Tx of Breast and Endometrial Cancer Flashcards
What are some ‘hormonally-responsive’ cancers?
breast and endometrial
prostate
adrenocortical carcinoma
What are the most common mutations seen in breast cancer (in order)?
Tp53 (27-37%)
PIK3CA (25-36%)
GATA3 (4-11%)
MAP3K1 (3-8%)
MLL3 (7%)
BRCA 1/2 (2-6%)
What is PIK3CA?
The catalytic subunit of PI3 kinase involved in cellular growth, survival and insulin signaling
What is MLL3?
Histone-lysine N-methyltransferase involved in transcriptional co-activation
How does BRCA 1/2 work on a basic level?
They mediate homologous recomination and cell cycle regulation when bound to different macrocomplexes. The results of BRCA mutations are DNA strand breaks, dysfunctional break repaire, and uncontrolled cell cycling
What are the tx options for mutated BRCA 1/2 carriers?
- prophylatic mastectomy and bilateral salpingo-oophorectomy (bilateral lastectomy decreases BC risk by 90%)
- chemoprevention using tamoxifen or raloxifene if BRCA 2 (because the majority of BRCA 2 tumors are ER+, while BRCA 1 tumors are ER-)
T or F. Raloxifene is approved for postmenopausal women only
T.
As with all solid tumors, the best means to eradicate a primary tumor that has not spread is to _______
surgically excise it
What does HER2/NEU stand for?
human epidermal growth factor 2. Note that tumors lacking ER, PR, or HER2 are called triple negative and have very poor prognoses
What are the best tx options for a ER+ tumor in a premenopausal women?
Since the main source of estrogen in pre-meno women is the ovaries, surgical removal of the ovaries or chemical castration with GnRH agonists or antagonists can be effective. Also, estrogen receptor modifiers can be used, although these drugs are more commonly employed in post-meno women
What are the best tx options for a ER+ tumor in a postmenopausal women?
The ovaries no longer produce estrogen so drugs against the HP axis are not effective, but peripheral aromatization of steroids becomes more pronounced in these women so along with the use of SERMs and selective estrogen receptor downregulators (SERDs), aromatase inhibitors are commonly used in this pop.
Describe estrogen signaling
Binding of estrogen leads to activation and dimerization of ERs, which translocate to the nucleus to activate gene expression via interaction with estrogen response elements (EREs). Other non-genomic effects of estrogen are mediated by interaction with tyrosine kinases (thus, drugs that only target the classical pathway may not be effective)
What are the anti-estrogen therapy options?
- SERDs
- SERMs
- Aromatase Inhibitors
NOTE: Initial response to tx may not be sustained in the long term as altern. roliferative pathways assume responsibility for driving proliferation
What is Fulvestrant (Faslodex)?
A BC SERD that binds to ERs and carries a bulky substituent the prevents crucial dimeriation of the ERs to allow it to translocate to the nucleus leading to reduced ER levels (pure antagonist; no estrogenic actins)
How is Fulvestrant given? Metabolism?
Monthly IM
Metabolism- hepatic; no DDs
What are the AEs of Fulvestrant?
PM symptoms including nausea, asthenia, pain, hot flashes, and HA
What are the FDA approved SERMs?
Tamoxifen and Raloxifene
What is unique about Tamoxifen and Raloxifene?
They product anti-estrogen effects on breast tissue BUT actually improve bone density by acting in a pro-estrogen manner in bone
How are SERMs given?
Daily PO
What are the AEs of the SERMs?
- increased bone density and apoliporprotein A1
- decreased serum cholesterol LDL
- retinal degeneration at high dose
- teratogenic
BBW of TAM?
endometrial hypertrophy, vaginal bleeding, and endometrial cancer
BBWs of TAM and Raloxifene?
DVT or PE, stroke
What is a second-generation SERM?
Toremifene- a derivative of tamoxifen with anti-estrogenic properties