Cancer 12: Cancer as a disease- Breast Cancer Flashcards
Leading cause of cancer death in female
Breast cancer is the leading female cancer
1 in 5 cancer deaths in females
Most common cancer in UK
What is happening to incidence of breast cancer
Currently, around 55,000 women develop breast cancer every year in the UK.
Breast cancer incidence is rising.
T/f breast cancer is the leading cause of cancer deaths in females in UK
F… In the UK breast cancer is the second most common cause of death from cancer in women after lung cancer and accounts for 7% of all cancer deaths.
What is the reason for the fall in breast cancer deaths since 1980s
Early Diagnosis, Chemo/Radiotherapies
Hormonal Therapies.
Most common type of breast cancer
Carcinoma (tumour of epithelial cells)
What is special about the breast as a gland
If is the only gland that develops post-natally.
Rudimentary gland before puberty.
The main spurt of growth occurs at puberty and is dependent on high levels of estrogen, as well as progesterone produced by the ovary
Following puberty, when might the breast develop more
Post pubertal growth…. cyclical increase in ductal branches (extensive branching into fat pad)
Occurs due to lactation cycle
AND
pregnancy
Conversion of the breast into a secretory gland requires differentiation and, interestingly, this is a reversible process such that milk is not continued to be secreted long after pregnancy
What happens to the breast in pregnancy
What occurs following pregnancy
Pregnancy is characterised by large increases in side branching and development of secretory acini from the terminal ductal alveoli. Following weaning the mammary gland regresses to a near pre-pregnancy state through a process involving extensive apoptosis .
T/f all breast development is dependent on oestrogen
F
Estrogen does not seem to be necessary for the prenatal development of the mammary gland, but is required for prepubertal and pubertal gland development.
Outline the cellular organisation of the ducts secreting milk
Lumen lined by epithelial cells
Then layer of myoepithelial cells
They make contact with the basement membrane
Outline the main two types of BC
invasive ductal carcinoma (up to 80% of all BC) and invasive lobular carcinoma (5-15%)
How do the most common breast cancers develop
The general picture that emerges for the most common BC types, invasive ductal carcinoma (up to 80% of all BC) and invasive lobular carcinoma (5-15%) is that these cancers all originate in the terminal duct lobular unit and progress from an
initial hyperproliferative stage,
to a pre-cancerous, in situ carcinoma stage
and then to invasive BC.
What does in situ refer to in breast cancer
Within in the duct
Which cells in the breast have oestrogen receptors
luminal epithelial cells have receptors required to respond to steroid hormones (particularly oestrogen). NOT all of the luminal cells have these receptors (they are expressed and down-regulated constantly). Between 10-20% of these luminal cells can response to oestrogen
What is benign carcinoma in situ
locally proliferating cells that may appear as a lump. They are easily diagnosed as non-cancer. However, this is a precursor state for the development of cancer
local proliferation of cells that are LUMINAL. They proliferate within the tubule, WITHOUT breaking away from the tube. There is no loss of the myoepithelial cells.
What is lobular carcinoma
So there are tumour cells have a tubular like arrangement (i.e. dervided from the lobule), but the myoepithelium has been lost because the carcinoma has now spread out of the lobule and is invasive
What is medullary carcinoma
The tumour cells are packed full of neuroendrocrine vesicles
neuroendocrine
This is a type of invasive ductal carcinoma
Outline the structure of the breast
The ducts are embedded in a fatty stromal tissue
T/F there is a cancer type for every cell type ijn the breast
T… including the stromal tissue
But most common are the ducts and the lobular carcinoma, which are epithelial
T/f most breast cancers are in the luminal epithelial cells, not in the myoepithelial cells
True, but myoepithelial cells are important cells for laying down the tubular structure of the breast (morphogenic) , and there are cancers of these cells too which are hard to treat
State the types of tumour cells in breast cancer
They can be lobular, medullary, but most (80%) are infiltrating ductal carcinoma
The carcinoma has no consistent structure in most cases and cannot be separated into subgroups (NOS= not otherwised specified)
In the not-otherwised specificied breast cancers (i.e. not lobular or medullary), how can you classify them
So this is 80% of breast cancers.
