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Spring 2018 Pharm Exam 2 > Lecture 5: Drugs for Breast CA > Flashcards

Lecture 5: Drugs for Breast CA Flashcards

1
Q

How are the subtypes of BCA determined?

A

immunochemistry

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2
Q

What are the 3 main subtypes of BCA

which is MC?
which has best prognosis?

A
  1. ER + BCA (MC & best prognosis)
  2. HER 2+ BCA
  3. Triple Negative BCA
    (ER-, PR-, HER2 not amplified)
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3
Q

Other than surgery and/or radiation what is the main Tx for ER+ BCA?

A 
hormone therapy (tamoxifen)
(+/- cytotoxic chemo)
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4
Q

Which pts respond best to tamoxifen for BCA?

A

ER+, PR+ & HER2- pts respond best

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5
Q

Other than surgery and/or radiation what is the main Tx for HER2+ BCA?

A

Target therapy w/biologics

Trastuzumab

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6
Q

Other than surgery and/or radiation what is the main Tx for Triple Negative BCA?

why does this CA have the worst prognosis

A

cytotoxic chemo

pts not candidates for ER+ (tamoxifen) or HER2+ (biologic) Tx –> CA wont respond to drugs b/c not rec +

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7
Q 
What class of drugs Tx PREmenopausal women?
POSTmenopausal women?

What drug class can tx both pre and post?

A 
PRE = GnRH agonists 
POST = Aromatase Inhibitors 
Both = SERMs (tamoxifen)
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8
Q

What does hormonal therapy target for BCA?

What 3 classes of drugs Tx ER + BCA?

A

Targets the HPG axis

  1. SERMs
  2. GnRH agonists
  3. Aromatase inhibitors
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9
Q

What are the two drugs in the SERM class that Tx ER+ BCA?

A
  1. Tamoxifen

2. Toremifene

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10
Q

What is major difference about Toremifene in regards to Tx population (vs. Tamoxifen)?

What can NOT approved to Tx?
What is its ONLY Tx indication?

A

ONLY Txs POST menopausal women

Not approved for DCIS (early stage dz) or risk reduction

Only approved to Tx metastatic ER+ BCA

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11
Q

What are the two active metabolites of Tamoxifen?

A
  1. 4-hdroxyTAM

2. Endoxifen

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12
Q

Where are 4-hdroxyTAM and Endoxifen antagonists? partial agonists?

A

antagonists in breast tissue (alpha/beta rec)

partial agonists in bone and endometrial tissue

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13
Q

What is the MOA of 4-hdroxyTAM and Endoxifen?

What does chronic inhibition cause? why?

A

block estrogen binding–> prevents transcription pro-proliferative/survival genes

chronic inhibition–> apoptosis
- higher activity of co-repressors

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14
Q

What is the RLS for endoxifen?

A

activity of liver enzyme CYP2D6

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15
Q

What are the 3 polymorphisms of CYP2D6?

which has worst survival?

A
  1. normally active/wild type allele (*1) - EM
  2. supraactive (*2xN) - UM
  3. Totally inactive allele (*4) - PM = worst survival
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16
Q

What is the MC AE a/w tamoxifen? What population is it worse in?

What does this S/E indicate?

A

Menopausal Sxs (hot flashes)

  • more severe in POSTmenopausal women
  • indicates drug is working
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17
Q

What are the 2 BBW a/w tamoxifen?

A
  1. incr risk of DVT, PE
    (agonist activity–> stim clotting factors)
  2. incr risk of endometrial CA if on drug more than 5 yrs
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18
Q

Why are pts not on tamoxifen more than 5 yrs?

A

incr risk of endometrial CA

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19
Q

6 uses/Tx for tamoxifen

A
  1. Metastatic BCA in women and men
  2. Adjuvant for metastatic BCA
  3. Adjuvant for DCIS
  4. BCA prevention in high risk pts
  5. DoC for EM & UM pts
  6. Txs early stage & metastatic ER+ BCA
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20
Q

What is the drug in the GnRH class that Txs ER+ BCA?

A

Leuprolide

21
Q

MOA for Leuprolide?

Overall result?

A

GnRH agonist in pituitary:
- constitently stim GnRH rec–> downreg/desensitization of GnRH rec

Result: decr levels of FSH and LH–> decr progesterone and estrogen

22
Q

What occurs w/Leuprolide admin in the first few wks/months?

A

before down regulation –> initial incr in FSH and LH rel–> incr testosterone and estrogen levels –> transient worsening of CA Sxs

23
Q

3 major AEs a/w Leuprolide?

CI of Leuprolide?

A
  1. Hot flashes
  2. osteoporosis
  3. Sexual dysfunction

CI = pregnancy

24
Q

What 2 situations is Leuprolide used for as adjuvant therapy?

