clinical oncology

Question 1

investigations for breast cancer

Answer 1

consultation, clinical examintation, mammography, core needle biopsy

Question 2

proportion of cancer deaths breast cancer is responsible for, and prevalence in UK

Answer 2

1/5 (leading female cancer), with 1/8 women in UK developing it

Question 3

why is the incidence of breast cancer rising

Answer 3

early diagnosis by self-detection (promoted by NHS)

Question 4

why is the mortality of breast cancer falling

Answer 4

early diagnosis, chemo/radiotherapies, hormonal (endocrine) therapies

Question 5

describe the breast and what causes its formation and when

Answer 5

very fatty organ formed during puberty due to high levels of oestrogen, as well as progesterone, from ovary; collection of ducts and glands that meet at nippe

Question 6

what type of cancer are most malignant breast cancers

Answer 6

in clinic, breast cancer is carcinoma (tumour of luminal epithelial cells); can rarely be sarcoma (but not “clinic breast cancer”)

Question 7

cellular organisation of mammary gland

Answer 7

luminal (inner epithelial) cells in centre, with a layer of myoepithelial cells (outer epithelial cells forming tubules; some slightly vacuolated) surround them, making contact with basement membrane; during lactation, myoepithelial cells contract to squeeze milk through lumen

Question 8

progression of normal to malignant breast: normal

Answer 8

myoepithelial cells, attached to basement membrane, surrounding luminal epithelial cells

Question 9

progression of normal to malignant breast: benign/in situ carcinoma

Answer 9

proliferation of luminal epithelial cells into luminal cells, forming benign carcinoma, with myoepithelial cells becoming residual

Question 10

progression of normal to malignant breast: 3 outcomes following benign/in situ carcinoma

Answer 10

medullary carcinoma (packed full of vesicles which don’t retain morphology of tubular-like structure), unspecified infiltrating ductal carcinoma, lobular carcinoma (tumour cells retain some morphology of tubular-like structure despite loss of myoepithelial cells)

Question 11

what carcinoma accounts for almost 80% of breast cancersm and has no special type of histological structure

Answer 11

infiltrating ductal carcinoma

Question 12

what does immunohistochemical staining use antibodies against in invasive breast cancer

Answer 12

human oestrogen receptor (ER)

Question 13

% of infiltrating ductal carcinomas that are ER positive

Answer 13

80% (hence ER becomes test for cancer)

Question 14

oestrogen-related risk factors for breast cancer

Answer 14

lifetime exposure of oestrogen, age of onset of menarche, age to first full-time pregnancy, some contraceptive pills, some HRT

Question 15

oestrogen receptor (ER) pathway causing cancer

Answer 15

oestogen passes through membrane (steroid) and binds to oestrogen receptor (associated with hsp90) in cytoplasm -> sheds hsp90 protein and binds to another oestrogen receptor -> enters nucleus -> gene expression induced by receptor dimer/oestrogen complex binding to specific DNA sequences (oestrogen response elements; within minutes of oestrogen binding) -> oestrogen-induced gene products increase cell proliferation, resulting in breast cancer

Question 16

4 important oestrogen regulated genes and function

Answer 16

progesterone receptor (PR; sensitising cells to respond to progesterone), cyclin D1 (regulation of cell cycle), c-myc (ensure survival and not apoptosis), TGF-a (direct growth factor)

Question 17

normal vs tumour cells responding to oestrogen

Answer 17

in normal cells, oestrogen binds to ER and causes proliferation of surrounding cells; in tumour, oestrogen drives growth of tumour cells as well

Question 18

fraction of premenopausal women with advanced breast cancer will respond to oophorectomy (removal of ovary)

Answer 18

1/3

Question 19

describe paradoxical nature of breast cancer in postmenopausal women, and how this happens; describe consequence

Answer 19

respond to high-dose synthetic oestrogen to cause breast tumour regression (hormonal pathways set up so if over-stimulated, receptor becomes down-regulated so lose ability to respond); would relapse with metastatic disease

Question 20

% of breast cancers where ER is overexpressed and respond to anti-oestrogens

Answer 20

70%; some ER negative also show some response to anti-oestrogens, but not all

Question 21

what does an increased level of ER expression indicate in women vs men

Answer 21

in women, better prognosis as treatment, but in men (rare) a worse prognosis as less effective treatment (partially driven by androgen receptor)

