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Year 2 - Cancer > Cancer 12: > Flashcards

Cancer 12: Flashcards

1
Q

what are the major statistics of breast cancer?

A
  • Breast cancer is the leading female cancer, accounting for almost 1 in 5 cancer deaths among women.
  • 1 in 8 women in the UK and the USA will develop the disease in their lifetime
  • Currently, around 55,000 women develop breast cancer every year in the UK.
  • breast cancer incidence has been increasing each year
  • breast cancer mortality has been falling each year
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2
Q

why has the mortality of breast cancer decreased?

A
  • chemo and radiotherapies are much better
  • earlier diagnosis due to public health message to women to check their breasts
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3
Q

what is special about the breast organ?

A
  • This is the only organ that develops after birth
  • During puberty the breast develops into a fatty glandular structure
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4
Q

what is the structure of the breast?

A
  • there is a tubular network of ducts and glands within the breast which comes together at the nipple
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5
Q

what is the phyllodes tumour?

A

this is a tumor in the fatty stromal area it is a very rare and very aggressive type of tumor

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6
Q

where does the majority of breast cancer originate from?

A
  • The majority of breast cancer (>90%) originates in the luminal epithelium
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7
Q

what is the cellular organization of the mammary gland?

how many layers of epithelial cells?

A
  • Between the tubules, you have fatty stromal cells
  • there are two layers of epithelial cells

luminal epithelial cells

myoepithelial cells (surround the luminal cells)

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8
Q

what do the Myoepithelial cells do?

A
  • the myoepithelial cells have a contractile phenotype
  • they contract when they receive the correct hormonal signals
  • they need to contract so they can force the milk out of the breast
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9
Q

why are myoepithelial cells important?

A
  • Myoepithelial cells are very important in the development of the gland
  • They are responsible for the formation of the tubules
  • the luminal cells lie passively underneath
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10
Q

what do the luminal epithelial cells do?

A
  • some of the luminal epithelial cells express estrogen receptors (10%-15%)
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11
Q

how do the cells in the breast respond to estrogen?

A
  • in a normal gland the response to estrogen is to stimulate growth
  • the oestrogen receptor positive cells do not grow in repsonse to oestrogen
  • instead the oestrogen receptor-positive cells produce growth factors that stimulate the growth of nearby cells
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12
Q

what happens to the oestrogen receptor cells in breast cancer?

A
  • the oestrogen receptor cells directly respond to their own signal and stimulate their own growth
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13
Q

what is a precancerous state of the breast cells?

A
  • when there is a proliferation of the luminal cells but the myoepithelium is still around it
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14
Q

what is a lobular carcinoma?

A
  • produce growth factors that stimulate the growth of nearby cells
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15
Q

what is a medullary carcinoma?

A
  • the tumor cells don’t look anything like the epithelial cells from the mammary gland
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16
Q

what are the majority of breast cancers?

A
  • they are nt medullary or lobular they are just breast carcinoma
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17
Q

what is a main histological test carried out on breast tumors?

A
  • stsaining of the tissue samples for the oestrogen receptor is carried out to classify the breast tumors as
  • ER-positive
  • ER-negative
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18
Q

what is being stained in the test for estrogen receptors ?

A
  • It is the nuclei that are being stained in this test because ER is a transcription factor that is found in the nucleus
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19
Q

what percentage is a positive ER?

A

80%

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20
Q

what are some risk factors for ER positive breast carcinoma ?

A
  • Early age of onset of menstruation
  • Late age to menopause
  • Age to first full=term pregnancy
  • Some contraceptive pills
  • Some HRTs
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21
Q

how does the oestrogen bind to the ER receptor?

what are the effects?

A
  • ER is a cytosolic receptor = inside the cell
  • it is bound to a heat-shock protein forming a dimer
  • estrogen is very lipophilic and ca pass through the cell membrane
  • once inside the cell the estrogen binds to the ER and displaces the heat shock protein
  • Two oestrogen receptors then come together to form a dimer, this dimerised protein enters the nucleus and locate DNA sequences in the genome that are response elements for this transcription factor
  • the most important target genes of the transcription factor are the following:

Progesterone receptor

Cyclin D1

C - Myc

TGF alpha

  • the oestrogen induced gene products result in increased cell proliferation resulting in breast cancer
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22
Q

why is the dimerisation of the ER significant?

A
  • the response elements are present in two halves so each half of the dimer will bind to each half of the response element
23
Q

how are pre menopausal women with breast cancer treated?

A
  • About 1/3 of PREmenopausal women with advanced breast cancer will respond to oophorectomy
  • this is removal of the ovaries
24
Q

how are post-menopausal women treated?

A
  • breast cancer in post-menopausal women responds to high dose therapy with synthetic estrogens this causes breast tumor regression
  • if you overstimulate this hormone system it will result in the downregulation of ER so the cells are no longer responsive to estrogen
25
Q

how common is ER overexpression?

what does the presence of ER suggest?

A
  • ER is overexpressed in 70% of breast cancers
  • Presence of ER is indicative of a BETTER PROGNOSIS
26
Q

what does an increased level of expression of ER in men suggest?

