Lecture 4 - Breast Cancer Flashcards
Tamoxifen
first generation SERM
application:
treat early stage or metastatic ER+ breast cancer in pre- or post-menopausal pts
decrease risk of cancer development
note that ER+/PR+/HER2- pts respond best to SERMs
MOA:
metabolized by CYP2D6 to active metabolites endoxifen and 4-hydroxyTAM that bind to ER-alpha, acting as antagonists in breast tissue to inhibit gene transcription, inhibit cell proliferation and promote apoptosis
acts as a partial agonist in endometrium to promote endometrial hyperplasia. there is a 4-6 fold increased incidence of endometrial cancer. Hence, not administered for more than 5-10 years.
SE:
menopausal sxs (hot flashes)
increased incidence of endometrial cancer
possible osteoporosis in pre-menopausal women (while being bone sparing in post-menopausal)
Contraindications:
hx of DVT or PE, pregnancy
What is the MOA for tamoxifen?
metabolized by CYP2D6 to active metabolites endoxifen and 4-hydroxyTAM that bind to ER-alpha, acting as antagonists in breast tissue to inhibit gene transcription, inhibit cell proliferation and promote apoptosis
acts as a partial agonist in endometrium to promote endometrial hyperplasia. there is a 4-6 fold increased incidence of endometrial cancer. Hence, not administered for more than 5-10 years.
What are the SE of tamoxifen?
menopausal sxs (hot flashes) increased incidence of endometrial cancer
possible osteoporosis in pre-menopausal women (while being bone sparing in post-menopausal)
What are the contraindications of tamoxifen?
hx of DVT or PE, pregnancy
What drugs should NOT be given with tamoxifen and why?
SSRIs since they inhibit CYP2D6 converting tamoxifen to active metabolites
How do pts become resistant to Tamoxifen?
down regulation of corepressors, ER alpha and beta
Toremifene
first generation SERM
treat metastatic ER+ breast cancer in POST-menopausal pts
MOA:
active antagonist at ER-alpha/beta
does NOT require activation via CYP2D6
insufficient clinical data at this time, but may act as partial agonist in endometrium to promote endometrial cancer
SE:
menopausal sxs, may increase incidence of endometrial cancers
Contraindications:
hx of DVT, pregnancy
has equal efficacy to tamoxifen in treating breast cancer
bone sparing effects in post-menopausal women
What is the MOA of toremifene?
active antagonist at ER-alpha/beta
does NOT require activation via CYP2D6
insufficient clinical data at this time, but may act as partial agonist in endometrium to promote endometrial cancer
What are the SE of toremifene?
menopausal sxs, may increase incidence of endometrial cancers
What are the contraindications of toremifene?
hx DVT
pregnancy
Anastrozole
aromatase inhibitor
treat early stage or metastatic ER+ breast cancer in POST-menopausal pts
aromatase inhibitors more effective than tamoxifen (greater survival) in post-menopausal women
MOA: prevent conversion of testosterone to estrogen by inhibiting aromatase (CYP19A1) in adipose tissues
Anastrozole is reversible inhibitor (Exemestane is suicide inhibitor)
SE:
hot flashes
osteopenia
osteoporosis
not effective in pre-menopausal women d/t functional ovaries in HPG axis overriding
What is the MOA of anastrozole and exemestane?
prevent conversion of testosterone to estrogen by inhibiting aromatase (CYP19A1) in adipose tissues
Anastrozole is reversible inhibitor (Exemestane is suicide inhibitor)
What are the SEs of anastrozole and exemestane?
hot flashes
osteopenia
osteoporosis
Leuprolide
GnRH agonist
treat metastatic or early stage ER+ breast cancer in PRE-menopausal women
may be combined with SERms
(ASCO considers Tamoxifen to be the best first treatment for early stage breast cancer)
MOA:
disrupts normal pulsatile stimulation of GnRH receptor by endogenous GnRH. this results in desensitization of GnRH receptors in the pituitary leading to decreased release of FSH and LH from the pituitary, which in turn decreases estrogen synthesis in the ovaries
SE:
hot flashes
osteoporosis
sexual dysfunction
contraindications:
pregnancy
may at first increase LH and FSH –worsening the cancer
What is the best treatment for early stage breast cancer?
per the ASCO
tamoxifen
What is the MOA of Leuprolide?
disrupts normal pulsatile stimulation of GnRH receptor by endogenous GnRH. this results in desensitization of GnRH receptors in the pituitary leading to decreased release of FSH and LH from the pituitary, which in turn decreases estrogen synthesis in the ovaries
may at first increase LH and FSH –worsening the cancer
What are the SE and contraindications of leuprolide?
SE:
hot flashes
osteoporosis
sexual dysfunction
contraindications:
pregnancy
Trastuzumab
biologic (cytotoxic drugs)
localized breast cancer with HER2 overexpression (HER2+)
metastatic HER2+ breast cancer
MOA: monoclonal Ab against HER2 extracellular domain IV to inhibit ligand-independent EGFR - HER2 dimerization and consequently inhibits RAS-MAPK signaling pathway; sensitizes cancer cells to cytotoxic chemotherapy; antibody-dependent cellular cytotoxicity
SE: hypersensitivity (infusion) reaction, nephrotic syndrome, interstitial lung disease; BBW - cardiomyopathy, fatal infusion rxn in the form of acute respiratory syndrome
Contraindication:
pregnancy
What is the MOA of trastuzumab?
monoclonal Ab against HER2 extracellular domain IV to inhibit ligand-independent EGFR - HER2 dimerization and consequently inhibits RAS-MAPK signaling pathway; sensitizes cancer cells to cytotoxic chemotherapy; antibody-dependent cellular cytotoxicity
What are the SE and contraindications of trastuzumab?
hypersensitivity (infusion) reaction, nephrotic syndrome, interstitial lung disease;
BBW - cardiomyopathy, fatal infusion rxn in the form of acute respiratory syndrome
Contraindication:
pregnancy
Pertuzumab
metastatic ER2+ breast cancer; used in conjunction with trastuzumab and docetaxel
MOA: monoclonal antibody binds HER2 extracellular domain 2 to prevent ligand - dependent dimerization with EGFR
SE:
cardiotoxicity, severe hypersensitivity, including anaphylaxis
BBW: embryo-fetal toxicity
What is the MOA for pertuzumab?
monoclonal antibody binds HER2 extracellular domain 2 to prevent ligand - dependent dimerization with EGFR
What are the SE of pertuzumab?
cardiotoxicity, severe hypersensitivity, including anaphylaxis
BBW: embryo-fetal toxicity
What are the subtypes of breast cancer?
ER+ (75% of all breast cancer, most likely to be PR+)
HER2+ (15-20%)
Triple negative (10-20%)