They are either oestrogen receptor positive or negative
The oestrogen receptors can be stained with antibodies.
If there are oestrogen receptors, it means the tumour grows in response to oestrogen
T/f most breast cancers are oestrogen positive
T! From the staining, pathologists can look at the strength of the staining and grade how oestrogen responsive it is (+,++,+++) for growth
What percentage of cancers are oestrogen receptor positive
80% (tested using staining)
How was oestrogen discovered
Thought to be a link between ovarian function and breast growth before oestrogen was discovered
Because during menopause, breasts atrophy
Because of this they tried ovariectomy as breast cancer treatment, which had success
They then tried to find what the ovary was producing that caused breast growth and found it to be oestrogen
What is the effect of oestrogen receptor binding in breast cancer
The estrogen Receptor is Activated upon binding estrogen,
Normally it is in the nucleus
Oestrogen binding causes release of a chaperone protein called HSP90
Oestrogen recepors dimerise and translocate to the nucleus and activate transcription. So TRANSCRIPTION FACTOR
Binds to TATA
Gene Expression is Induced by Binding to Specific DNA Sequences called estrogen Response Elements,
The estrogen-Induced Gene Products Increase Cell Proliferation, Resulting in Breast Cancer.
What are important oestrogen regulated genes
Progesterone Receptor (PR)
Cyclin D1: regulator of cell cycle
c-myc: protein involved in regulation of apoptosis
TGF-a: GF that influences cellular growth
Why are oestrogen receptor positive breast cancers also progesterone responsive
Oestrogen receptors (the transcription factor activated upon oestrogen binding) upregulates the progesterone receptor
Pathologists stain for the progesterone too, to show that the oestrogen receptor is not only overexpressed (shown by oestrogne receptor staining) but also that the oestrogen receptor is ACTIVE (as it is upregulating Progesterone receptor) and thus suitable for targeting for treatment
What was the first form of endocrine therapy for breast cancer
Actually giving lots of a highly synthetic form of oestrogen
Because the cells then sense there is too much receptor activation, they downregulate receptor production and this has a negative effect on cell growth
An the tumour could shrink (not a greawt therapy but important it showed that breast cancers can be affected by oestrogen)
But synthetic
SYNTHETIC OESTROGENS ARE NOT WELL TOLERATED DRUGS. Secondly, resistance often follows remission. Patients can get metastatic disease. Thirdly, these drugs must be given in high dose (and have many side effects)
What is the primary treatment for breast cancer.
What is the problem with this therapy in general for cancer
Surgery (to remove)
In the process of tumour removal (even mastectomy), tumour cells from the site being operated on can be released into the circulation.
They could form secondary tumours (metastases)
What is the solution to cancer cells spreading during surgery
ADJUVANT THERAPY= chemo and radiotherapy
What adjuvant therapies are available in breast cancer
Chemo, radio and endocrine therapy
In which case might adjuvant therapy be given in advance of therapy
When tumours are big, to reduce tumour size prior to surgeons operating on them
What are the mechanisms of endocrine therapy used for breast cancer
Ovarian suppression (stop ovaries making oestrogen in pre-menopause women)
Blocking estrogen production by enzymatic inhibition (in pre and post menopausal women)
Inhibiting estrogen responses
T/F post menopausal women make oestrogen
T!
Outline how oestrogen is produced in premenopausal and post menopausal women
PRE ONLY:
LHRH (=GnRH) produced by thalamus
LHRH causes FSH and LH release by pituitary gland
These then act on the ovary, to cause oestrogen production (by aromatisation of an androgen called androstenodione to oestrogen)
Oestrogen can then act on oestrogen responsive tissue i.e. breast
IN BOTH PRE AND POST MENOPAUSAL WOMEN:
LHRH causes pituitary to releases ACTH as well as FSH and LH.
