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Canc > Cancer 12: Cancer as a disease- Breast Cancer > Flashcards

Cancer 12: Cancer as a disease- Breast Cancer Flashcards

1
Q

Leading cause of cancer death in female

A

Breast cancer is the leading female cancer

1 in 5 cancer deaths in females

Most common cancer in UK

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2
Q

What is happening to incidence of breast cancer

A

Currently, around 55,000 women develop breast cancer every year in the UK.

Breast cancer incidence is rising.

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3
Q

T/f breast cancer is the leading cause of cancer deaths in females in UK

A

F… In the UK breast cancer is the second most common cause of death from cancer in women after lung cancer and accounts for 7% of all cancer deaths.

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4
Q

What is the reason for the fall in breast cancer deaths since 1980s

A

Early Diagnosis, Chemo/Radiotherapies

Hormonal Therapies.

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5
Q

Most common type of breast cancer

A

Carcinoma (tumour of epithelial cells)

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6
Q

What is special about the breast as a gland

A

If is the only gland that develops post-natally.

Rudimentary gland before puberty.

The main spurt of growth occurs at puberty and is dependent on high levels of estrogen, as well as progesterone produced by the ovary

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7
Q

Following puberty, when might the breast develop more

A

Post pubertal growth…. cyclical increase in ductal branches (extensive branching into fat pad)

Occurs due to lactation cycle

AND

pregnancy

Conversion of the breast into a secretory gland requires differentiation and, interestingly, this is a reversible process such that milk is not continued to be secreted long after pregnancy

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8
Q

What happens to the breast in pregnancy

What occurs following pregnancy

A

Pregnancy is characterised by large increases in side branching and development of secretory acini from the terminal ductal alveoli. Following weaning the mammary gland regresses to a near pre-pregnancy state through a process involving extensive apoptosis .

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9
Q

T/f all breast development is dependent on oestrogen

A

F

Estrogen does not seem to be necessary for the prenatal development of the mammary gland, but is required for prepubertal and pubertal gland development.

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10
Q

Outline the cellular organisation of the ducts secreting milk

A

Lumen lined by epithelial cells

Then layer of myoepithelial cells

They make contact with the basement membrane

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11
Q

Outline the main two types of BC

A

invasive ductal carcinoma (up to 80% of all BC) and invasive lobular carcinoma (5-15%)

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12
Q

How do the most common breast cancers develop

A

The general picture that emerges for the most common BC types, invasive ductal carcinoma (up to 80% of all BC) and invasive lobular carcinoma (5-15%) is that these cancers all originate in the terminal duct lobular unit and progress from an

initial hyperproliferative stage,

to a pre-cancerous, in situ carcinoma stage

and then to invasive BC.

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13
Q

What does in situ refer to in breast cancer

A

Within in the duct

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14
Q

Which cells in the breast have oestrogen receptors

A

luminal epithelial cells have receptors required to respond to steroid hormones (particularly oestrogen). NOT all of the luminal cells have these receptors (they are expressed and down-regulated constantly). Between 10-20% of these luminal cells can response to oestrogen

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15
Q

What is benign carcinoma in situ

A

locally proliferating cells that may appear as a lump. They are easily diagnosed as non-cancer. However, this is a precursor state for the development of cancer

local proliferation of cells that are LUMINAL. They proliferate within the tubule, WITHOUT breaking away from the tube. There is no loss of the myoepithelial cells.

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16
Q

What is lobular carcinoma

A

So there are tumour cells have a tubular like arrangement (i.e. dervided from the lobule), but the myoepithelium has been lost because the carcinoma has now spread out of the lobule and is invasive

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17
Q

What is medullary carcinoma

A

The tumour cells are packed full of neuroendrocrine vesicles

neuroendocrine

This is a type of invasive ductal carcinoma

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18
Q

Outline the structure of the breast

A

The ducts are embedded in a fatty stromal tissue

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19
Q

T/F there is a cancer type for every cell type ijn the breast

A

T… including the stromal tissue

But most common are the ducts and the lobular carcinoma, which are epithelial

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20
Q

T/f most breast cancers are in the luminal epithelial cells, not in the myoepithelial cells

A

True, but myoepithelial cells are important cells for laying down the tubular structure of the breast (morphogenic) , and there are cancers of these cells too which are hard to treat

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21
Q

State the types of tumour cells in breast cancer

A

They can be lobular, medullary, but most (80%) are infiltrating ductal carcinoma

The carcinoma has no consistent structure in most cases and cannot be separated into subgroups (NOS= not otherwised specified)

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22
Q

In the not-otherwised specificied breast cancers (i.e. not lobular or medullary), how can you classify them

A

So this is 80% of breast cancers.

