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Year 2 - MCD Cancer > CasaD - Breast Cancer > Flashcards

CasaD - Breast Cancer Flashcards

1
Q

Although the incidence of BC is increasing, mortality is decreasing - why is this?

A

Due to
• early diagnosis
• chemo
• hormonal therapies

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2
Q

What is unique about breast cancer?

A

ONLY organ to develop AFTER birth

• hence EVERY part of the gland (all cells) can have a type of cancer

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3
Q

Where does most breast cancer originate in?

A

Luminal epithelium

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4
Q

Explain mammary gland organisation

A

Between the tubules are fatty stromal cells

There are two layers of epithelial cells:
• Luminal epithelial cells
• Myoepithelial cells – contractile cells

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5
Q

Where can oestrogen receptors be found?

A

ONLY expressed by luminal epithelial cells

• BUT NOT all the luminal cells express the receptor

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6
Q

Explain the oestrogen receptor response in a NORMAL vs. BC state

A

NORMAL response to oestrogen
• stimulate growth via production of GFs by the luminal cells expressing receptors (not the cells themselves)

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

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7
Q

Schematic diagram of the progression of normal to malignant breast tissue?

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 carcinomas.

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8
Q

What is the major histological type of invasive BC?

A

IDC - infiltrating ductal carcinoma

Feature NO special histological features
• 80% of BCs are ‘OR’ +VE

OR

Positive (immunohistochemically staining)

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9
Q

How is staining carried out for BCs?

A

Immunohistochemically staining
• using ABs against the human ‘OR’ (oestrogen receptor) is informative
• This stain marks the nucleus as ‘OR’ is a steroid receptor.

> 80% of breast cancers are OR+.

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10
Q

RFs for BC?

A
  • Early menstruation
  • Late menopause
  • HRT
  • Contraceptive pill
  • Pregnancy
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11
Q

Explain how the ‘OR’ is activated

A

Inside the cell, the OR is bound to a heatshock protein to form a dimer
• Oestrogen (lipophilic) then passes through the membrane
• it 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
• pull them together (response elements are also in two halves and need a dimer to activate them)

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12
Q

What are some important oestrogen regulated genes

A
  • Progesterone receptor (PR)
  • Cyclin D1
  • C-myc
  • TGF-alpha
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13
Q

Oestrogen can also affect some BCs like it affects the normal breast - explain this

A

Approx 1/3 of PRE-MENOPAUSAL 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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14
Q

OR is over-expressed in around 70% of BCs - explain this

A

Presence is indicative of a BETTER prognosis

OR+ cases can have
• oestrogen withdrawn OR antagonised with anti-oestrogens
to result in ~70% response in OR+ cancers and 10-15% in OR- cancers.

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15
Q

Prognosis if OR expression in females vs. males

A

Females = GOOD prognosis

Males = BAD prognosis

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16
Q

Major treatment approaches for BC?

A
  • Surgery
  • Radiation therapy
  • Chemotherapy
  • Endocrine therapy
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17
Q

What is the gold-standard/cornerstone treatment for BC?

A

Endocrine therapy - includes:
• Ovarian supression
• Blocking oestrogen production via. enzymatic inhibition
• Inhibition of oestrogen responses

18
Q

2 types of therapy that can be used which targets the ovaries?

A

Ovarian ablation (surgical)

vs.

Suppression (endocrine)

19
Q

Why is Ovarian Ablation carried out?

A

The ovary is the major source of oestrogens and so ablation aims to eliminate this source. This is done via:
o Surgical oophorectomy
o Ovarian irradiation

The major problems with this is
• morbidity & irreversibility
so there are more medical suppression techniques

20
Q

Explain Ovarian Suppression

A

Reversible/reliable medical ovarian ablation is achieved with
• LHRH (LH-Releasing Hormone) agonists!!

These bind in the pituitary gland:
• down-regulate & suppress LH release
• inhibit ovarian function (including oestrogen production)

21
Q

Examples of LHRH?

A

LH-Releasing Hormone

  • Goserelin
  • Buserelin
  • Leuprolide
  • Triptorelin
22
Q

What are the hormonal targets for BC?

A

• LHRH agonists

• Aromatase inhibitors
- prevent conversion of androgens –> osterogens

• Antioestrogens

23
Q

Main Anti-Oestrogen drug that can be used?

