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[ONCG2004] Lung, Breast, And Prostate Cancer > 9. Oestrogen And Anti-Oestrogens > Flashcards

9. Oestrogen And Anti-Oestrogens Flashcards

1
Q

Describe the structure of the breast

A
  • adipose tissue surrounds duct/lobule systems.
  • lobule contains alveoli
  • alveoli is made up of a milk-containing lumen, rounded by epithelial cells.
  • myoepithelial cells line the ductules.
  • capillaries surround alveoli
  • ampulla carries milk from ducts out the nipple (lactiferous duct)
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2
Q

What hormones in the menstural cycle does the pituitary gland secrete?

A

FSH / LH

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3
Q

Which hormone increases womb wall lining?

A

Progesterone

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4
Q

What is the predominant intracellular oestrogen?

A

17b-estradiol (E2)

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5
Q

What cells secrete E2 during the menstrual cycle?

A

Granulosa cells in the ovary

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6
Q

What does the hypothalamic pituitary-ovarian (HPO) axis regulate?

A

The ovarian production of oestrogen

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7
Q

Which enzyme mediates oestrogen biosynthesis in post menopausal women?

What tissues is this enzyme found in?

A

Aromatase, found in adipose tissue mainly, also in liver & adrenal glands

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8
Q

At what points of the menstrual cycle do these hormones peak:
- progesterone
- estrogen
- testosterone

A
  • P: slightly during follicular, highly mid-luteal
  • E: highly just before ovulation/end of follicular, and during luteal. It is very low during menstruation
  • T: during ovulation
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9
Q

Describe the changes in hormones during the menstrual cycle

A
  • E2 production rises 8-10 fold during ovulation
  • LH and FSH are released in response to GnRH at the end of follicular phase, ~day 13
  • LH stimulates androgen production. FSH upregulates aromatase, converting androgen to estrogen.
  • High levels of oestrogen act via negative feedback to dampen oestrogen production, inhibiting GnRH, LH, and FSH
  • Cycle continues
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10
Q

When is swelling/tenderness of the breast most and least prominent during the menstrual cycle?

A
  • Most: during the second half
  • Least: 7-10 days after the beginning of the menses
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11
Q

How do oestrogen and progesterone affect breast changes during the menstrual cycle?

A
  • Oestrogen: mammary ducts enlarge and proliferate during luteal phase (stimulate duct growth)
  • Progesterone: growth of lobules and alveoli, breasts increase in size, tenderness, and retain more fluid (stimulate secretory alveoli formation)
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12
Q

Describe the breast pathology during phase 1-4 of the menstrual cycle

A

-1: distinction between epithelial/myoepithelial is not clear
-2: increase in distinction
-3: larger lobules with increased number of terminal duct units
-4: extensive vacuolation within lobules (fluid collection/retention)

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13
Q

What does GnRH stand for?

A

Gonadotropin-Releasing Hormone

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14
Q

What is another name for aromatase?

What enzyme family does it belong to?

A

CYP19A1

Cytochrome P450 family

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15
Q

What stimulates the conversion of androgens to estrogen in:

  • premenopausal women
  • postmenopausal women
A
  • Premenopausal: Gonadotropins (LH & FSH) stimulate ovary to produce estrogen from androgens via aromatase enzyme
  • Postmenopausal: Adrenocorticotropic hormon (ACTH) stimulates adrenal gland to produce estrogen from androgens via aromatase
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16
Q

How does oestrogen cause the synthesis of ER associated proteins?

A

Oestrogen binds to ER
Homodimers bind to DNA
Activate ER regulated genes
Synthesis of ER associated proteins that can change cell behaviour

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17
Q

What are the 2 was to activate estrogen?

A
  • Through estradiol direct binding to ERa
  • Through dimeristation of Her2/3, IGFR, EGFR, causing phosphorylation of ERa
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18
Q

T or F: 70% of breast tumours show high expression of ER

A

true

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19
Q

What kind of prognosis is high expression of ER associated with?

A
  • Negative nodal status (no spread)
  • Low tumour grade
  • Correlates with improved overall survival and disease-free survival
  • Well differentiated
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20
Q

What are the 2 types of endocrine therapy against oestrogen?

A

A) anti-oestrogen: competitive binding, blocks estradiol signalling
B) oestrogen deprivation: aromatase inhibitors block conversion of androgen to estrogen

21
Q

What % of ER+ tumours respond to endocrine treatment?

A

60%

22
Q

What does SERM stand for?

