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REPRO > PHARM_breast & endometrial cancer > Flashcards

PHARM_breast & endometrial cancer Flashcards

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
Q

the SERMs Tamoxifen & Raloxifene have estrogenic activity on ____________ and have antiestrogenic activity on __________________

A
  1. bone structure

2. breast tissue

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26
Q

at high doses what can the SERMs do to the eyes?

A

retinal degeneration

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27
Q

what are the adverse effects of the SERMs?

A
  • retinal degen. at high doses
  • teratogens
  • thromboembolic dz, stroke (BBWs–> BOTH)
  • endometrial hypertrophy vaginal bleeding, endometrial cancer (BBWs–>TAM)
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28
Q

endometrial hypertrophy, vaginal bleeding and endometrial cancer are all BBWs associated with which SERMs?

A

tamoxifen, raloxifene

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29
Q

MOA of toremifene

A

2nd Gen. SERM derived from tamoxifen used for PM women

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30
Q

What is the must know BBW for toremifene?

A

prolongs QT interval (avoid in pre-existing condition & w/ CYP3A4 inhibitors)

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31
Q

Which CYP enzyme metabolizes toremifene?

A

CYP3A4 (important because if the pt takes drugs that inhibit CYP3A4 then there is BBW risk for prolonged QT)

32
Q

toremifene has an AE of prolonged QT and is contraindicated in pts with what pathologies? (2)

A
  1. endometrial cancer/hyperplasia

2. thromboembolic dz

33
Q

which drug has antiestrogenic effects on breast and proestrogenic effects on the endometrium?

A

tamoxifen

34
Q

which CYP enzyme metabolizes tamoxifen?

A

CYP2D6

35
Q

CYP2D6 metabolizes tamoxifen to what 2 metabolites with higher potencies?

A

4OHtamoxifen & enoxifen

36
Q

aromatase inhibitors block which CYP enzyme?

A

CYP19A1

37
Q

when aromatase inhibitors block CYP19A1 they are preventing the formation of what 2 estrogens?

A

estrone (from androstenedione) & estradiol (from Testosterone)

38
Q

the aromatase inhibitors bind to what part of the CYP19A1 enzyme?

A

heme center

39
Q

which of the 3 aromatase inhibitors has a steroidal structure and is an irreversible inhibitors?

A

exemestane

40
Q

which 2 aromatase inhibitors are nonsteroidal and are reversible inhibitors?

A

anastrozole

letrozole

41
Q

how are the aromatase inhibitors administered?

A

daily oral

42
Q

how are the aromatase inhibitors metabolized?

A

hepatic metabolism

43
Q

what are the adverse effects of aromatase inhibitors?

A

hot flashes, nausea, hair thinning (no effect on adrenal steroids or other hormones)
-more arthralgia & diarrhea but fewer gynecologic symptoms than tamoxifen

44
Q

which class of antibreast cancer drugs can cause arthralgia and diarrhea but fewer gynecologic symptoms than tamoxifen?

A

aromatase inhibitors

45
Q

the ATLAS trial showed that 10 yrs of tamoxifen therapy provides substantial survival benefit that outweighs what aspect of treatment?

A

risk of developing endometrial cancer

46
Q

what are the 2 ways you can test to see her HER2 therapy will work?

A

IHC or FISH

47
Q

trastuzumab MOA

A

binds to juxtraglomerular region of the extracellular domain of HER2 and prevents the proliferative signaling

48
Q

Pertuzumab MOA

A

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
Q

lapatinib MOA

A

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
Q

Trastuzumab, T-DM1, and pertuzumab are all 3 humanized antibodies based on what?

A

IgG1 kappa Immunoglobulin

51
Q

a lot of mAbs have what set of adverse effects?

A

hypersensitivity and sequelae like asthenia, fatigue, GI upset

52
Q

what are the BBW for trastuzumab?

A

Cardiomyopathy
pregnancy
Infusion reactions including: (Respiratory distress syndrome & Respiratory insufficiency)

53
Q

What are some rare and unique adverse effects to pertuzumab?

A

decreased LVEF, neutropenia & leukopenia

54
Q

what is the must know BBW for pertuzumab?

A

teratogenicity

55
Q

what are the “serious” AEs of lapatinib?

A

ILD/pneumonitis

QT prolongation

56
Q

what is the must know BBW for lapatinib?

A

liver disease (can lead to increased drug levels & persistence)

57
Q

how does using a GnRH agonist like goserelin work on hormonally responsible tumors in premenopausal women?

A

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
Q

what AE can you expect with goserelin treatment when beginning therapy?

A

initial transient dz flare w/ bone pain (mets), hypercalcemia and breast enlargement or tenderness

59
Q

what is the common theme of AE of goserelin?

A

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
Q

how does everolimus work?

A

mTOR inhibitor that blocks cell proliferation & survival

61
Q

everolimus is often used in conjunction with what other drug?

A

exemestane

62
Q

what are the BBWs for everolimus?

A

risk of opportunistic infections-neoplasia; lymphoma/SCC

63
Q

what is the purpose of drugs/radiation in triple negative breast cancer?

A

used in adjuvant role to prevent recurrence of dz or neoadjuvant role prior to surgery

64
Q

which breast cancer drug has a max cumulative dose associated with cardiac issues?

A

doxorubicin

65
Q

what kind of prognosis do progesterone negative breast cancers have?

A

poor

66
Q

Progesterone + tumors has what effect on overall survival?

A

is predictive of better overall survival

67
Q

when women use HRT with both estrogen and progesterone they are at increased risk for what>

A

invasive breast cancer

68
Q

which chemo agents would you use in HER-2 negative early dz?

A

anthracycline & taxane based combo

69
Q

what are some factors that affect tamoxifen resistance?

A
  • 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
Q

the GnRH agonist is most beneficial in women who dont undergo _______________

A

adjuvant chemotherapy

71
Q

what is the drug of choice for adjuvant therapy of premenopausal and post-men. women who can’t take aromatase inhibitors?

A

tamoxifen

72
Q

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?

A

aromatase inhibitors

73
Q

what are some common AE of lapatinib therapy?

A 
GI issues
hand-foot syndrome
rash pain
headache
backache
74
Q

everolimus binds to what structure and forms a 3 way complex with mTOR that blocks protein action and downstream consequences?

A

FKBP-12

75
Q

what are the BBWs for everolimus?

A

risk of opportunistic infections

neoplasias-lymphoma/SCC

REPRO (13 decks)

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