Treatment Of Breast And Endometrial Cancer

Front 1

Name the aromatase inhibitors:

Back 1

Anastrozole

Exemestane

Letrozole

Front 2

Name the SERDs and SERMs:

Back 2

Raloxifene

Tamoxifen

Toremifene

Fulvestrant

Front 3

Name the GnRH agonist:

Back 3

Goserelin

Front 4

Name the HER-2/neu antibodies:

Back 4

Pertuzumab

Trastuzumab

Ado-Trastuzumab

Emtasine

Front 5

Name the TKI:

Back 5

Lapatinib

Front 6

Name the mTOR inhibitor:

Back 6

Everolimus

Front 7

Tumor suppressors involved in repair of double strand breaks (overall incidence 2-6%):

Back 7

BRCA1 and BRCA 2

Front 8

Catalytic subunit of PI3 kinase; key signal transduction enzyme involved in cellular growth, survival and insulin signaling (2nd highest incidence = 25-36%)

Back 8

PIK3CA

Front 9

Tumor suppressor; key regulator of cell cycle, DNA repair, apoptosis (highest incidence 27-37%)

Back 9

TP53

Front 10

Transcription factor which regulates luminal epithelial cell differentiation in the mammary gland (overall incidence = 4-11%):

Back 10

GATA3

Front 11

Kinase that activates ERK and JNK kinase pathways (overall incidence 3-8%):

Back 11

MAP3K1

Front 12

Histone-lysine N-methyltransferase involved in transcriptional co-activation (overall incidence = 7%)

Back 12

MLL3

Front 13

What are the consequences of BRCA1/2?

Back 13

DNA strand breaks

Dysfunctional strand breaks

Uncontrolled cell cycling through abrogation of the normal checkpoint machinery.

All of this leads to increased division of cells carry DNA damage and to the process of carcinogenesis.

Front 14

What are some treatment options for BRCA1/2 mutation carriers? Which one is chemoprevention effective for (1 or 2)? Why?

Back 14

Surgery

SERMs (tamoxifen or raloxifene) = BRCA 2

60-75% of BRCA2 = estrogen +

Front 15

Who should get genetic testing for BRCA1/2 mutations?

Timing, previous cancers, which sex with BC, family history, ancestry

Back 15

Front 16

What are the possible hormone receptor statuses in BC?

What can be used to treat (mechanistically) is ER+? What about HER-2?

Do triple negatives carry a good or bad prognosis?

Back 16

Estrogen, progesterone, and HER-2/neu

ER+ = drugs to block receptor binding or prevent generation of estrogen hormone itself

HER-2 = Mabs or RTKIs

Triple - = no targets -> poor prognosis

Front 17

What is the primary source of estrogen BEFORE menopause?

What could be some treatment options here?

Back 17

Ovaries

Surgically remove them, chemical castration with GnRH agonists or antagonists that down regulate HP axis, SERM to block estrogen receptor in tumor (usually for PM women however)

Front 18

What treatment should you use in PM women?

Back 18

Aromatase inhibitors, SERMS, and SERDS due to lack of ovaries as a source of estrogen

Front 19

Describe the process of estrogen activation of the receptor:

Back 19

Binding => activation and dimerization of ER => translocation to nucleus => activates target gene expression via ERE (estrogen response element)

Membrane bound ER => non-genomic action through interaction with growth factor receptor tyrosine kinase

Front 20

Again, what are the three types of anti-estrogen therapy? How long will it take to detect a response?

Back 20

Front 21

What is the only SERD used to treat BC? What BC women and what ages? What is the mechanism of action? How administered? What are some adverse effects (think menopause)?

Back 21

Front 22

What are the two SERMS? What two general effects do they produce? What are the effects on bone, mammary tissue, bone metabolism, serum cholesterol, LDL, lipoproteins, and apolipoprotein-A1, retinal degeneration, growing babies in the womb?

BBW for both?

BBW for just TAM?

Back 22

Front 23

Which SERM is a derivative of tamoxifen with ANTIESTROGENIC properties? How administered? Metabolized by what CYP? Is it harmful to growing babies? Dangerous heart effects? When should you avoid giving the drug?

Back 23

Front 24

How does a drug like tamoxifen possess both agonistic and antagonistic actions?

Back 24

ER bound by antagonist => dimerizes => co-repressors => deacetylase I => stabilize nucleosome structure and prevent mRNA production

Decreases estrogen activity in breast tissue, acts as agonist in endometrial tissue => proliferation and an increased risk of cancer.

Front 25

What can be a problem with tamoxifen in poor-metabolizers?

Back 25

Poor metabolizers => sub-clinical effect of the drug

Front 26

What do aromatase inhibitors block?

Where does the drug bind?

Back 26

CYP19A1 mediated production of estrone and estradiol => starve the tumor cell of continued proliferative signaling.

Drug binds to the heme center of CYP protein.

Front 27

What are the three aromatase drugs? What is the only one with a steroidal structure? Which are are reversible/irreversible? What are some common adverse effects?

These drugs have more _____ and _____ but fewer ___ symptoms than tamoxifen.

Back 27

Front 28

What does the American Society of Clinical Oncology recommend with regard to postmenopausal women with hormone receptor-positive early breast cancer?

Back 28

Better to use AIs alone or with tamoxifen

Front 29

Is tamoxifen better to give for 10 years or 5 years? Think about endometrial cancer in PM women.

Back 29

Front 30

What is a positive HER2 in terms of IHC and ISH?

When do you test?

Do you delay treatment decision if initial test result is equivocal?

Back 30

Front 31

Where does Trastuzumab bind? What does it block? Draw out the pathway.

