Oncologic Endocrine Therapies (Wendt) Flashcards
Give three examples of hormone-dependent cancers.
breast cancer, prostate cancer, endometrial cancer
What hormone is the prime target in breast and endometrial cancers?
estradiol
What hormone is the primary target in prostate cancer?
dihydrotestosterone
List the steps of molecular action for steroid hormones.
- Most hydrophobic steroids are bound to plasma protein carriers. Only unbound hormones can diffuse into the target cell.
- Steroid hormone receptors are in the cytoplasm or nucleus.
- The receptor-hormone complex binds to DNA and activates or represses one or more genes.
- Activated genes create new mRNA that moves back to the cytoplasm.
- Translation produces new proteins for cell processes.
- Some steroid hormones also bind to membrane receptors that use second messenger systems to create rapid cellular responses.
What are the two ways in which endocrine therapies can inhibit steroid signaling?
- Stop steroid receptor function
- Decrease production of steroids
Which two receptors are measurable in breast cancer tumors?
estrogen and progesterone receptors (ER and PR)
Well-differentiated tumors are more likely to be ____, while poorly differentiated tumors are generally ____.
ER+; ER-
Which tumor grade are more sensitive to cytotoxic agents?
poorly differentiated tumors
The presence of which receptor strongly correlates with the likelihood of response to hormone therapy?
estrogen receptor (ER)
*even stronger correlation for ER+/PR+ tumors*
PR is ________ inducible and is a measure of biological response to _________.
estrogen; estrogen
True or false: hormone therapy in breast cancer is generally limited to ER+/PR+ tumors
true
How is hormone therapy typically used in ER+/PR- breast cancer?
as an adjunct to other chemotherapy
Which hormone is produced in the pituitary gland?
LH
Estrogen receptors primarily bind estrogen where in the cell?
in the cytoplasm
What enzyme converts androstenedione to estrone?
CYP19
What are the 4 molecular subtypes of breast cancer?
- Triple negative (ER-/PR-/HER2-)
- HER2+
- Luminal A
- Luminal B
What molecular subtype makes up the majority of breast cancers?
luminal A
Identify the drug based on its structure.
Tamoxifen (Nolvadex)
Identify the drug based on its structure.
Toremifene (Fareston)
Identify the drug based on its structure.
Clomiphene (Clomid)
Identify the drug based on its structure.
Fulvestrant (Faslodex)
Identify the drug based on its structure.
Raloxifene (Evista)
What SERM is a prodrug that must be metabolized to 4-OH-TAM?
Tamoxifen
Describe the pharmacologic actions of Tamoxifen (agonist or antagonist).
both agonist and antagonist
Which CYP converts tamoxifen to high-affinity hydroxylated and demethylated metabolites?
CYP2D6
What are the consequences of Nolvadex binding to estrogen receptors?
inhibits translocation and DNA binding
What estrogen agonist effects are seen with tamoxifen?
- 3-fold increase in incidence of endometrial cancer
- Preservation of bone density in postmenopausal women
What estrogen antagonist effect is seen with tamoxifen?
hot flashes
Regarding menopause, which group(s) is tamoxifen effective in?
both pre- and postmenopausal women
What is tamoxifen’s PRIMARY indication?
resected ER+/PR+ breast cancer (3-5 years Rx)
Besides resected ER+/PR+ breast cancer, what is tamoxifen also used to treat?
metastatic ER+/PR+ breast cancer
What was the first drug approved for breast cancer prevention?
Tamoxifen (Nolvadex)
Tamoxifen is known to be much less effective in which patients?
those with a common CYP2D6 variant
What beneficial uterine effect does raloxifene have (differs from tamoxifen)?
NO endometrial hyperplasia
What drug class does fulvestrant (Faslodex) belong to?
selective estrogen receptor down-modulator (SERD)
What drug is considered to be a “pure” ER antagonist with NO agonist effects?
fulvestrant (Faslodex)
What happens after Faslodex binds to ER and inhibits DNA binding?
rapid receptor degradation
What indication is fulvestrant (Faslodex) approved for?
treatment of metastatic ER+ breast cancer in postmenopausal women whose cancer has progressed on other antiestrogen therapy
What is one possible explanation for the relative lack of cross-resistance that Faslodex has with other antiestrogens?
it has the same target (ER) but different mechanism (receptor degradation)
What is fulvestrant’s route of administration?
