Lecture 3 - Hormonal basis of cancer

Question 1

what are cancers that are regulated by hormones?

Answer 1

Breast, endometrium, ovary, prostate, testes, thyroid, osteocarcinoma
Cervical cancer, vaginal cancer etc.

Exogenous and endogenous hormones drive cell division.

The more cells divide the more chance they get more mutations,.

Contraceptives, HRT small increased risk of HR cancer.

Question 2

give examples of sex hormones and their descriptions

Answer 2

breast cancer - related organs is ovaries and relate chrome is oestrogen, progesterone

thyroid cancer = related organ is thyroid, pituitary gland. related hormones are T3, T4, TSH

bone cancer - related organ is pituitary gland, related hormone is GH

ovarian cancer - related organ is ovaries, uterus, Fallopian tubes. related hormones are oestrogen and progesterone

prostate cancer - prostate, tests, testosterone and androgen

Question 3

what are possible carcinogenic mechanisms of oestrogen?

Answer 3

1. Estrogen binds to receptor and sends grow signal to cell
2. Estorgen also directly induces cell growth pathways such as ERK, PI3K
3. Estrogen metabolism makes nasty metabolites which can cause DNA damage
4. Estrogen downregulates DNA damage repair so cancer cells continue to grow gathering more mutations

Question 4

what are risk factors for breast cancer?

Answer 4

Early menarche- internal hormones (hormones in body earlier- longer?)

Late menopause- internal hormones

Post-menopausal obesity – fat cells make extra
hormones and GF. hormones and GF tell cells in out body to divide more, increases changes of cancer cells being produced which can then divide and turn into tumour.

Hormone replacement therapy – (additional hormones in the body

Question 5

describe combined and single HRT with cancer

Answer 5

Hormone replacement therapy (HRT) slightly increases the risk of breast cancer, ovarian cancer, and
sometimes womb cancer.

• combined HRT slightly increases the risk of breast cancer- higher risk the longer the use
  -combined HRT slightly increases the risk of ovarian cancer. When HRT is stopped, the increased risk
  starts to go back down.
  
  • combined HRT does not affect womb cancer risk.

For Oestrogen only HRT- slight increase in risk for breast and ovarian
- significant risk of womb cancer

HRT is an effective treatment for symptoms of menopause. For most people, the benefits of taking HRT
outweigh the risks.

Question 6

describe breast cancer

Answer 6

2nd most common cancer death.

improvement in detection, iso incidence has increased, leading to improved treatment and mortality decreased

Question 7

how do we target the oestrogen receptor?

Answer 7

Reduce/block the formation of estrogen(s)?
Aromatase inhibitors e.g. Aromasin

Block estrogen interaction with ER?
ER antagonists e.g. Tamoxifen

Question 8

Explain ER breast cancers types and treatment for it.

Answer 8

75% of breast cancer are ER psotive. these women can be treated with hormone replacement therapy

ER positive breast cancer is when the caner cells have oestrogen receptors which allow oestrogen to bind to them and cause cell proliferation. However, ER+ can be treated with HRY such as tamoxifen which inhibits the oestrogen receptor.

ER negative breast cancer is when the cancer cells don’t have oestrogen receptors and so is not controlled by oestrogen and there is cell proliferation

Question 9

what are good and bad effects of tamoxifen?

Answer 9

tamoxifen also recduces recurrence rate

good effects:
reduces risk of ER+ breast acne, more effective against invasive breast cancer, benefits persist when its no longer taken, strengthens bones and lowers LDL cholesterol

bad effects: increases risk f uterine cancer, increases risk of blood clots, causes menopause-like symptoms

Question 10

what are differences in tamoxifen and ai inhibitors?

Answer 10

normally, androgens produce oestrogen’s which bind to ER and eventually increase proliferation.

Tamoxifen prevents
Binding or E to ER

AI prevents production
Of Es

Question 11

explain HER2 and breast cancer

Answer 11

HER2 is a protein found in excess in a subtype of breast cancer.

in normal cell, HER2 receptors send signals telling cells to grow and divide.

in cancerous breast/ stomach cells, too many HER2 receptors send more signals, causing cells to grow too quickly

Herceptin (trastuzumab) binds to the HER2 proteins receptors and decreases the signals for cells to divide. Binding of her pectin to cells also induced anti-tumour response.

