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What is SERM?
- Selective Estrogen Receptor Modulators
- designer estrogens—
- Exert both estrogenic and antiestrogenic actions on ER positive breast tumors
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What are the SERMs?
- tamoxifen
- fulvestrant
- toremifene
- raloxifene
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What SERMs have both estrogenic and anti-estrogenic activity?
Tamoxifen, toremifene, and raloxifene
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What SERMs are only anti-estrogenic?
Fulvestrant
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By what route is Tamoxifen (Nolvadex) given?
Oral
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What I steh MOA of Tamoxifen (Nolvadex)?
- Non-steroidal antiestrogen with both estrogen receptor antagonist and agonist properties ON BREAST CANCER TISSUES
- Antagonist: prevents receptor stimulation by estradiol
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Why would some people be Tamoxifen (Nolvadex) resistant?
They have PM expression of CYP2D6
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What are the Pharmacokinetics of Tamoxifen (Nolvadex)?
- PRODRUG: CYP2D6 to active metabolites
- Phenytoin accelerates metabolism
- Ketoconazole, erythromycin inhibit metabolism
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What are the indications for Tamoxifen (Nolvadex)?
- Pre- and post-menopausal breast cancer if estrogen receptors are present
- Breast cancer prophylaxis
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What are the SE for Tamoxifen (Nolvadex)?
- menopausal symptoms:
- estrogen deficiency
- nausea
- hot flashes
- Others (estrogenic effects):
- thromobophlebitis,
- endometrial cancer
- maintain bone mineral density
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What is the route of administration for Fulvestrant (Faslodex)?
IM
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What is the MOA for Fulvestrant (Faslodex)?
- “Pure antiestrogen” –steroid structure
- Derivative of tamoxifen
- Binds to estrogen receptors which causes:
- Prevention of estrogen binding
- Downregulation
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What are the indications for Fulvestrant (Faslodex)?
- Active against tamoxifen resistant strains.
- Metastatic breast cancer in postmenopausal women
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What are the Side effects for Fulvestrant (Faslodex)?
- GI disturbances
- hot flashes
- no thromboembolism
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How does Fulvestrant (Faslodex) compare to anaastrazole?
As effective as anastrozole
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Does Fulvestrant (Faslodex) cause thromboembolism?
No
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What is the route of administration for toremifene (Farston)?
Oral
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What is the Mechanism of Action for toremifene (Farston)?
Anti-estrogen receptor analog of tamoxifen
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What metabolizes toremifene (Farston)?
CYP 450
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What are the indications for toremifene (Farston)?
Postmenopausal metastatic breast cancer ER +
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What are the SEs for toremifene (Farston)?
- Hot flashes
- Thrombophlebitis
- Endometrial cancer
- Cross-resistance with other anti-estrogens
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Is toremifene (Farston) a good choice for a patient who is resistant to other SERMs?
No, cross-resistant
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What is the MOA of raloxifene (Evista)?
Blocks estrogen receptors on breast cancer cells thereby preventing receptor stimulation by estradiol
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What are the important pharmacokinetic parameters of raloxifene (Evista)?
Extensive first-pass metabolism
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What are the indications for raloxifene (Evista)?
- Osteoporosis
- Approved as a postmenopausal prophylactic for breast cancer
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What are the SEs for raloxifene (Evista)?
Hot flashes, thromboembolism, fetal abnormalities, no endometrial cancer
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What are the Aromatase Inhibitors?
- anastrozole—nonsteroidal
- letrozole—nonsteroidal
- exemestane—steroidal
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Which Aromatiase inhibitors are steroidal?
Exemestane
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Which Aromatiase inhibitors are non-steroidal?
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What are the drug types used for Breast cancers?
- SERMs
- Aromatase Inhibitors
- HER-2 receptor inhibitors
- Anti-mitotic breast cancer drugs
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Why can’t you use Aromatase inhibitors in pre-menopausal women?
They reduce estrogen and thus cause the Hypothalamus and pituitary to produce more LH, FSH and GTRH
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Can you use Aromatase inhibitors in pre- or post-menopausal women?
ONLY POST
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What is the route of administration for anastrozole (Arimidex) and letrozole (Femara)?
Oral
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What is the indication for anastrozole (Arimidex) and letrozole (Femara)?
Approved for use against breast cancer in post menopausal women with ER positive breast tumors
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What is the MOA for anastrozole (Arimidex) and letrozole (Femara)?
Interfere with aromatase which plays a critical role in the production of estrogen in postmenopausal women from androgen produced in the adrenal gland (not from ovaries)
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What are the Side effects of anastrozole (Arimidex) and letrozole (Femara)?
- nausea,
- hot flashes,
- headache,
- fewer adverse effects than tamoxifen (no estrogenic activity)
- no significant thromboembolism,
- arthritis,
- bone density
- Hypercholesteremia
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Do anastrozole (Arimidex) and letrozole (Femara) cause endometrial cancer?
No
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Exemestane (Aromasin) has what route of administration?
Oral
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What is the MOA for Exemestane (Aromasin)?
- Irreversible, “suicide” inhibitor of aromatase,
- LACK of cross-resistance with other non-steroidal aromatase inhibitors, anastrozole and letrozole
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If a patient is not successful on anastrazole or letrozole, could they use Exemestane (Aromasin)?
Yes, not cross resistant
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What are the indications for Exemestane (Aromasin)?
Metastatic breast cancer in postmenopausal women, ER+
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What are the SEs for Exemestane (Aromasin)?
- Similar to other aromatase inhibitors:
- nausea,
- hot flashes,
- headache,
- fewer adverse effects than tamoxifen (no estrogenic activity)
- no significant thromboembolism,
- arthritis,
- bone density
- Hypercholesteremia
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What does HER-2 stand for?
Human Epidermal Growth Factor Receptor 2
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What is the general mechanism of HER-2 inhibitors?
- Biological Response Modifiers
- Signal Transduction Inhibition Targeted Drug Therapy
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What HER2 inhibitors are available?
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How is trastuzumab (Herceptin) administered?
Infused
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What is the MOA of trastuzumab (Herceptin)?
- Monoclonal antibody against the HER2 protein
- Inhibits growth-promotion
- Ligand for the HER-2/neu receptor found in 30% of breast cancer cells
- Interferes with signal transduction and causes apoptosis
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What are the indications fro trastuzumab (Herceptin)?
Breast cancer HER2 receptor positive
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What are the SE for trastuzumab (Herceptin)?
- Flu like symptoms (fever, chill)
- Cardiotoxicity (Main one to worry about)
- Pulmonary events and potentially fatal allergic reactions
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Does trastuzumab (Herceptin) cause Bone marrow suppression?
No
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Does trastuzumab (Herceptin) cause alopecia?
No
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trastuzumab (Herceptin) is often used in combination with what other drugs and why?
- trastuzumab, doxorubicin and cyclophosphamide followed by paclitaxel
- Good SE complementation
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What is the route of administration for lapatinib (Tykerb)?
Oral
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What is the MOA for lapatinib (Tykerb)?
- Tyrosine kinase signal transduction inhibitor
- Binds to the intracellular domain of the EGFR (ErbB1) and HER-2/neu (ErbB2) receptors and competes with ATP
- Prevents phosphorylation = prevents receptor activation
- Causes apoptosis and suppression of tumor cell growth
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What are the indications for lapatinib (Tykerb)?
Breast cancer HER2 receptor positive
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What are the SE for lapatinib (Tykerb)?
- GI (diarrhea)
- skin
- less cardiotoxicity than trastuzumab
- myelosuppression
- Drug-drug interactions with inducers and inhibitors of the CYP3A4
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