Anti-cancer Endocrine therapies- EXAM 1

Question 1

Understand the use of corticosteroids in lymphoid cancers

Answer 1

glucorticoids have anti-cancer effects in treatment of blood cancers
Used as a palliative care to reduce inflammation, edema, and manage pain during chemotherapy
- can be used to reduce hypersnesitivity reactions, nausea and vomiting, and immune related adverse effects

Question 2

Understand the underlying principles governing the antineoplastic activity
of hormonal therapies

Answer 2

Primarly targeting estradiol and dihydrotestosterone
Two major strategies to endocrine therapies are stopping the steroid receptor function and decreasing the production of steroids

Question 3

Understand diagnostic determinants required for endocrine therapy.

Answer 3

ER+ tumors will be treated with endocrine therapy (around 10% ER positive means patient can benefit from endocrine therapy)
this is an extremely important determinate in therapy

Question 4

Understand the mechanism of action of the aromatase inhibitors.

Answer 4

Aromatase catalyzes the demethylation of the enone ring of androgens to the aromatic ring in estrogens

Adipocyters are a source of estrogen in postmenopausal women

primary application is estradiol suppression in postmenopausal women

Question 5

Understand the mechanisms of action and side effects of GnRH analogs.

Answer 5

constant administration of GnRH analogues leads to desensitization which leads to decrease in FSH release thus leading to decrease in aromatase and decrease in estrogen

Question 6

Understand the mechanisms of action of the AR antagonists, compared to
5-alpha-reductase and CYP17 inhibitors.

Answer 6

5-alpha reductase converts testosterone to dihydrotestosterone rapidly and irreversibly, binding of dihydrotestosterone to AR leads to translocation to the nucleus and action of genes that drive the cell
AR antagonists block the binding of AR to DNA

Question 7

Appreciate general mechanisms of intrinsic and acquired resistance to endocrine therapies.

Answer 7

Mutation in AR can arise that result in adrogen independent activation and prevent binding of AR antagonists
refered to as castration resistant prostate cancer which is when the tumor becomes more aggressive and resistant to most treatments

Question 8

Tamoxifen (nolvadex)

Answer 8

FIRST drug approved for breast cancer prevention in high risk patients
Orally available
Selective estrogen receptor modulator
has both agonist and antagonist activities
Antagonist effects: in the brain and breast: blocks estrogen dependent breast cancer cell proliferation, hot flashes due to anti-estrogen effects

Agonist effects: in the bone and endometrium: incidence of endometrial cancer increased 3-fold, preservation of bone density in postmenopausal women

Question 9

Raloxifene

Answer 9

SERM
has same effects as tamoxifen but is an antagonist in the uterus so it DOES NOT cause endometrial hyperplasia which differs from Tamoxifen

Question 10

Fluvestrant (faslodex) and Elacestrant

Answer 10

Selective estrogen receptor down-modulators (SERD)
These are pure ER antagonists and have absolutely no agonist effects
Fulvestrant (IMdosing) vs. elacetrant (POdosing)
For treatment of ER+ metastatic breast cancer in postmenopausal women who have progressed on other antiestrogen therapy

Question 11

Imidazole based non-steroidal aromatase inhibitors

Answer 11

Anastrozole (arimidex) and letrozole (femara)
Competitive inhibitors
treatment of breast cancer in postmenopausal women
First line therapy or when started after 3-5 years on tamoxifen
taken orally daily

Question 12

Steroidal aromatase inhibitor

Answer 12

Exemestane (Aromasin)
acts as a false substrate that aromatase convers to reactive intermidiate that binds irreversibly at the active site and inactivates the enzyme
Tx: estrogen responsive breast cancer in postmenopausal women who have progressed on antiestrogen therapy

Question 13

Which compound directly inhibits the activity of the estrogen receptor throughout the body?
A. Letrozole
B. Exemestane
C. Tamoxifen
D. Fulvestrant

Answer 13

D. Fulvestrant

Question 14

GnRH analogs

Answer 14

Leuprolide acetate ( lupron), Goserelin (zoladex), Triptorelin (trelstar)

Primary indication for women is for premenopausal breast cancer

Question 15

Summary of hormonal therapy in breast cancer

Answer 15

For POSTmenopausal women w/ER+ disease
- tamoxifen (SERM w/ antagonist and agonist effects)
- nonsteroidal aromatase inhibitors (anastrozole, letrozole)
- Steroidal aromatase inhibitor (exemestane)
- pure anti-estrogens (fluvestrant)

For PREmenopausal women
- GnRH agonists (goserelin and leuprolide)
- surgical oophorectomy
- tamoxifen

Question 16

GnRH antagonists in MEN

Answer 16

degarelix (firmagon), relugolix (orgovyx)
advanced prostate cancer with need for androgen deprivation therapy
Will not result in flare of testosterone production

Question 17

Abiraterone (zytiga)

Answer 17

inhibits the function of 17 alpha hydroylase and cyp17,20 ltase

Question 18

AR antagonists

Answer 18

Enzalutamide (Xtandi), Apalutamide (Erleada), Darolutimide (Nubeqa)
Prevents AR translocation to the nucleus by preventing binding of AR to DNA in the cytoplasm

approved for both metastatic and nonmetastatic prostate cancer