Breast cancer Flashcards
What is the most frequent cancer in women?
Breast cancer (1/3 female cancer in UK)
How common in breast cancer?
Quite common
- 1.67M new cases world wide in 2012
- 55,000 new cases annually in UK
What percentage of breast cancers are hereditary and what gene mutations cause them?
7-10%
BRCA1/2
What are the rest of breast cancer (which aren’t hereditary)?
Sporadic (about 90% are)
What % of breast cancers are preventable?
27%
What is the >10 yr survival for breast cancer (female only) in UK?
78%
Why can breast cancer in men be worse than for women?
It is diagnosed late because they dont expect it and most cases are sporadic –> worse prognosis
What decreases breast cancer risk in post menopausal women?
Physically active
fewer menstrual cycles (when they start and when menopause starts)
increased parity
breastfeeding >6 months
What hormone is involved in breast cancer development?
oestrogen
What is the earliest evidence of oestrogen’s importance in breast cancer?
In Italian villages in 1700s it was shown that nuns had higher incidence of cancer than villagers (who had kids)
What has been happening to breast cancer incidence in the UK since 1980s?
It has been increasing
- partially due to mammographic screening being introduced in 1988
- also had a spike due to a hormone replacement therapy
- we like to think it is leveling off now
What oncogenic events lead to cancer development
DNA damage
Proto-oncogenes
Tumour suppressor gene damage –> decreased apoptosis
Angiogenic factors release
What can cause DNA damage?
UV light
irradiation (e.g. women who had TB X-rays after war)
chemicals (e.g. alcohol)
What is a proto-oncogen?
A normal gene which, when altered by mutation, becomes an oncogene that can contribute to cancer.
Tend to drive cell cycle
Give an example of a tumour suppressor gene
p53
Where do the growth factors for cancer and its supporting blood vessels come from?
Cancer cells and surrounding cells
Give examples of proto-oncogens
C Myc
Ras
What pattern of expression do oncogenes have?
Dominant
What cause most breast cancer deaths?
Metastases
What is the seed and soil theory of cancer?
Cancer cells will only metastasize to sites depending on the primary cancer (selectivity of sites)
What are the main breast cancer metastasis sites?
Through blood and lymph: brain, liver, bone (due to specific chemoattractant molecles)
Creeping across breast: lung
What is the ‘golden standard’ test for diagnosing metastases?
Check if it has spread to lymph node
Sentinal lymph node status
What are stage 1 metastases?
local
What are stage 2 metastases?
loco-regional
What are stage 3 metastases?
regional/distant
What are stage 4 metastases?
regional and distant
Obviously early diagnosis is important to prevent metastasis. But why shouldn’t we do mammographic screenings?
Because we don’t want false postives (including people who have cancer which will never kill them)
Because since we do not know how serious it is we may over-treat the patient
What has been happening to breast cancer mortality since 1975 and why?
It has significantly decrease by about -38% due to improved treatment and introduction of tamoxifen
Quickly go over the different cell types and what they do in the normal breast
Luminal epithelial cells: produce milk
Myoepithelial cells: contract to eject milk
Intralobular fibroblasts sit around these
All of this is regulated hormonally
Which cell type do most solid tumours (not just breast) come from?
Epithelial cells
Breast: luminal epithelial cells (95% of cancers)
Why are women more sussceptible to breast cancer
Oestrogen
It helps cell division- e.g. Monthly increase in cellularity to prep for pregnancy
What kind of tumours are those that arise from myoepithelial cells?
benign
What kinds of tumours are those that arise from intralobular fibroblasts?
Fibrocystic diseases - common and benign
What do you see in histological slide of cancer cells?
De-differentiation
increased mitoses
pleomorphic neuclei
Are most diagnosed breast cancers in situ or invasive?
In situ
This is why we might be over treating
How is breast cancer diangosed?
Found during screening
Symptomatic disease diagnosis
Checked with triple assessment
Further checking of receptor biology
What is pleomorphism?
variable size/ shape of nuclei, increased nuclear size, hyperchromasia (increased DNA content)
What is the triple assessment?
