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Flashcards in Hormonally responsive cancers Deck (78):
1

name the aromatase inhibitors for breast cancer

anastrozole
exemestane
letrozole

2

name ther SERDS and SERMS for breast ca

raloxifene
tamoxifen
toremifene
fulvestrant

3

name the GnRH agonist for breast CA

gosorelin

4

name the Her-2/neu antibodies in breast ca

pertuzumab
trastuzumab (herceptin)
ado-trastuzumab
emtasine

5

name the TKI used in breast ca

lapatinib

6

mtor inhibitor useful in breast ca

everolimus

7

name the mutations common in breast CA

most common-PIK3ca and TP53
-BRCA1//2, GATA3, MAP3K1, MLL3
breast CA-->heterogenous accumulation of these thangs

8

consequence of BRCA1/2 mutations

1. DNA strand breaks
2. dysfunctional break repair
3. uncontrolled cell cycling through abrogation of the normal checkpoint

9

BRCA1/2 tumors and EReceptor status

60-75% of BRCA2 tumors are ER +
ONLY 10-30% of BRCA1 tumors are ER +
(really says 70-90% are negative)

10

treatment options for BRCA1/2 + patients

prophyllactic mastectomy and BSO, SERM (only if BRCA2 will this have a 50% chance in reducing risk),

11

triple negative Breast CA's treated with

conventional therapy-cytotoxic therapy-poor prognosis

12

ER+ tumors are driven by

estrogen

13

primary source of estrgoen pre-menopause

ovaries

14

tx of estrogen driven tumor before menopause

surgical removal of ovaries
>chemical castration with GnRH agonists/antagonists (block HP control)
>SERM (generally saves for Post Menopausal)

15

drugs generally saved for Post menopausal estrogen sensitive breast cancers

SERMS

16

source of Estrogen in post menopausal women

peripheral conversion of estrone in fat cells

17

drugs INEFFECTIVE after menopause

drugs targeting HP axis
(GnRH agonist/atagonist)

18

drug classes effective in Post Menopausal estrogen fed breast cancer

1. SERMS
2. SERDS
3. Aromatase inhibitors

19

only two targets in ER + breast cancer for which agents currently exist

MTOR inhibition
EGFR/HER2-RTK action
Overall production of Estrogen

20

therapy failure with agents that target only classicla pathway

the cells are stil undergoing non-genomic actions carried out by estrogen (previously unrecognized)

21

will anti-estrogen therapy work on ER- or Pr+ tumors

yes-clinical response in 8-12 weeks
*average remission 6-12 months-sometimes many years

22

MOA for Fulvestrant

SERD
_binds ER but has bulk substrate which inibits dimerization in nucleus and signalling, achieves sustained down-regulation of EReceptors

23

Fulvestrant indicated for

Er+ METASTATIC breast CA in Post Menopausal women with DISEASE PROGRESION FOLLOWING ANTI-ESTROGEN THERAPY

24

inhibites receptoir dimerization in the nucleus leading to icnreased turnover and disruption of nuclear localization

Fulvestrant--> SERD

25

side effects of Fulvestrant

PM symptoms
-VMS
-irritability
-N/V
-ASthenia
-pain
-HA

26

failure of therapy with SERMS and SERDs

estrogen independent cell growth

27

Effects of SERMS in woman body

estrogenic effects on bones, anti-estrogenic signalling effects on the breast tissue

28

ROAdministration for SERMS

daily PO=tamoxifene
monthlY IM=Raloxifen

29

BBW for tamoxifen only

Endometrial hypertrophy, Vaginal bleeding, Endometrial Cancer

30

bbw for Tam and Ral BOTH

thromboembolic disease (DVT or PE), Stroke

31

other outcomes of SERM use

dec. bone metabolism
inc density of bone
impove lipid profile
retinal degen. at high dose
teratogenic*****

32

safer, more convenient serm

raloxifen

33

BBW for toremifene

Prolongs QT
*therfore avoid with other 3A4 inihibitors

34

all SERMS are

teratogens

35

avoid toremifine if hx of

endometrial cancer/hyperplasia
thromboembolic disease,

36

what determines if SERM will be antag or agonistic in given tissue

whether it binds co-activators upon dimerization in nucleus or co-repressors (though histone deacetylase 1)

37

concern for tamoxifene

poor metabolizers (defective CYP2d6) will not produce as much of the MORE HIGHLY active offspring product 4OH tamoxifen--> less effective

38

cyp involved in tamoxifen administration and efficacy

CYP2D6

39

MOA for aromatase inhibitors

Block CYP19A1 mediated prodcution of estrone (fat) and estradiol, thereby starving the tumor cell of continued proliferation signal

40

Steroidal aromatase inhibitor

exemestane
-->irreversible inhibitor

41

Non-Steroidal Aromatase inhibitor

Anastrazole, Letrozole
-->reversible inhibition

42

side effects of aromatase inhibitors

menopause symptoms
*less gyn symptoms that tamoxifen
*new research says tamoxifene for 10 years is better