They are either oestrogen receptor positive or negative

The oestrogen receptors can be stained with antibodies.

If there are oestrogen receptors, it means the tumour grows in response to oestrogen

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23
Q

T/f most breast cancers are oestrogen positive

A

T! From the staining, pathologists can look at the strength of the staining and grade how oestrogen responsive it is (+,++,+++) for growth

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24
Q

What percentage of cancers are oestrogen receptor positive

A

80% (tested using staining)

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25
Q

How was oestrogen discovered

A

Thought to be a link between ovarian function and breast growth before oestrogen was discovered

Because during menopause, breasts atrophy

Because of this they tried ovariectomy as breast cancer treatment, which had success

They then tried to find what the ovary was producing that caused breast growth and found it to be oestrogen

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26
Q

What is the effect of oestrogen receptor binding in breast cancer

A

The estrogen Receptor is Activated upon binding estrogen,

Normally it is in the nucleus

Oestrogen binding causes release of a chaperone protein called HSP90

Oestrogen recepors dimerise and translocate to the nucleus and activate transcription. So TRANSCRIPTION FACTOR

Binds to TATA

Gene Expression is Induced by Binding to Specific DNA Sequences called estrogen Response Elements,

The estrogen-Induced Gene Products Increase Cell Proliferation, Resulting in Breast Cancer.

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27
Q

What are important oestrogen regulated genes

A

Progesterone Receptor (PR)
Cyclin D1: regulator of cell cycle
c-myc: protein involved in regulation of apoptosis
TGF-a: GF that influences cellular growth

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28
Q

Why are oestrogen receptor positive breast cancers also progesterone responsive

A

Oestrogen receptors (the transcription factor activated upon oestrogen binding) upregulates the progesterone receptor

Pathologists stain for the progesterone too, to show that the oestrogen receptor is not only overexpressed (shown by oestrogne receptor staining) but also that the oestrogen receptor is ACTIVE (as it is upregulating Progesterone receptor) and thus suitable for targeting for treatment

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29
Q

What was the first form of endocrine therapy for breast cancer

A

Actually giving lots of a highly synthetic form of oestrogen

Because the cells then sense there is too much receptor activation, they downregulate receptor production and this has a negative effect on cell growth

An the tumour could shrink (not a greawt therapy but important it showed that breast cancers can be affected by oestrogen)

But synthetic
SYNTHETIC OESTROGENS ARE NOT WELL TOLERATED DRUGS. Secondly, resistance often follows remission. Patients can get metastatic disease. Thirdly, these drugs must be given in high dose (and have many side effects)

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30
Q

What is the primary treatment for breast cancer.

What is the problem with this therapy in general for cancer

A

Surgery (to remove)

In the process of tumour removal (even mastectomy), tumour cells from the site being operated on can be released into the circulation.

They could form secondary tumours (metastases)

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31
Q

What is the solution to cancer cells spreading during surgery

A

ADJUVANT THERAPY= chemo and radiotherapy

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32
Q

What adjuvant therapies are available in breast cancer

A

Chemo, radio and endocrine therapy

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33
Q

In which case might adjuvant therapy be given in advance of therapy

A

When tumours are big, to reduce tumour size prior to surgeons operating on them

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34
Q

What are the mechanisms of endocrine therapy used for breast cancer

A

Ovarian suppression (stop ovaries making oestrogen in pre-menopause women)

Blocking estrogen production by enzymatic inhibition (in pre and post menopausal women)

Inhibiting estrogen responses

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35
Q

T/F post menopausal women make oestrogen

A

T!

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36
Q

Outline how oestrogen is produced in premenopausal and post menopausal women

A

PRE ONLY:

LHRH (=GnRH) produced by thalamus

LHRH causes FSH and LH release by pituitary gland

These then act on the ovary, to cause oestrogen production (by aromatisation of an androgen called androstenodione to oestrogen)

Oestrogen can then act on oestrogen responsive tissue i.e. breast

IN BOTH PRE AND POST MENOPAUSAL WOMEN:

LHRH causes pituitary to releases ACTH as well as FSH and LH.

