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Repro > Sweatman - Tx of Breast/Endo Cancer > Flashcards

Sweatman - Tx of Breast/Endo Cancer Flashcards

1
Q

What 6 gene mutations are implicated in breast cancer?

A
  • BRCA1/2: tumor suppressors involved in repair of double strand breaks (2-6%)
  • PIK3CA: catalytic subunit of PO3 kinase; key signal transduction enzyme in cellular growth, survival, and insulin signaling (25-36%)
  • TP53: tumor suppressor, key regulator of cell cycle, DNA repair, apoptosis (27-37%)
  • GATA3: transcription factor that regulates luminal epi cell differentiation in mammary gland (4-11%)
  • MAP3K1: kinase that activates ERK and JNK kinase pathways (3-8%)
  • MLL3: histone-lysine N-methyltransferase involved in transcriptional coactivation (7%)
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2
Q

What are the cellular roles of BRCA1 and 2?

A
  • Homologous recombination (HR) DNA repair during S and G2 phases of the cell cycle
  • In response to DNA damage, BRCA1/2 mediate HR and cell cycle regulation when bound to different macrocomplexes
  • Mutations in BRCA1/2 => DNA strand breaks, dysfunctional break repair, uncontrolled cell cycling via abrogation of the normal checkpoint machinery
    1. INC division of cells carrying DNA damage and to the process of carcinogenesis
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3
Q

What are the options for mutant BRCA1/2 carriers?

A
  • SURGERY: prophylactic mastectomy (DEC breast cancer risk by 90%) + bilateral salpingo-oophorectomy
  • CHEMO: Tamoxifen or Raloxifene (SERMs) = 50% risk DEC for BRCA2, but no effect for BRCA1
    1. BRCA2: 60-75% ER+
    2. BRCA1: 70-90% ER-
  • NOTE: Tamoxifen use infrequent (6%) and Raloxifene (FDA approved for post-menopausal women only) used even less (3%)
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4
Q

What clinical features warrant referral for genetic testing for BRCA1/2 mutations?

A
  • Early-onset breast cancer: <50, 45
  • Ovarian, fallopian tube, or 1o peritoneal cancer
  • Ppl w/2 or more 1o breast cancers, or breast AND ovarian cancer
  • Male breast cancer
  • 2 or more ppl in family w/breast and/or ovarian cancer
  • Ashkenazi Jewish ancestry
  • Testing for BRCA1/2 NOT universal for all patients
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5
Q

What is the best way to eradicate a primary, solid tumor that has not metastasized?

A

Surgically excise it

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6
Q

What 3 hormone receptors are critical in breast cancer tx decisions? Why?

A
  • ER: drugs can be used to block receptor binding, or prevent generation of estrogen in post-meno women
  • PR
  • Her-2/neu: can be targeted with MAb’s or RTKI’s to block proliferative signaling pathway
  • NOTE: triple negative tumors have a poor prognosis, and are treated with conventional therapies
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7
Q

What are the tx options for pre-meno women with ER+ breast cancer?

A
  • Ovaries are the 1o source of estrogen pre-meno, so tx options are:
    1. Sx removal of ovaries
    2. Chemo castration w/GnRH agonists or antags that downregulate HP axis control
    3. SERM can also be used to block ER in tumor and prevent estrogen binding (more commonly used in PM women
  • NOTE: drugs not currently employed to limit peripheral aromatization of steroids
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8
Q

What are the tx options for post-meno women with ER+ breast cancer?

A
  • Ovaries are no longer the source of estrogen in these pts, so drugs targeting HP axis ineffective
  • Instead, these are used:
    1. Aromatase INH
    2. SERMs
    3. SERDs
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9
Q

How does estrogen proliferative signaling work?

A
  • Estrogen binding to ER = activation/dimerization, then translocation to nucleus, activating target gene expression via ERE, coactivators, and o/transcription factors -> current drugs target these effects
  • Can also have non-genomic actions via mem-bound ER -> interaxn w/GF receptor tyrosine kinases or downstream molecules (MAPK, PI3K)
    1. Explanation for tx failure w/drugs targeting only classical genomic pathway
    2. Clinical trials underway now to target these
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10
Q

What are the anti-estrogen Rx’s for breast cancer? Timing of clinical response?

