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PHARM_breast & endometrial cancer Flashcards

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1
Q

name the 3 aromatase inhibitors

A

anastrozole
letrozole
exemestane (steroidal)

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2
Q

name the GnRH agonist

A

Goserelin

histrelin

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3
Q

name the breast cancer mutation: tumor suppressors involve in repair of double strand breaks (2-6% of breast cancers)

A

BRCA1 & BRCA2

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4
Q

name the breast cancer mutation: key signal transduction enzyme involved in cellular growth, survival & insulin signaling (25-36% of breast cancers)

A

PIK3CA; catalytic subunit of PI3 kinase

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5
Q

name the breast cancer mutation:

tumor suppressor; key regulator of cell cycle, DNA repair, apoptosis (37-37& of breast cancers)

A

TP53

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6
Q

name the breast cancer mutation: transcription factor which regulates luminal epithelial cell differentiation in the mammary gland (4-11% of breast cancers)

A

GATA3

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7
Q

name the breast cancer mutation: kinase that activates ERK & JNK kinase pathways (3-8% of breast cancers)

A

MAP3K1

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8
Q

name the breast cancer mutation: histone-lysine N-methyltransferase involved in transcriptional coactivation (7% of breast cancers)

A

MLL3

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9
Q

what happens when BRCA1/2 fails?

A

DNA strand breaks, dysfunctional break repair, uncontrolled cell cycling

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10
Q

you would use the SERMs on which types of breast cancers?

A

BRCA2 mutations

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11
Q

70-90% of _________ tumors are ER-

A

BRCA1

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12
Q

what is the best way to eradicate a primary tumor that has not metastasized?

A

surgically cut it out

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13
Q

what are some clinical features that warrant referral for genetic testing for BRCA1/2 mutations?

A
  • early onset breast cancer (<45y/o)
  • ovarian, fallopian tube or primary peritoneal cancer
  • indiv. w/ 2 or more primary breast cancers, or breast and ovarian cancer in same pt
  • male breast cancer
  • 2 or more pts in same family w/ breast and/or ovarian cancer
  • ashkenazi jew
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14
Q

what is the prognosis related to triple negative breast cancer?

A

very poor; can only use conventional agents

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15
Q

what kind of drug can you use to block the estrogen receptor in the breast cancer tumor and prevent any estrogen from providing a proliferative signal?

A

SERM (usually reserved for Post-menopausal women)

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16
Q

what are the treatment options for premenopausal women with ER+ tumors?

A

surgical removal or chemical castration w/ GnRH agonists or antagonists that downregulate the HP axis control

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17
Q

what is the main source of estrogen in premenopausal women?

A

ovaries

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18
Q

what is the main source of estrogen in postmenopausal women?

A

peripheral aromatization

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19
Q

what are the treatment options for a postmenopausal woman with an ER+ tumor?

A

aromatase inhibitors, SERMS, SERDS

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20
Q

what happens after about 8-12 wks of anti-estrogen therapy in a woman with ER+ or PR+ tumors?

A

she’ll have response in about 8-12 wks with an avg remission about 6-12 months (sometimes yrs)

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21
Q

how does fulvestrant work?

A

SERD; steroid that binds to ER but carries bulky substituent that prevents dimerization of the ERs in the nucleus

  • NET EFFECT: sustained down reg. in ER expression
  • no estrogenic actions
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22
Q

describe the structure of fulvestrant?

A

steroid with bulky substituent

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23
Q

how much estrogenic activity does fulvestrant have?

A

NONE!

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24
Q

what are the adverse effects of fulvestrant?

A

typical Post men.Symproms that are indicative of loss of estrogen activity (Nausea, asthenia, pain, vasodilation & headache)