Question 22

4 major treatment approaches for breast cancer

Answer 22

surgery, radiotherapy, chemotherapy, endocrine therapy

Question 23

what is the primary therapy for breast cancer usually

Answer 23

mastectomy (removal of breast) or lumpectomy (removal of tumour and small amount of normal tissue around it)

Question 24

what is removed in breast surgery and why

Answer 24

(sentinel) lymph nodes to see if cancer cells have spread to lymphatics

Question 25

what is conducted following a lumpectomy (breast-conserving surgery)

Answer 25

radiotherapy

Question 26

endocrine therapy: define adjuvant therapy

Answer 26

treatment given after primary therapy to increase the chance of long-term disease-free survival by treating any metastasis broken off from tumour mass; less common to do this before surgery as most detected before becoming too big to be operable (before had to shrink down before surgery)

Question 27

3 levels of endocrine therapy

Answer 27

ovarian suppression in premenopausal women, blocking oestrogen production by enzymatic inhibition, inhibiting oestrogen responses (anti-oestrogen)

Question 28

hypothalamo-pituitary-ovarian axis (only premenopausal)

Answer 28

hypothalamus -(peptide GnRH)-> pituitary -(peptides FH and LSH)-> ovary -> large quantities of oestrogens and progesterone to target cells e.g. mammary glands

Question 29

hypothalamo-pituitary-adrenal axis (pre/post menopausal)

Answer 29

hypothalamus -(CRH)-> pituitary -(ACTH)-> adrenal gland -> androgens, which are converted to oestrogens peripherally (aromatisation), including in ovary, but especially fatty tissue e.g. mammary glands; corticosteroids and progesterone released

Question 30

hypothalamo-pituitary-prolactin/growth hormone axis

Answer 30

hypothalamus -(dopamine inhibition, TSH and GHRH)-> pituitary -> prolactin and growth hormone

Question 31

what is the major source of oestrogen biosynthesis in pre-menopausal women

Answer 31

ovary

Question 32

2 methods of ovarian ablation

Answer 32

surgical oophorectomy, ovarian irradiation (focused radiation)

Question 33

2 problems of surgical or irradiation ovarian ablation

Answer 33

morbidity, irreversibility (can't have children)

Question 34

how can GnRH agonists achieve reversible and reliable medical ovarian ablation (can stop to allow pregnancy, then resume treatment after)

Answer 34

GnRH agonists bind to GnRH receptors in pituitary -> cell surface receptor down-regulation due to overstimulation -> suppression of LH release -> inhibition of ovarian function, including oestrogen production

Question 35

most common GnRH agonists

Answer 35

goserelin

Question 36

what inhibitors target ovarian production of oestrogens and progesterones, both from ovary and peripheral conversion of androgens from adrenal glands

Answer 36

aromatase inhibitors

Question 37

what other treatment can prevent oestrogen action

Answer 37

anti-oestrogens

Question 38

structure of oestrogens and anti-oestrogens

Answer 38

anti-oestrogens have similar structure to oestrogen, so bind to oestrogen receptor, which can't then bind to DNA

Question 39

major anti-oestrogenic therapy which is endocrine treatment of choice for metastatic disease in postmenopausal patients

Answer 39

tamoxifen (efficacy and low incidence of side effects)

Question 40

how does tamoxifen work

Answer 40

competitive inhibitor of oestadiol binding to ER, negating stimulatory effect of oestrogen and causing cell to be held at G1

Question 41

most common side effect of tamoxifen

Answer 41

hot flushes

Question 42

how is tamoxifen given

Answer 42

as prohormone (tamoxifen citrate), which is metabolised in GI tract and liver

Question 43

what class of drugs does tamoxifen belong to

Answer 43

selective oestrogen receptor modulators (SERMs)

Question 44

advantageous oestrogenic effects of tamoxifen on bone

Answer 44

prevents osteoporosis by maintaining bone density, as antagonist in breast but agonist in bone

Question 45

advantageous oestrogenic effects of tamoxifen on CVS

Answer 45

prevents atherosclerosis and lowers low-density cholesterol, as antagonist in breast but agonist in CVS

Question 46

3 consequences of tamoxifen in uterus

Answer 46

agonist in endometrium, so causes endometrial thickening, hyperplasia and fibroids