A
  • Clinical response in 8-12 weeks
    1. Avg remission 6-12mos, but sometimes can last many years
  • Selective estrogen receptor downregulators (SERDs)
  • Selective estrogen receptor modulators (SERMs)
  • Aromatase inhibitors (AI)
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11
Q

Fulvestrant

A
  • SERD: for ER+ metastatic BC in PM women w/disease progression after anti-estrogen therapy
  • Pure antagonist w/no estrogenic actions
  • MOA: steroidal drug binds to ER, but carries a bulky substituent that prevents ER dimerization in nucleus
    1. Impaired dimerization, INC turnover, disrupted nuclear localization, degradation (DEC ER levels)
  • Monthly IM for sustained plasma levels; hepatic metabolism w/no drug interaxns
  • AE’s: PM symptoms -> nausea, asthenia, pain, hot flashes (vasodilation), headache
  • Failure of therapy: estrogen-independent cell growth
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12
Q

Tamoxifen/Raloxifene

A
  • SERM’s: ER agonist/antag at ER subtypes alpha and beta -> estrogen effect on bone + anti-estrogen effect on mammary tissue (tissue-specific actions)
  • Daily PO (Tam); monthly IM (Ral)
    1. DEC bone metabolism + INC BMD
    2. DEC serum chol, LDL, lipoproteins, and INC apolipoprotein A1
    3. Retinal degeneration at high doses
    4. Teratogens
  • BBWs: thromboembolic disease (DVT, PE), stroke
    1. TAM: + endometrial hypertrophy, vaginal bleeding, endometrial cancer
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13
Q

Toremifene

A
  • SERM: derivative of Tamoxifen w/anti-estrogenic props (for PM women)
  • PO daily, CY3A4 metabolism (no active products)
  • Teratogen
  • Similar AE’s, but also prolongs QT (BBW)-> avoid in pre-existing condition and w/3A4 inhibitors
  • No other BBWs, but recommended to AVOID w/hx of:
    1. Endometrial cancer/hyperplasia
    2. Thromboembolic disease
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14
Q

How can a single drug have agonistic and antagonistic actions?

A
  • Depends on the CONTEXT of ER expression
  • ER dimerizes in nucleus, and recruites co-activator proteins that help in mRNA synthesis -> when bound by an antagonist (Tam), it still dimerizes, but recruits a different set of proteins called co-repressors that act via histone deacetylase I to stabilize nucleosome structure and prevent mRNA production
  • Expression pattern of both ancillary proteins and ER can therefore modulate Tam’s (and o/SERM) agonist (bone, endometrium) and antag (breast) effects
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15
Q

How can patient enzyme expression impact the efficacy of Tamoxifen therapy?

A
  • Tamoxifen is metabolized via CYP2D6 to 4OH-tam and enoxifen, which have a MUCH HIGHER POTENCY than the parental agent
  • Recent concern for potential sub-optimal clnical effect in poor metabolizers
  • Clinical trials have failed to establish this link, but that doesn’t mean it does not exist
    1. There is no requirement or recommendation for this testing at the time by the FDA, but testing companies exist
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16
Q

What is the MOA of the AI’s?

A
  • In PM women, continued estrogenic action can arise from peripheral aromatization of endogenous steroids
  • Aromatase inhibitors block CYP19A1-mediated production of estrone and estradiol, starving the tumor of continued proliferative signaling
    1. Blocks androstenedione -> estrone, and testosterone -> estradiol rxns
17
Q

AI’s

A
  • Non-steroidal (reversible INH): Anastrozole, Letrozole
  • Steroidal (irreversible INH): Exemestane
    1. No cross-resistance b/t non-ster and steroidal
  • Daily oral; hepatic metabolism
  • AE’s: hot flashes, nausea, hair thinning, but NO effect on adrenal steroids, or thyroid and other hormones
  • Teratogens
  • INC arthralgia and diarrhea, but DEC gyn symptoms when compared to Tamoxifen
  • Drug actions are HIGHLY SPECIFIC; no effects on other organs or hormones
18
Q

What is the optimal length of therapy for SERMs/AIs?

A
  • American Society of Clinical Oncology recommends all PM women w/hormone+ early breast cancer receive adjuvant AI tx
  • Options incl 5 years of AI, or sequential therapy w/2-3 years of Tam, then 2-3 years of AI for a total of 5 years
  • Optimal duration of therapy and regimen unknown: ATLAS trial showed substantial survival benefit w/10 years Tam tx, clearly outweighing INC risk of endo cancer by orders of magnitude
19
Q

What are the testing guidelines for HER2 therapy?

A
  • Use of these drugs requires confirmation of over-expression of target by appropriate genetic tests
  • Immunohistochemistry (IHC) or in situ hybridization (ISH) assay
    1. + = IHC3+ or ISH+; equivocal = IHC2+ or ISH equivocal; - = IHC1+, IHC0, or ISH-
  • Must request testing for every 1o invasive cancer, and on metastatic site if stage IV -> recommend targeted tx if the test is (+)
  • Delay tx decision if initial test equivocal; must NOT recommend targeted tx after (-) test
    1. May consider HER2-targeted tx if test still unequivocal, even after reflex testing with alternative assay
20
Q

What are the binding sites of the Her2+ breast cancer ab’s and ib?

