Breast Cancer Drugs – Flashcards
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Types of Breast Cancer Drugs 1.) SERM's 1a.) Estrogen receptor antagonist 2.) Aromatase Inhibitors 3.) GnRH agonist 4.) Biologic
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1.) Tamoxifen, (Toremifene), Raloxifene 1a.) (Fluvestrant) 2.) Anastrozole, Exemestane, (Letrozole) 3.) Leuprolide, Goserelin 4.) Trastuzumab, Trastuzmab-emtansine, Pertuzumab
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How are breast cancers classified for deciding treatments? What % is in each category?
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IHC 1) ER+ 75% (60% are responsive to tamoxifen) 2) HER2+ 15-20% 3) Triple Negative (ER, PR, HER2) 10-20%
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Which breast cancer drugs are used to treat • ER+ pre-menopausal women • ER+ post-menopausal women • HER+ breast cancers • osteoporosis (post-menopausal) • dec risk of cancer development • triple negative breast cancer
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• Tamoxifen (SERM) & GnRH agonist • SERMs & Aromatase Inhibitors • Biologics (Trastuzumab, Trastuzumab-emtansine, Pertuzumab) • Raloxifene (SERM) • Tamoxifen (SERM) • Pembrolizumab
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*SERMS* (MOA)
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= Selective Estrogen Receptor Modulators • Antagonists of ER-a/ER-b in breast tissue • Partial agonist of ER-a/b in bone &/or endometrium
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Tamoxifen (MOA, uses)
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• 1st generation SERM • USES: ER+, pre/post-menopausal B.C. (metastatic, post-Tx, DCIS, prevention) • MOA: *Pro-drug* (metabolized by *CYP2D6*) > endoxifen & 4-hydroxyTAM > bind to ER-a/b (a) breast - antagonist (inhibits gene transcription/cell proliferation & promotes apoptosis) (b) endometrial - partial agonist (4-6x inc risk of hyperplasia; SO don't use more than 5 years; can follow with 5 yrs of aromatase inhibitors)
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Tamoxifen (SE, CI, key points)
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• SE: Menopausal symptoms & Risk endometrial cancer • CI: Hx of DVT/PE & SSRI (CYP2D6 inhibitor) • Resistance (30-40% after 5 years) • Genotype for CYP2D6 is controversial (subtypes 1 & 2xN are metabolize it well enough)
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Raloxifene (MOA, uses)
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2nd generation SERM • USES: Prevent ER+ breast cancer in high-risk post-menopausal & for tx osteoporosis • MOA: *active drug* a) breast: antagonist b) bone: agonist
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Raloxifene (SE, CI, key points)
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• SE: Hot flashes • CI: Hx of DVT/PE & pregnancy • Less risk of endometrial cancer than 1st gen SERM, BUT only ~70% efficacy of tamoxifen on BC risk
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*Aromatase Inhibitors* (MOA, types & differences)
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= inhibit conversion of testosterone to estrogen by inhibiting aromatase (CYP19A1) in adipose tissue • Anastrozole/Letrozole (reversible inhibitor) • Exemestane (irreversible/suicide inhibitor)
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Aromatase Inhibitors (uses)
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• Early stage/metastatic ER+ BC in post-menopausals • Adjuvant monotherapy for max of 5 yrs • Adjuvant therapy following 5 yrs of tamoxifen (esp. useful in women after cross into menopause)
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Aromatase Inhibitors (SE, CI)
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• SE: hot flashes, osteopenia/porosis • CI: not effective in pre-menopausal women since AI cannot overcome HPG axis (acts on adipose tissue!)
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*GnRH agonists* (types, MOA)
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(Leuprolide) = synthetic hormones that act as agonists at GnRH receptor in anterior pituitary • disrupt normal pulsatile stimulation of GnRH-R by overstimulating > desensitization • lower GnRH > low LH/FSH > estrogen & testosterone • key: transient worsening of S/S before desensitization
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Leuprolide (uses)
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1) adjuvant for pre-menopausal metastatic ER+ BC > can combine with SERMs 2) adjuvant for metastatic prostate cancer > can combine with androgen R antagonists)
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Leuprolide (SE & CI)
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#1) transient worsening of symptoms before GnRH-R desensitization (higher estrogen/testosterone levels) • Other SE: hot flashes, osteoporosis, sexual dysfncn • CI: pregnancy
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*Biologics* (overall use & MOA)
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HER2+ breast cancer monoclonal antibodies (Ab)
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How is HER2 tested for in BC patients?