ACTH stimulates androgen production from the adrenal cortex (zona reticularis)

The androstenedione (androgen produced from adrenal cortex) is then converted to oestrogen in peripheral tissues, I.E THE OVARY in pre-menopausal women and in other sites (see later) for post menopausal) by aromatisation

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37
Q

How can the amount of oestrogen being produced by the ovary be reduced

A
  1. Ovarian ablation

2. Ovarian suppression

38
Q

What occurs in ovarian ablation

A

Surgical oophorectomy
Ovarian irradiation

Both procedures have morbidity and are irreversible (problems for child bearing age

so

Medical ovarian ablation developed to

39
Q

What is medical ovarian ablation

A

LHRH AGONIST

It doesn’t make more LH and FSH

LHRH agonists bind to LHRH receptors in the pituitary leading to receptor down-regulation and suppression of LH release and inhibition of ovarian function, including estrogen production.

40
Q

What type of receptor is LH

A

Is it a peptide hormone receptor

41
Q

Give exampls of medical ovarian ablation therapy

A

LHRH agonists include “Goserelin”, “Buserelin”, “Leuprolide” and “Triptorelin”

42
Q

Why is medical ovarian ablation therapy useful

A

IT IS FULLY REVERSIBLE

Don’t have to remove or kill ovaries

After treatment,

During pregnancy and childbirth can be taken off this to allow ovarian function

43
Q

T/f oestrogen receptor presence is indicative of better breast cancer prognisus

A

T in females but associated with worse prognosis in males

44
Q

When is medical ovarian ablation used, i.e. just primary or?

A

It is used during primary breast cancer or for metastasised breast cancer

45
Q

Why are ovarian ablations not used in all breast cancer patients

A

Because the vast majority of breast cancer patients are post-menopausal so the ovaries aren’t really making oestrogen anyway

46
Q

In addition to ovarian ablation, what other therapies might be used

A

Aromatise inhibitors or

antioestrogens

47
Q

What do antioestrogens do

A

They inhibit oestrogen activity

They are still lipophilic like oestrogen so can pass through the plasma membrane

They bind with high affinity to ER

But then, they inhibit gene transcription by the receptor

e.g. tamoxifen and ICI 182, 780 (=NOLVADEX)

48
Q

How does tamoxifen work and antioestrogens in general

A

Tamoxifen is a competitive inhibitor of estradiol binding to the ER

Antiestrogens negate the stimulatory effects of estrogen by blocking the ER, CAUSING THE CELL TO BE HELD AT G1 OF THE CELL CYCLE phase of the cell cycle (c-myc is transcribed by oestrogen).

49
Q

What is the endocrine treatment of choice in metastatic diseaseof breast cancer

A

Tamoxifen

50
Q

Side effects with tamoxifen

A

Hot flushes (29%) and nothing else!

51
Q

What is the drug class of tamoxifen

A

SERM (selective estrogen receptor modulators)

52
Q

Outline the effects of tamoxifen on bone

A

TAMOXIFEN= OESTROGENIC EFECTS IN BONE.

So anti-oestrogenic on breast and oestrogen effects on bone

Osteoporosis. estrogen is important to maintain bone in premenopausal women. After menopause, hormone replacement therapy is often recommended to prevent the development of osteoporosis. Clearly, the long-term administration of an antiestrogen has the potential to precipitate premature osteoporosis; so as a SERM, tamoxifen avoids this

53
Q

Outline the effects of oestrogen on CVS

A

TAMOXIFEN=OESTROGENIC EFFECTS ON THE CVS

Oestrogen is cardio-protective! So you want oestrogenic effects for CVS.

Tamoxifen is anti-oestrogenic for breast, but oestrogenic for CVS

Eostrogen is LDL lowering and HDL increasing. After menopause, CHD risk same in women as men due to lack of oestrogen.

