- IMRT
—brachytherapy
Hormone treatment for prostate cancer
Patients too frail for surgery/radiotherapy
Metastatic disease
Neoadjuvant- prior to definitive radiotherapy to reduce tumour bulk
Incidence breast cancer
Breast cancer is the most common cancer in the UK
Around 56000 women and 375 men are diagnosed with breast cancer each year in the UK
One woman in 8 will be diagnosed with breast cancer in her lifetime
Around 12000 women and 80 men will die from breast cancer each year
Risk factors breast cancer
Age (non modifiable)
Geographic location
Oestrogen exposure
Family history NM
Previous breast cancer
Exogenous hormones
BMI (modifiable)
Ionising radiation
High breast density
NHS breast cancer screening programme
Introduced 1988 (Forrest report)
50-70 (47-73) years ago
3 yearly intervals
Digital mammograms
2012-2013:
-number of screened 1970955
-rate per 1000 women screened: 8.3
Estimated deaths prevented: 1000
Socioeconomic factors
High SES-> higher incidence of breast cancer
Age at first pregnancy
Number of children
Reproductive factors
Early onset menarche
Late menopause
Older age at first pregnancy
Nulliparity. Each birth reduces the risk by 7% (15% in women with a twin birth)
Longer duration of breastfeeding
Lifestyle factors
Obesity:
-activation of IGF1 and insulin signalling pathways
-activation of PI3K/Akt/mTOR signalling pathways
-increased production of oestrogen from adipose tissue
-increased production of adipokines (eg leptin)
Alcohol:
-effect of acetaldehyde; reduced oestrogen metabolism
-epigenetic changes (DNA methylation)
BRCA genes
0.2-0.3% in general population
3% in women with breast cancer
6% in women with breast cancer onset before age 40 years
Most of the BRCA1 breast cancers are a basal-like subtype
BRCA2 is the major high penetrance predisposition gene for luminal (estrogen receptor ER positive) breast cancers
What news in genetics
PALB2 gene
CHEK2
ATM
MSH2
RAD51C
100000 genome project
Histological types of breast cancer
In situ: DCIS, LCIS
Invasive (at least 17 subtypes):
-ductal- NST commonest 75%
-lobular 15%
-tubular 1-2%
-mucinous <5%
-medullary
-metaplastic
-papillary
-adenoid cystic
Histological types of breast cancer- in situ
DCIS: incidence increasing, 30-50% chance of progressing to invasive cancer deepening on grade
LCIS: marker of increased risk (8-10 fold) for ILC rather than a true precursor
Transition from in situ to metastatic BCa
Normal: basement membrane intact, normal cell arrangement
In situs: more nuclei because more mitosis but basement membrane remains fine
Invasive cancer: basement membrane has been breached and things have started migrating
Metastatic cancer: cancer cells migrates via BV/LN to other organs
Histological types of breast cancer- invasive
Ductal/NST
Lobular
Tubular
Mucinous
Papillary
Others
Molecular subtypes
Basal-like (BRCA1/triple negative)- 10-20%
Luminal A (ER+, HER2-)-50-60%
Luminal B (ER+, HER2+)- 10-20% (triple positive)
HER2- 10-15%
Claudin-low- 12-14%
Normal like- 5-10%
Management of breast cancer
Diagnosis
Surgery
Adjuvant therapy
Neoadjuvant therapy
Management of breast cancer diagnostic team
Breast clinician (consultant surgeon)
Radiologist and radiographer
Pathologist
Breast care nurse
Nurse practitioner
Clinic staff
Administrative staff
Dedicated MDT coordinator
Management of breast cancer. Cancer treatment team
Clinical oncologist
Medical oncologist
Breast surgeon
Medical geneticist
Data management personnel
Research nurse
Lymphoedema specialist
Medical prosthetist
Clinical psychologist
Palliative care team
Diagnosis breast cancer triple assessment
Clinical:
-inspection and palpation of the breasts (nipple changes, skin changes and visible lumps)
-checking lymph nodes in the neck and axilla
Radiological:
-mammogram/USS
-MRI
Pathological:
-biopsy- FNA, core biopsy
Histological types
Invasive ductal NST cancer
Invasive lobular cancer
Inflammatory breast cancer 1-5% of all cancers
Pagets disease of the nipple
Current treatment options
Neo-adjuvant therapy:
-endocrine (aromatase inhibitors)
-chemotherapy (anthracyclines and taxanes)
-herceptin/pertuzumab/lapatinib
Surgery
Adjuvant therapy:
-endocrine
-chemotherapy
-radiotherapy
-biological agents (immunomodulators)
Surgery
Wide local excision: breast conserving surgery
Oncoplastic procedures
Mastectomy : simple mastectomy, skin sparing mastectomy
Axillary lymph nodes:
-sentinel lymph node biopsy
-axillary node sampling
-axillary node clearance
Endocrine therapy
Tamoxifen- a competitive inhibitor of oestradiol
Aromatase inhibitors- significantly lower serum estradiol concentration
Ovarian suppression- GnRH agonists suppress ovarian function, surgical oophorectomy
Radiotherapy
Following WLE
Post mastectomy (size, grade, lymph node status, surgical margins)
Reduce local recurrence by 70%
Chemotherapy
Neo-adjuvant chemo
Oncotype test
Adjuvant chemo:
-size, grade, lymph node status, receptor status
-cycles of chemo
-side effects
Biological therapies
Extracellular mAbs:
-herceptin/trastuzumab (HER2)
-pertuzumab HER2
Intracellular TKIs:
-lapatinib (EGFR/HER2)
Prevention
Diet
Alcohol intake
Regular exercise
Chemical exposure (plastic containers)
Immunotherapy
PDL1 testing on breast cancer cells in triple negative breast cancer
PDL1 is aprotein on the breast cancer cells
The future breast cancer
Tumour vaccines:
-tumour antigens- MUC1, HER2
-tumour cells
-dendritic cells/T cells
-exosomes
Oncolytic viral therapy
Gene therapy
