Exam 2: Drugs for Breast Cancer

Question 1

what is the most commonly diagnosed cancer in women?

Answer 1

breast cancer

(2nd leading cause of cancer death in women)

Question 2

what are the three major sub-types of breast cancer?

Answer 2

1. Estrogen receptor positive (ER+ most are also PR+) - about 75%
2. HER2 +ve - about 15-20%
3. Triple negative - 10-20% (BRCA-1 majority)

Question 3

what type of breast cancer is most responsive to Tamoxifen?

Answer 3

ER+/PR+/HER2-

Question 4

what type of breast cancer is not responsive to hormone therapy or targeted therapy?

Answer 4

triple negative breast cancer (worst prognosis)

Question 5

what type of breast cancer has the best prognosis?

Answer 5

ER+

HER2 (less so)

triple negative (worst)

Question 6

what are the SERMS?

Answer 6

selective estrogen receptor modulators

tamoxifen

toremifene

raloxifene

Question 7

what are the common adverse effects of tamoxifen?

Answer 7

• menopausal symptoms (hot flashes) - 64% more severe in post-menopausal
• increased risk of DVT/PE
• increased risk of endometrial cancer (after 5 years 4-6 x)
• 30-40% become resistanct after about 5 years

Question 8

how is tamoxifen metabolized?

Answer 8

pro-drug metabolized by CYP2D6

to endoxifen and 4-hydroxyTAM that bind to ER-alpha

Question 9

which SERM can be used in pre-menopausal women?

Answer 9

tamoxifen

Question 10

what SERM is the only one approved by the FDA for metastatic ER+ breast cancer?

Answer 10

Toremifene

(post-menopausal)

Question 11

what is the current ASCO and FDA position on genotyping for tamoxifen therapy?

Answer 11

It is not recommended

Question 12

how do leuprolide and goserelin act?

Answer 12

acts as an agonist at the GnRH receptor in the pituitary

Question 13

what can happen early in treatment with GnRH drugs?

Answer 13

in the first few weeks to months, prior to GnRH receptor down-regulation, increase LH and FSH levels, increase in testosterone/estrogen and a potential transient worsening of cancer symptoms

Question 14

what are the aromatase inhibitors?

Answer 14

anastrozole

letrozole

exemestane

Question 15

can you use aromatase inhibitors in pre-menopausal women?

Answer 15

No. They have functional ovaries and their natural axis can overcome the effects of AIs.

Question 16

what is the distinguishing feature of HER2 positive cells

Answer 16

>6 copies of the HER2 gene - identified by FISH or immunohistochemistry

HER2 activates the RAS-MAPK pathway

Question 17

what is the chemical name for Herceptin?

Answer 17

trastuzumab

Question 18

How does trastuzumab work?

Answer 18

it is a monoclonal Ab that selective targets the extracellular HER2 protein to disrupt dimerization with EGFR protein and activation of the RAS-MAPK pathway

Question 19

About what percentage of patients will have a distant recurrence of their breast cancer within 5-10 years of treatment?

Answer 19

30%

Question 20

what are two FDA approved tests for prognostication of recurrence?

Answer 20

MammaPrint

OncotypeDX

Question 21

What is the RS score?

Answer 21

Recurrence score

Question 22

what effect does Tamoxifen have on the endometrium?

Answer 22

acts as a partial agonist in the endometrium to promote hyperplasia, which creates a 4-6 fold increased risk of endometrial cancer

limit administration for this reason to 5-10 years

Question 23

What are the common and serious s/e of tamoxifen?

Answer 23

menopausal symptoms (e.g., hot flashes)

increased risk of endometrial cancer

Question 24

What is the MoA of tamoxifen?

Answer 24

pro-drug metabolized by CYP2D6 to active metabolites that acts as an ANTAGONIST to estrogren receptors in the breast tissue to inhibt gene transcription, cell proliferation and promote apoptosis

Question 25

what are the contraindications to tamoxifen?

Answer 25

history of DVT or PE Pregnancy (for invasive cancers, weigh risks and benefits)

Question 26

what is the effect of tamoxifen on bone?

Answer 26

bone sparing in post-menopausal may cause osteoporosis in pre-menopausal

Question 27

what drug class should you avoid combining with tamoxifen?

Answer 27

SSRIs - they will inhibit pro-drug conversion

Question 28

what is a key problem with long-term tamoxifen use besides endometrial cancer?

Answer 28

resitstance - believed to possibly be due to down-regulation of co-repressors, ER-alpha/beta

Question 29

Is toremifene associated with increased risk of endometrial cancer?

Answer 29

maybe - insufficient clinical data, but may act as a partial agonist in the endometrium to promote cancer

Question 30

what are the contraindications to toremifene and raloxifene?

Answer 30

history of DVT, pregnancy (post-menopausal anyway)

Question 31

do toremifene and roloxifene have the same risk of resistance with long term use as tomoxifen?

Answer 31

yes

Question 32

which of the SERMs is the least efficacious in treating breast cancer?

Answer 32

raloxifene (70% efficacy of tamoxifen)

Question 33

what is the efficacy of toremifene in treating breast cancer?

Answer 33

equal to tamoxifen

Question 34

what is another indication for raloxifene?

Answer 34

treatment of osteoporosis - agonist-like effects on bone

Question 35

Do toremifene and raloxifene require activation by CYP2D6?

Answer 35

No

Question 36

what are the aromatase inhibitors?

Answer 36

anastrozole exemestane

Question 37

anastrazole is a \_\_\_\_\_\_\_\_?

Answer 37

aromatase inhibitor

Question 38

exemestane is a \_\_\_\_\_\_\_\_\_\_\_\_\_?

Answer 38

aromatase inhibitor

Question 39

who can take aromatase inhibitors?

Answer 39

early stage or metastatic ER+ post-menopausal patients

Question 40

why can't we use the aromatase inhibitors in pre-menopausal women?

Answer 40

because functional overies in the h-p-g axis overomes the AT effects

Question 41

what are the side effects of the aromatase inhibitors?

Answer 41

hot flashes osteopenia osteoporosis

Question 42

what is the mechanism of action of anastrozole?

Answer 42

prevents conversion of testosterone to estrogen by inhibiting aromatase (CYP19A1) in adipose tissue anastrazole is a reversible inhibitor

Question 43

what is the mechanism of action of exemestane?

Answer 43

prevents conversion of testosterone to estrogen by inhibiting aromatase in adipose tissue

Question 44

what is a GnRH agonist

Answer 44

Leuprolide

Question 45

what is leuprolide indicated for?

Answer 45

treatment of metastatic or early stage ER+ breast cancer in pre-menopausal patients \*can combine with SERMs \*ASCO prefers Tamoxifen for early stage bc

Question 46

what is the mechanism of action of GnRH agonists

Answer 46

They disrupt the normal pulsatile stimulation of GnRH receptors by endogenous GnRH, leading to decreased release of FSH and LH from the pituitary, which in turn decreases estrogen synthesis from the ovaries