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Year 2 MCD - Cancer > Cancer as a Disease: Breast Cancer > Flashcards

Cancer as a Disease: Breast Cancer Flashcards

1
Q

How many people develop and dies from breast cancer?

A

1/8 develop

1/5 die

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2
Q

What is happening to the incidence and mortality?

A

incidence is increasing and mortality is falling – early diagnosis, chemo, hormonal therapies

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3
Q

Where does most breast cancer originate?

A

luminal epithelium

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4
Q

How is the mammary gland organised?

A

Between the tubules are fatty stromal cells

There are two layers of epithelial cells:

  • Luminal epithelial cells
  • Myoepithelial cells – contractile cells

Oestrogen receptors are only expressed by luminal epithelial cells (but not all the luminal cells express the receptor)

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5
Q

What is the normal and breast cancer response to oestrogen?

A

NORMAL – stimulate growth via production of growth factors by the luminal cells expressing receptors (not the cells themselves)

Breast cancer – REVERSAL – oestrogen-responsive cells directly respond to oestrogen as a GF and stimulate their own growth

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6
Q

What are the types of carcinoma?

A

Benign/carcinoma-in-situ – proliferation of luminal cells but the myoepithelium is still around it

Lobular carcinoma – resemblance of the architecture of the gland

Medullary carcinoma – no resemblance to the gland

  • Majority of cancers are not either lobular or medullary so are just called breast

IDC – infiltrating ductal carcinoma – feature no special histological features – 80% of breast cancers

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7
Q

How are breast cancers stained?

A

Immunohistochemically staining using ABs against the human OR (oestrogen receptor) - marks the nucleus as OR is a steroid receptor

*>80% of breast cancers are OR+

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8
Q

What are some risk factors for breast cancer?

A
  • lifetime exposure to oestrogen
  • early menstruation
  • HRT
  • late menopause
  • contraceptive pill
  • pregnancy
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9
Q

What happens at the oestrogen receptor?

A
  • Inside the cell, the OR is bound to a heatshock protein to form a dimer
  • Oestrogen (lipophilic) then passes through the membrane, binds to the OR and displaces the heatshock protein. 2 ORs then dimerise
  • Dimerised ORs enter the nucleus and bind to the DNA response elements and pull them together (response elements are also in two halves and need a dimer to activate them)
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10
Q

What are some oestrogen regulated genes?

A
  • progesterone receptor (PR)
  • cyclin D1
  • c-myc
  • TGF-a
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11
Q

What is the oestrogen paradox in breast cancer?

A

Oestrogen can also affect some breast cancers like it affects the normal breast - approx. 1/3rd of premenopausal women will respond to an oophorectomy

Paradoxically, breast cancer in post-menopausal women respond to high-dose oestrogen therapy – due to downregulation of ORs as there is a high concentration of oestrogen

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12
Q

How does OR expression affect prognosis?

A
  • OR expression in females = GOOD PROGNOSIS

- OR expression in males = BAD PROGNOSIS

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13
Q

What are the treatment options?

A
  • Surgery
  • Radiation therapy
  • Chemotherapy
  • Endocrine therapy – the gold-standard or cornerstone treatment:
    > Ovarian suppression
    > Blocking oestrogen production by enzymatic inhibition
    > Inhibition of oestrogen responses
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14
Q

How are the ovaries ablated?

A
  • Surgical oophorectomy
  • Ovarian irradiation
  • major problems with this is morbidity and irreversibility so there are more medical suppression techniques
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15
Q

What happens in ovarian suppression?

A

Reversible/reliable medical ovarian ablation is achieved with LHRH (LH-Releasing Hormone) agonists which bind in the pituitary gland and down-regulate and supress LH release and inhibit ovarian function (including oestrogen production)

LHRH examples – Goserelin, Buserelin, Leuprolide, Triptorelin

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16
Q

What are hormonal targets for treatment?

A
  • LHRH agonists
  • Aromatase inhibitors – prevent conversion
  • Antioestrogens
17
Q

What is tamoxifen?

A

OR-blocker or a SERM – competitive inhibitor

  • This negates the effects of oestrogens so the cell is arrested at the G1 phase
  • Oestrogenic in bone and the CVS (decrease risk of osteoporosis and atherosclerosis risk)

Tamoxifen is the drug of choice for metastatic cancer in post-menopausal patients

Few side effects – bar hot flushes

18
Q

What are toremifene, faslodex and raloxifene?

A

Toremifene = analogue of tamoxifen

Faslodex = no oestrogen-like activity but effective at controlling oestrogen-stimulated growth

  • Pure anti-oestrogen
  • Decreases tumour cell invasion and the stimulation of occult endometrial carcinoma

Raloxifene = anti-tumour agent in animals

  • Oestrogenic in bone
  • No activity in breast or uterus
  • Treats osteoporosis
19
Q

What have tamoxifen trials shown?

A
  • 38% reduction in overall breast cancer incidence
  • No effect on OR-breast cancer incidence
  • No association between prevention and patient age
20
Q

What are the side effects of tamoxifen as a prophylactic drug?

A
  • endometrial cancer
  • stroke
  • DVT
  • cataracts
21
Q

What is the main source or oestrogen in post menopausal women?

A

conversion of adrenal hormones (androstenedione and testosterone) -> oestrone

  • occurs at the extra-adrenal or peripheral sites – liver, fat and muscle.

** catalysed by aromatase enzyme complex

22
Q

What is aromatase? What does it do?

A

complex with:

  • Cytochrome P450 haem containing protein
  • Flavoprotein NADPH CYP450 reductase

Aromatase catalyses 3 steroid hydroxylations involved in conversion of androstenedione to oestrone

Aromatase can also metabolise androstenodione to produce oestrogen sulphate (circulates in plasma)

23
Q

What are the types of aromatase inhibitors?

A

Suicide inhibitors e.g Exemestane

  • Competitive 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

Competitive inhibitors e.g Anastrozole
- Binds irreversibly to aromatase

24
Q

What are the uses of progestins?

A
  • Endocrine treatment of uterine and breast cancers with proven antineoplastic properties
  • Metastatic breast cancer as a 2nd or 3rd line therapy (e.g. Megetrol acetate)
25
Q

How do you combat resistance to endocrine therapy?

A

As the patients become resistant to endocrine therapy (anti-oestrogens (tamoxifen) and inhibitors of oestrogen synthesis (Exemestane)), the solution is to CONTINUE this therapy and add:
- Additional inhibitors of oestrogen action

Year 2 MCD - Cancer (15 decks)

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