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MCD: Cancer > Breast cancer > Flashcards

Breast cancer Flashcards

1
Q

What is the leading female cancer?

A

Breast cancer

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2
Q

What proportion of cancer deaths in women does breast cancer account for?

A

Almost 20% (1 in 5)

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3
Q

What proportion of women in the UK and US will develop breast cancer in their lifetime?

A

1 in 8

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4
Q

How many women develop breast cancer per year in the UK?

A

55,000

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5
Q

Why is breast cancer mortality falling?

A

Early diagnosis

Chemotherapies/ radiotherapies

Hormonal therapies

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6
Q

How has breast cancer incidence changed since 1979?

A

Risen- from 75 cases per 100,000 to 167 cases per 100,000 in 2014.

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7
Q

What is the primary function of the mammary gland?

A

Produce milk to feed neonate.

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8
Q

What does post-pubertal development of the mammary gland result in?

A

Cyclical increases in ductal branching, resulting in extensive branching in the fat pad.

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9
Q

When does the main spurt of growth of the mammary gland occur, and what is it dependent on?

A

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

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10
Q

What happens to the mammary gland during and after 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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11
Q

Describe the cellular organisation of the mammary gland.

A

A layer of myoepithelial cells, some of which are slightly vacuolated, is seen just around the luminal cells, making contact with the basement membrane.

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12
Q

What is the most common type of breast cancer?

A

Carcinoma (tumour of epithelial cells).

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13
Q

Describe the progression of normal to malignant breast.

A

Local proliferation of luminal cells within tube- benign in situ carcinoma.

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 breast cancer.

Lobular cancer- cancer cells try to form tube-like structures but fail.

Medullary carcinoma- packed full of vesicles rich in neuroendocrine peptides and hormones.

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14
Q

What proportion of breast cancers does infiltrating ductal carcinoma account for?

A

Almost 80%

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15
Q

What proportion of breast cancers are oestrogen-receptor positive?

A

About 80%

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16
Q

How is it determined whether a breast cancer is oestrogen-receptor positive or negative?

A

Core needle biopsy

Immunohistochemical staining using antibodies against the human oestrogen receptor (ER) is informative.

Different pathology labs have different cutoff points for calling the cancer either ER-positive or ER-negative.

For example, if less than 10% of the cells stain positive (fewer than 1 in 10), one lab might call this a negative result, another might consider this positive, even though it is a low test result.

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17
Q

What are important risk factors for breast cancer growth?

A

Age of onset of menarche.

Age to first full-term pregnancy.

Some contraceptive pills.

Some hormone-replacement therapies.

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18
Q

What hormone regulates breast cancer growth?

A

Oestrogen.

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19
Q

How is the oestrogen receptor activated?

A

Upon binding oestrogen.

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20
Q

What induces gene expression of the oestrogen receptor?

A

Binding to specific DNA sequences- oestrogen response elements.

If oestrogen can bind to oestrogen receptor in cytoplasm, HSP90 is displaced and the oestrogen receptor can dimerise with another.

Ligand-bound dimerised oestrogen receptor enters nucleus, binds as a transcription factor to oestrogen responsive sequences encoded in the genome to drive the expression of oestrogen regulated genes.

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21
Q

What do oestrogen-induced gene products do?

A

Increase cell proliferation, resulting in breast cancer.

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22
Q

What is the oestrogen receptor?

A

Ligand-activated transcription factor.

Protein that exists in the cytoplasm of the cell, bound to heat shock 90 protein (HSP90).

23
Q

What proportion of premenopausal women with advanced breast cancer will respond to oophorectomy?

A

Approximately 1/3.

24
Q

List some important oestrogen regulated genes.

A

Progesterone receptor (PR).

Cyclin D1.

c-myc.

TGF-alpha.

25
Q

What proportion of breast cancers is oestrogen receptor over-expressed in?

A

Around 70%- better prognosis.

26
Q

What are the major treatment approaches for breast cancer?

A

Surgery

Radiation therapy

Chemotherapy

Endocrine therapy

27
Q

What is the primary therapy for cancer?

A

Usually includes surgery- a mastectomy (removal of the breast) or a lumpectomy (surgery to remove the tumour and a small amount of normal tissue around it; a type of breast-conserving surgery).

During either type of surgery, one or more nearby lymph nodes are also removed to see if cancer cells have spread to the lymphatic system.

When a woman has breast-conserving surgery, primary therapy almost always includes radiation therapy (randomized prospective trials that have investigated radiation use provide conclusive evidence that radiation reduces ipsilateral breast cancer recurrences).

28
Q

What is adjuvant therapy for breast cancer?

A

Any treatment given after primary therapy to increase the chance of long-term disease-free survival.

