What are some 'hormonally-responsive' cancers?
breast and endometrial
What are the most common mutations seen in breast cancer (in order)?
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
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?
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?
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?
What are the AEs of the SERMs?
-increased bone density and apoliporprotein A1
-decreased serum cholesterol LDL
-retinal degeneration at high dose
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
How is Toremifene given?
PO Daily (CYP 3A4 interactions)
AEs of Toremifene?
-less BBWs than first gen but does increase QT interval
-No other BBWs but avoid with Hx of endometrial cancer/hyperplasia or TE disease
How can a SERM have both estrogenic and atni-estrogenic properties?
When an ER is bound by an antagonist like tamoxifen it recruits a different set of co-repressors to prevent mRNA production
Tamoxifene and CYP2D6
There is a belief that the efficacy of Tamoxifen is based on a pt's ability to metabolize the drug via CYP2D6. However, there is no current FDA requirement for cyp testing
What Cyp do aromatase inhibitors block (primarily used in Post-meno women)?
What are the current aromatase inhibitors on the market?
Anastrozole, Letrozole, and Exemestane
All 4 drugs show similar activtiy (non-steroidal are reversible inhibitors and the steroidal are irrverisble), although non-cross-resistane can occur
How are the AIs given?
Daily PO (hepatic metabolism)
What are the AEs of AIs?
-hot flashes, nausea, hair thinning
T or F. The use of AIs in postmenopausal women offers similar to mre effective treatment of BC than tamoxifen alone
How long should tamoxifen be used to provide the best treatment of breast cancer without raising the risk of endometrial cancer
10 yrs of tamoxifen provides substantial benefit that clearly outweights the risk of endometrial cancer. Additional info is needed for hazards in the second decade of use
What are the drugs for HER + BC?
Trastuzumab binds the extracellular region of HER2 and Pertuzumab binds to the dimerization domain, blocking ligand-dependent hetero-dimerization of HER2 with other epidermal growth factor receptors including HER 3 and 4.
Trastuzumab emtansine (T-DM1) binds to the receptor which, upon internalization, allows the thioester-linked chemotherapeutic to act on microtubules.
T or F. All 3 HER drugs are humanized ABs based on IgG1 kappa immunoglobulin
What is a TKI designed for HER targeting?
Lapatinib is a small TKI that inhibits HER1 and 2 by binding to the intracellular domain of the ErbB1 and B2 receptors and competing with ATP to inhibit phosphorylation of the receptor, and thus, its activation
HER2 MAB therapy is used commonly in conjunction with ______
taxane therapy (remember, MABs are given via injection)
AEs of HER2 MABs?
-infusion or hypersensitivity rxns
-common AEs: Gi disturbances, asthenia, blood dyscrasia, and fatigue
Other AEs of Trastuzumab?
-respiraotry distress/insufficiency and pneumonia
How is Lapatinib metabolized?
extensive hepatic; CYP3A4/5 (liver disease will increase levels and elevate LFTs)
AEs of Lapatinib?
Common: Gi disturbances, anemia, and thrombocytopenia, hand-foot syndrome, rash pain, headache and backache
Serious: interstitial lung disease/pneumonitis; QT prolongation
What is the rational in using a GnRH agonist in premenopausal BC?
Agonism of the HPG axis with continuous administration of a GnRH agonist will transiently increase hormone levels (and may cause discomfort) BUT in the long run will have the effect of down-regulating secretion of hormones (In about 2-4 weeks usually)
What is a GnRH angonist used in premenopausal BC tx?
Goserelin- long term therapy is well tolatered (SQ injection in upper abdominal wall)
What are the AEs of Goserelin?
Common AEs of a hypo-estrogenic state including amenorrhea, hote flashes, decreased libido, depression, sweating, etc
Also, decreased bone density
What is the function of mTOR?
mTOR regulates cell proliferation, angiogenesis, and cell metabolism by activating or inhibiting protein synthesis upon receipt of appropriate biochemical signals
Everolimus, a mTOR inhibitor, is used in conjunction with Exemestane in what cancer tx?
advanced ER+, HER2 - tumors
What are the AEs of everolimus?
risk of opportunistic infection or neoplasia, most commonly lymphoma and SCC
hyperglycemia and hyperlipidemia, hyper TAG
How is triple neg BC treated?
Excision of primary tumor and lymph nodes is the standard practice for early stage disease and conventional chemo is used for advanced tx.
Describe ER-PR Receptor Crosstalk
In tumors that are PR-, estrogen binding to receptors results in activation of gene expression programs that promote cell proliferation BUT
In tumors that are both PR and ER +, progesterone stimulated PR interacts with and redirects the intact ER transcriptional complex to novel binding sites that promote cell differentiation and apoptosis
What is the role of Denosumab in BC tx?
This drug prvents bone breakdown commonly seen in BC tx due to bone mets or anti-estrogen therapy, by inhibiting RANKL
What are some drugs used in Endometrial Cancer Tx?
What is Medroxyprogesterone?
a progestin contraceptive that binds to progestin receptors and blocks GnRH release
AEs of Depo-provera?
How does Megestrol work?
It suppresses LT release and enhances estrogen degradation and promotes differentiation/maintenance of endometrial tissue
AEs of Megestrol?
Weight gain (increased appetite), hot flashes, malaise, lethargy, sweating, and rash
-tumor flare and hypercalcemia in BC pts. with bony mets
-thrombophlebitis, thrombo- or pulmonary-embolism