A

Selective estrogen-receptor modulator

23
Q

Describe the mechanism of tamoxifen

A
  • Binds to ER, leads to dimerisation
  • Conformational change in the activating function-2 (AF2) domain of ER and binding to oestrogen-response elements (EREs)
  • Leads to persistent bye less efficient transcription of oestrogen-dependent genes
24
Q

T or F: tamoxifen induces a conformational change of ER that switches off transcription of ER-dependent genes

A

F: the conformational change of tamoxifen is different from E2
Leads to less efficient transcription of genes, doesn’t completely switch off

25
Q

Describe the action of aromatase inhibitors

A
  • prevents peripheral conversion to oestrogen
  • depletes oestrogen by aromatase inhibitors, inhibiting transcription of ER target genes
26
Q

With what cohort of patients should aromatase inhibitors be given as a first-line therapy?

A

Postmenopausal women wilt ER+ invasive breast cancer at high/medium risk of disease recurrence

27
Q

Describe the action of exemestane (aromasin), what type of drug is it?

A
  • Sterodial aromatase inhibitor
  • Forms irreversible covalent bonds with aromatase
  • Blocks conversion of test -> E2, and androstenedione -> E1
  • Inhibition occurs through competitive binding of aromatase to heme group of cytochrome P450, decreasing oestrogen biosynthesis
28
Q

How is E2 (estrone) formed?

A

From androstenedione via aromatase

29
Q

What are 2 examples of non-steroidal aromatase inhibitors?

A
  • Anastrozole (arimidex)
  • Letrozole (Femara)
30
Q

How do non-steroidal aromatase inhibitors work?

A
  • Has reversible action
  • Binds reversibly to aromatase by competing with endogenous ligands for site of aromatase
  • Forms non-covalent reversible bond to the haem iron atom in active site
31
Q

How is ER tested for?

A

By immunohistochemistry

32
Q

What % are the boundaries for high, medium, and negative IdC via IHC?

A

High - 90-95%
Medium - 50-75%
Negative: 0%

33
Q

What % of tumour nuclei are considered ER positive?

A

1-100%

34
Q

What % of cell staining ER+ is endocrine therapy limited?

A

1-10%

35
Q

When are breast tissue samples considered negative?

A

If <1-0% of cell nuclei are stained

36
Q

What roles does progesterone have in adult breast tissue?

A

Differentiation and proliferation

37
Q

T or F:
1. Progesterone is a downstream indication of ER activity
2. PR cannot be used as a surrogate marker of Er activity in breast cancer
3. ER+ tumours can be PR+ or PR-

A
  1. T
  2. F
  3. T
38
Q

Rank ER/PR phenotypes according to highest-lowest incidence

A

Highest:
ER+/PR+
ER-/PR-
ER+/PR-
ER-/PR+

39
Q

What % response to tamoxifen do these phenotypes have:
- ER+/PR+
- ER+/PR-
- ER-/PR+
- ER-/PR-

A
  • ER+/PR+: 77
  • ER+/PR-: 27
  • ER-/PR+: 46
  • ER-/PR-: 11
40
Q

What kind of ER/PR phenotypes has the worst prognosis?

A

ER+ with lower/negative expression of PR

41
Q

What phenotype calls for endocrine therapy and chemotherapy combination?

A

When the patient’s endocrine response is uncertain or a low positive

42
Q

What are the 4 subtypes of breast cancer and what markers are they positive/negative for?

A
  • Luminal A: ER+ &/or PR+, HER2-, low Ki67
  • Luminal B: ER= &/or PR+, HER2+ or -, high Ki67
  • HER2+: ER-, PR-, HER2+
  • Trip Neg/ Basal: ER-, PR-, HER2-, CK5/6+ &/or HER1+
43
Q

What % do each type of breast cancer make up?

A

Luminal A: 42-59%
Luminal B: 6-19%
HER2+: 7-12%
Trip Neg: 15-20%

44
Q

What is oncotype DX?

A

A genetic test

45
Q

What does oncotype DX help with?

A
  • making decisions about chemo after surgery
  • for patients with ER=, LN-, HER2- early stage with intermediate risk of recurrence (locally advanced)
46
Q

What 16 reference genes are used for oncotype DX breast recurrence score test? What hallmarks are they from?

A

Sustained proliferative signalling:
- Ki67, STK15, Survivin, Cyclin B1, MYBL2, ER, PR, Bcl2, SCUBE2, GRB7, HER2

Deregulating cellular energetics:
- GSTM1

Revisiting cell death:
- BAG1

Inflammation:
- CD68

Invasion & metastasis:
- Stromelysin 3, Cathepsin L2

47
Q

What material and technique is used for oncotype DX?

A

PCR based assay on formalin-fixed paraffin tissue (FFPE) material

48
Q

What are the recurrence score tests boundaries for oncotype DX?

A

Low risk: <18
Intermediate: 18-31
High: >31

49
Q

What RS group benefits the most from tamoxifen combined with chemo (compared to just tamoxifen)

A

High RS, 28% benefit

[ONCG2004] Lung, Breast, And Prostate Cancer (8 decks)

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