Even in early-stage breast cancer, cells may break away from the primary tumour and spread to other parts of the body (metastasise).

Therefore, doctors give adjuvant therapy to kill any cancer cells that may have spread, even if they cannot be detected by imaging or laboratory tests.

29
Q

What are the different types of endocrine therapy for breast cancer treatment?

A

Ovarian suppression.

Blocking oestrogen production by enzymatic inhibition.

Inhibiting oestrogen responses.

30
Q

What is the purpose of ovarian ablation and suppression?

A

The ovary is the major source of oestrogen biosynthesis in pre-menopausal women.

Ovarian ablation aims to eliminate this source.

31
Q

How can ovarian ablation be carried out?

A

Surgical oophorectomy.

Ovarian irradiation.

The major problems associated with these procedures are morbidity and irreversibility.

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

Reversible and reliable medical ovarian ablation can be achieved using luteinising hormone releasing hormone (LHRH) agonists.

32
Q

Give examples of LHRH agonists.

A

Goserelin

Buserelin

Leuprolide

Triptorelin

33
Q

How do LHRH agonists work to inhibit ovarian function?

A

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

34
Q

What is tamoxifen?

A

Competitive inhibitor of oestradiol binding to the oestrogen receptor.

Selective oestrogen receptor modulator (SERM).

35
Q

What is the action of anti-oestrogens?

A

Negate the stimulatory effects of oestrogen by blocking the oestrogen receptor, causing the cell to be held at the G1 phase of the cell cycle.

36
Q

Discuss the pharmacokinetics of tamoxifen.

A

Administered as tamoxifen citrate.

Undergoes extensive metabolism in the GI tract and the liver, particularly by hydroxylation to generate 4-hydroxytamoxifen (OHT) and endoxifen.

37
Q

What is the endocrine treatment of choice in postmenopausal metastatic breast cancer patients?

A

Tamoxifen- approximately 1/3 respond.

38
Q

What are the side effects of tamoxifen?

A

Few reported- hot flushes (29%) most commonly reported during tamoxifen therapy.

39
Q

What is the significance of tamoxifen treatment for breast cancer and osteoporosis risk?

A

Oestrogen 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 anti-oestrogen has the potential to precipitate premature osteoporosis.

Tamoxifen has oestrogenic effects in bone.

40
Q

What is the significance of tamoxifen treatment for breast cancer and atherosclerosis risk?

A

Oestrogen lowers low-density lipoprotein (LDL) cholesterol levels and raises high-density lipoprotein (HDL) cholesterol levels.

Following menopause, women are at the same risk of coronary heart disease as men.

It can be argued that the long-term administration of anti-oestrogen could produce a population at risk of premature coronary heart disease.

Tamoxifen has oestrogenic effects in the cardiovascular system.

41
Q

What are some undesirable effects of tamoxifen treatment?

A

Anecdotal reports associating the administration of tamoxifen for advanced breast cancer with subsequent thromboembolic episodes.

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

42
Q

List problems associated with using tamoxifen in prevention.

A

Increased incidence of endometrial cancer.

Stroke.

Deep vein thrombosis.

Cataracts.

43
Q

What is the major source of oestrogen derived from in postmenopausal women?

A

Conversion of the adrenal hormones androstenedione (A) and, to a lesser extent, testosterone, to oestrone (E2), rather than from the ovaries.

This enzymatic conversion occurs at extra-adrenal or peripheral sites such as fat, liver and muscle.

Catalysed by the aromatase enzyme complex.

44
Q

What is aromatase?

A

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

45
Q

What are the actions of aromatase?

A

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

Aromatase can metabolise androstenedione, which is produced by the adrenal glands.

This leads to the production of oestrone sulphate, which is circulated in the plasma.

46
Q

How are aromatase inhibitors classified?

A

Mechanism-based, or suicide, inhibitors (type I).

Competitive inhibitors (type II).

47
Q

What is the dominant naturally occurring progestin?

A

Progesterone.

48
Q

How are progestins used?

A

In the endocrine treatment of uterine and breast cancer with clinically proven anti-neoplastic properties.

Second- or third-line therapy following SERM.

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

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

49
Q

What is the principal progestin used for metastatic breast cancer treatment?

A

Megestrol acetate.

50
Q

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

A

90%

51
Q

What proportion of women attend breast screening appointments?

A

70%

52
Q

How is breast cancer screened for in the UK?

A

The breast screening programme uses mammography to screen all women between 50 and 64 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..

53
Q

How many women are screened for breast cancer each year in the UK?

A

More than 1.2 million.

54
Q

What proportion of women screened for breast cancer in the UK are asked to return for more tests?

A

6%

MCD: Cancer (17 decks)

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