ACTH stimulates androgen production from the adrenal cortex (zona reticularis)
The androstenedione (androgen produced from adrenal cortex) is then converted to oestrogen in peripheral tissues, I.E THE OVARY in pre-menopausal women and in other sites (see later) for post menopausal) by aromatisation
How can the amount of oestrogen being produced by the ovary be reduced
- Ovarian ablation
2. Ovarian suppression
What occurs in ovarian ablation
Surgical oophorectomy
Ovarian irradiation
Both procedures have morbidity and are irreversible (problems for child bearing age
so
Medical ovarian ablation developed to
What is medical ovarian ablation
LHRH AGONIST
It doesn’t make more LH and FSH
LHRH agonists bind to LHRH receptors in the pituitary leading to receptor down-regulation and suppression of LH release and inhibition of ovarian function, including estrogen production.
What type of receptor is LH
Is it a peptide hormone receptor
Give exampls of medical ovarian ablation therapy
LHRH agonists include “Goserelin”, “Buserelin”, “Leuprolide” and “Triptorelin”
Why is medical ovarian ablation therapy useful
IT IS FULLY REVERSIBLE
Don’t have to remove or kill ovaries
After treatment,
During pregnancy and childbirth can be taken off this to allow ovarian function
T/f oestrogen receptor presence is indicative of better breast cancer prognisus
T in females but associated with worse prognosis in males
When is medical ovarian ablation used, i.e. just primary or?
It is used during primary breast cancer or for metastasised breast cancer
Why are ovarian ablations not used in all breast cancer patients
Because the vast majority of breast cancer patients are post-menopausal so the ovaries aren’t really making oestrogen anyway
In addition to ovarian ablation, what other therapies might be used
Aromatise inhibitors or
antioestrogens
What do antioestrogens do
They inhibit oestrogen activity
They are still lipophilic like oestrogen so can pass through the plasma membrane
They bind with high affinity to ER
But then, they inhibit gene transcription by the receptor
e.g. tamoxifen and ICI 182, 780 (=NOLVADEX)
How does tamoxifen work and antioestrogens in general
Tamoxifen is a competitive inhibitor of estradiol binding to the ER
Antiestrogens negate the stimulatory effects of estrogen by blocking the ER, CAUSING THE CELL TO BE HELD AT G1 OF THE CELL CYCLE phase of the cell cycle (c-myc is transcribed by oestrogen).
What is the endocrine treatment of choice in metastatic diseaseof breast cancer
Tamoxifen
Side effects with tamoxifen
Hot flushes (29%) and nothing else!
What is the drug class of tamoxifen
SERM (selective estrogen receptor modulators)
Outline the effects of tamoxifen on bone
TAMOXIFEN= OESTROGENIC EFECTS IN BONE.
So anti-oestrogenic on breast and oestrogen effects on bone
Osteoporosis. estrogen is important to maintain bone in premenopausal women. After menopause, hormone replacement therapy is often recommended to prevent the development of osteoporosis. Clearly, the long-term administration of an antiestrogen has the potential to precipitate premature osteoporosis; so as a SERM, tamoxifen avoids this
Outline the effects of oestrogen on CVS
TAMOXIFEN=OESTROGENIC EFFECTS ON THE CVS
Oestrogen is cardio-protective! So you want oestrogenic effects for CVS.
Tamoxifen is anti-oestrogenic for breast, but oestrogenic for CVS
Eostrogen is LDL lowering and HDL increasing. After menopause, CHD risk same in women as men due to lack of oestrogen.