Clinical
Imaging: X ray/ MRI
Pathology (checking histology)
Do we see the same pathological changes in all cancers?
No
What receptors are checked for in breast cancers and with what?
Oestrogen receptor: Immunohistochemistry
Progesterone receptor: Immunohistochemistry
HER2: Immunohistochemistry and FISH
Are there any breast cancers that can’t be diagnosed with receptor biology?
Yes, triple negative breast cancer (there are other subtypes)
What kind of hormone is oestrogen?
steroid
How is oestrogen made?
By aromatase enzyme system from cholesterol
Where is oestrogen made?
pre-menopause: ovaries
Post menopause: mainly adipose tissue (like to obesity and breast cancer)
What does oestrogen do (role in cancer)?
regulates growth and differentiation in breasts, ovaries, skeleton and cardiovascular system
What kinds of oestrogen are there and which ones are more relevant to breast cancer?
Oesterone (E1) binds to ERalpha - least abundant, post-menopausal
Oestrodiole (E2) binds to ERa and ERb - most potent and abundant in both men and women
Oestriol (E3) binds to ERb during pregnancy and in fetus; adult levels v. low
What are the hypotheses for oestrogen induced carcinogenesis?
E binds to oestrogen receptor–> increased proliferation of mammary cells –> increased likelihood of mutations during DNA synthesis
E metabolites bind DNA : produce (depurinating) DNA adducts (this leads to genotoxicity and possible mutations)
Are E metabolites carcinogenic?
Yes
Describe the structure of the oestrogen receptor
Two types:
Intracellular nuclear hormone receptors
Homo- or hetero- dimerise (i.e.αα or ββ or αβ)
G protein coupled receptor GPR30 (less well understood)
What kind of oestrogen receptor has most breast cancer research been done on?
nuclear hormone receptors
ERα
(ESR1 gene product, breast and ovary)
ERβ
(ESR2 gene product, diverse tissue distribution)
What are the structural domains of the oestrogen receptor?
AF-1 and AF-2: transcription factors (activation domain)
DBD: DNA binding domain
LBD:ligand binding domain
What do the AF1/2 domains do?
bind regulatory regions of DNA and control transcription. May act independently or in combination
What does DBD do?
anchors the receptor on the DNA at sites known as ‘hormone response elements’ or oestrogen response elements
What does the LBD do?
binding site for oestrogen
Why do we have trouble studying the ER protein?
the protein is so big that we can only crystallize parts of the domain
How does ER activation lead to cell proliferation?
E binds ER at LBD
ER moves to nucleus
Receptor dimerisation (homo and /or hetero)
Dimers bind DNA via DBD
Recruitment of co- regulatory proteins
Gene transcription
How does the oestrogen receptor activate cell proliferation?
it may complex with EGFR and on-receptor tyrosine kinases (e.g. Src) - increased Ca2+ and nitric oxide production
MAPK/ERK pathway
PI3K/AKT pathway
may activate G protein coupled GPR30
What are the treatments for breast cancer?
Surgery Radiotherapy Chemo Hormone therapy Biological therapy
What is the log and kill hypothesis?
states that a defined chemotherapy concentration, applied for a defined time period, will kill a constant fraction of the cells in a population, independent of the absolute number of cells.
How can the log and kill hypothesis be applied to treatment after surgery?
After significant debulking via surgery, chemo is used to kill a certain number of cells in each round, decreasing total tumour mass (despite regrowth between treatments).
The surgical debulking gives the constant log and kill process an added advantage (like a start line moved forward)
So, why is surgery important for breast cancer?
Surgery is important for preventing metastases and improving the effect of chemotherapy
TRUE or FALSE? A much lower dose of radiation is used for radiotherapy than for imaging
FALSE
A much higher dose is used
What is the mechanism of radiotherapy?