54
Q

Bad effects of tamoxifen

A

Hot flushes

Reports assicating tamoxifen with thromboembolic events (i.e. oestrogen is pro-thrombotic in 60+ or when high atherosclerosis)

Tamoxifen is known to produce endometrial thickening, hyperplasia, and fibroids following several years of therapy

55
Q

Good effects of tamoxifen

A

-Reduces breast cancer (anti-oestrogenic)

Pro-estrogenic:

  • LIVER AND HEART: Lowers cholesterol, reduces atherosclerosis and heart attacks
  • BONE: Maintains density to help prevent bone loss
56
Q

Bad effects of tamoxifen

A

HYPOTHALAMUS
Increases vasomotor symptoms

EYE
Increases cataracts

LIVER
Increases thromboembolism

UTERUS
Promotes endometrial cancer, fibroids, polyps & vaginal discharge

REMEMBER YOU’RE GIVING IT AS ANTI-OESTROGENIC ON BREAST, BUT IT IS PRO-OESTROGENIC ON UTERUS, WHICH PROMOTES ENDOMETRIAL CANCER

57
Q

Use of:

  • Toremifene
  • ICI, 182 780 (=faslofex)
  • Raloxifene
A

Toremifene- Structural derivatve. Similar anti/pro oestrogenic activity

Faslodex- pure antioestrogen… advantages over tamoxifen in reducing tumour cell invasion and reducing stimulation of occult endometrial carcinoma. 1st line therapy for advanced breast cancer, 2nd line for patients in whom primary tamoxifen fails.

Raloxifene- antitumor in animals, agonist in bone so used for osteoporosis for post menopausal women (no activity in breast and uterus, according to this ppt.)

58
Q

T/f tamoxifen reduces incidence of contralateral breast caner

A

T. Tamoxifen reduces the incidence of contralateral breast cancer by a third

59
Q

T/f giving tamoxifen in high breast cancer risk patients reduces breast cancer incide

A

T; 38% reduction in overall breast cancer incidence
No effect on ER negative Breast Cancer incidence
No association between prevention and patient age

60
Q

What are high risk patients for breast cancer

A

Previous benign breast pathology (5 years)

Previous family history

61
Q

What is the problem with using tamoxifen prophylactically

How can you overcome

A

Increase incidence of endometrial cancer

Stroke

Deep Vein Thrombosis

Cataracts

To overcome:

Raloxifene/faslodex (SERM), which is antioestrogenic

Aromatase inhibitor

62
Q

What is the major source of oestrogen in post menopausal women

A

not from the ovaries but from the conversion of the adrenal hormones Androstenedione (A) and, to a lesser extent, Testosterone, to Estrone (E2).

63
Q

Where can post-menopaisal women convert their adrenal hormones to estrogen (E2), see slide 37

How is this done

A

extra-adrenal or peripheral sites such as fat, liver, and muscle.

Catalysed by aromatase enzyme complex.

64
Q

Outline the enzyme converting adrenal androgens to estrogen in post menpausal women

What does it catalyse

A

Aromatase consists of a complex containing a cytochrome P450 heme containing protein as well as the flavoprotein NADPH cytochrome P450 reductase.

catalyzes three separate steroid hydroxylations involved in the conversion of androstenedione to estrone.

65
Q

What kind of estrogen results from aromatisation reactions, and what reactant is used

A

Aromatase can metabolise androsteindione, which is produced by the adrenal glands. This leads to the production of Estrone Sulphate, which is circulated in the plasma

66
Q

State the 2 types of aromatase inhiubitors

A

Type 1:Irreversible… bund to aromatase and degrade it (covalently linked)

Type 2: Reversible…. competes for andrestenedione for the active site

67
Q

Give an example of type I and type II aromatase inhibiutors

A 
1= Exemestane
2= Anastrozole
68
Q

Post menopausal wonen only make tiny amounts of oestrogen anyway so why does the production of it need to be inhibited using aromatase inhibitors

A

The breast cancers are oestrogen positive

Oestrogen in post menopausal women is made in the fatty tissue (from adrenal androgens)

The breast is a fatty tissue

So the oestrogen is being made in the locality of the tumour!

BAD

69
Q

Who are aromatase inhgibits most useful in

A

Post menopausal women

AND

premenopausal women (better oestrogen suppression achieved with both tamoxifen and aromatise inhibitors! Because pre-menopausal women also make oestrogen via this adrenal route AND because aromatase is still required in the ovary to make oestrogen via the ovarian pre-menopausal route)
https://www.google.co.uk/search?q=oestrogen+production+in+ovary&rlz=1C1GCEJ_enGB817GB820&source=lnms&tbm=isch&sa=X&ved=0ahUKEwi25ZTewOjgAhXMRRUIHUwoBy8Q_AUIDigB&biw=958&bih=959#imgrc=3dTsGijUYsR63M:)
70
Q

