Thatcher - Breast Cancer Flashcards

1
Q

Types of Breast Cancer:

Triple Negative Cancer

A
  • 13 Different Diseases
    • but 1 group, different underlying CAUSES
  • Only 1 type of treatment = Radiation / Chemotherapy
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2
Q

Types of Breast Cancer:

HER2 Cancer

A

GF Receptors

  • Treatment = HER-2 Inhibitors
    • herceptin = Antibodies
    • With or withought chemotherapy
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3
Q

Types of Breast Cancer:

Luminal A

ER+ / PR+ / Her2+

A

45%, bost prevelant type

  • Treatment: Endocrine Therapy
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4
Q

Types of Breast Cancer:

Luiminal B

ER+, PR+, Her2+/lowKi67 or Her2-/highKi67

A
  • Treatment = Hormone (endocrine) Therapy
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5
Q

ER-alpha

A

Estrogen Receptor discovered in 1958

  • ER+ Breast cancer growth & survival driven by the effect of estrogens –> ER-a
    • =First drug targets
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6
Q

History of Endocrine Therapy

Clomiphene

A
  • ​1950’s MER25 + Clomiphene = First Anti-oestrogens
    • Identified as antifertility agents
  • ​1960’s
    • Approved for ovulation induction
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7
Q

History of Endocrine Therapy

Tamoxifen

A
  • 1960’s - Serendipitous discovery
    • Tamoxifen ID’ as antifertility agent (contraception)
  • 1970’s
    • Approved for Treatment for advanced breast cancer
      • also Induction of ovulation
    • ​Demonstrated to block Estrogen Receptor
  • ​​1980’s
    • Determed help breast cancer survival
  • 1990’s
    • TAMOXIFEN APPROVAL BY FDA
      • for reduction of risk of breast cancer
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8
Q

History of Endocrine Therapy

Raloxifene

A
  • 1980’s
    • ID as anti-oestrogen
    • Used for POST MENOPAUSAL TREATMENTS
      • DISCONTINUED AT TREATMENT FOR BREAST CANCER
  • ​​1990’s
    • Raloxifine APPROVED BY FDA FOR OSTEOPOROSIS PREVENTION
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9
Q

History of Endocrine Therapy

Fulvestrant

A

ER Downregulator (SERD)

discovered in 2000’s

  • Also discovered serendipitously
  • 3rd generation
  • ​​Considered as Selective Oestrogen Receptor DOWNREGULATOR
    • ​= SERD
    • for POST-menopausal
    • “chemo-prevention”
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10
Q

History of Endocrine Therapy

Estrogens / DES

(diethylstilbestrol)

A

First Discovery as targets of ER in 1950’s

POTENT ER AGONIST

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11
Q

History of Endocrine Therapy

Anastrazole

A

Discovered in 1990’s

–> POST MENOPAUSAL AROMATASE INHIBITOR

AI’s

Prevents Synthesis of Estrogen

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12
Q

Tamoxifen

(novaldex)

A

Selective Estrogen Receptor Modulator

SERM

  • Discovered serendipitously in 1970’s as post-coital contraceptive
  • Effective against endocrine dependent breast cancer = ER+
  • Antagonist in Breast
  • Agonist in Endometrium
    • Incidence of OVARIAN CANCER due to this
      • ​positive outweighs negative
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13
Q

Raloxifene

(Evista)

A

SERM

  • No advantage over tamoxifen in breast cancer
    • tumors resistant to tamoxifen were cross-resistant to raloxifene
    • does not have agonist activity in endometrium –> possibly less side effects
  • Antagonist in breast & endometrium
  • Agonist in BONE
    • –> Repositiones for POST-MENOPAUSAL OSTEOPOROSIS
      • ​& breast cancer chemoprevention
        *
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14
Q

SERM

MOA

A
  • Stabilized ANTAGONIST conformation
    • CO-REPRESSOR BINDING –> estrogen receptor
      • _​_collects differents proteins on the dna
    • STILL RESULTS IN TRANSCRIPTION
      • ​but produces DIFFERENT protein products
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15
Q

Estradiol MOA

A
  • Estrogen –> Estrogen Receptor –> Agonist conformation
    • = COACTIVATOR COMPLEX
      • Collects specific proteins –> DNA
    • Transcriptional Activation
    • –> Cell survival & Proliferation genes
      • –> Breast Cancer
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16
Q

Why is Tamoxifen chosen for

PRE-Menopausal women?

A

It is NOT CHEMICAL CASTRATION

does NOT antagonize estrogen EVERYWHERE

specifically not Ovaries (so ovulation can still occur)

Considered a SELECTIVE ER modulator (SERM)

17
Q

Anastrazole

A

Aromatase Inhibitor = AI

  • Aromatase (CYP450 Enzyme) –> synthesis of estrogens
  • Chosen for POST-Menopausal Women
    • Blocks synthesis of estradiol
      • so it effects ALL estrogen receptors (including those in ovaries)
  • –> Fulvestrant is chosen after
    • = SERD
18
Q

Fulvestrant

A

Selective Estrogen Receptor DOWNREGULATOR

SERD

  • Antagonist @ ER
  • ​​Promotes Receptor DEGRADATION
    • triggers ubiquinylation & proteasome degradation
    • for Post-Menopausal women, following AI’s (anastrazole)
  • Poor Bioavailability = IM injection
    • ​poor pharmakinetics
  • Non-steroidal
    • ​does not have COOH side chain
19
Q

SERM Resistance

A

Result in need for SERDS

  • 50% of ER antagonist become resistant
    • Estrogen receptor is LOST
    • Estrogen receptor can MUTATE
      • ACTIVATED w/o estradiol
      • Phosphoralated
      • or WORK in PRESENCE of tamoxifen (serms)
20
Q

Serm Resistance Mechanisms

A
  • Increased expression of GF receptors
  • Upregulation of P13K (survival) or RAS (proliferative) pathways
    • p13k is most common signaling pathway in cancer__​
  • Modification in cell-cylcer regulators
  • Increase Phosphorylation of ER
  • Altered ligand uptake
  • Receptor loss/mutation
  • Increase AP-1 DNA inding
  • Increased nuclear coactivators
21
Q

Combination Therapies

A

​Purpose –> Targets 2 pathways

to PREVENT RESISTANCE

by eliminating residual cancerous cells

  • FIRST
    • First line study comparing Fullvestrant vs Anastrazole
  • FACT
    • Combo of Fulvestrant + Anastrazole
  • PALOMA3
    • Palbociclib + Fulvestrant Vs Fulvestrant alone
  • BOLERO-2
    • Everolimus + Tamoxifen vs Just Tamoxifen
22
Q

Why is it Difficult to research Cancer Therapies?

A
  • Hard to move backwards
  • Typically new therapies / combination therapies are used on patients that were ALREADY TREATED w/ other therapies
    • YOU GET THE SICKER PATIENTS
      • further along cancer treatment
23
Q

Combination Therapies

W/ SERMs / SERDs

A
  1. PI3K/Akt inhibitor (AZD2014 and BYL719)
  2. mTOR inhibitor (everolimus/ Afinitor)
  3. CDK4/6 inhibitor (palbociclib/ Embrance)

Other:

  1. HSP90 inhibitor/ mutant ER (Entinostat)
  2. HDAC6 inhibitor (vorinostat)
24
Q
A