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)
