Endocrine therapies Flashcards
Breast cancer
estradiol
Endometrial cancer
estradiol
Prostate cancer
DHT
Adipocytes
source of estrogen in postmenopausal women
Normal action of steroids
- Lipophilic steroids are transported by protein carrier and release from carrier into blood diffusing into the cell
- Steroid hormones bind to estrogen/androgen receptors in cytoplasm
- Translocated from the cytoplasm to nucleus binding to DNA activating/repressing one or more genes
- Activated genes create new mRNA that moves back to cytoplasm to produce new proteins
How do we inhibit steroid signaling?
- Stop steroid receptor function
- Stop production of steroids
HPA Axis
GnRH in hypothalamus activates the release of LH and FSH in the anterior pituitary gland
LH and FSH stimulate the production of estrogens and androgens
LH: actives cholesterol side chain cleavage
FSH: activates aromatase
NEGATIVE FEEDBACK LOOP
Well-differentiated
More likely to be ER+
Poorly differentiated
More likely to be ER-
Luminal A/B
Receptor expression: ER+/PR+
Histologic grade: low grade (well-differentiated)
Tx: endocrine therapy
HER2
Receptor expression: HER2 (oncogene)
Histologic grade: high grade (low differentiated)
Tx: anti-HER2 therapy
Basal-like (BRCA1)
Receptor expression: ER-, PR-, HER2-
Histologic grade: high grade (low differentiated)
Tx: chemotherapy
Claudin-low
Receptor expression: ER-, PR-, HER2-
Histologic grade: high grade (low differentiated)
Tx: chemotherapy
Prostate cancer and hormones
- DHT binds to AR receptor in the prostate cells
- DHT-AR complex is activated and translocated to nucleus.
- DNA binding stimulates transcription of AR responsive genes
Biomarker for Prostate cancer
Prostate Specific Antigen
Low PSA level: normal
High PSA level: Prostate cancer OR
UTI, vigorous exercise, ejaculation, anal sex, certain medications
> 6.5 ng/mL=prostate cancer
Glucocorticoids
Methylprednisolone, prednisolone, dexamethasone
Anti-cancer effects:
Pediatric acute lymphoblastic leukemia (ALL)
Multiple myeloma
Lymphomas
Palliative to reduce inflammation, edema, and pain during chemo
Reduce hypersensitivity reactions, N/V, and immune-related effects
Tamoxifen
PRODRUG
Metabolized by CYP2D6 into 4OH-TAM
If poor metabolizer, do not use tamoxifen
MOA:
Antagonist (CoR): Blocks estrogen-dependent breast cancer cell proliferation, Hot flashes/thermoregulation
Agonist (CoA): preservation of bone density in pre/post menopausal women, VTE and clot risk, endometrial hyperplasia
Fulvestrant, Elecestrant
SERD
MOA: Full ER antagonist with no agonist effects @ high doses that binds to ER and inhibits DNA binding causing rapid receptor degradation
Indication: Treatment of metastatic ER+ breast cancer in POSTMENOPAUSAL women who have progressed on antiestrogens
Administration:
Fulvestrant:IM
Eleacetrant: oral
Anastrozole, Letrozole
Non-steroidal aromatase inhibitors
MOA: potent and selective competitive inhibitors of aromatase
Indication: treatment of breast cancer in POSTMENOPAUSAL women
Administration: oral
Side effects: osteoporosis (low bone density)
Exemestane
Steroidal aromatase inhibitor
MOA: structurally similar to androstenedione acting as a false substrate that aromatase converts to a reactive intermediate
Intermediate binds irreversibly at the active site
Indication: breast cancer in postmenopausal women who have progressed on antiestrogen therapy
SE: hot flashes, peripheral edema and weight gain, increased cholesterol levels
Leuprolide, Goserelin, Triptorelin
GnRH agonists
Chronic administration downregulates pituitary GnRH receptors and leads to pituitary desensitization–> decreases LH and FSH production lead to decreased aromatase leading to decreased estrogen and androgen
Severe loss of estrogen/androgen within 3-4 weeks
SAR: Modified 6th and 10th amino acids to increase potency and t1/2 life
Treatment of breast cancer in PREMENOPAUSAL women
Palliative treatment of advance prostate cancer
SubQ depot
Flare up
SE: hot flashes, gynecomastia, sexual dysfunction
Degarelix, Relugolix
GnRH antagonists
Treatment of advanced prostate cancer with need for androgen deprivation therapy
NO FLARE
SE: gynecomastia, sexual dysfunction
Enzalutamide
MOA: binds to the AR and prevents translocation to the nucleus and DNA binding
Treatment of non-metastatic and metastatic prostate cancer
Abiraterone (Zytiga)
inhibits 17-alpha hydroxylase and 17,20 lyase
SE: increased cholesterol levels
