endocrine therapies Flashcards
Study steroid hormone biosynthesis Be able to draw out
Endocrine Therapies, slide 3
what is the most active estrogen in the body?
estradiol
what is the most active testosterone in body
DHT
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
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
leading cancer for men? women?
prostate; breast
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
what are the two major strategies to endocrine therapy? (inhibition of steroid signaling)
- stop steroid receptor function
- decrease production of steroids
GnRH –> LH/FSH –> ovaries/testes is a _________ feedback loop
negative
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+
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
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
What enzyme converts androstenedione to estrone?
a. CYP19
b. 5alpha-reductase
c. 17, 20 lyase
d. P450scc
a. CYP19
____ tumors will be treated with endocrine therapy. ER status can be _____geneous. ~____% positivity are considered for endocrine therapy
ER+; hetero; 10%
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
triple negative breast cancers (ER-, no HER2, no BRCA mutation) are treated with ______
cytotoxics
luminal B/A are the ___most/least___ differentiated breast cancer subtype
most (ER+)
least differentiated –> most differentiated
claudin > basal > HER2 > luminal
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)
endocrine drugs ending with -fen are modulators or degraders?
-strant?
-fen –> SERMs (modulators)
tamoxifen, toremifene, clomiphene
-strant –> SERDs (degraders)
fulvestrant, raloxifene
what is the most commonly used endocrine therapy for ER+ breast cancers?
tamoxifen (prodrug)
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
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
t/f tamoxifen has both agonists & antagonist activities
true
t/f tamoxifen is effective in both pre- and postmenopausal women
true
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)