IM injection once a month
What characteristic of fulvestrant limits its effectiveness?
poor solubility
What does aromatase do?
- catalyzes the demethylation of the enone ring of androgens to the aromatic ring in estrogens
- converts androstenedione ➝ estrone and testosterone ➝ estradiol
Aromatase inhibitors block the synthesis of which hormone?
estrogens
Where does estrogen originate from in postmenopausal women?
adipocytes
The primary target of aromatase inhibitors is not the ovary but _________.
peripheral (adipose) tissue
What is the primary application of aromatase inhibitors?
estradiol suppression in postmenopausal women
Identify the drug based on its structure.
Anastrozole (Arimidex)
Identify the drug based on its structure.
Letrozole (Femara)
Give two examples of imidazole-based non-steroidal aromatase inhibitors.
anastrazole and letrozole
Are letrozole and anastrozole competitive or non-competitive inhibitors of aromatase activity?
competitive inhibitors
What is the PRIMARY indication for non-steroidal aromatase inhibitors (letrozole and anastrozole)?
treatment of breast cancer in postmenopausal women
What are the two timing options available for non-steroidal aromatase inhibitors?
- taken as first-line therapy (highly effective)
- started after 3-5 years of tamoxifen use
What is the route of administration for both letrozole and anastrozole?
orally every day
What could be considered a downside of taking letrozole or anastrozole over tamoxifen?
its minimal toxicity increases the extent of bone density loss, leading to increased fractures
Identify the drug based on its structure.
Exemestane (Aromasin)
Identify the compound based on its structure.
Androstenedione
Give two examples of steroidal aromatase inhibitors.
exemestane and androstenedione
What drug is considered to be a “suicide inhibitor”?
Exemestane (Aromasin)
How does Aromasin work?
acts as a false substrate that aromatase converts to a reactive intermediate; this reactive intermediate binds irreversibly at the active site and inactivates the enzyme
What is the route of administration for exemestane?
orally every day
What is the PRIMARY indication for Aromasin?
the treatment of estrogen-responsive breast cancer in postmenopausal women who have experienced cancer progression on antiestrogen therapy
Although exemestane exhibits minimal toxicity, what side effects are commonly seen with this drug?
- hot flashes
- occasional peripheral edema and weight gain
- increased cholesterol levels
Which compound directly inhibits the activity of the estrogen receptor throughout the body?
Fulvestrant (Faslodex)
How does FSH affect aromatase and estrogen levels in the body?
directly related (decreased FSH = decreased aromatase and estrogen)
Acute administration of GnRH analogs induces a surge of which hormones?
LH and FSH (agonist effect)
Chronic administration of GnRH analogs downregulates pituitary receptors and ultimately leads to what?
pituitary desensitization
Give two examples of GnRH analogs.
Leuprolide acetate (Lupron) and Goserelin (Zoladex)
What long-term side effects are associated with GnRH analogs?
hot flashes, sexual dysfunction
What is the PRIMARY indication for the use of Lupron and Zoladex?
treatment of breast cancer in premenopausal women
List the 5 hormonal therapies that can be used for breast cancer in postmenopausal women.
- tamoxifen
- anastrozole
- letrozole
- exemestane
- fulvestrant
List the 4 hormone therapies that can be used for breast cancer treatment in premenopausal women.
- tamoxifen
- leuprolide
- goserelin
- surgical oophorectomy
All patients that initially respond to endocrine therapies will develop _______________.
resistance
What condition drives resistance?
tumor heterogeneity
As of recent, what are several anti-estrogens being combined with in advanced breast cancer?
cyclin-dependent kinase (CDK) inhibitors
Prostate cancer is a _______-progressing disease.
slowly
Prostate cancer is staged using which methodology?
the Gleason Scale
What is the most important risk factor for prostate cancer?
age (extremely rare prior to age 40)
What is the mechanism of prostate cancer proliferation?
- Testosterone is rapidly and irreversibly converted by Type II 5-alpha reductase to DHT in prostate cells.