Question 12

what are other mechanism of action of Herceptin?

Answer 12

1. Antibody dependent cell-mediated cytotoxicity (ADCC)
2. Lysis of HER2-expressing cells through complement (C’) activation

most common side effects are: infusion reactions (itching, flushing, nausea), headache & abdominal pain.

Question 13

what is triple negative breast cancer?

Answer 13

lack of oestrogen, progesterone and HER2 - no targeted therapies

much more aggressive. younger age diagnosis, high grade, large tumour size and aggressive relapse

Question 14

what are treatment options for hormone replacement positive breast cancer patients?

Answer 14

surgery, chemo, radiotherapy,

targeted: tamoxifen and other anti-endocrine therapy

Question 15

what are treatment options for HER positive breast cancer?

Answer 15

surgery chemo, radio

targeted: Herceptin and other anti-HER2 therapy

Question 16

what are triple negative BC treatments

Answer 16

surgery, chemo, no targeted theory

Question 17

describe options for chemotherapy before vs after surgery

Answer 17

Option: chemotherapy before surgery to shrink a large cancer enough to make an operation possible. Or it might mean that you can have an area of the breast removed, instead of needing a mastectomy.

Option: Chemotherapy after the operation to reduces the risk of the breast cancer coming back.
combination of chemotherapy drugs

Question 18

what are common combination chemotherapy drugs given?

Answer 18

F - Fluorouracil (5FU)
E- Epirubicin
C - Cyclophosphamide
T - Docetaxel (Taxotere)

Question 19

describe prostate cancer

Answer 19

most common cancer diagnosed and 2nd most common cause of death due to cancer in men

in first instance, prostate cancer is locally invasive and androgen dependant. all patients have at least 5 year survival program followup diagnosis.

prosate cancer recurs after treatment and spreads t other parts of body. continues to grow when male hormones are reduced. incurable and survival program is 16-18 months

Question 20

what are treatment strategies for prostate cancer?

Answer 20

All strategies coupled with active surveillance – monitoring the levels of Prostate Specific Antigen (PSA)
Surgery – radical prostatectomy
Radiotherapy – brachytherapy
Chemotherapy
Androgen Depravation Therapy (ADT)
- AR antagonists (steroidal vs. non-steroidal; e.g. chlormadinone acetate vs. flutamide)
- Inhibitors of androgen synthesis e.g abiraterone – inhibits extragonadal and intratumoral synthesis of androgens

Question 21

what is the role of androgens in promoting prostate cell growth?

Answer 21

The major androgen in males
is testosterone
Other androgens include DHT
Androgens are also the
precursors to estrogen in males
and females

Question 22

what are the principles of ADT?

Answer 22

prostate cells are physiologically dependant on androgens to grow, function and proliferate.

testosteron is the primary male androgen. the testes are a major source of testosterone.

dihydrotestosterone DHT is a metabolite of testosterone and is a more potent androgen.

testosterone does not cause prostate cancer but promotes and encourages growth

androgen deprivation can help induce apoptosis ir prevent further growth by surgical or medical castrstration: stop reproduction of testosterone or

anti-androgen therapy; inhibits the action of testosterone preventing its interaction with the receptors on the prostate cancer cells

Question 23

what are androgen biosynthesis?

Answer 23

used as anti-androgen theory:
drugs inhibits androgen biosynthesis such as ketoconazole, abiraterone, TAK-700 and TOK-001

Question 24

what is androgen receptor blockers

Answer 24

androgen receptor blockers prevent testosterone(androgen) from binding to the androgen receptors causing less testosterone which causes the cancer.

these drugs include: bicalutamide, nilutamide, flutamide, anzalutamide and ARN-509

Question 25

what is the mechanism of action of enzalutamide?

Answer 25

enzalutamide prevents the binding of androgens to testosterone to the androgen receptor. this inhibits androgen nucleus translocation and inhibits Androgen mediated DNA binding