A
  • Trastuzumab: binds juxtaglomerular region of the EC domain of Her2 (all ab’s IgG1kappa)
  • Pertuzumab: binds EC dimerization domain (sub-domain II), and blocks the ligand-dependent hetero-dimerization of Her2 with other epidermal growth factor receptors, incl Her3 and Her4
  • Trastuzumab emtansine (T-DM1): binds receptor that, upon internalization, allows thioester-linked chemotherapeutic to act on microtubules
  • Lapatinib: small-molecule TKI that ING HER1 and HER2 -> binds IC domain of ErbB1 and ErbB2 receptors and competes with ATP (INH of ATP binding prevents receptor activation by preventing their phosphorylation)
21
Q

What are the dosing and AE’s of Trastuzumab and Pertuzumab?

A
  • Dosing: IV Q21D -> long half-lives
  • Reaction: hypersensitivity rxns w/first dose -> GI upset, asthenia, blood dyscrasias, fatigue
  • Trastuzumab AE’s:
    1. Common: peripheral edema, rash, weight gain dizziness, URTI’s, pharyngitis, fatigue
    2. Rare: cardiomyopathy and HF, renal failure, hepatotoxicity, pneumonia, resp failure
  • Pertuzumab AE’s:
    1. Common: alopecia, loss of appetite
    2. Rare: DEC LVEF, neutropenia, leukopenia
22
Q

What are the BBW’s for the MAb’s (chart)?

A
  • Respiratory distress syndrome and respiratory insufficiency sequelae of Trastuzumab infusion rxns
  • NOTE: Pertuzumab only has a BBW for pregnancy
23
Q

Lapatinib metabolism and AE’s

A
  • Extensive hepatic metab: CYP3A4 and 5 -> liver disease BBW bc will lead to INC levels, persistence
    1. Elevates LFT’s: routine monitoring required
    2. No clinically significant drug-drug interaxns
  • Common AE’s: GI, anemia, rash pain, back ache, headache, hand-foot syndrome, thrombocytopenia
  • Serious AE’s: interstitial lung disease/pneumonitis, QT prolongation
    1. Contraindicated for concurrent use w/drugs with similar AE’s
24
Q

How does GnRH agonist tx work for breast cancer?

A
  • Normal GnRH release pulsatile, but agonist tx is CONTINUOUS -> down-regulates GnRH receptor in pituitary, and DEC FSH, LH production
    1. Serum conc of estradiol falls to post-meno levels in 2-4 wks
  • Initial transient disease flare: bone pain (mets), hypercalcemia, breast enlargement/tenderness (temporary pain -> tx w/ analgesics)
25
Q

Goserelin admin and side effects

A
  • GnRh agonist; long-term tx well tolerated: SC injection q28d in upper abdominal wall
  • Common AE’s (due to hypo-estrogenic action): hot flashes, amenorrhea, DEC libido, vaginal dryness, depression, sweating, gynecomastia (flare), N/V, headache, peripheral edema, lethargy, anorexia
  • DEC bone density (osteopenia/porosis) may be irreversible -> risk factors: chronic alcohol/tobacco, family hx, chronic drugs DEC bone mineralization
    1. This effect is more or less significant depending on individual pt circumstances
26
Q

What is mTOR? How is it blocked?

A
  • Central regulator of cell proliferation, cell metab, and angiogenesis via activation or INH of protein synthesis on receipt of appropriate biochem signals
  • Drug binds FKBP-12 and forms a 3-way complex with mTOR that blocks protein action and down-stream consequences (small molecule INHs)
27
Q

Everolimus use, metab, AE’s, labs

A
  • Used in advanced ER+, Her-2(-) tumors (Luminal A) with exemestane (steroidal, irreversible AI)
  • CYP3A4 and P-gp substrate; 3A4, 2D6 INH and P-gp INH (will cause other drugs metabolized by these CYPs or kicked out by P-gp to last longer, or be at higher concentration than anticipated)
  • BBW: risk of opportunistic infections, neoplasia (lymphoma, SCC)
  • Non-infectious pneumonitis: sometimes fatal
  • AE’s: blood dyscrasias, hyperglycemia, hyper-lipidemia, hyperTGemia, elevated creatinine, elevated liver enzymes
    1. N/V, diarrhea, pain, constipation
  • LABS: blood glucose, CBC w/differential, LFTs, serum bilirubin-creatinine-lipid profile, phosphate, TGs
  • Classified as a: macrolide immunosuppressant, or proliferation signal inhibitor
28
Q

How is tripe negative breast cancer (TNBC) treated?

A
  • Excision of primary tumor and lymph nodes std practice for early disease
  • Drugs/radiation adjuvants to prevent recurrent disease or neoadjuvant role prior to excision
  • Advanced tumor (metastatic disease): systemic tx w/conventional chemo -> TNBC is insensitive to some of the most effective drugs that target proliferative signaling, incl. Her-2 and endocrine therapies
29
Q

What is the algorithm for tx of TNBC?

