Treatment of Breast and Endometrial Cancer Flashcards
What is the only way to treat Triple negative breast cancer?
- what is the best method of treating this cancer?
Triple Negative Breast Cancers: ONLY treated with CONVENTIONAL agents excision of the cancer and surrounding nodes is your best option
A woman presents at age 45 with dilated cardiomyopathy after treatment for breast cancer at age 25, what drug likely caused this side effect?
***cumulative dose effect of doxorubicin may present as a women who develops heart failure at a young age following breast cancer treatment***
What are the standand Adjuvant therapies for breast cancer?
- what classes of anti-cancer drugs are these?
Cyclophosphamide (Alkylating agent) + Doxorubicin (Chelating, Topo inbitor = anthracyclin) +/- Taxane or 5-FU
Why are drugs that block ER not more effective at treating estrogen sensistive breast cancer?
Estrogen mediates effects in the cell genomically through the ER, but also can bind to cell surface receptors to have more immediate effects.
**this is why we need to use mTOR inhibitors like Everolimus**
If someone with a BRCA mutation refuses to undergo a prophylactic mastectomy, but is willing to take drugs, then what drugs can you give them?
Chemoprevention of breast cancer can be done with Tamoxifen or Raloxifene (SERMs)
**This is hardly ever used for BRCA 1 mutations because these cancers are most often ER-
What are aromatase inhibitors not used in younger women?
Peripheral Conversion of Androgen to Estrone in PREmenopausal women is insignificant compared to the estrogen produced by their ovaries
**Also Aromastase inhibitors are teratogens***
Why is the progesterone receptor even evaluated in breast cancers?
*While no drugs target the progesterone receptor directly, presence of the progesterone receptor alone diverts estrogen effects from being proliferative and more towards differentiation and apoptosis*
T or F: Anti-estrogen therapy is very effective at CURING cancer.
False, average remission time for Anti-Estrogen therapy is 6-12 months
What is the function of the BRCA genes and where in the cell cycle are they most important?
- *Gene Mutations in Breast Cancer:**
- BRCA1/2: important for homologous recombination (DNA repair) in the S and G2 phases of the cell cycle. Loss of these genes allow for progression of the cell cycle in the presence of aberrant DNA.
What drugs act as aromatase inhibitors?
Anastrozole, Letrozole, Exemestane
What are the only groups that are approved to take aromatase inhibitors in the treatment of breast cancer?
**name these drugs**
ONLY used in postmenopausal women. This is because peripheral fat stores are the primary location of aromatase, which converts circulating androgens into estrogen, which feed the cancer.
Anastrozole, Letrozole, Exemestane
Aromastase Inhibitors
- ADMINISTRATION
- MOA
- Name them
Anastrozole, Letrozole, Exemestane
ADMINISTRATION
Daily ORAL
MOA
Inhibition of the Aromatase enzyme in fat tissue (of post-menopausal women) to prevent androgen conversion into estrogen
Aromase Inhibitors
- Adverse Effects (compare these to tamoxifen)
- Indication (type of breast cancer)
- NAME THEM
Anastrozole, Letrozole, Exemestane
ADVERSE EFFECTS
Hot flashes, Hair thinning, Arthralgia, Diarrhea
FEWER gyn symptoms than Tamoxifen (b/c there is no proestrogeninic effect of these drugs)
*****TERATOGEN****not an issue in post-menopausal women
INDICATION
ER+ breast cancer in post-menopausal women
Aromatase Inhibitors
- Contraindications
- what would you do if a cancer became resistant to Letrozole?
- Name them
Anastrozole, Letrozole, Exemestane
CONTRAINDICATION
Pregnancy – not an issue since they’re only indicated for post-menopausal women
***Exemestane – IMPORTANTLY has a steroidal structure while the other 2 do not so cross resistance between steroidal (Exemestane) and non-steriodal (Anastrozole, Letrozole) agents is not a problem.
What SERMS are used in the treatment of breast cancer?
Raloxifene/Tamoxifen
Are SERDs and SERMs typically used in pre or post menopausal women?
Can be used in pre or postmenopausal women, but typically only used in postmenopausal women.
In tissues where SERMs act to deactivate the cells, what do they do upon entering the cell?
- name the SERMs
The ability of SERMs to have activating properties in some tissues and deactivating properties in other tissues depends on the proteins that it recruits when it gets there. In tissue that get deactivated the ER+Tamoxifen complex activates a HDAC (histone deacetylase) that acts to repress mRNA production.
SERMs = Raloxifene/Tamoxifen/Toremifene
Raloxifene/Tamoxifen
- Administration
- MOA
Raloxifene/Tamoxifen
ADMINISTRATION
PO
MOA
SERMs = Selective Agonists of ER and antagonists of others and thus have effects of decreasing hormone stimulation of breast cancer and increasingbone density and positive effects on cholesterol.
