Breast and Endometrial Cancer Flashcards
Most common genetic mutations associated w/ breast cancer?
- PIK3CA (subunit of PI3K)
- TP53 (tumor suppressor gene – cell cycle, apoptosis, dna repair regulator)
- GATA3 (TF regulating luminal epithelial cell differentiation in mammary glands)
- BRCA1/2 (Tumor suppressor, double strand DNA break regulator)
- MLL3 (transcriptional coactivator)
- MAP3K1 (Kinase activator of ERK and JNK)
Primary source of estradiol in pre and post menopausal women? Treatment options for each?
Pre = Ovaries –> aromatase inhibitors are useless in this population!
– Treatment: Sx or chemical ovary castration, SERMs
Post = Peripheral aromatase in fat tissue –> aromatase inhibitors are very effective
– Treatment: Aromatase Inhib, SERMs, SERDs
BRCA 1 and 2 mutations: consequence of mutation? differences between 1 and 2?
BRCA1 – associated w/ triple neg Br cancer (+/- medullary carcinoma) and with serous ovarian cancer
BRCA2 – associated w/ male breast cancer and luminal breast cancer
Mechanism of Estrogen signaling?
- Genomic actions: binds ER –> ER dimerization –> ER:ER translocates to nucleus and interacts with E Response Element/TFs/Coactivators –> activates expression of target genes
- Non Genomic actions: ER interacts with Tyrosine Kinases / downstream actors –> may explain FAILURE OF GENOMIC PATHWAY TARGETED THERAPY
SERDs (selective estrogen receptor downregulators): MOA, AEs
Fulvestrant = steroidal
MOA: Binds ER w/ a bulky substitute that prevents dimerization in nucleus –> increased turnover –> decreased #ER expression BUT NO ESTROGENIC EFFECTS!
AEs: (PM symptoms) nausea, asthenia, pain, vasodilation (hot flashes), HA
Rx failure? est-independent cell growth
SERMs (Selective estrogen receptor modulators): MOA, AEs
1st gen: Tamoxifen, Raloxifene = NON-steroidal structures
2nd gen: Toremifene
MOA: ER agonist/antagonists – location dependent based on alpha and beta subtypes. Estrogen agonist @ bone ie BONE SPARING, est antagonist @ mammary tissue.
AEs: Teratogen,
BBW: Endometrial hypertrophy –> cancer, vaginal bleeding, Thromboembolic disease (DVT/PE) –> Strokes
Contraindications: Pregnancy, diabetes, HTN, Smokers, taking aromatase inhibitors, uterine/endometrial cancer…
Toremifene
2nd generation SERM
Uses: used in Post menopausal women, doesn’t carry BBW but still a teratorgen + AE of QT PROLONGATION
Metabolism: Cyp3A4
Is Cyp2d6 genotyping required for Tamoxifen use?
Tamox is metabolized by CYP2D6, and there is evidence that Tamoxifen’s metabolites are more potent Est antagonists, but inconclusive if testing is needed/if tamox is less effective in individuals w/ dec CYP2D6 activity.
How do SERMs act as both agonists and antagonists?
Agonists at bone/endometrial estrogen receptors but antagonists at mammary tissue ie bone density sparing!
??
Anastrozole, Letrozole, Exemastane: MOA, AEs
Aromatase Inhibitors
Structures: only Exemestane has steroidal structure (irreversible inhibitor)
MOA: highly specific aromatase inhibition (no effects observed on other organs/hormones)
AEs: hot flashes, nausea, hair thinning, ARTHRALGIA
Which aromatase inhibitor has a steroidal structure?
Exemestane –> IRREVERSIBLE inhibitor
Aromatase therapy/Tamoxifen recommendation?
Tamox/Aromatase Inhibitor sequential therapy = better outcomes!
“all post menopausal women w/ hormone receptor + early BC should receive adjuvant aromatase inhibitor therapy – options include 5 years AI or sequential therapy, 2-5 yr tamoxifen therapy followed by 2-5 year AI”
Risk - benefit of longer duration tamoxifen therapy vs. risk of endometrial cancer?
10 years tamox / AI treatment provide substantial survival benefit, outweighing risk of endometrial cancer.