A
  1. PREmenopausal metastatic ER+ BCA

2. Metastatic prostate CA

25
Q

2 main drugs for aromatase inhibitors?

which one is IRREV?

A
  1. Anastrozole

2. Exemestane = irreversible

26
Q

What is the MOA for Anastrozole & Exemestane?

A

inhbit aromatase CYP19A1–> prev conversion of testosterone to estrogen

27
Q

Why are aromatase inhibitors not effective in pre-menopausal women?

A

Still have fxnl ovaries–> decr estrogen levels–> less neg feedback–> more testosterone produced –> overcomes AI’s effects

28
Q

How long can Anastrozole and Exemestane be given as adjuvant monotherapy?

When using Anastrozole and Exemestane in sequential adjuvant therapy how long is total Tx time? What drug initially given?

A

5 yrs

total Tx time for sequential therapy = 10 yrs
- first give tamoxifen for 5 yrs, then give AI for addtl 5 yrs

29
Q

What drug class Txs HER2+ BCA?

what are the 2 main drugs in this class?

A

class = biologics (monoclonal Abs)

Drugs

  1. Trastuzumab
  2. Pertuzumab
30
Q

How many copies of HER2 gene in normal cells?

How many copies of HER2 gene in BCA cells?

A

normal cells = 2 copies

BCA cells = 6 copies

31
Q

What 2 methods used to determine HER2+ cells?

What will be seen w/each method indicating HER2+ cells ?

A
  1. FISH mapping –> pink spots

2. Immunochemistry–> brown staining of membrane

32
Q

How do normal and BCA cells in EGF and HER2 receptor signaling?

A
  1. Normal cells = ligand dependent dimerization

2. BCA cells = ligand INdependent dimerization

33
Q

How does ligand INdependent dimerization in BCA cells lead to CA?

A

persistent activation of RAS-MAPK pathway–> uncontrolled cell proliferation

34
Q

Major difference in MOA b/t Trastuzumab and Pertuzumab?

A

Trastuzumab - blocks ligand INdependent dimerization

Pertuzumab - blocks ligand dependent dimerization

35
Q

MAIN 2 MOA for Trastuzumab? end result?

A
  1. Monoclonal Ab: binds to HER2 rec–> downregulation

2. Inhibits ligand dependent dimerization & RAS-MAPK activation–> inhibits prolif and induces apoptosis

36
Q

Other 2 MOAs for Trastuzumab:

  • sensitizes CA cells to cytotoxic chemo
  • Kills CA cells by recruiting host immune cells
A

`

37
Q

Main S/E a/w Trastuzumab?

A

Infusion rxn

38
Q

Infusion rxn w/Trastuzumab:

  • caused by?
  • Sxs?
  • Tx?

note: normally occur w/in 1st minutes, improves after 1st Tx

A

d/t rel of histamines and cytokines

Sxs = fever and chills, N/V, pain, HA, dizziness, rash

Tx = acetaminophen, diphenhydramine

39
Q

What are the 2 BBWs for Trastuzumab?

A
  1. Cardiomyopathy (see CHF, decr LV EF)

2. Fatal infusion rxn (ARDs)

40
Q

What is the major problem w/ Trastuzumab?

solution?

A

resistance develops in most w/in 1 yr

solution = give Laptinib as replacement therapy

41
Q

What is the 1st line Tx for metastatic HER2+ BCA or early primary HER2+ BCA

A

Trastuzumab+ Laptinib

42
Q

3 indications/uses for Trastuzumab

A
  1. HER2+ localized BCA (adjuvant)
  2. Metastatic HER2+ BCA
  3. Metastatic HER2+ GASTRIC CAs
43
Q

What is Pertuzumab typically used in combo w/?

What 3 drug combo improved progression free survival?

Note: txs all stages HER2+ BCA

A

Trastuzumab and docetaxel

Trastuzumab + Pertuzumab + docetaxel

44
Q

What are the names of the 2 genomic approaches to predicting BCA recurrence?

A
  1. MammaPrint

2. Oncotype DX

45
Q

What is unique about MammaPrint

A

It is receptor INdependent–> can be used on all subtypes of BCA (ER, PR, HER2)

46
Q

Which genomic approach is indicated for pts < 61 w/early stage tumors < 5 cm and LN (-)

A

MammaPrint

47
Q

What does lower recurrence score for Oncotype DX indicate?

A

better prognosis

48
Q

Which type of tumors based on Oncotype DX will benefit from combo Tx of Tamoxifen + chemo (improved 10 yr survival)

A 
High RS (recurrence score tumors)
- score > 31
49
Q

What Tx should be give to Low-RS tumors (<18) based on Oncotype DX? why?

A

ONLY give tamoxifen–> little/no benefit to combo and chemo drugs = toxic/fatal

Spring 2018 Pharm Exam 2 (6 decks)

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