43

how to test for Her2 Neu overespression

ISH or IHC

44

MOA for trastuzumab

bind Juxtaglomerular regio of extracellular HER2 domain

45

MOA for Pertuzumab

binds EC dimerization domain (subdomain II)-->inhibits Her2 from dimerizing with Her3 and her4

46

Trasztuzumab DM1 MOA

bind to receptor and is internalized...then thioester-linked chemotherapeutic agent acts on microtubules

47

MOA for lapatinib

TKI, BINDS intracellularly and inhibits HER1/2 by binding to ErbB1 and ErbB2 receptors and comepting with ATP

48

linker-cytotoxic combination used in Her2+ breast CA's

Ado-Trastuzumab-AKA Kadcyla-AKA TDM1

trastuzumab +emantsine (cytotoxic) microtubule inhibitor-makes up T-DM1

49

mab with cardiopulmonary , reno-heaptic AE's

trastuzumab

50

BBW for Trastuzumab

Cardiomyopathy
Infusion reactions
Pregnancy
Respiratory Distress Syndrome
Respiratory insufficiency
(RDS and RIS can eb sequelae of infusion rxns)

51

BBW for pertuzumab

pregnancy

52

BBW for Ado-Trastuzumab

Heart failure
hepatic disease
pregnancy
ventricular dysfunction

53

BBW for Lapatanib

Liver Disease-will increase persistence

54

hand-foot syndrome, rash, GI issue are seen with which agent

lapatinib-. Small Molecule TKI

55

serious AE's seen with Lapatinib

intersitial lung disease/pneumonitis, QT prolongation
*cannot use with drugs hosting similar side effects

56

high levels of sex steroid inhibits

FSH LH release from AP--> thus less estrogen mad in the ovaries

57

continueal drug stimulation of GnRH receptors in the anterior pituitary -->results in

receptor downregulation-> less FSH and Lh secreted

58

how long does it take for GnRH agonsit to work

Estrogen levels fall to PM levels in 2-4 weeks--> can acutally cause disease flair prior to this
downregulation
Ex bone pain with mets, breast enlargement/tenderness

59

GnRH agonist

Goserelin

60

AE's with goserelin

PM symptoms->tough on bones esp.

61

MTOR inhibitors work via what mechanism

binf to FKBP12 and forma a three way complex with mTOR that blocks protein action and downstream conseuquences

62

mTOR signalling in viv does what

angiogenesis
Proliferation
Cell metabolism

63

BBW for Everolimus (mTOR inhibitor)

risk of opportunisitic infections-NEOPLASIA, SCC/LYMPHOMA
*THIS SHIT IS AN IMMUNUPRESSANT

64

when is everolimus emplyed

Advances ER+, Her2-ve tumors with EXEMESTANE (STEROIDIAL)

65

STANDARD OF CARE FOR TNBC'S

EXCISION OR PRIMARY TUMOR AND ADJACENT LYMPH NODES
*IF ADVANCES-CYTOTOXIC THERAPY

66

ADJUVANT

TO PREVENT RECURRANCE

67

NEOADJUVANT

TO SHRINK AND IMPROVE SURGICAL OUTCOMES

68

DO ALL PATIENTS WITH TNBC REQUIRE ADJUVANT THERAPY?

NOPE--> LOOK AT TNM STAGING
(LN+-ADJUVANT
LN- AND >1CM) FOR SURE

69

AE OF DOXORUBICIN

cardiomyopathy

70

standard adjuvant care of BC with either poor signature or, LN + or LN-ve and greater than Icm

ALL INVOLVE Doxorubicin (an anthrachyline--cumulative max dose)
Doxorubicin-A
Cyclophosphamide-C
T=docetaxel
Ca CAF, AC-t, TC, CAF
*no evidecne any one regimine is better than the other

71

Progesterone signalling is now known to be controlled by

controlled both by the process of SUMOylation ( a form of ubiquitination) and by post-translational phosphorylation on as many as 10 sites.

72

PRogesterones role in breast cancer (present in about 40% of cells, however these effects are suspected to be paracrine because the cells responsive to Pr themselves are of non-proliferative potential)

stimulates cyclical proliferation of the mature breast epithelium and activates mammary stem cell pools or occult tumor initiating cells

73

worse prognosis PR + or negative

negative

74

PR late in disease contributes to tumor progression in that...

PR signalling pathways naturally/unatrually supress tumor invasion and mets through maintaining epithelial cell phenotype and imeding the EMT

75

sum up PR in breast cancer

enhances proliferation of PR- cells in a paracrine fashion, then late impede EMT

76

CEE + MPA=

increased risk of invasive breast cancer

77

CEE ALONE=

21% decrease in BC

78

Drugs for endometrial cancer

Medoxyprogesterone (progestin) "Depo-Provera"
Megestrol-synthetic oral progestin