Where does Pertuzumab bind?

Where does trastuzumab emtansine (T-DM1) bind?

Back 31

Trastuzumab => juxtraglomerular region of extracellular domain of HER2

Pertuzumab => extracellular dimerizaton doman (subdomain II) => blocks heterdimerization of HER2 with epidermal growth factors (HER3 and 4)

Trastuzumab emtansine (T-DM1) => receptor, upon internalization => allows thioester-linked chemotherapeutic to act on microtubules

Front 32

What is a small-molecule tryosine kinase inhibitor that inhibits HER1 and HER2?

Where does it bind?

What does inhibition of ATP prevent?

Back 32

Lapatinib

Intracellular domain of the ErbB1 and ErbB2 receptors and competes with ATP

Inhibition of ATP => prevents phosphorylation of the receptors and thus prevents receptor activation.

Front 33

What is an antibody-drug conjugate designed to selectively bind to HER2-overexpressing tumor cells?

What are the two components? What is the linker?

What happens inside the cell? (location and actions of DM1)?

Back 33

Front 34

When comparing pertuzumab and trasuzumab, comment on the half-lives, precautions, and common AEs of both.

What are some differences in AEs between the two?

What are some rare AEs of each?

Back 34

Front 35

What is the BBW for Pertuzumab? Trastuzumab? Ado-trastuzumab?

Back 35

Front 36

What is the only RTKI approved for the treatment of BC? Metabolism (CYP)?

Common AEs?

Serious AEs?

Back 36

Front 37

What do drugs that act on the HPA initially cause a transient disease flare that may produce discomfort? What are some of these discomforts?

Back 37

Front 38

What is the only GnRH approved to treat breast cancer? Is long term therapy well tolerated? What are some common side effects (think low estrogen)? What is the effect on bone density?

Back 38

Front 39

What is a central regulator of cell proliferation, angiogenesis, and cell metabolism?

What is the effect of small molecule inhibitors on this?

What drug is used?

Back 39

mTOR

Block mTOR action and prevent cell proliferation and survival

Everolimus

Front 40

Which BCs is everolimus used for?

Metabolized by what? Inhibits what?

Increased risk of what infections?

What type of adverse effects?

Back 40

Front 41

What is the treatment for triple - breast cancer (early stage, prior to excision, advanced tumor)?

Back 41

Front 42

What is used to indicated the drug or choice and/or whether or not adjunctive drug treatment is necessary immediately following surgical excision of the primary tumor?

Back 42

Tumor genotyping

Front 43

Tumor with a genetic signature of highly invasive and rapidly proliferating disease are excellent candidates for _______.

Back 43

Immediate adjuvant therapy

Front 44

What are the implications of doxorubicin (anthracycline) in many of the regimens?

Back 44

Cardiac issues in years following successful survival of BC.

Front 45

What are the two specific progesterone receptor proteins? Places where they are located? What process controls PR activity?

Back 45

A and B

Brina CNS, CV, breast, uterus

Front 46

Is PR in primary breast cancer a favorable diagnosis? What about predictor of overall survival? Loss of PR in ER+ tumors is associated with a more ____ tumor phenotype, _____ responsiveness to endocrine therapies, and a ____ overall survival.

Back 46

Front 47

From the WHI, which is associated with an increased risk of invasive BC, decreased risk?

Combination of estrogen and progestin

Estrogen alone

Back 47

Front 48

What are the two drugs for endometrial cancer? Which is a progestin contraceptive that binds to progestin receipts and blocks GnRH release (AEs)?

Which is a synthetic oral progestin that suppresses pituitary LH release and enhances estrogen degradation? (AEs)?

Back 48

Front 49

Primary source of estradiol in premenopausal women is where?

Peripheral tissues

Hypothalamus

Pituitary

Ovaries

Back 49

Ovaries

Front 50

Which drug class is completely useless in premenopausal women?

Back 50

Aromatase inhibitors (there's just too many because of the amount of estrogen coming from the ovaries)

Front 51

In which of the following patients would tamoxifen be contraindicated?

Back 51

Diabetes

High BP

Smoker

Taking aromatase inhibitor

Pregnant = teratogen because you are withdrawing estrogen activity (same as aromatase inhibitors and SERDs)

Diagnosed uterine cancer

Front 52

67 year old is 5 year survivor completed tamoxifen regimen, what drug should she be put on now??

Back 52

Aromatase inhibitor => seem to produce a better outcome

New guidelines: use the aromatase inhibitors first, if already on tamoxifen, wait until treatment over then give aromatase inhibitor

Front 53

What are some things to worry about with tamoxifen?

Back 53

Thromboembolic disease

Visual disturbances (estrogen has a protective effect in the eye => predisposes to increased incidence in cataracts if removed)

Front 54

Which would be more likely to occur in those taking exemestane than in those taking raloxifene?

Back 54

Joint stiffness

Front 55

What drug to worry about with cardiac effects?

Back 55

Doxorubicin

Front 56

Which other drug causes risks of cardiotoxicity?

Back 56

Trastuzumab

Front 57

Which increases pain arising from bone metastases of breast cancer?

Back 57

Goserelin (GnRH agonist)

Front 58

Corneal chanes, visual impairment, and cataracts are more likely to occur inpatients with what drug?

Back 58

Tamoxifen

Front 59

Which of the following prevents heterodimerization of EGFR receptors and subsequent activation of proliferative signaling?

Back 59

Pertuzumab

Front 60

Tamoxifen is more effective for which tumor type (BRCA1 or BRCA2)?

Back 60

BRCA2

Front 61

Inhibitio of CYP19A1 (aromatase) is by which drug?

Back 61

Letrozole