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• FISH to count # copies of HER2 genes (normal = 2) • IHC
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Trastuzumab (Aka, MOAx3)
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• aka: Herceptin • MOA: monoclonal Ab that targets HER2 extracellular domain to inhibit *ligand-independent* HER2 dimerization, thereby... 1) inhibiting RAS-MAPK signaling pathway 2) sensitizes cancer cell to cytotoxic chemo 3) Ab-dependent cellular cytotoxicity (Ab recruitment)
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Trastuzumab (use)
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HER2+ (a) localized: adjuvant therapy with paclitaxel or docetaxel (mitotic spindle poisons) (b) metastatic: monotherapy or with paclitaxel
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Trastuzumab (SE)
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1) *infusion reaction* (40% of pt, tx with meperidine, acetominophen, or diphenhydramine) 2) nephrotic syndrome 3) interstitial lung disease 4) BLACK BOX: cardiomyopathy (CHF/dec LV-EF) & fatal infusion rxn with ARDS
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Trastuzumab (resistance, adjuvants)
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• Most patients develop resistance by 1 year • Binds subdomain IV of ERBB; allows ligand-dependent dimerization (use w/ pertuzumab) • Can also use with *Lapatinib* (RTK competitive inhibitor)
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Pertuzumab (MOA, uses)
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• MonoAb that binds extracellular HER2 domain to prevent *ligand dependent dimerization* - Binds ERBB subdomain 2 • Use for metastatic HER2+ BC with trastuzumab & docetaxel
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Pertuzumab (SE, CI)
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• SE: hypersensitivity (severe), cardiotoxicity • BLACK BOX: embryo-fetal toxicity (CI pregnancy)
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Trastuzumab-emtansine (aka, MOA, use) - not on drug list!
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• T-DM1 • MonoAb coupled with emtansine (DM1), a mitotic spindle poison that binds beta-tubulin to prevent polymerization; DM1 released after lysosomal internalization of the Ab-complex • Components: Ab, Drug (DM1), Linker molecule • Use: Metastatic HER2+ BC resistant to trastuzumab &/or taxanes (ie: paclitaxel)
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Trastuzumab-emtansine (T-DM1) - (SE, CI) - not on drug list!
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1) infusion reaction 2) BLACK BOX: hepatotoxicity, liver failure 3) BLACK BOX: cardiotoxicity 4) BLACK BOX: embryo-fetal toxicity • CI: pregnancy
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Treatment for triple negative BC (+MOA) - not on drug list!
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• *Pembrolizumab* = Ab targeting PD-1, immune inhibitory pathway, preventing immune suppression! - Tumor cells normally evade immune detection by using IFN-gamma (release by activated T-cells) to upregulate PD-1, which allows them to bind PD-1R on T-cells and inactivate them - This has been approved for melanoma and non-small cell lung carcinoma already
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What is the rate of recurrance after treatment of early stage breast cancers?
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Within 5-10 years, 30% will have distance recurrence (mets)
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What are the prognostic applications of Oncotype DX & MammoPrint tests for BC?
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= Genetics tests to see which patients are at risk of recurrence after treatment; helps to decide whether a women with early stage cancer will benefit from chemo (along with hormonal therapy) • mammoPrint = 70 genes • oncotype Dx = 21 genes (recurrent score >31)
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CASE: A lymph node negative BC with oncotype recurrent score of 35, will receive combo Tx of tamoxifen & chemo (5FU, MTX, cyclophosphamide), which gene would you genotype prior to Tx initiation?
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DPD gene (dihydropyrimidine dyhydrogenase) - excessive metabolism of 5FU > fatal myelosuppression (in some patients)