- DHT binds to AR in prostate cells.
- DHT-AR complex is activated and translocated to the nucleus.
- DNA binding stimulates transcription of AR-responsive genes.
AR is a ____________ receptor.
cytoplasmic
What is PSA?
Prostate Specific Antigen; it’s normal for all men to have some PSA in their blood, but >6.5 ng/ml could be suggestive of prostate cancer.
Besides prostate cancer, what other conditions can increase PSA levels?
- UTI
- vigorous exercise
- prostate stimlation/recent ejaculation/anal sex
- certain medications
Although there may be transient increases in testosterone, the use of GnRH analogs in men will often lead to what in 3-4 weeks?
chemical castration
What is the PRIMARY indication for GnRH analogs in men?
palliative treatment of advanced prostate cancer
What is a short-term side effect of leuprolide and goserelin in men?
transient worsening of symptoms related to initial agonist effects (“flare”)
What are the long-term side effects associated with the use of GnRH analogs in men?
testosterone-deficient “feminization”; gynecomastia and sexual dysfunction
List two GnRH receptor antagonists.
abarelix (Plenaxis) and degarelix (Firmagon)
Identify the drug based on its structure.
Abarelix (Plenaxis)
Identify the drug based on its structure.
Degarelix (Firmagon)
What drug is administered IV once a month and indicated for the treatment of advanced prostate cancer?
Degarelix (Firmagon)
What is abiraterone’s mechanism of action?
inhibits the function of 17-alpha hydroxylase and C17,20 lyase
What role does CYP17 play in prostate cancer?
catalyzes the conversion of pregnenolone and progesterone to DHEA and androstenedione
What is a common side effect of abiraterone (Zytiga)?
increased cholesterol
List two 5-alpha reductase inhibitors.
finasteride (Propecia) and dutasteride (Avodart)
What is Propecia’s mechanism of action?
inhibits type II isoform of 5-alpha reductase
What is Avodart’s mechanism of action?
inhibits type I and type II isoform of 5-alpha reductase
Identify the drug based on its structure.
Finasteride (Propecia)
Identify the drug based on its structure.
Dutasteride (Avodart)
List three androgen receptor (AR) antagonists.
Enzalutamide (Xtandi), Apalutamide (Erleada), and Darolutamide (Nubeqa)
Identify the drug based on its structure.
Enzalutamide (Xtandi)
Identify the drug based on its structure.
Apalutamide (Erleada)
Identify the drug based on its structure.
Darolutamide (Nubeqa)
How do androgen receptor antagonists work?
they prevent AR translocation to the nucleus, which ultimately inhibits AR binding to DNA
What are AR antagonists indicated for?
both metastatic and non-metastatic prostate cancer
What trials brought into question the “wait and watch approach” to prostate cancer?
SPARTAN, PROSPER, and ARAMIS trials
177Lu-PSMA-617 is essentially a radioisotope conjugated to a peptide that binds what?
PSMA (Prostate Specific Membrane Antigen)
What is a possible upside of 177Lu-PSMA-617?
177Lu radiation only works over short distances, so damage is only done to surrounding tissues.
What are the two first-line options for mCRPC post-docetaxel prostate cancer?
abiraterone and enzalutamide
How does resistance to endocrine therapy in prostate cancer develop?
mutations in AR can arise, resulting in androgen-independent activation and the prevention of binding to AR antagonists
this is known as castration resistant prostate cancer (CRPC)
What is unique about the action of tamoxifen as compared to fulvestrant?
it activates ER in bone
True or false: ovarian cancer is a hormone-responsive cancer type.
false
Which of the following is a nonsteroidal aromatase inhibitor?
A
Which of the following is only used in the postmenopausal setting: letrozole, tamoxifen, leuprolide, or raloxifene?
letrozole
What compound acts directly on androgen receptors?
abiraterone
How does the hypothalamis-pituitary axis work?
The hypothalamus produces the peptide hormone GnRH, which acts on the pituitary gland to stimulate LH and FSH production.
What is meant by pituitary desensitization?
Continual stimulation of the pituitary gland via prolonged adminsitration of GnRH analogs leads to a decrease in GnRH receptors and diminished production of LH and FSH.
