Exam 2: Drugs for Breast Cancer Flashcards
what is the most commonly diagnosed cancer in women?
breast cancer
(2nd leading cause of cancer death in women)
what are the three major sub-types of breast cancer?
- Estrogen receptor positive (ER+ most are also PR+) - about 75%
- HER2 +ve - about 15-20%
- Triple negative - 10-20% (BRCA-1 majority)
what type of breast cancer is most responsive to Tamoxifen?
ER+/PR+/HER2-
what type of breast cancer is not responsive to hormone therapy or targeted therapy?
triple negative breast cancer (worst prognosis)
what type of breast cancer has the best prognosis?
ER+
HER2 (less so)
triple negative (worst)
what are the SERMS?
selective estrogen receptor modulators
tamoxifen
toremifene
raloxifene
what are the common adverse effects of tamoxifen?
- menopausal symptoms (hot flashes) - 64% more severe in post-menopausal
- increased risk of DVT/PE
- increased risk of endometrial cancer (after 5 years 4-6 x)
- 30-40% become resistanct after about 5 years
how is tamoxifen metabolized?
pro-drug metabolized by CYP2D6
to endoxifen and 4-hydroxyTAM that bind to ER-alpha
which SERM can be used in pre-menopausal women?
tamoxifen
what SERM is the only one approved by the FDA for metastatic ER+ breast cancer?
Toremifene
(post-menopausal)
what is the current ASCO and FDA position on genotyping for tamoxifen therapy?
It is not recommended
how do leuprolide and goserelin act?
acts as an agonist at the GnRH receptor in the pituitary
what can happen early in treatment with GnRH drugs?
in the first few weeks to months, prior to GnRH receptor down-regulation, increase LH and FSH levels, increase in testosterone/estrogen and a potential transient worsening of cancer symptoms
what are the aromatase inhibitors?
anastrozole
letrozole
exemestane
can you use aromatase inhibitors in pre-menopausal women?
No. They have functional ovaries and their natural axis can overcome the effects of AIs.
what is the distinguishing feature of HER2 positive cells
>6 copies of the HER2 gene - identified by FISH or immunohistochemistry
HER2 activates the RAS-MAPK pathway
what is the chemical name for Herceptin?
trastuzumab
How does trastuzumab work?
it is a monoclonal Ab that selective targets the extracellular HER2 protein to disrupt dimerization with EGFR protein and activation of the RAS-MAPK pathway
About what percentage of patients will have a distant recurrence of their breast cancer within 5-10 years of treatment?
30%
what are two FDA approved tests for prognostication of recurrence?
MammaPrint
OncotypeDX
What is the RS score?
Recurrence score
what effect does Tamoxifen have on the endometrium?
acts as a partial agonist in the endometrium to promote hyperplasia, which creates a 4-6 fold increased risk of endometrial cancer
limit administration for this reason to 5-10 years
What are the common and serious s/e of tamoxifen?
menopausal symptoms (e.g., hot flashes)
increased risk of endometrial cancer
What is the MoA of tamoxifen?
pro-drug metabolized by CYP2D6 to active metabolites that acts as an ANTAGONIST to estrogren receptors in the breast tissue to inhibt gene transcription, cell proliferation and promote apoptosis
what are the contraindications to tamoxifen?
history of DVT or PE
Pregnancy
(for invasive cancers, weigh risks and benefits)
what is the effect of tamoxifen on bone?
bone sparing in post-menopausal
may cause osteoporosis in pre-menopausal
what drug class should you avoid combining with tamoxifen?
SSRIs - they will inhibit pro-drug conversion
what is a key problem with long-term tamoxifen use besides endometrial cancer?
resitstance - believed to possibly be due to down-regulation of co-repressors, ER-alpha/beta
Is toremifene associated with increased risk of endometrial cancer?
maybe - insufficient clinical data, but may act as a partial agonist in the endometrium to promote cancer
what are the contraindications to toremifene and raloxifene?
history of DVT, pregnancy (post-menopausal anyway)
do toremifene and roloxifene have the same risk of resistance with long term use as tomoxifen?
yes
which of the SERMs is the least efficacious in treating breast cancer?
raloxifene (70% efficacy of tamoxifen)
what is the efficacy of toremifene in treating breast cancer?
equal to tamoxifen
what is another indication for raloxifene?
treatment of osteoporosis - agonist-like effects on bone
Do toremifene and raloxifene require activation by CYP2D6?
No
what are the aromatase inhibitors?
anastrozole
exemestane
anastrazole is a ________?
aromatase inhibitor
exemestane is a _____________?
aromatase inhibitor
who can take aromatase inhibitors?
early stage or metastatic ER+ post-menopausal patients
why can’t we use the aromatase inhibitors in pre-menopausal women?
because functional overies in the h-p-g axis overomes the AT effects
what are the side effects of the aromatase inhibitors?
hot flashes
osteopenia
osteoporosis
what is the mechanism of action of anastrozole?
prevents conversion of testosterone to estrogen by inhibiting aromatase (CYP19A1) in adipose tissue
anastrazole is a reversible inhibitor
what is the mechanism of action of exemestane?
prevents conversion of testosterone to estrogen by inhibiting aromatase in adipose tissue
what is a GnRH agonist
Leuprolide
what is leuprolide indicated for?
treatment of metastatic or early stage ER+ breast cancer in pre-menopausal patients
*can combine with SERMs
*ASCO prefers Tamoxifen for early stage bc
what is the mechanism of action of GnRH agonists
They disrupt the normal pulsatile stimulation of GnRH receptors by endogenous GnRH, leading to decreased release of FSH and LH from the pituitary, which in turn decreases estrogen synthesis from the ovaries
