endocrine therapies Flashcards by Hannah Eberle

Study steroid hormone biosynthesis Be able to draw out

Endocrine Therapies, slide 3

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what is the most active estrogen in the body?

estradiol

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what is the most active testosterone in body

DHT

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glucocorticoids have anti-_____ effect in tx of _____ cancers including __________, ___________, _________

The most common glucocorticoids are: _________, __________, _________

Used as palliative care to reduce inflammation, edema & manage pain. can be used ro reduce hypersensitivity rxns, n/v & immune-related AEs

cancer; blood; ALL, multiple myeloma, lymphomas

methylprednisolone, prednisone & dexamethasone

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Hormonal therapies are ________ specific – only for hormone-dependent cancers,
i.e. Hormones regulate the proliferation in these cancers
>______
>______
>_________

Primarily targeting _______ (breast, endometrial) and ________(prostate)

Produced in _____, _____, _____ & ______

_________Disease
>Breast cancer
>Prostate cancer
>Endometrial cancer

estradiol; dihydrotestosterone
adrenal glands, ovary, testis, and adipocytes

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leading cancer for men? women?

prostate; breast

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steroid hormones: molecular action steps
1. most hydro—— steroids are bound to plasma protein carriers. only unbound hormones can diffuse into the target ——
2. steroid hormone receptors are in the _______ or _______
3. the receptor-hormone complex binds to ______ & activates or represses 1 or more genes
4.activated genes create new ____ that moves back to the cytoplasm
5. _———produces new proteins for cell processes
6. some steroid hormones also bind to membrane receptors that use _______ messenger systems to create rapid cellular responses

phobic; cell
cytoplasm or nucleus
DNA
mRNA
translation
second

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what are the two major strategies to endocrine therapy? (inhibition of steroid signaling)

stop steroid receptor function
decrease production of steroids

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GnRH –> LH/FSH –> ovaries/testes is a _________ feedback loop

negative

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Estrogen receptors (ER) and progesterone receptors (PR) are measurable in tumors

Well differentiated tumors are more likely to be __ER+ or ER-__ poorly differentiated tumors are generally __ER+; ER-__

> Remember that poorly differentiated tumors have _______growth fractions and are generally ___less/more___ sensitive to cytotoxic agents

Highly significant correlation between presence of _______receptor and the likelihood of response to hormone therapy

Correlation is even stronger for _______ tumors

PR is ______inducible and is a measure of biological response to estrogen

Hormone therapy in breast cancer generally limited to ______tumors

ER+; ER-

higher; more

estrogen

ER+/PR+

estrogen

ER+/PR+

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Which hormone is produced in the pituitary gland?

a. GnRH
b. LH
c. estrogen
d. progesterone

b. LH

FSH is also produced in pituitary gland; they are activated by GnRH

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Estrogen receptor primarily binds estrogen where in the cell?

a. On the plasma membrane
b. In the mitochondria
c. In the cytoplasm
d. In the nucleus

c. In the cytoplasm
once bound then it moves to nucleus

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What enzyme converts androstenedione to estrone?

a. CYP19
b. 5alpha-reductase
c. 17, 20 lyase
d. P450scc

a. CYP19

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____ tumors will be treated with endocrine therapy. ER status can be _____geneous. ~____% positivity are considered for endocrine therapy

ER+; hetero; 10%

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breast cancer is made up at least _#___ distinct disease. List the 4.

what diagnostics are used to determine subtypes?

4
claudin-low
basal-like
HER2-enriched
Luminal B/A

molecular diagnostics

see endocrine therapies, slide 17

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triple negative breast cancers (ER-, no HER2, no BRCA mutation) are treated with ______

cytotoxics

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luminal B/A are the ___most/least___ differentiated breast cancer subtype

most (ER+)

least differentiated –> most differentiated
claudin > basal > HER2 > luminal

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what subtype of breast cancer is the least common? mostcommon?

HER2+ (more high grade, poor prognosis, chemo therapy, trastuzumab tx)

luminal A (ER+/PR+, low grade, endocrine therapy used)

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endocrine drugs ending with -fen are modulators or degraders?
-strant?

-fen –> SERMs (modulators)
tamoxifen, toremifene, clomiphene

-strant –> SERDs (degraders)
fulvestrant, raloxifene

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what is the most commonly used endocrine therapy for ER+ breast cancers?

tamoxifen (prodrug)

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tamoxifen is a _____drug that must be metabolized to _____. pts with variant CYP____ should not use tamoxifen due to ___more/less___ active drug

prodrug; 4-OH-TAM
2D6; less active drug

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CYP2D6 converts tamoxifen to __low/high___ affinity hydroxylated and demethylated metabolites

Binding to ______ receptor will have affects on both translocation and DNA binding in a tissue-specific manner.

