Block 4: Chemotherapy-Breast And Prostate

Front 1

what is the most common cancer in women? Etiology

Back 1

Breast Cancer
180,000 new cases/yr
45,000 deaths/yr

Front 2

Lifetime risk of development of breast cancer?

Back 2

1 in 8

Front 3

Which two hormones are important in the etiologies of breast cancer?

Back 3

Estradiol
Progesterone

Front 4

Risk factors assoc. w/increased exposure to estrogen and progesterone

Back 4

Early menarche
Late menopause
Obesity (postmenopausal)
HRT

Front 5

Protective factors assoc. w/decreased estrogen and progesterone

Back 5

Lactation
Early age @ first full term pregnancy
Exercise

Front 6

Genetics associated w/breast cancer

Back 6

p53 mutations in Li-Fraumeni syndrome, less than 1%
BRCA-1 mutation in familial breast and ovarian cancer
BRCA-2 in familial female and male breast cancer

Front 7

Breast cancer treatments

Back 7

Surgical removal of the tumor and axillary lymph nodes
Radiation therapy
Adjuvant drug therapy

Front 8

Adjuvant Drug therapy for breast cancer

Back 8

Cyclophosphamide
Methotrexate
5-FU
Doxorubicin and analogues
Vinblastine
Vincristine
Prednisone

Front 9

Therapy after metastasis

Back 9

Chemo only
ONLY 10-20% remission

Front 10

Name two anti-estrogen drugs

Back 10

Tamoxifen
Raloxifene

Front 11

Tomoxifen MOA

Back 11

Competitive partial agonist-inhibitor think of as a functional competitive receptor antagonist

Prevents estrogen binding to estrogen receptor

Front 12

Tamoxifen's affinity for the estrogen receptor

Back 12

10 fold lower than estrogen

Front 13

PK of Tamoxifen

Back 13

Well absorbed after oral admin
Eliminated in feces and some in urine
Two phase elimination

Front 14

Describe Tamoxifen's two phase elimination

Back 14

1st phase- t1/2 = 7-14 hours
2nd phase- t1/2 = 7-14 days

The point: much longer t1/2 than estradiol

Front 15

Dosing of Tamoxifen

Back 15

2X daily of 10mg for 2-5 years.

Front 16

Stats for Tamoxifen-
Risk reduction

Back 16

Reduces recurrence by 30% and death by 20%
When used in combo risk reduced by another 30%

Front 17

Who is Tamoxifen most useful in?

Back 17

Post-menopausal women w/estrogen receptor (+) breast cancer

Front 18

What treatment is best for premenopausal women or those w/estrogen receptor poor tumors?

Back 18

Polychemotherapy

Front 19

SMILE

Back 19

:)

Front 20

Adverse Rxns to Tamoxifen
*considered one of the least toxic drugs

Back 20

Hot flashes
Nausea and vomiting
Vaginal bleeding
Dermatitis
Endometrial carcinoma
Thromboembolic events

Front 21

How can we prevent the hot flashes in women taking Tamoxifen?

Back 21

Megestrol or SSRIs (again!)

Front 22

Tamoxifen and prevention

Back 22

Reduces risk of breast cancer by 45% in healthy women who are at High Risk for breast cancer

Front 23

Potential beneficial side effects of Tamoxifen

Back 23

Reduces total cholesterol and preserves bone density in postmenopausal women
*Due to estrogen like effects

Front 24

Raloxifene-benefit?

Back 24

A SERM
Possible lower incidence of uterine cancer

Front 25

Name a true estrogen receptor antagonist

Back 25

Fulvestrant

Front 26

How do you give Fulvestrant?
Who do you give it to?

Back 26

Once a month i.m.
Postmenopausal women whose cancer progresses on tamoxifen or other anti-estrogen

Front 27

Name 3 aromatase inhibitors

Back 27

Aminoglutethimide
Anastrozole
Letrozole

Front 28

Who do you use aromatase inhibitors on?

Back 28

Postmenopausal women whose cancer progresses despite tamoxifen treatment

Front 29

Aminoglutethimide MOA and specificity (take a deep breath)

Back 29

(-) one of the P450 enzymes that converts cholesterol into pregnolone--> all classes of cholesterol reduced

Also (-) conversion of androstenedione--> estrone and estradiol in the peripheral tissues by the aromatase enzyme

Front 30

PK of Aminoglutetimide

Back 30

Administered orally
t1/2 = 10-20 hours

Front 31

Clinical use for aminoglutetimide

Back 31

2nd line (after tamoxifen) for metastatic breast cancer

Front 32

Dosing for aminoglutetimide

Back 32

125 mg 2X/day
increase 250 mg 2X/day with 20 mg hydrocortisone (compensates for its steroid synthesis inhibition)

Front 33

Adverse Rxn of Aminoglutetimide

Back 33

Lethargy
Blurry vision
Drowsiness
Maculopapular rash

Front 34

Which drug Tamoxifen or Aminoglutetimide yields adverse rxns more often.