Bad effects of tamoxifen
Hot flushes
Reports assicating tamoxifen with thromboembolic events (i.e. oestrogen is pro-thrombotic in 60+ or when high atherosclerosis)
Tamoxifen is known to produce endometrial thickening, hyperplasia, and fibroids following several years of therapy
Good effects of tamoxifen
-Reduces breast cancer (anti-oestrogenic)
Pro-estrogenic:
- LIVER AND HEART: Lowers cholesterol, reduces atherosclerosis and heart attacks
- BONE: Maintains density to help prevent bone loss
Bad effects of tamoxifen
HYPOTHALAMUS
Increases vasomotor symptoms
EYE
Increases cataracts
LIVER
Increases thromboembolism
UTERUS
Promotes endometrial cancer, fibroids, polyps & vaginal discharge
REMEMBER YOU’RE GIVING IT AS ANTI-OESTROGENIC ON BREAST, BUT IT IS PRO-OESTROGENIC ON UTERUS, WHICH PROMOTES ENDOMETRIAL CANCER
Use of:
- Toremifene
- ICI, 182 780 (=faslofex)
- Raloxifene
Toremifene- Structural derivatve. Similar anti/pro oestrogenic activity
Faslodex- pure antioestrogen… advantages over tamoxifen in reducing tumour cell invasion and reducing stimulation of occult endometrial carcinoma. 1st line therapy for advanced breast cancer, 2nd line for patients in whom primary tamoxifen fails.
Raloxifene- antitumor in animals, agonist in bone so used for osteoporosis for post menopausal women (no activity in breast and uterus, according to this ppt.)
T/f tamoxifen reduces incidence of contralateral breast caner
T. Tamoxifen reduces the incidence of contralateral breast cancer by a third
T/f giving tamoxifen in high breast cancer risk patients reduces breast cancer incide
T; 38% reduction in overall breast cancer incidence
No effect on ER negative Breast Cancer incidence
No association between prevention and patient age
What are high risk patients for breast cancer
Previous benign breast pathology (5 years)
Previous family history
What is the problem with using tamoxifen prophylactically
How can you overcome
Increase incidence of endometrial cancer
Stroke
Deep Vein Thrombosis
Cataracts
To overcome:
Raloxifene/faslodex (SERM), which is antioestrogenic
Aromatase inhibitor
What is the major source of oestrogen in post menopausal women
not from the ovaries but from the conversion of the adrenal hormones Androstenedione (A) and, to a lesser extent, Testosterone, to Estrone (E2).
Where can post-menopaisal women convert their adrenal hormones to estrogen (E2), see slide 37
How is this done
extra-adrenal or peripheral sites such as fat, liver, and muscle.
Catalysed by aromatase enzyme complex.
Outline the enzyme converting adrenal androgens to estrogen in post menpausal women
What does it catalyse
Aromatase consists of a complex containing a cytochrome P450 heme containing protein as well as the flavoprotein NADPH cytochrome P450 reductase.
catalyzes three separate steroid hydroxylations involved in the conversion of androstenedione to estrone.
What kind of estrogen results from aromatisation reactions, and what reactant is used
Aromatase can metabolise androsteindione, which is produced by the adrenal glands. This leads to the production of Estrone Sulphate, which is circulated in the plasma
State the 2 types of aromatase inhiubitors
Type 1:Irreversible… bund to aromatase and degrade it (covalently linked)
Type 2: Reversible…. competes for andrestenedione for the active site
Give an example of type I and type II aromatase inhibiutors
1= Exemestane 2= Anastrozole
Post menopausal wonen only make tiny amounts of oestrogen anyway so why does the production of it need to be inhibited using aromatase inhibitors
The breast cancers are oestrogen positive
Oestrogen in post menopausal women is made in the fatty tissue (from adrenal androgens)
The breast is a fatty tissue
So the oestrogen is being made in the locality of the tumour!