Question 47

3 other consequences of tamoxifen in liver, cataracts and vasculature

Answer 47

increased thromboembolism in liver, increased cataracts, increased vasomotor symptoms

Question 48

3 additional drugs used in treatment of all stages of breast cancer

Answer 48

toremifene (very similar to tamoxifen), faslodex, raloxifene

Question 49

consequence of faslodex

Answer 49

oestrogen with huge side chain, purely blocking oestrogen effects causing osteoporosis and CVD

Question 50

advantage and disadvantage of raloxifene

Answer 50

antagonist of tumour growth and treats osteoporosis, but less effective in breast cancer

Question 51

what else does tamoxifen reduce the incidence of by 1/3, indicating possible use as prophylactic therapy (prevention)

Answer 51

incidence of contralateral breast cancer (new breast cancer in other breast), indicating use as prophylaxis (prevention)

Question 52

4 problems associated with using tamoxifen in prevention, hence use of other SERMs or aromatase inhibitors as preventives

Answer 52

increased incidence of endometrial cancer, stroke, DVT, cataracts

Question 53

major source of oestrogen in postmenopausal women, and where conversion occurs

Answer 53

conversion of adrenal hormones (e.g. androstenedione) to oestrogen, occuring at extra-adrenal or peripheral sites e.g. fat (mammary glands), liver and muscle

Question 54

what enzyme complex catalyses conversion of adrenal hormones to oestroen

Answer 54

aromatase enzyme complex

Question 55

what does the aromatase enzyme complex consist of

Answer 55

complex containing cytochrome P450 haem-containing protein and flavoprotein NADPH cytochrome P450 reductase

Question 56

how many steroid hydroxylations are involved in conversion of androstenedione to oestroen, and what is the prodiuct of the first hydroxylation and significance

Answer 56

3, with estrone sulphate produced in first hyroxylation which is circulated in plasma and taken up by cells and sulphate removed

Question 57

2 types of aromatase inhibitors which inhibit production of oestrogen

Answer 57

type 1 (irreversible mechanism-based suicide by binding to active site covalently), type 2 (reversible at active site so competetive)

Question 58

example of type 1 and type 2 aromatase inhibitors

Answer 58

type 1 is exemestane, type 2 is arimidex

Question 59

response rates to ER+ and PR+ breast cancer and significance

Answer 59

highest, indicating targeting PR is also useful (give progestin to over stimulate pathway and cause down-regulation of receptors)

Question 60

what is the dominant naturally occuring progestin, and property of progestins that allow use in endocrine treatment of breast and uterine cancers

Answer 60

progesterone, and they are antineoplastic

Question 61

when is progestin therapy used to treat breast cancer

Answer 61

following selective oestrogen therapy

Question 62

what is the principal progestin used for treating metastatic breast cancer

Answer 62

megestrol acetate

Question 63

describe prevalence of resistance to anti-oestrogens used to treat breast cancer

Answer 63

significant proportion of patients presenting with breast cancer, and all patients with metastatic disease, become resistant to each individual endocrine therapy (eventual relapse), even though most cases continue to demonstrate oestrogen responses and contain ER (due to mutation of ER)

Question 64

how to overcome problem of resistance to tamoxifen and other anti-oestrogens

Answer 64

continue using as they are successful, but require additional therapeutic agents/strategies for endocrine resistant, metastatic disease (e.g. inhibitors of CDKs)

Question 65

5 other risk factors of breast cancer besides those related to oestrogen exposure

Answer 65

obesity (fat converts androgen to oestrogen), diet, physical inactivity, height, medication (e.g. aspirin)

Question 66

describe criteria for screening for breast cancer (mammography)

Answer 66

all women between 50-64 once every 3 years; after cancer annual surveillance for at least 5 years to ensure disease free, so know if breast cancer has recurred or is new

Question 67

2 types of ER positive (80% of breast cancers) breast cancer, and treatment

Answer 67

luminal B/C and luminal A; treated with hormone therapy

Question 68

3 types of ER negative breast cancer, and treatment

Answer 68

basal like, ErbB2 positive, normal-like; treated with chemotherapy

Question 69

4 types of basal like ER negative breast cancer

Answer 69

metaplastic, medullary, mucinous, others

Question 70

treatment for ErbB2 positive ER negative breast cancer

Answer 70

herceptin

Question 71

biggest detection of breast cancer

Answer 71

self-detection