Back 34

Aminoglutetimide

Front 35

Anasterozole and Letrozole

Back 35

Nonsteroidal aromatase inhibitors, doesn't have the mineral and glucocorticoid effect

Front 36

Can Anasterozole be used as 1st line therapy

Back 36

Yes

Front 37

Name 2 progesterone agonists

Back 37

Megesterol
Medroxyprogesterone

Front 38

Dosage of Megesterol/
Medroxyprogesterone

Back 38

160 mg/day for treatment of advanced breast cancer

Front 39

SE of progesterone agonists?
How can that be used effectively?

Back 39

Stimulate apetite--wt. gain
Used to treat anorexia/cachexia related to cancer and AIDS

Front 40

Name two Gonadotropin-releasing hormone agonists

Back 40

Leuprolide
Goserelin

Front 41

MOA of Leuprolide and Goserelin (yup, deep breath again)

Back 41

GnRH agonists w/increase affinity
Induce intial gonadotropin release (2-4 wks)
After flare FSH and LH cells get desensitized and plasma estradiol and progesterone levels.

Front 42

Admin of Leuprolide and Goserelin

Back 42

i.m. or s.c. in a parenteral sustained microcapsule prep.

Front 43

Clinical use of Leuprolide and Goserelin

Back 43

Metastatic breast cancer in PREMENOPAUSAL women

MAIN USE: Prostate cancer

Front 44

Adverse Rxns to Leuprolide and Goserelin

Back 44

Hot flashes
Sweating
Nausea
*due to ablation of sex hormones

Front 45

Herceptin (aka trastuzumab)

Back 45

A humanized monoclonal Ab agonist against the HER2/erbB2 receptor

*HER2/erbB2 recetptor is overexpressed (25-35%) in breast cancer

Front 46

What family of receptors does the HER2/erbB2 receptor belong to?

Back 46

Epidermal growth factor receptor family

Front 47

Stats for prostate cancer
New cases/deaths/lifetime risk

Back 47

Most common cancer in men- 240,000 new cases/yr
40,000 deaths/yr
lifetime risk is 1 in 6

Front 48

Etiology of Prostate cancer

Back 48

Main risk factor is AGE
Rare prior to age 40
(+) correlation between testosterone levels and risk
Mutations in androgen receptor gene may play a role

Front 49

Treatment for prostate cancer

Back 49

Surgical removal
Radiation therapy
Hormonal therapy for advanced dz

Front 50

Deferred therapy

Back 50

Watchful waiting, treatment postponed until tumor becomes symptomatic

*Important in elderly individuals when you're weighing expected lifespan with quality of life after surgery

Front 51

Prevention of Prostate Cancer

Back 51

50 I.U./day of Vit. E~ reduce risk by 1/3
150-200 mcg/day selenium~ reduce risk by 2/3
Lycopene (red pigment in tomatoes) also reduces risk

Front 52

Different kinds of Hormone Therapy for Prostate Cancer

Back 52

1. Nonsteroidal antiandrogens
2. Steroidal antiandrogens
3. Gonadotropin-releasing hormone agonists
4. Adrenal Enzyme synthesis inhibitors

Front 53

Non-steroidal antiandrogens

Back 53

Flutamide
Bicalutamide

Front 54

MOA of Flutamide

Back 54

Prevents binding of DHT to its receptor

Front 55

PK and admin of Flutamide

Back 55

Orally 3X/day because of short t1/2 (7-8 hours)

Front 56

Clinical use for Flutamide

Back 56

Metastatic prostate cancer

Front 57

Adverse Rxns of Flutamide

Back 57

Diarrhea (most common)
Gynecomastia (give drug w/GnRH inhibitor)
Hepatotoxicity (rare)

Front 58

Bicalutamide

Back 58

More recent nonsteroidal antiandrogen
May be more effective than Flutamide

Front 59

Name two steroidal antiandrogens

Back 59

Megesterol
Medroxyprogesterone
*except the intrinsic steroidal side effects

Front 60

Name two Gonadotropin-releasing agonists

Back 60

Leuprolide
Goserein
*note equivalent antitumor effect as surgical castration or diethylstilbestrol treament.

Front 61

Adrenal enzyme synthesis inhibitors, MOA, use

Back 61

Ketconazole~ antifungal drug
(-) P450 enzymes involved in steroid synthesis
Good 2nd line agent