Raloxifene/Tamoxifen
- adverse effects (how do these differ between the two drugs?)
- BBWs
Raloxifene/Tamoxifen
ADVERSE EFFECTS
**Teratogens
** Retinal Degeneration at High Doses
- ***************BBWs********************
- *Tamoxifen only:** Endometrial Hypertrophy/Polyps, Vaginal Bleeding, Endometrial Cancer
BOTH:Thromboembolism, Stroke
Raloxifene/Tamoxifen
Indication
Contraindication
Raloxifene/Tamoxifen
INDICATION
Post-menopausal women with ER + breast cancer
CONTRAINDICATION
Pregnancy, but this isn’t an issue in post-menopausal women
Toremifene has fewer BBWs than Raloxifene and Tamoxifen, but what BBW does it has that is different than these two drugs?
Toremifene - prolongs the QT interval
**So avoid this drug with any pre-existing heart conditions**
- *Toremifine**
- Administration
- MOA (why might these people experience less activity with drug compared to others in its class?)
Toremifene
ADMINISTRATION
PO DAILY, CYP3A4 metabolized (watch out for grapefruit juice etc.)
MOA
SERMs = Selective Agonists of ER and antagonists of others and thus have some effects of increased bone density and positive effects on cholesterol.
Derivative of Tamoxifen
**Slow CYP2D6 metabolizers may experience less drug activity due to less production of ENOXIFEN – an extremely active metabolite of tamoxifen.
Toremifene
- Adverse Effects
ADVERSE EFFECTS
BBW specific to Toremifene: PROLONGS QT interval/PRO-ARRYTHMOGENIC
Similar Side effects but not BBWs as tamoxifen (see below)
Teratogen
Retinal Degeneration at High Doses
Tamoxifen: Endometrial Hypertrophy, Vaginal Bleeding, Endometrial Cancer, Thromboembolism, Stroke
Toremifene
- Indication
- Contraindication
INDICATION
Postmenopausal women with ER+ Breast cancer
CONTRAINDICATION
Pregnancy, but this isn’t an issue in post-menopausal women
Name the SERMs.
- how are they different from the SERDs?
- Name the SERD.
SERMs:
- Tamoxifene, Raloxifene, and Toremifene
- *SERDs (Fulvestrant)
- are PURE antagonists with NO ESTROGENIC EFFECTS**
Fulvestrant
- Administration
- MOA
Fulvestrant
Administration
Monthly IM injections
MOA
SERD not SERM so = PURE ANTAGONIST with NO estrogenic effects, bulky adduct prevents ER receptor dimerization
- *Fulvestrant**
- Adverse Effects
- Indication
Adverse Effects - **Make sense on the basis of the MOA**
Mostly perimenopausal symptoms of Nausea, asthenia, pain, vasodilation (HOT FLASHES), and headache
- *Fulvestrant**
- Indication
- Contraindication
Indication
ER+ Breast Cancer in Post-menopausal women following failed anti-estrogen therapy
Contraindication
ER negative Cancers
What drugs act on the HER2 signaling pathway?
- what are the different points at which they work?
(there are 4 drugs)
Trastuzumab - bind Juxtaglomerular region of HER2
Pertuzumab - binds binds the extracellular dimerization domain of HER2
Lapatinib - binds the ATP binding site on the HER2 TKI
Everlolimus - blocks mTOR (downstream from receptor)
Her-2/Neu Antibodies (2 of them)
- Administration
- MOA
Pertuzumab/Trastuzumab
ADMINISTRATION
IV administration with TAXANES
MOA
- *Pertuzumab** - Binds to HER2 receptor to block the extracellular dimerization domain
- *Trastuzumab** - binds to the Juxtagolmerular region of the extracellular HER2 domain
HER-2/neu antibodies
- name them.
- Adverse Effects (how do these differ between the two drugs?)
Pertuzumab/Trastuzumab
ADVERSE EFFECTS
INFUSION RXNS are especially prominent with Trastuzumab
BOTH: HEART FAILURE, Respiratory distress, GI upset, Blood Dyscrasia, Hepatotoxicit and pneumonia
BBW (traztuzumab)
PREGNANCY, HEART/HEPATIC TOXICITY, RESPIRATORY ISSUES (Traztuzumab)
What HER2-neu antibody do you not have to give with a Taxane?
- explain
Ado-Trastuzumab Emtasine
ADMINISTRATION
IV administration
MOA
Binds to HER2 receptor causing internalization like Trastuzumab, but it has an anti-microtubule agent attached to it that acts upon entering the cell
Indication for HER-2 antibody drugs?