A
  • Algorithm for adjuvant tx after resection of 1o tumor based on likelihood of disease recurrence within 5 years
    1. If low likelihood (<0.5cm), risk of chemo with Anthracycline/Taxane-based therapy greater than potential benefit provided
  • Memory tool: triple negATive breast cancer
30
Q

How is tumor genotyping used in breast cancer tx?

A
  • Used to indicate drugs of choice for a particular pt, and can also be used to aid in decision as to whether or not adjunctive drug tx is necessary immediately following surgical excision of the primary tumor
  • GOOD prognostic indicators (good signature): risks of adjunctive tx may outweight benefit -> pt better managed by “watch and wait” approach
  • POOR “signature:” will most likely have aggressive disease course, and are better managed with immediate and comprehensive adjunctive drug tx
  • NOTE: also a panel of BIOMARKERS now being used to aid in making these decisions (image attached to front of card)
31
Q

What are the standard adjuvant chemo regimens? AE you should worry about?

A
  • Stage I, II, IIIA, and operable IIIC Her2(-)
  • AC: cyclophosphamide, doxorubicin (has a MAX CUMULATIVE DOSE -> many women go on to have cardiac issues in yrs following survival of BC)
  • AC-T: cyclophosphamide, doxorubicin, taxol
  • CAF: cyclophosphamide, doxorubicin, fluorouracil
  • TAC: cyclophosphamide, doxorubicin, docetaxel
  • TC: cyclophosphamide and docetaxel
  • No compelling evidence one regimen is better than the other
32
Q

How is progesterone involved in breast cancer at a molecular level?

A
  • Directly regulates gene transcription via 2 specific P-receptor proteins, A and B in target tissues like the breast, uterus, CNS, and CV systems
  • Proteins arise from a single gene; ligand-inducible transcription factors regulating expression of genes by binding P-responsive elements on DNA
  • PR activity controlled by SUMOylation (form of ubiquitination) + post-translational phosphorylation on as many as 10 sites
  • PR can modulate lg # of effects in the cell, incl repressive control over ER acivity
33
Q

How does PR expression affect breast cancer prognosis?

A
  • PR+ in 1o breast cancer = favorable prognosis: more differentiated, less invasive phenotype
    1. Also a predictor of better overall survival
  • Loss of PR in ER+ tumors associated with more aggressive tumors phenotype, reduced response to endocrine therapies, and overall shorter survival
34
Q

How does PR expression affect breast cancer?

A
  • Adult: PR expressed in 40% of cells and PR+ cells largely non-proliferative -> reside by proliferative PR(-) cells, suggesting paracrine mechanism for P-induced proliferation
  • Progesterone is a risk factor for breast cancer and promotes pre-neoplastic progression by stimulating cyclic proliferation of mature breast epithelium and by activating mammary stem cell pools or occult tumor initiating cells
  • Alterations in the progesterone/PR signaling axis, incl switch from paracrine to autocrine regulation of proliferation, contribute to progression
35
Q

How does PR affect more advanced stage breast cancer and prognosis?

A
  • PR, either independent of P or in response to P, suppresses tumor invasion and metastasis through maintaining epithelial cell phenotype and impeding the epithelial-mesencyhmal transition (EMT)
  • PR negative tumors tend to have a more dismal prognosis
36
Q

How does HRT affect breast cancer?

A

NO FREAKING IDEA

  • Menopausal hormone tx has complex pattern of risks and benefits
  • Findings from the 2 WHI hormone therapy trials do NOT support use of this therapy for chronic disease prevention
  • But, appropriate for symptom mgmt in some women
37
Q

Medroxyprogesterone MOA, AE’s

A
  • Depo-provera: progestin contraceptive used in tx of endometrial cancer
  • Binds progestin receptors and blocks GnRH release, causing reduction in HP stimulation of hormonally responsive tissue
  • AE’s: amenorrhea, edema, anorexia, weakness
38
Q

Megestrol MOA and AE’s

A
  • Synthetic oral progestin used in tx of endometrial cancer, and sometimes used for breast cancer
  • Suppresses pituitary LH release and enhances estrogen degradation
  • Promotes differentiation/maintenance of endometrial tissue
  • AE’s: weight gain (INC appetite), hot flashes, malaise, asthenia, lethargy, sweating (diaphoresis), and rash (unspecified)
    1. Tumor flare and hypercalcemia in BC pts with bony mets
    2. Thrombophlebitis, thrombo- or pulmonary embolism
  • Also used to tx anorexia or cachexia in AIDS or cancer pts bc of effect this drug has upon appetite

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