antiestrogens to treat breast cancer

Question 1

protective factors against breast cancer

Answer 1

reduced estrogen/progesterone exposure
lactation
early age for first pregnancy
exercise

Question 2

risk factors for breast cancer

why?

Answer 2

increased exposure to estrogen/progesterone
early menarche
late menopause
obesity (postmenopausal)
HRT

why? –> E stimulates TGFalpha production and TGF alpha causes breast cell proliferation

Question 3

treatment for postmenopausal , ER-negative

Answer 3

a high risk group

treat w chemo

Question 4

treatment for postmenopausal, ER positive

Answer 4

tamoxifen, raloxifene, or aromatase inhibitor alone or w chemo
high risk - same three with chemo

Question 5

treatment for premenopausal, ER negative

Answer 5

a high risk group

treat w chemo

Question 6

treatment for premenopausal, ER positive

Answer 6

tamoxifen, raloxifene, alone or with chemotherapy, or GnRH agonist

if high risk, chemo plus tamoxifen or raloxifene with GnRH agonist

Question 7

if HER2 is expressed, breast tumor is considered high risk and is treated with

Answer 7

chemo, trastuzumab and an antiestrogen if ER positive

Question 8

three genetic changes common to breast cancer

Answer 8

• P53 mutations in Li-Fraumeni syndrome
• BRCA1- familial female breast & ovarian cancer
• BRCA2-familial female & male breast cancer

Question 9

after metastasis begins, the only way to treat disseminated cells is

Answer 9

chemotherapy

Question 10

three antiestrogens

Answer 10

tamoxifen
raloxifene
fulvestrant

Question 11

tamoxifen

Answer 11

a SERM, competitive partial agonist-inhibitor —-prevents estrogens binding to ER (e receptor)
• Sometimes can induce estrogen-like effects; initially acts as antagonist in breast tissue but as an agonist in endometrial tissue
• Oral drug; activated by CYP2D6; has LONGER half-life than estradiol
• Reduces recurrence of breast cancer; most useful in high risk postmenopausal women with ER+ breast cancer

• Not effective in ER- cancer or premenopausal women
• One of the least toxic antineoplastic agents!
• Side effects: hot flashes, endometrial carcinoma (E agonist in the uterus), thromboembolic events (E agonist increases clotting factors and decreases antithrombin 3), drug drug itxn (don’t use with SSRIs (fluoxetine for depression) since they inhibit CYP2D6)
• Other benefits: reduces total cholesterol and preserves bone density

Question 12

why stop using tamoxifen after 5 years?

Answer 12

ONLY use up to 5 years  after 5 years, it will begin to act as a partial agonist in breast tissue

Question 13

raloxifene

Answer 13

a SERM
• As effective as tamoxifen in preventing breast cancer with FEWER side effects  LOWER incidence of uterine cancer and blood clots!
• Very low toxicity – hot flashes, N/V, less likely thromboembolic events and endometrial carcinoma

Question 14

Fulvestrant

Answer 14

– a true estrogen receptor antagonist; has no estrogen agonist effects
• Use for postmenopausal women whose cancer doesn’t halt with tamoxifen or raloxifene

Question 15

Anastrozole, Letrozole, and Exemestane

Answer 15

Selective and irreversible aromatase inhibitors
– (have little/no effect on mineralocorticoid or glucocorticoid synthesis); continue to be effective past 5 years! And no risk of endometrial cancer or thromboembolic events!! VERY effective; approved for first line therapy as alternative to tamoxifen
• Anastrozole – as effective as tamoxifen for advanced breast cancer; fewer and less severe hot flashes

Question 16

Trastuzumab

Answer 16

monoclonal antibody against the HER2/erbB-2 receptor
• HER2/erbB2 is a member of the epidermal growth factor receptors and overexpressed in breast cancer
• Used for breast cancers that express this receptor
• Side effects; cardiomyopathy, especially when combined with anthracyclines (doxorubicin)

Question 17

lapatinib

Answer 17

orally active tyrosine kinase inhibitor that targets both erbB receptors (EGFR and Her2/neu)
• For advanced breast cancer expressing high levels of HER2 that no longer respond to trastuzumab
• Lapatinib + chemotherapy doubles the time to progression vs chemo alone!

Question 18

Leuprolide and Goserelin

Answer 18

Gonadotropin-releasing Hormone Agonists
GnRH agonists with high affinity for GnRH receptors
• GnRH agonists induce an initial increase in gonadotropin release that stimulates increased Estrogen and progesterone, but after this initial flare up, FSH and LH producing cells get desensitized and plasma estradiol and progesterone levels are suppressed to postmenopausal levels/castrate levels
• Prevent flare up with co-administration of an E receptor antagonist
• Used for metastatic breast cancer in PREmenopausal women; also for prostate cancer
• Side effects due to ablation of sex steroid concentrations: hot flashes, sweating, nausea (reverse with low level of progesterone analogue)

Question 19

abarelix

Answer 19

GnRH antagonist

• reduces amount of testosterone made to treat prostate cancer