Trastuzamab, Ado-Trastuzumab/emtansine MOA, AEs
MOA: Binds HER2 extracellular/juxtaglomerlar region
Ado/emtansine trastuzumab = Mab trastu + cytotoxic DM1 + linker: Mab binds Her2 receptor –> internalized / borken apart in lysosome –> DM1 thioester links microtubules –> prevents cell division
AEs: hypersensitivity w/ initial dose, GI upset, asthenia, blood dyscrasias, fatigue, peripheral edema, rash, weight gain, dizziness, URTIs/Pharyngitis, (rare cardiomyopathy/HF, renal fail, hepatotoxicity, PNA, resp fail)
Pertuzumab MOA, AEs
MOA: binds extracellular domain of HER2 and prevents heterogenous dimerization with HER3/4
AEs: hypersensitivity reaction w/ initial dosing, Alopecia, anorexia, GI upset, asthenia, blood dyscrasia, fatigue, (rare dec LVEF, neutropenia, leukopenia)
Trastuz/Pertuz BBWs
Trastuzumab: Cardiomyopathy, infusion reaction, pregnancy, ARDS/insufficiency due to infusion reaction
Ado Trastuz: HF, Hepatic disease, pregnancy, ventricular dysfunction
Pertuzumab: Pregnancy
Lapatinib MOA, AEs
RTKI – only one approved for breast cancer
MOA: binds HER2 intracellular domain @ ErbB1 or 2, inhibits/competes with ATP and prevents TK phosphorylation/activation
AEs: contraindicated w/ liver disease ( extensive CYP3A4 and 5 hepatic metabolism, but no significant Rx-Rx interaction), GI issues, anemia, thrombocytopenia, Hand foot syndrome, rash, HA, backache,
Serious AEs: interstitial lung disease, PNA, QT PROLONGATION
Goserelin: MOA, AEs, Patient population?
MOA: GnRH agonist (will have an initial LH/FSH surge)
AEs: Bone pain @ mets/breast tenderness with initial dosing, hypoestrogenic effects (amenorrhea, hot flashes, dec libido, vaginal dryness, sweating, depression, gynecomastia), HA, peripheral edema, lethargy/anorexia
Patient pop: premenopausal women w/ hormone responsive tumors
mTOR action/mechanism
biochemical signals –> mTOR pathways –> inc or dec protein synthesis –> Central regulator of:
1) cell proliferation
2) angiogenesis
3) cell metabolism
Everolimus: MOA, AEs, tumor type
MOA: mTOR inhibitor via FKBP12 receptor (macrolide immunosuppressant and proliferation signal inhibitor / analog of sirolimus)
AEs: opportunistic infections, neoplasia (lymphoma, SCC), non-infectious PNA, blood dyscrasias, hyperglycemia/ hyperlipidemia/hyperTG, elevated Cr and LFTs, diarrhea
– Get CBC, LFTs, bilirubin, Cr…
Pt/Tumor type: advanced ER+/HER2- tumors
WITH AI EXEMESTANE
What drug do you use conjunctively with everolimus (mTOR inhibitor)?
Exemestane (Aromatase inhibitor)
Approach to triple negative Br Ca treatment?
1) surgical removal of primary tumor/LNs (early stage)
2) Adjuvant Rx/Radiation
3) Conventional Chemo (advanced/metastatic disease)
- -> Rx intervention dictated by: tumor size/LN involvement
How could progesterone receptor positive cells contribute to malignant progression? Why do progesterone receptor negative tumors have a dismal prognosis?
–> Normally PR + cells function in a paracrine manner – switch to an autocrine mechanism could support progression
–> PR+ cells normally suppress tumor invasion in more advanced stages (either via P independent or in response to P) – PR- tumors = more likely to invade.
Estrogens Effects on vision?
Estrogen has “protective” effects on eyes/vision:
- low estrogen/below physiological levels = increased risk of cataracts/vision changes/retinal degeneration
ex) SERMs like Tamoxifen and Raloxifen
- low estrogen/below physiological levels = increased risk of cataracts/vision changes/retinal degeneration
- but pharmacologic levels can also be harmful/cause vision changes/cataracts
ex) Hormone replacement
- but pharmacologic levels can also be harmful/cause vision changes/cataracts
HRT – risks of combined therapy? estrogen alone?
Combined = increased risk of invasive breast cancer
Estrogen alone = protective effect against breast cancer
Medroxyprogesterone (deprovera), Mergesterol: MOA, AEs, other uses
Medroxyprogesterone
MOA: binds progestin receptor –> xGnRH
AEs: amenorrhea, edema, anorexia
uses: contraception
Mergesterol
MOA: suppresses pituitary LH release + inc estrogen degradation + promotes differentiation/maintenance of endometrial tissue
AEs: weight gain, hot flashes, asthenia, sweating, rash, tumor flare, hyperCa (in BC pts with bone mets), blood dyscrasias
uses: anorexia in AIDS patients