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25
the SERMs Tamoxifen & Raloxifene have estrogenic activity on ____________ and have antiestrogenic activity on __________________
1. bone structure | 2. breast tissue
26
at high doses what can the SERMs do to the eyes?
retinal degeneration
27
what are the adverse effects of the SERMs?
- retinal degen. at high doses - teratogens - thromboembolic dz, stroke (BBWs--> BOTH) - endometrial hypertrophy vaginal bleeding, endometrial cancer (BBWs-->TAM)
28
endometrial hypertrophy, vaginal bleeding and endometrial cancer are all BBWs associated with which SERMs?
tamoxifen, raloxifene
29
MOA of toremifene
2nd Gen. SERM derived from tamoxifen used for PM women
30
What is the must know BBW for toremifene?
prolongs QT interval (avoid in pre-existing condition & w/ CYP3A4 inhibitors)
31
Which CYP enzyme metabolizes toremifene?
CYP3A4 (important because if the pt takes drugs that inhibit CYP3A4 then there is BBW risk for prolonged QT)
32
toremifene has an AE of prolonged QT and is contraindicated in pts with what pathologies? (2)
1. endometrial cancer/hyperplasia | 2. thromboembolic dz
33
which drug has antiestrogenic effects on breast and proestrogenic effects on the endometrium?
tamoxifen
34
which CYP enzyme metabolizes tamoxifen?
CYP2D6
35
CYP2D6 metabolizes tamoxifen to what 2 metabolites with higher potencies?
4OHtamoxifen & enoxifen
36
aromatase inhibitors block which CYP enzyme?
CYP19A1
37
when aromatase inhibitors block CYP19A1 they are preventing the formation of what 2 estrogens?
estrone (from androstenedione) & estradiol (from Testosterone)
38
the aromatase inhibitors bind to what part of the CYP19A1 enzyme?
heme center
39
which of the 3 aromatase inhibitors has a steroidal structure and is an irreversible inhibitors?
exemestane
40
which 2 aromatase inhibitors are nonsteroidal and are reversible inhibitors?
anastrozole | letrozole
41
how are the aromatase inhibitors administered?
daily oral
42
how are the aromatase inhibitors metabolized?
hepatic metabolism
43
what are the adverse effects of aromatase inhibitors?
hot flashes, nausea, hair thinning (no effect on adrenal steroids or other hormones) -more arthralgia & diarrhea but fewer gynecologic symptoms than tamoxifen
44
which class of antibreast cancer drugs can cause arthralgia and diarrhea but fewer gynecologic symptoms than tamoxifen?
aromatase inhibitors
45
the ATLAS trial showed that 10 yrs of tamoxifen therapy provides substantial survival benefit that outweighs what aspect of treatment?
risk of developing endometrial cancer
46
what are the 2 ways you can test to see her HER2 therapy will work?
IHC or FISH
47
trastuzumab MOA
binds to juxtraglomerular region of the extracellular domain of HER2 and prevents the proliferative signaling
48
Pertuzumab MOA
binds to extracellular dimerization domain (subdomain II) and blocks ligand-dependent hetero-dimerization of HER2 w/ other epidermal growth factor receptors including HER3 & HER4
49
lapatinib MOA
small molecule TKI that inhibits HER1 & HER2 by binding to intracellular domain of the ErbB1 & ErbB2 receptors and competes w/ ATP. inhibiting ATP prevents phosphorylation of the receptors and thus prevents receptor activation
50
Trastuzumab, T-DM1, and pertuzumab are all 3 humanized antibodies based on what?
IgG1 kappa Immunoglobulin
51
a lot of mAbs have what set of adverse effects?
hypersensitivity and sequelae like asthenia, fatigue, GI upset
52
what are the BBW for trastuzumab?
Cardiomyopathy pregnancy Infusion reactions including: (Respiratory distress syndrome & Respiratory insufficiency)
53
What are some rare and unique adverse effects to pertuzumab?
decreased LVEF, neutropenia & leukopenia
54
what is the must know BBW for pertuzumab?
teratogenicity
55
what are the "serious" AEs of lapatinib?
ILD/pneumonitis | QT prolongation
56
what is the must know BBW for lapatinib?
liver disease (can lead to increased drug levels & persistence)
57
how does using a GnRH agonist like goserelin work on hormonally responsible tumors in premenopausal women?
agonist treatment is continuous-->down-regulation of GnRH receptor on the pituitary gland & ultimately decreased prod. of FSH & LH (eventually etradiol levels fall to post-menopausal levels in 2-4 wks)
58
what AE can you expect with goserelin treatment when beginning therapy?
initial transient dz flare w/ bone pain (mets), hypercalcemia and breast enlargement or tenderness
59
what is the common theme of AE of goserelin?
all related to hypo-estrogenic state (w/ classic postmenopausal symptoms) -decreased bone density, osteopenia/osteoporosis (risk factors include chronic EtOH abuse &/or tobacco abuse, fam. hx. of osteoporosis; chronic drugs which decrease bone mineralization)
60
how does everolimus work?
mTOR inhibitor that blocks cell proliferation & survival
61
everolimus is often used in conjunction with what other drug?
exemestane
62
what are the BBWs for everolimus?
risk of opportunistic infections-neoplasia; lymphoma/SCC
63
what is the purpose of drugs/radiation in triple negative breast cancer?
used in adjuvant role to prevent recurrence of dz or neoadjuvant role prior to surgery
64
which breast cancer drug has a max cumulative dose associated with cardiac issues?
doxorubicin
65
what kind of prognosis do progesterone negative breast cancers have?
poor
66
Progesterone + tumors has what effect on overall survival?
is predictive of better overall survival
67
when women use HRT with both estrogen and progesterone they are at increased risk for what>
invasive breast cancer
68
which chemo agents would you use in HER-2 negative early dz?
anthracycline & taxane based combo
69
what are some factors that affect tamoxifen resistance?
- variable expression of ER - interference w/ binding of co-activators & repressors - alt. splicing of ER mRNA variants - modulation of ER expression by EGFR1 & EGFR2 - CYP2D6 genotype
70
the GnRH agonist is most beneficial in women who dont undergo _______________
adjuvant chemotherapy
71
what is the drug of choice for adjuvant therapy of premenopausal and post-men. women who can't take aromatase inhibitors?
tamoxifen
72
which class of drugs has a higher risk of osteoporosis, fractures, CV dz and hypercholesterolemia than tamoxifen, but lower risk of venous thrombosis & endometrial cancer?
aromatase inhibitors
73
what are some common AE of lapatinib therapy?
``` GI issues hand-foot syndrome rash pain headache backache ```
74
everolimus binds to what structure and forms a 3 way complex with mTOR that blocks protein action and downstream consequences?
FKBP-12
75
what are the BBWs for everolimus?
risk of opportunistic infections | neoplasias-lymphoma/SCC

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