A
  • good prognosis in women
  • worse prognosis in men
27
Q

what are the three types of endocrine therapy used in breast cancer?

A
  • Ovarian suppression
  • Blocking oestrogen production by enzymatic inhibition
  • Inhibiting oestrogen responses
28
Q

where is oestrogen made for pre-menopausal women?

where is oestrogen made for post menopausal women?

A
  • pre-menopausal women = ovaries
  • post-menopausal women = aromatisation of androgens in peripheral tissues (fat)
29
Q

what is the function of Ovarian Ablation?

how is it carried out?

A

Aims to eliminate this source of estrogen

  • Surgical oophorectomy
  • Ovarian irradiation
30
Q

what are the major problems with ovarian ablation?

A
  • Results in morbidity and irreversibility so one cannot have children
31
Q

what is medical ovarian ablation?

A
  • in order to overcome the problems of ovarian ablation
  • medical ovarian ablation achieves reversible effects using luteinizing hormone-releasing hormone (LHRH) agonists
  • LHRH agonists bind to LHRH receptors in the pituitary leading to receptor downregulation and suppression of LH
  • this results in inhibition of ovarian function including estrogen production
32
Q

examples of LHRH agonists?

A
  • goserelin
  • buserelin
  • triptorelin
  • leuprolide
33
Q

what is the action of anti oestrogens such as tamoxifen?

A
  • Tamoxifen is an ER receptor blocker (competitive inhibitor)
  • Tamoxifen negates the stimulatory effects of estrogen so prevents the cells proliferating
34
Q

what is the most common side effect of Tamoxifen?

A
  • hot flushes
35
Q

what is Tamoxifens other feature?

A

Tamoxifen is a SERM (selective oestrogen receptor modulator)

  • this means although Tamoxifen blocks estrogen it still allows the beneficial effects :
  • Tamoxifen is oestrogenic in bone, protects against osteoporosis
  • Tamoxifen is oestrogenic on the cardiovascular system so decreases atherosclerosis risk
36
Q

what is a negative side effect of tamoxifen?

A
  • increases the risk of thromboembolic events
  • it can cause endometrial hyperplasia (increases risk of endometrial cancer)
37
Q

what is Faslodex?

advantages over tamoxifen?

A
  • shows no estrogen-like activity in laboratory tests
  • but effective in controlling oestrogen-stimulated growth
  • Faslodex is a pure anti-oestrogen
  • Faslodex offers advantages over tamoxifen by decreasing tumour cell invasion and the stimulation of occult endometrial carcinoma
38
Q

what is Raloxifene?

A
  • It is an agonist in bone but has no activity in the breast or uterus
  • It is used in the treatment of osteoporosis in post-menopausal women
39
Q

how might tamoxifen be used for preventative measures?

A
  • tamoxifen reduces contralateral breast cancer by a third
  • this has lead to trials of tamoxifen being able to prevent breast cancer
  • the trials have focussed on treating high-risk patients
40
Q

what are the major problems with using Tamoxifen in prevention?

A
  • Endometrial cancer
  • Stroke
  • DVT
  • Cataracts

To overcome these problems, prevention trials are being conducted with:

Raloxifene/Faslodex (SERMs)

Aromatase inhibitors

41
Q
A
42
Q

in postmenopausal women what is the major source of estrogen?

A
  • the major source of oestrogen derives not from the ovaries but from the conversion of the adrenal hormones to oestrone
  • this conversion occurs at peripheral sites such as fat, liver and muscle
  • The conversion is catalysed by the aromatase enzyme complex
43
Q

what does the aromatase complex consist of?

A
  • CYP450 heme-containing protein
  • NADPH CYP450 reductase
44
Q

what are the two types of aromatase Inhibitors in Breast Cancer?

A
  • Suicide Inhibitors
  • Competitive Inhibitors
45
Q

how do suicide inhibitors work?

A
  • compete with the natural substrate for binding to the active site
  • The enzyme then specifically acts on the inhibitor to yield reactive alkylating species, which form covalent bonds at or near the active site of the enzyme
  • this means that the enzyme is irreversibly inactivated
46
Q

example of suicide inhibitor?

side effects?

A
  • Exemestane
  • mild side effects including : hot flushes, nausea, fatigue
47
Q

how do competitive inhibitors work?

A
  • binds reversibly to the active site of the enzyme and prevent product formation only as long as the inhibitor occupies the catalytic site
48
Q

example of competitive inhibitor?

A
  • Anastrozole
49
Q

how are progestins used in the treatment of breast cancer?

A
  • Progestins are used in the endocrine treatment of uterine and breast cancer
  • it has anti-neoplastic properties
  • progestin therapy for metastatic breast cancer is the second or third like therapy
  • the main progestin is megestrol acetate
50
Q
A
51
Q

what is a major issue with endocrine therapies?

A
  • a significant proportion of patients presenting with breast cancer become resistant to endocrine therapies
  • ALL patients with metastatic disease become resistant to endocrine therapies
52
Q

how is screening for breast cancer carried out?

A

*

53
Q

show a basic patient history of breast cancer ?

A

Year 2 - Cancer (15 decks)

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