Thatcher - Breast Cancer Flashcards
Types of Breast Cancer:
Triple Negative Cancer
- 13 Different Diseases
- but 1 group, different underlying CAUSES
- Only 1 type of treatment = Radiation / Chemotherapy
Types of Breast Cancer:
HER2 Cancer
GF Receptors
- Treatment = HER-2 Inhibitors
- herceptin = Antibodies
- With or withought chemotherapy
Types of Breast Cancer:
Luminal A
ER+ / PR+ / Her2+
45%, bost prevelant type
- Treatment: Endocrine Therapy
Types of Breast Cancer:
Luiminal B
ER+, PR+, Her2+/lowKi67 or Her2-/highKi67
- Treatment = Hormone (endocrine) Therapy
ER-alpha
Estrogen Receptor discovered in 1958
-
ER+ Breast cancer growth & survival driven by the effect of estrogens –> ER-a
- =First drug targets
History of Endocrine Therapy
Clomiphene
- 1950’s MER25 + Clomiphene = First Anti-oestrogens
- Identified as antifertility agents
- 1960’s
- Approved for ovulation induction
History of Endocrine Therapy
Tamoxifen
- 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
- Approved for Treatment for advanced breast cancer
-
1980’s
- Determed help breast cancer survival
- 1990’s
-
TAMOXIFEN APPROVAL BY FDA
- for reduction of risk of breast cancer
-
TAMOXIFEN APPROVAL BY FDA
History of Endocrine Therapy
Raloxifene
- 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
History of Endocrine Therapy
Fulvestrant
ER Downregulator (SERD)
discovered in 2000’s
- Also discovered serendipitously
- 3rd generation
- Considered as Selective Oestrogen Receptor DOWNREGULATOR
- = SERD
- for POST-menopausal
- “chemo-prevention”
History of Endocrine Therapy
Estrogens / DES
(diethylstilbestrol)
First Discovery as targets of ER in 1950’s
POTENT ER AGONIST
History of Endocrine Therapy
Anastrazole
Discovered in 1990’s
–> POST MENOPAUSAL AROMATASE INHIBITOR
AI’s
Prevents Synthesis of Estrogen
Tamoxifen
(novaldex)
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
-
Incidence of OVARIAN CANCER due to this
Raloxifene
(Evista)
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
*
-
& breast cancer chemoprevention
-
–> Repositiones for POST-MENOPAUSAL OSTEOPOROSIS
SERM
MOA
-
Stabilized ANTAGONIST conformation
-
CO-REPRESSOR BINDING –> estrogen receptor
- __collects differents proteins on the dna
-
STILL RESULTS IN TRANSCRIPTION
- but produces DIFFERENT protein products
-
CO-REPRESSOR BINDING –> estrogen receptor
Estradiol MOA
-
Estrogen –> Estrogen Receptor –> Agonist conformation
- = COACTIVATOR COMPLEX
- Collects specific proteins –> DNA
- Transcriptional Activation
- –> Cell survival & Proliferation genes
- –> Breast Cancer
- = COACTIVATOR COMPLEX
Why is Tamoxifen chosen for
PRE-Menopausal women?
It is NOT CHEMICAL CASTRATION
does NOT antagonize estrogen EVERYWHERE
specifically not Ovaries (so ovulation can still occur)
Considered a SELECTIVE ER modulator (SERM)
Anastrazole
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)
- Blocks synthesis of estradiol
-
–> Fulvestrant is chosen after
- = SERD
Fulvestrant
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
SERM Resistance
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)
Serm Resistance Mechanisms
- 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
Combination Therapies
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
Why is it Difficult to research Cancer Therapies?
- 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
-
YOU GET THE SICKER PATIENTS
Combination Therapies
W/ SERMs / SERDs
- PI3K/Akt inhibitor (AZD2014 and BYL719)
- mTOR inhibitor (everolimus/ Afinitor)
- CDK4/6 inhibitor (palbociclib/ Embrance)
Other:
- HSP90 inhibitor/ mutant ER (Entinostat)
- HDAC6 inhibitor (vorinostat)
