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Cancer > Cancer as a disease – Breast Cancer > Flashcards

Cancer as a disease – Breast Cancer Flashcards

1
Q

What is special about the breast as an organ?

A

It is the only organ that develops after birth

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2
Q

Where do the vast majority of breast cancers originate?

A

In the luminal epithelium of the breast (> 90%)

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3
Q

Describe the two layers of epithelial cells in the mammary gland.

A

Luminal epithelium

Myoepithelium

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4
Q

What is found between the tubules?

A

Fatty stromal cells

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5
Q

What is special about the myoepithelial cells?

A

They are contractile cells - help luminal epithelial cells secrete milk

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6
Q

Where are oestrogen receptors expressed in the breast?

A

They are ONLY expressed by luminal cells

But not all luminal cells express oestrogen receptors (only about 10-15%)

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7
Q

Describe the response to oestrogen in a normal breast.

A

The response to oestrogen is to stimulate growth.
The cell that express oestrogen receptors do NOT grow in response to oestrogen
They produce growth factors the stimulate the growth of nearby cells.

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8
Q

How is this response to oestrogen different in breast cancer?

A

The cells displaying oestrogen receptors directly respond to oestrogen as a growth factor and stimulate their own growth

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9
Q

What is the difference between lobular and medullary carcinoma? What do they both arise from?

A

Lobular – the tumour has some resemblance of the architecture of the gland (tubular)
Medullary – the tumour cells don’t look anything like the epithelial cells from the mammary gland

Initially begins as a benign/in-situ carcinoma (=proliferation of luminal cells but the myoepithelium is still around it)

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10
Q

What specific type of breast cancer accounts for almost 80% of breast cancers?

A

Infiltrating ductal carcinoma

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11
Q

What percentage of breast cancers is oestrogen receptor (ER) positive?
How do you determine if the breast cancer is ER+?

A

80%

Immunohistochemically staining using antibodies against the human oestrogen receptor.

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12
Q

State some risk factors for breast cancer.

A
  • Early age of onset of menstruation
  • Late menopause
  • Age to first full-time pregnancy
  • Contraceptive pills
  • Some hormone-replacement therapies
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13
Q

Where is the oestrogen receptor normally located?

A

It is found in the cytosol bound to a heatshock protein (hsp90)

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14
Q

What happens when oestrogen binds to ER?

A

Oestrogen (lipophilic) passes through the membrane, binds to the ER and displaces the heatshock protein.

  • Two ERs then dimerise.
  • The dimer then enters the nucleus to bind to response elements in the DNA sequence => regulates transcription.
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15
Q

What are important target genes for the ER transcription factor?

A

Progesterone receptor
Cyclin D1
c-myc
TGF-alpha

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16
Q

Why does high dose therapy with synthetic oestrogens cause breast tumour regression in post-menopausal women with breast cancer?

A

High-dose therapy overstimulates the hormonal system leading to downregulation of ER so the cells are no longer responsive to oestrogen

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17
Q

How does the presence of ER affect prognosis in males and females?

A

Good prognosis in female breast cancer

Worse prognosis in male breast cancer

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18
Q

The major treatment options for breast cancer are?

A

o Surgery.
o Radiation therapy.
o Chemotherapy.
o Endocrine therapy

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19
Q

What are three methods of reducing oestrogen action in the breast (endocrine therapy)?

A

Ovarian suppression
Blocking oestrogen production by enzymatic inhibition
Inhibiting oestrogen responses

20
Q

Where does oestrogen come from in post-menopausal women?

A
  • Aromatisation of androgens in peripheral fatty tissues

- Adrenal gland (stimulated by ACTH)

21
Q

What’s the major source of estrogen biosynthesis in pre-menopausal women?

A

The ovaries

22
Q

What is the aim of ovary ablation? What are two methods of ovary ablation?

A

Aims to eliminate the source of oestrogen form the ovaries and therefore treat breast cancer for premenopausal women.
Methods:
- Surgical oophorectomy
- Ovarian Irradiation

23
Q

What are the problems associated with these methods of ovary ablation?
Overcome these problems?

A

Morbidity and Irreversibility

To overcome these problems treatments to produce medical ovarian ablation have been developed.