- contraindication?
INDICATION
HER-2 positive breast cancer
CONTRAINDICATION
CHF, Liver Disease, Respiratory Disease (epecially trastuzumab)
What HER2-TKIs are used in the Tx of HER2 positive breast cancer?
- administaration
- MOA
Lapatinib
ADMINISTRATION
Oral
MOA
Inhibitor of HER1 and HER2 by binding to the intracellular ErbB1 and 2 domains to PREVENT ATP binding (like all TKIs)
Lapatinib (HER2 - TKI blocker)
- Adverse Effects
ADVERSE EFFECTS
Common: ELEVATED LFTs, Hand-foot syndrome, rash, GI toxicity, Anemia
Serious: INTERSTITIAL LUNG Dz./pneumonitis; QT prolongation
Lapatinib
- Indication
- Adverse Effects
INDICATION
HER2 positive Breast Cancer
CONTRAINDICATION
BBW: Liver Disease or Dysfunction => toxicity following normal dosing regimen
T or F: GnRH agonists and antagonists are only used for breast cancer treatment in pre-menopausal women
True, this is because the HPO axis is firing (producing lots of FSH), but ovarian estrogen is not significant in postmenopausal women.
GnRH agonist used in breast cancer?
- Administration
- MOA
Goserelin
ADMINISTRATION
SC injection
MOA
Persistent Agonism of the GnRH receptor leads to increased FSH and LH levels followed by DOWNREGULATION of the receptor
Gosrelelin (GnRH agonist)
- Adverse Effects
Goserelin
ADVERSE EFFECTS
Hypo-estrogeneic state = Decreased Bone Density (perpetuated by EtOH and tobacco use; FHx of Osteoporosis); Amenorrhea, Hot Flashes, Decreased Libido/vaginal dryness, emotional lability, sweating
What drug used to treat ER positive, HER2 negative breast cancer increases the patient’s risk of neoplasia and lymphoma?
EVEROLIMUS
Everolimus
Administration
MOA
Everolimus
ADMINISTRATION
ORAL?
MOA
Binds FKBP-12 that forms a 3 way complex with mTOR that prevents it from performing its usual functions of promoting synthesis of proteins involved in Angiogenesis, Cell metabolism, and Proliferation.
Everolimus
- Adverse Effects
Everolimus
ADVERSE EFFECTS
Non-infectious Pneumonitis, Blood dyscrasias, Hyperglycemia, Hyperlipidemia/triglyceridemia, ELEVATED CREATININE
BBW:
RISK OF OPPORTUNISTIC INFECTIONS, NEOPLASIA, LYMPHOMA, SCC
Everolimus
- Indication
INDICATION
Used with exemestane in advanced ER+, HER-2 negative tumors
What mAb is used to treat the symptoms that are produced when cancer metastasizes to bone?
- Administration
- MOA
Denosumab
ADMINISTRATION
Parental
MOA
mAb against RANKL preventing osteoclast stimulation
Denosumab
- Adverse Effects
- Indication
ADVERSE EFFECTS
Weakened immune system
INDICATION
- *Metastasis to bone** – males and females with hormone sensitive cancers are at an especially increased risk because they are probably blocking estrogen production needed to maintain bone
- *Especially useful in tumors secreting PTHrP**
**No contraindications mentioned**
What progesterone analogs are used in the treatment of Endometrial Cancer?
- which might be effective in breast cancer too? why?
**medroxyprogesterone and Megostrol
Megostrol may be useful in treating breast cancer by exerting a cytotoxic effect on BC cells by interfering with the availability, stability, and turnover of estrogen and the interacting with estrogen and progesterone receptor complexes**
Medroxyprogesterone
- Administration
- MOA
Medroxyprogesterone
ADMINISTRATION
SC? Or IM? – as a depot
MOA
Binds to PROGESTIN receptors to block GnRH release
Often used as a contraceptive
Medroxyprogesterone
Adverse Effects
Indication
Medroxyprogesterone
ADVERSE EFFECTS
Amenorrhea, edema, anorexia, weakness, WEIGHT GAIN
INDICATION
Endometrial Carcinoma
Cachexia tx in AIDS and Cancer patients
Megestrol
- Administration
- MOA
ADMINISTRATION
Oral
MOA
Synthetic progestin used to block LH release from the pituitary and enhance estrogen degradation
Megestrol
- Adverse Effects
Megestrol
ADVERSE EFFECTS
Tumor Flare and Hypercalcemia in BC pts with bony metastasis
Thrombophlebitis, Thrombo- or pulmonary embolism
Megestrol
- Indication
INDICATION
Endometrial Carcinoma. Occasionally breast Carcinoma