BAD
Who are aromatase inhgibits most useful in
Post menopausal women
AND
premenopausal women (better oestrogen suppression achieved with both tamoxifen and aromatise inhibitors! Because pre-menopausal women also make oestrogen via this adrenal route AND because aromatase is still required in the ovary to make oestrogen via the ovarian pre-menopausal route) https://www.google.co.uk/search?q=oestrogen+production+in+ovary&rlz=1C1GCEJ_enGB817GB820&source=lnms&tbm=isch&sa=X&ved=0ahUKEwi25ZTewOjgAhXMRRUIHUwoBy8Q_AUIDigB&biw=958&bih=959#imgrc=3dTsGijUYsR63M:)
When is ovarian ablation most useful
Premenopausal
T/f aromatase inhibitea have lots of side effects
F, they are safe
Progesterone receptor is regulatedby what
It is a gene upregulated by the estrogen receptor complex
T/F progesterone is implicated in breast cancer
t
T/F estrogen and progesterone positive breast cancers respond better to endocrine therapy
T… because this shows that the estrogen receptor is actually functional if the progesterone receptor is actually upregulated too and this means the ER is more likely to be involved in the proliferative process
Outline progesterone related treatment for breast cancer
Give high progestins to downregulate progesterone receptor
Progesterone is poorly absorbed. What has been used to help this
The poor absorption of progesterone has been overcome with some of the synthetic derivative progestins
What does progestin response in the human breast involve duirng cancer
Progestin response in the human breast is complex and influences both proliferation and differentiated function.
What properties do progestins have in cancer treatment
Antineoplastic
T/F progestin therapy is first line in breast cancer
Progestin therapy for metastatic breast cancer has been used principally as a second- or third-line therapy following selective estrogen
Which progestin is used for metastatic breast cancer
. The principal progestin used for metastatic breast cancer has been megestrol acetate
What is problem with endocrine therapies in breast cancer
A significant proportion of patients presenting with breast cancer and, all patients with metastatic disease, become resistant to endocrine therapies.
IF YOU HAVE CANCER CELLS IN THE LYMPH NODES ALREADY, THEN THERE IS UNLILELY TO BE A 5 YEARS DISEASE FREE WINDOW, AND THEY ARE LIKELY TO BECOME RESISTANT TO ENDOCRINE THERAPY
T/f the breast tumours which become resistant to endocrine therapy (which is in particular those associated with metastatic disease) are not estrogen responsive, which is why they don’t respond to our treatment
F… most cases continue to demonstrate estrogen responses and contain estrogen receptor
(I.E. they are still oestrogen responsive but just don’t respond to our treatment anymore)
What proportion of ER-positive disease responds to endocrine therapy
> 60% of ERa-positive tumours respond to endocrine therapy
antioestrognes, inhibitors of oestrogen synthesis
Outline the pattern of treatment effectiveness with breast cancer
Initial response but eventual relapse
Relapse due to resistance during prolonged endocrine therapy
NOT due to tumours becoming ER-independent
Recent data shows that resistant tumours have mutated ER
What can occur if there is resistance to tamoxifen
Although 15% of patients who develop resistance to tamoxifen lose ERa expression, the majority of patients remain ERa positive and often respond to a switch to aromatase inhibitors or pure antiestrogens, indicative of a continued role for ERa in endocrine resistance
Risk factors for breast cancer
OESTROGEN EXPOSURE
Early age of onset of menarche Late age to menopause Age at first full-term pregnancy Some forms of the contraceptive pill Hormone Replacement Therapy Obesity Diet, physical activity, height, medication (Aspirin)
Why does BMI affect breast cancer risk
There is more adiposity so more oestrogen
Outline breast cancer screening
Age?
How often?
The breast screening programme uses mammography to screen all women between 50 and64 who are registered with a GP in the UK.
The screening age is being extended to age 70 across the country.
Each patient is asked to attend for a test once every 3 years.
T.f breast tumours are mostly first spotted by the screening programme
F- More than 90% of breast tumours are first spotted by women themselves.
How has breast cancer classifcatin changed
SWITCH TO MOLECULAR CLASSIFICATION
ER+ve= luminal A (responds to hormone therapy) and luminal b/c (doesnt respond to hormonal therapy)
Er-ve= normal-like, ErbB2+ve (use herceptin), basal-like
Basically the ER-ve are more responsive to growth factor
What are luminal B tumours
tumours belonging to the so-called luminal B class, tumours express high Ki67, human epidermal growth factor receptor 2 (HER-2) overexpression or a high score on the Oncotype DX gene expression profile. LUM B, is inherently more aggressive, requires more aggressive therapy and thus is generally treated with both endocrine therapy and chemotherapy,