24
Q

Describe a reversible and reliable medical ovarian ablation technique.

A

LHRH agonists bind to LHRH receptors in the pituitary leading to receptor downregulation and suppression of LH release => inhibition of ovarian function, including oestrogen production.

25
Q

Give examples of LHRH agonists

A

Goserelin
Buserelin
Triptorelin
Leuprolife

26
Q

Name a drug that acts as a competitive inhibitor of estradiol binding to the ER (an anti-oestrogen). State the effect on the cells expressing ER.

A 
Tamoxifen
Antiestrogens (may resemble oestradiol in structure) negate the stimulatory effects of estrogen by blocking the ER, causing the cell to be held at the G1 phase of the cell cycle.
27
Q

Tamoxifen is the endocrine treatment of choice for what and in which patients?
What are the side effects, if any?

A

Tamoxifen is the endocrine treatment of choice for metastatic disease in postmenopausal patients.

Few side effects reported (maybe hot flushes)

28
Q

What is a SERM?

A

Selective oestrogen receptor modulator

29
Q

Why is tamoxifen considered a SERM?

A

It is anti-oestrogenic in the breast
BUT
It has oestrogenic effects in bone and cardiovascular system.
(oestrogen is important to maintain bone and lowers LDL + raises HDL, so its a good thing that tamoxifen binds to ERs and has those properties but importantly is anti-oestrogenic in breasts)

30
Q

What are the problems associated with tamoxifen, especially when used as a prophylactic drug?

A

Tamoxifen is known to produce endometrial hyperplasia => increased incidence of endometrial cancer (oestrogenic in the uterus)

Increased risk of:

  • Thromboembolic events; DVT or stroke
  • Eye cataracts
31
Q

Name a drug that is a structural derivative of tamoxifen with similar antiestrogenic and estrogenic properties.

A

Toremifene

32
Q

Describe the anti-oestrogen drug ICI 182,780 (Faslodex)

A

Pure anti-oestrogen, showing no oestrogen like activity at all.

33
Q

What is raloxifene? What is it used in the treatment of?

A

A SERM – it is oestrogenic in bone and anti-oestrogenic in the breast and uterus.
Used in the treatment of osteoporosis in post menopausal women.

34
Q

Can tamoxifen be used as a preventative treatment for breast cancer?

A

Yes,

Tamoxifen reduces the incidence of contralateral breast cancer by a third

35
Q

Which adrenal hormones are aromatised in post-menopausal women? Aromatised into what kind of oestrogen? Where in the body does this conversion take place?

A

Androstenedione (and testosterone, to a lesser extent)

Oestrone (E2) (and Oestrone sulphate)

Occurs at peripheral sites such as fat, liver, and muscle.

36
Q

This conversion is catalysed by by what complex?

What does this complex consist of?

A

This conversion is catalyzed by the aromatase enzyme complex.
Consists of a CYP450 heme containing protein and the flavoprotein NADPH CYP450 reductase.

37
Q

What are the two types of aromatase inhibitor?

A

Suicide inhibitors

Competitive inhibitors

38
Q

How do suicide inhibitors work?

A

Compete with androstenedione and testosterone for binding to aromatase.
Enzyme acts on the inhibitor to create reactive alkylating species which covalently bond the active site of the enzyme => irreversibly inactivated.

39
Q

Give an example of a suicide inhibitor.

A

Exemestane

40
Q

Give an example of a competitive aromatase inhibitor.

A

Anastrozole

41
Q

What can progestin therapy be used for?

A

For metastatic breast cancer (as a second- or third-line therapy following SERM)

42
Q

Name the main progestin used for metastatic breast cancer?

A

Megestrol acetate

43
Q

Explan the big problem with prolonged endocrine therapy?

A

A significant proportion of patients presenting with breast cancer and, all patients with metastatic disease become resistant to endocrine therapies => eventual relapse
- Recent data shows that resistant tumours have mutated ER (so not becoming ER-independent)

44
Q

Women in which age range are targeted for breast cancer screening? How often are they asked to go for screening?

A

50-64 yrs (this is being extended to 70 yrs)

Every 3 years

45
Q

What proportion of breast tumours are first spotted by the women themselves?

A

> 90%

Cancer (15 decks)

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