Estrogen antagonist effects
>Blocks estrogen-dependent breast cancer cell proliferation
>Hot flashes due to anti-estrogen effects

Estrogen agonist effects
>Incidence of _______cancer increased 3-fold
>Preservation of bone density in postmenopausal women

high

estrogen

endometrial

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t/f tamoxifen has both agonists & antagonist activities

true

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t/f tamoxifen is effective in both pre- and postmenopausal women

true

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t/f Primary use is treatment for resected ER+/PR+ breast cancer, but not for tx of metastatic ER+/PR+ breast cancer

false; also used for tx of metastatic ER+/PR+ breast cancer

what is the first drug approved for breast cancer PREVENTION in high risk pts?

tamoxifen (decrease risk by 50%, use up to 5 years)

t/f SERMS can act as either agonists or antagonists

true; will bind to co-activator or co-repressor depending on tissue (tissue-specific)

list the notable differences b/t tamoxifen & raloxifene (SERMs)

tamoxifen: endometrial hyperplasia raloxifene: no endometrial hyperplasia, less osteoporosis risk (blocks bone resorption & ^ bone mass)

what is the main drug in the SERD class? does it have ER antagonist or agonist effects? how is it administered

fulvestrant; pure ER antagonist, NO agonist effects; IV elacestrant is also in class (PO dosing)

what is the MOA of fulvestrant?

binds to ER & inhibits DNA binding --> rapid receptor degradation no activation of receptor

Fulvestrant (SERD) is approved for treatment of ____ _______ breast cancer in ______ menopausal women who have progressed on other antiestrogen therapy

ER+, metastatic, postmenopausal

aromatase inhibitors prevent the conversion of ______ to _____. (prevent the demethylation of enone ring)

androgens to estrogens

what is another name for aromatase?

CYP19

aromatase catalyzes the __________ of the _____ ring of _________ to the aromatic ring in _______ aromatases convert _______ > ______ + __________ > _________

demethylation; enone; androgens; estrogens androstenedione > estrone & testosterone > estradiol

t/f aromatase inhibitors block synthesis of estrogens, androgens and progesterone

false; only blocks synthesis of estrogens

_______ are a source of estrogen in postmenopausal women

Adipocytes >Androstenedione produced in adrenal gland and released to circulation >Aromatase in adipocytes converts androstenedione > estrone >Estrone then converted to estradiol

what is the primary target of aromatase inhibitors?

peripheral tissue (adipose tissue) – NOT OVARY

aromatase inhibitors are used primarily as estradiol suppression in ________menopausal women

post

what are the 2 non-steroidal aromatase inhibitors

anastrozole & letrozole (imidazole-based)

t/f anastrazole & letrozole are non-steroidal

true

Letrozole (Femara) and Anastrozole (Arimidex) >Potent and selective ______inhibitor of aromatase activity >Primary indication is treatment of ____cancer in ____menopausal women >Drug is highly effective as ____ line therapy OR when started after _____years of tamoxifen Rx >Taken orally everyday >Minimal toxicity ____increases/decreases____ extent of bone density loss

competitive breast; post first, 3-5 years increases - increased fractures vs. tamoxifen

what are the 2 steroidal aromatase inhibitors

exemestane & androstenedione

what steroidal aromatase inhibitors is referred to as the suicide inhibitor?

exemestane (aromasin)

Exemestane (Aromasin) Acts as false substrate that aromatase converts to reactive intermediate Intermediate binds -__reversibly/irreversibly___ at _____ site and inactivates enzyme Taken _____ everyday Primary indication is the treatment of _________-responsive breast cancer in ______-menopausal women who have progressed on antiestrogen therapy Not used in _____menopausal women Minimal toxicity >Hot flashes >Occasional peripheral edema and weight gain >___decreased/increased___ cholesterol levels

irreversibly; active orally estrogen post pre increased

Which compound directly inhibits the activity of the estrogen receptor throughout the body? a. Letrozole b. Exemestane c. Tamoxifen d. Fulvestrant

d. Fulvestrant letrozole & exemestabe are AIs, indirectly inhibits tamoxifen is a modulator so it only works in some tissues

Which compound is referred to as a SERM? a. Letrozole b. Exemestane c. Tamoxifen d. Fulvestrant

c. Tamoxifen letrozole is non steroidal AI exemestane is steroidal AI fulvestrant is SERD

what hormone can direclty activate/increase expression of estrone & estradiol

FSH (acts on aromatase)

-Chronic administration of GnRH analogues ___up/down___ regulates pituitary GnRH receptors and causes pituitary _________. -Decreased FSH, leads to ____i or d_____aromatase, and ___i or d__estrogen.