A

Tamoxifen

24
Q

What is Tamoxifen

A

OR-blocker
OR
a SERM (selective oestrogen receptor modulator)

It is a competitive inhibitior!

25
Q

How does Tamoxifen work?

A

Negates the effects of oestrogens
• so the cell is arrested at the G1 phase

Also has oestrogenic effects in the BONE & CVS
• so decreases risk of oestoporosis & atherosclerosis

26
Q

When is Tamoxifen normally used?

A

It is the endocrine treatment for metastatic disease in POST-menopausal patients
• around 1/3 patients respond

27
Q

What are some side-effects associated with Tamoxifen?

A

Hot flushes

Increased risk of
• thromboembolic events
AND
• can cause endometrial hyperplasia (endometrial cancer possibility)

28
Q

Desirable effects of oestrogen vs. negative effects?

A

Brain
• +VE = improves cognitive function

Breast
• +VE = programs glands to produce milk
• -VE = promotes breast cancer

Liver & Heart
• +VE = lowers cholesterol, reduces atherosclerosis and HAs
• -VE = increases thromboembolism in LIVER

Uterus
• +VE = programs uterus to nourish a foetus
• -VE = promotes endometrial cancer

Bone
• +VE = maintains density to help prevent bone loss

ONENOTE!!

29
Q

Toremifene?

A

Analogue of Tamoxifen

30
Q

Faslodex?

A

NO oestrogen-like activity
BUT
Effective at controlling oestrogen-stimulated growth

  • pure anti-oestrogen
  • decreases tumour cell invasion & stimulation of occult endometrial carcinoma
31
Q

Raloxifene?

A

Anti-tumour agent

  • osterogenic in bones
  • no activity in breast OR uterus
  • treats osteoporosis
32
Q

What has Tamoxifen trials shown?

A

Tamoxifen reduces the incidence of contralateral breast cancer by a third

Tamoxifen trials have shown:
o 38% reduction in overall breast cancer incidence
o No effect on OR- breast cancer incidence
o No association between prevention and patient age

33
Q

Problems associated with Tamoxifen as a PROPHYLACTIC drug?

A
  • Endometrial cancer
  • Stroke
  • DVT
  • Cataracts

Due to these, prevention trials are being conducted with Raloxifene/Faslodex (SERMs) and aromatase inhibitiors

34
Q

In POST-menopausal women, what is their main source of oestrogen?

A

From the CONVERSION of the adrenal hormones androstenedione and testosterone (to a lesser extent) to oestrone (O2/E2), rather than from the ovaries directly
o This conversion occurs at the extra-adrenal or peripheral sites – liver, fat and muscle.
o Catalysed by the aromatase enzyme complex

35
Q

Explain Aromatase

A

Aromatase is 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 androstenedione to produce oestrone sulphate (circulates in plasma)

36
Q

What are the 2 types of Aromatase inhibitors

A

Suicide inhibitors: 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: Anastrozole
• Binds reversibly to aromatase

37
Q

Drugs associated with the main 2 types of aromatase inhibitors?

A

Suicide inhibitors
• Exemestane

Competitive inhibitors
• Anastrozole

38
Q

Main progestin in the body?

A

Progesterone

39
Q

Issues with the main progestin in the body and its uses?

A

Due to the POOR ABSORPTION of synthetic progesterone, synthetic derivatives have been made

Uses:
o Endocrine treatment of uterine and breast cancers with proven anti-neoplastic properties
o Metastatic breast cancer as a 2nd or 3rd line therapy (e.g. Megestrol acetate)

40
Q

What eventually happens to patients with BC and all patients with metastatic disease?

A

Become RESISTANT to endocrine therapies

• however, most cases continue to demonstrate oestrogen responses & contains ORs (which we can then inhibit)

41
Q

As patients become resistance to endocrine therapy & inhibitors of oestrogen synthesis, what is the solution?

A

Endocrine therapy - anti-oestrogens (Tamoxifen)
Inhibitors of oestrogen synthesis - (Exemestane)

Solution is to CONTINUE therapy and add:
• ADDITIONAL inhibitors of oestrogen action

Year 2 - MCD Cancer (14 decks)

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