When is ovarian ablation most useful

A

Premenopausal

71
Q

T/f aromatase inhibitea have lots of side effects

A

F, they are safe

72
Q

Progesterone receptor is regulatedby what

A

It is a gene upregulated by the estrogen receptor complex

73
Q

T/F progesterone is implicated in breast cancer

A

t

74
Q

T/F estrogen and progesterone positive breast cancers respond better to endocrine therapy

A

T… because this shows that the estrogen receptor is actually functional if the progesterone receptor is actually upregulated too and this means the ER is more likely to be involved in the proliferative process

75
Q

Outline progesterone related treatment for breast cancer

A

Give high progestins to downregulate progesterone receptor

76
Q

Progesterone is poorly absorbed. What has been used to help this

A

The poor absorption of progesterone has been overcome with some of the synthetic derivative progestins

77
Q

What does progestin response in the human breast involve duirng cancer

A

Progestin response in the human breast is complex and influences both proliferation and differentiated function.

78
Q

What properties do progestins have in cancer treatment

A

Antineoplastic

79
Q

T/F progestin therapy is first line in breast cancer

A

Progestin therapy for metastatic breast cancer has been used principally as a second- or third-line therapy following selective estrogen

80
Q

Which progestin is used for metastatic breast cancer

A

. The principal progestin used for metastatic breast cancer has been megestrol acetate

81
Q

What is problem with endocrine therapies in breast cancer

A

A significant proportion of patients presenting with breast cancer and, all patients with metastatic disease, become resistant to endocrine therapies.

IF YOU HAVE CANCER CELLS IN THE LYMPH NODES ALREADY, THEN THERE IS UNLILELY TO BE A 5 YEARS DISEASE FREE WINDOW, AND THEY ARE LIKELY TO BECOME RESISTANT TO ENDOCRINE THERAPY

82
Q

T/f the breast tumours which become resistant to endocrine therapy (which is in particular those associated with metastatic disease) are not estrogen responsive, which is why they don’t respond to our treatment

A

F… most cases continue to demonstrate estrogen responses and contain estrogen receptor

(I.E. they are still oestrogen responsive but just don’t respond to our treatment anymore)

83
Q

What proportion of ER-positive disease responds to endocrine therapy

A

> 60% of ERa-positive tumours respond to endocrine therapy

antioestrognes, inhibitors of oestrogen synthesis

84
Q

Outline the pattern of treatment effectiveness with breast cancer

A

Initial response but eventual relapse
Relapse due to resistance during prolonged endocrine therapy
NOT due to tumours becoming ER-independent
Recent data shows that resistant tumours have mutated ER

85
Q

What can occur if there is resistance to tamoxifen

A

Although 15% of patients who develop resistance to tamoxifen lose ERa expression, the majority of patients remain ERa positive and often respond to a switch to aromatase inhibitors or pure antiestrogens, indicative of a continued role for ERa in endocrine resistance

86
Q

Risk factors for breast cancer

A

OESTROGEN EXPOSURE

Early age of onset of menarche
Late age to menopause
Age at first full-term pregnancy
Some forms of the contraceptive pill
Hormone Replacement Therapy
Obesity
Diet, physical activity, height, medication (Aspirin)
87
Q

Why does BMI affect breast cancer risk

A

There is more adiposity so more oestrogen

88
Q

Outline breast cancer screening

Age?
How often?

A

The breast screening programme uses mammography to screen all women between 50 and64 who are registered with a GP in the UK.
The screening age is being extended to age 70 across the country.

Each patient is asked to attend for a test once every 3 years.

89
Q

T.f breast tumours are mostly first spotted by the screening programme

A

F- More than 90% of breast tumours are first spotted by women themselves.

90
Q

How has breast cancer classifcatin changed

A

SWITCH TO MOLECULAR CLASSIFICATION

ER+ve= luminal A (responds to hormone therapy) and luminal b/c (doesnt respond to hormonal therapy)

Er-ve= normal-like, ErbB2+ve (use herceptin), basal-like

Basically the ER-ve are more responsive to growth factor

91
Q

What are luminal B tumours

A

tumours belonging to the so-called luminal B class, tumours express high Ki67, human epidermal growth factor receptor 2 (HER-2) overexpression or a high score on the Oncotype DX gene expression profile. LUM B, is inherently more aggressive, requires more aggressive therapy and thus is generally treated with both endocrine therapy and chemotherapy,

Canc (16 decks)

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