Photons from high energy radiation enter the tissue and exit and cause damage to DNA - therefore causes cell death
Radiotherapy is delivered in a fractionated manner
The total treatment is divided up into several, smaller doses
Is radiotherapy effective if done alone?
No you must do it in combination with other things like cancer
Does radiotherapy cause cancer?
No
How does ionising radiation work?
Electrons are released from the atoms of the molecules in the tissue causing formation of ions
When and how was chemotherapy discovered?
A reduction in WBCs (especially B cells) noted in soldiors exposed to mustard gas - nitrogen mustard
2 doctors used nitrogen mustard to treat lymphomas
How does nitrogen mustard work?
alkylating agent
How do most chemotherapies work?
Damaging or preventing DNA synthesis
What kind of cells does chemo work best on?
Rapidly dividing ones
How do alkylating agents work?
They form cross links between DNA strands and stop them from unwinding
Especially making covalent cross link on N7 of guanine in DNA –> cytotoxicity
How does cyclophsphamide work?
More complicated than nitrogen mustard
activated by P450 –> alkylating agent
What are antimetabolites?
Analogs of naturally occuring metabolites of RNA and DNA synthesis which lead to nucleotide depletion/incorporation in DNA and thus lead to cell death
What are plant alkaloids
Enter the cell–> bind to tubulin and inhibit beta and alpha tubulin assembly –> cannot make mitotic spindle in M phase
Name types of chemo
Alkylating agents (cyclophosphamide, nitrogen mustard) Antimetabolites Plant alkaloids antitumour antibiotics Topiramase inhibitors
What are antitumour antibiotics?
natural products made by streptomyces bacteria which block cell growth by interfering with DNA and genetic material in cell
Where was vinca alkaloid found?
Pacific Yew tree
Give examples of antitumour antibiotics
Doxorubicin and derivative epirubicin, bleomycin, mitomycin C, actinomycin, topiramase inhibitors, etoposidem mitoxantrone
What do topiramase 1 and 2 inhibitors do?
Topiramase 1 and 2 inhibitors (slop unwinding during replication and transcription –> causes breaks in DNA–> apoptosis)
What are chemo side effects?
Nausea Vomitting Dyspepsia Loss of appetite Tinnitus Blurred vision Fever Hypersensitive skin rash WBCs can't divide - infections Gut cells don't divide - GI problems Loss of hair Effects on fingernails
What treatment did Beatson give patients with advanced breast cancer (pre-menopausal)?
Remove ovaries (start menopause)
What proportion of breast cancer patients were found to respond to endocrine manipulations?
one-third
What are some methods of hormonal manipulation
Ovarian ablation
Selective ER modulators(SERMS)
Aromatase inhibitors
What was the first precision med in cancer?
SERMS
Name a SERM and how it works?
Tamoxifen
metabolised by P450 in liver (similar to E2) and made into active form –> competes with E2 at ER –> binding leeds to G0/1 arrest
What is the active form of tamoxifen?
4-hydroxytamoxifen
TRUE or FALSE Tamoxifen looks like E2 and thus binds to the same place in the ER
FALSE it looks completely different and binds to a different bit
How effective are SERMs?
Very
Tamoxifen 5yr post-op: 50% less recurrences, 25% increased survival
10yrs post-op 16% difference in breast cancer recurrence
Why are SERMs so effective?
70% of breast cancers are ER +ve
What are the side effects of tamoxifen and why do they occur?
Good: Protects post-menopausal women from osteoporosis - acts as ER agonist in bone
Bad:
- significantly increases uterine cancer risk - partial agonist in endometrium
- Increased CVD risk due to increased triglyceride component in serum
- cancer cell resistance
Does tamoxifen work in most meopausal women?
Sometimes
Who are aromatase inhibitors for?
Post-menopausal women
Give examples of aromatase inibitors
anastrazole, letrozole and exemestane
How do aromatase inhibitors work?
Bind to aromatase and prevent synthesis of oestrogens from parent compounds (e.g. androgens)
How are aromatase inhibitors different from SERMs?
They work upstream to prevent synthesis of endogenous oestrogens
