Early menstruation Late menopause HRT Contraceptive pill Pregnancy

CasaD - Breast Cancer Flashcards by Rama Jha

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

Due to
• early diagnosis
• chemo
• hormonal therapies

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What is unique about breast cancer?

ONLY organ to develop AFTER birth

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

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Where does most breast cancer originate in?

Luminal epithelium

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Explain mammary gland organisation

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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Where can oestrogen receptors be found?

ONLY expressed by luminal epithelial cells

• BUT NOT all the luminal cells express the receptor

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

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

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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What is the major histological type of invasive BC?

IDC - infiltrating ductal carcinoma

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

Positive (immunohistochemically staining)

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How is staining carried out for BCs?

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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RFs for BC?

Early menstruation
Late menopause
HRT
Contraceptive pill
Pregnancy

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Explain how the ‘OR’ is activated

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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What are some important oestrogen regulated genes

Progesterone receptor (PR)
Cyclin D1
C-myc
TGF-alpha

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

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

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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Prognosis if OR expression in females vs. males

Females = GOOD prognosis

Males = BAD prognosis

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Major treatment approaches for BC?

Surgery
Radiation therapy
Chemotherapy
Endocrine therapy

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

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

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

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Ovarian ablation (surgical)

vs.

Suppression (endocrine)

Why is Ovarian Ablation carried out?

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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

Explain Ovarian Suppression

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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)

Examples of LHRH?

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LH-Releasing Hormone

Goserelin
Buserelin
Leuprolide
Triptorelin

What are the hormonal targets for BC?

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• LHRH agonists

• Aromatase inhibitors
- prevent conversion of androgens –> osterogens

• Antioestrogens

Main Anti-Oestrogen drug that can be used?

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Tamoxifen

What is Tamoxifen

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

It is a competitive inhibitior!

How does Tamoxifen work?

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

When is Tamoxifen normally used?

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

What are some side-effects associated with Tamoxifen?

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

Desirable effects of oestrogen vs. negative effects?

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!!

Toremifene?

Analogue of Tamoxifen

Faslodex?

NO oestrogen-like activity BUT Effective at controlling oestrogen-stimulated growth * pure anti-oestrogen * decreases tumour cell invasion & stimulation of occult endometrial carcinoma

Raloxifene?

Anti-tumour agent * osterogenic in bones * no activity in breast OR uterus * treats osteoporosis

What has Tamoxifen trials shown?

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

Problems associated with Tamoxifen as a PROPHYLACTIC drug?

* Endometrial cancer * Stroke * DVT * Cataracts Due to these, prevention trials are being conducted with Raloxifene/Faslodex (SERMs) and aromatase inhibitiors

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

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

Explain Aromatase

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)

What are the 2 types of Aromatase inhibitors

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

Drugs associated with the main 2 types of aromatase inhibitors?

Suicide inhibitors • Exemestane Competitive inhibitors • Anastrozole

Main progestin in the body?

Progesterone

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

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)

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

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

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

Endocrine therapy - anti-oestrogens (Tamoxifen) Inhibitors of oestrogen synthesis - (Exemestane) Solution is to CONTINUE therapy and add: • ADDITIONAL inhibitors of oestrogen action

CasaD - Breast Cancer Flashcards

(41 cards)