down; desensitization decreased; decreased

Gonadotropin Releasing Hormone analogs: >Peptide analogs of the neurohormone GnRH with modified amino acids to __increase/decrease__ potency and reduce degradation. >Depot formulation suitable for slow-release following ___SUBQ or IM_____injection >Acute administration induces surge of _____and ____ (agonist effect) -Acute __increase/decrease___ in all steroid hormone levels -Corresponding transient _increase/decrease___in tumor growth -Severe loss of estrogen within ____--weeks -Inhibition of estrogen-dependent breast cancers in women

increase SUBQ LH & FSH increase increase 3-4 weeks

what are the 3 LHRH/GnRH analogs? The analogs __increase/decrease___ the half life of the peptide

triptorelin (Trelstar), Leuprolide (Lupron), Goserelin (Zoladex) increase

GnRH Analogs [leuprolide, goserelin, triptorelin] Transient worsening of symptoms related to initial _____ effects long term side effects > _______ >_________ primary indication for women with ____menopausal breast cancer side effects in women typical of antiestrogenic effects

agonist hot flashes, sexual dysfunction premenopausal

SEE SUMMARY OF HORMONAL THERAPY IN BREAST CANCER tx for postmenopausal w ER+ vs. premenopausal

post: Tamoxifen Nonsteroidal aromatase inhibitors (anastrozole, letrozole) Steroidal aromatase inhibitor (exemestane) Pure anti-estrogens (fulvestrant) Pre: GnRH agonists (goserelin and leuprolide) Surgical oophorectomy Tamoxifen

t/f most prostate cancer is localized

true

prostate cancer is ___slow or fast___ progressing disease what is the median age of diagnosis & death

slow diagnosis: 66 death: 80

how is prostate cancer staged? How many stages? is 1 well or poor differentiated?

gleason score/scale 5 1 is well differentiated, 5 is poor

what is the most important risk factor in prostate cancer?

age, extremely rare <40, rate incease after 40 & is the steepest of any cancer

Testosterone is rapidly and __reversibly/irreversibly_____ converted by ____________ to ________in prostate cells

irreversibly; Type II 5-a reductase to DHT

DHT binds to which receptor in prostate cells

androgen receptor (AR)

when activated the DHT-AR complex is translocated where?

nucleus DNA binding stimulates transcription of AR responsive genes which drive cell growth

AR is a ________ receptor and can be ___increased or decreased____ in prostate cancer

cytoplasmic; increased (amplified)

A ___high or low___ level of PSA is indicative of prostate cancer

high UTI, vigorous exercise, prostate stimulation & some meds can also increase PSA

what level of PSA (prostate specific antigen) is suggestive of prostate cancer?

>6.5 ng/mL

A 65 y.o. male, with prostate cancer has a radical prostatectomy, and his PSA levels drop from 10 ng/ml to undetectable. On his three year follow up appointment his PSA level is at 5 ng/ml. What does this mean?

cancer is likely back, need PET scan

like in women, prolonged tx with GnRH analogues leads to a ___increase/decrease___ in LH production. There is a transient ___increase/decrease___ of testosterone, but overall resuts in "chemical castration" in ____ weeks

decrease increase; 3-4 weeks

GnRH analogs in MEN leuprolide, goselerin triptorelin primary indication is for palliative tx of advanced __________ cancer. transient wosening of sxs related to inital ______ effects {"flare"} long term sxs related to testosterone-deficient "feminization" -_______ -_______ ONLY USED IN ADVANCED CANCERS

prostate; agonist -gynecomastia -sexual dysfunction

GnRH Antagonists in MEN (2) -___________ -__________ What hormones are blocked? (2) primary indication is for advanced prostate cancer with need for __________ sxs are gynecomastia & sex dysfunction

degarelix, relugolix FH & LSH androgen deprivation therapy

Will degarelix or relugolix result in flare of testosterone production

MOA for abiraterone (zytiga)

inhibits funciton of 17a-hydrolase & C17,20 lyase (cyp17) >CYP17 catalyzes the conversion of pregnenolone and progesterone to >DHEA and androstenedione. >Steroid analogue >Much higher step in hormone synthesis

what is a common side effect of abiraterone (zytiga)

Common side effect is increased levels of cholesterol

what are the 3 androgen receptor (AR) antagonists?

enzalutamide, apalutamide, darolutamide

Enzalutamide (Xtandi), Apalutamide (Erleada), Darolutimide (Nubeqa) >Higher affinity binding to AR than previous “-lutamides” >Prevents __________ to the nucleus Inhibits AR binding to DNA Approved for both _____ + ______ prostate cancer.

>AR translocation >metastatic and non-metastatic

t/f apalutamide is approved for non metastatic prostate cancer

true

why is 5-alpha reductase controversial for use in prostate cancer?

Controversial! The opinion right now is that it should not be used in prostate cancer as it might increase the chance for high-grade prostate cancers

what are the mechanisms of resistance to endocrine therapy; prostate cancer

>Mutations in AR can arise that result in androgen independent activation and prevent binding of AR antagonists. >Overall, this is referred to castration resistant prostate cancer (CRPC).

endocrine therapies Flashcards

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