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PHAM02 > breast cancer SD > Flashcards

breast cancer SD Flashcards

1
Q

What is tissue involution?

A

changes in the breast with increasing age

involutional changes are changes due to altered sex steroid levels that accopany decreasing ovarian fxn

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2
Q

Sx of breast disease

A

lumpiness

pain

palpable mass

nipple discharge

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3
Q

most common type of benign breast tumour

A

fibroadenoma

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4
Q

2 types of breast carcinomas

A
  1. non-invasive
    - ductal carcinoma in situ DCIS
    - lobular carcinoma in situ LCIS
  2. invasive/infiltrating carcinoma
    - infiltrating ductal carcinoma
    - invasive lobular carcinoma
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5
Q

tests for metastases

A
  • lymph node ultrasound/biopsy
  • MRI scan
  • CT scan
  • liver ultrasound
  • bone scan
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6
Q

stages of BC

A

STAGE 0: DCIS, pre-invasive BC, cancer cells are in breast ducts and have not started to spread into surrounding breast tissue

STAGE 1: cancer is small and only in breast tissue or might be in lymph nodes close to breast, early stage

STAGE 2: cancer is in breast or in nearby lymph nodes or both, early stage

STAGE 3: cancer has spread from breast to lymph nodes close to breast or to skin of breast or chest wall, locally advanced breast cancer

STAGE 4: cancer has spread to other parts of the body

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7
Q

How is the ER/PR/HER2 receptor status determined?

A

immunohistochemistry

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8
Q

What does triple positive BC mean?

A

ER +ve
PR +ve
HER2 +ve

-> no mutations, could be early stage cancer

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9
Q

Which ER type is in breast?

A

ER alpha

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10
Q

What type of drug is Tamoxifem?

A

SERM

-> doesn’t allow helix H12 to fit correctly, antagonist effect

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11
Q

What does tamoxifen prevent?

A

prevents ER gene co-activation

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12
Q

How does Tamoxifen work?

A
  • binds to ER at helix H12
  • masks the AF2 site
  • leads to less co-activator recruitment
  • partial agonist/antagonist
  • activates other genes - pro-apoptotic genes, dec proliferation
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13
Q

2 actions of SERMs (tamoxifen and raloxifine)

A
  • estrogenic and antiestrogenic actions depending on target tissue
  • antiestrogenis in mammary tissue
  • proestrogenic on uterine epithelium and bone
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14
Q

How can Tamoxifen resistance occur?

A
  • loss of ER expression in patient
  • activating ER mutations
  • ER is hypersensitised to low oestrogen levels
  • increased oestrogen levels -> competition
  • pharmacologic tolerance, inc efflux OR dec influx of the drug by membrane pump glycoproteins (Tamoxifen pumped out of cell)
  • R crosstalk (HER2)
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15
Q

How do aromatase inhibitors work?

A

inhibit aromatase converting androgens to oestrogens

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16
Q

examples of reversible aromatase inhibitors

A

aminoglutethimide - poor selectivity

anastrazole, Letrozole - bind to haem group of aromatase and prevents binding to steroid

17
Q

example of irreversible aromatase inhibitors

A

Exemestane

18
Q

Fulvestrant

A
  • new ER antagonist
  • brand = Faslodex
  • SERD - selective ER degrader
  • binds tightly to ER
  • masks both AF1 & AF2 sites
  • causes receptor instability
  • ER is degraded by the proteome
19
Q

difference between Fulvestrant and Tamoxifen

A

masks both AF1 and AF2 sites

doesn’t allow ER into nucleus

20
Q

Tx if patient ER +ve

A

Tamoxifen

21
Q

Tx if patient HER2 +ve

A

Herceptin

22
Q

What can ER crosstalk with?

A

HER2 receptor

23
Q

What family is HER2 from?

A

EGFR family

24
Q

How do the HER activating ligands work?

A

HER 1, 3 and 4 require HER 2

HER 2 binds to HER 1, 3 or 4, dimerises and becomes active

25
Q

normal vs malignant growth with HER2 R

A
  • low HER 2 - weak signalling, normal growth
  • high HER 2 - potent signalling, malignant growth
26
Q

What type of receptor is HER2?

A

cell surface tyrosine kinase receptor

27
Q

% of BC that overexpress HER2

A

20-30%

28
Q

Tx to block HER2

A

Herceptin - Trastuzumab

MAb

well tolerated

29
Q

s/e with Herceptin

A

CV dysfunction

30
Q

monitoring for Herceptin

A

cardiac fxn

31
Q

What protein does HER2 use to activate proliferation/attract blood vessels?

A

VEGF

32
Q

HER2 p95 fragment

A
  • HER2 can undergo proteolytic cleavage in overexpressing cells
  • leads to extracellular domain fragment being shed
  • leaves active p95 domain
  • poor prognosis
33
Q

6 MOA of Herceptin

A
  1. blocks cleavage, prevents autophosphorylation
  2. blocks dimerisation (of other HER R)
  3. endocytosis of HER2
  4. activation of antibody dependent cell mediated cytotoxicity: ADCC (immune system attack HER2)
  5. blocks VEGF and tumour vascularisation
  6. upregulates p27 to block cell cycle
34
Q

How can you get Herceptin resistance?

A
  1. HER2 p95 fragment generation
  2. epitope masking by mucin
  3. epitope masking by CD44

-> Herceptin can’t bind when any of these happen

35
Q

What region does Herceptin bind to on HER2?

A

region 4

36
Q

drug for Herceptin resistance and MOA

A
  • Pertuzumab
  • binds to region 2 (not 4 - Herceptin)
  • overcomes resistance by p95 clevage and masking
37
Q

Where does Pertuzumab bind to on HER2?

A

region 2

38
Q

When is Pertuzumab licenced to be given?

A

in combination with docetazel and trastuzumab (Herceptin)

39
Q

Trastuzumab Emtansine -> Kadcyla

A
  • antibody-drug conjugate:
  • Trastuzumab linked to DM1 (microtubule inhibitor)
  • effect = prevention of microtubule polymerisation and initiation of apoptosis (by DM1)
  • licenced for Tx of HER2 +ve, unresectable, locally advanced/metastatic BC
  • previosuly received trastuzumab + taxane (separate or combination)
  • should have:
  • received Tx for locally advanced/metastatic disease OR
  • developed disease recurrence during/within 6mths of completing adjuvant therapy

PHAM02 (32 decks)

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